I reviewed somewhere around four thousand papers from the peer-reviewed scientific literature to gather material for this book. If this were itself a scientific paper, most would be cited within the text as they are mentioned, and then keyed to a references section. But my experience as a reader of nonfiction books is that all those parentheses with researcher names in the text are distracting and take me out of the story that the author has woven together. My aim in compiling these notes is to provide backup support for factual assertions (for example, statistics on the prevalence of a certain disease) and for descriptions of experiments (such as the inverting prism goggles) so that interested readers can follow up. In each case, I tried to cite something that was representative of the issue, often a meta-analysis or review that itself covers hundreds of articles, rather than the string of empirical papers that led up to that review.
For a more complete story, a full bibliography (in APA format) is available on my website at DanielLevitin.org , and the references listed here contain many more references themselves.
1 It has been tied to diabetes in pregnancy: N. Bakalar, “Lack of Sleep Tied to Diabetes in Pregnancy,” The New York Times , October 18, 2017, http://www.nytimes.com .
2 postpartum depression in new fathers: D. Quenqua, “Can Fathers Have Postpartum Depression?,” The New York Times , October 17, 2017, http://www.nytimes.com .
3 Alzheimer’s disease (AD) is now the third leading cause of death: B. James et al., “Contribution of Alzheimer Disease to Mortality in the United States,” Neurology 82, no. 12 (2014): 1045–1050.
4 two-thirds of the overall risk that you’ll get Alzheimer’s: This may be a confusing way to look at it, but standing at the beginning of your life, as a newborn, that’s how the risk ratios work out. Obviously if you experience a number of environmental factors—toxins, repeated blows to the head—that end up causing Alzheimer’s, your personal risk of environmental causes rises to 100 percent; Klodian Dhana, Denis A. Evans, Kumar B. Rajan, David Bennett, and Martha Clare Morns, Impact of Healthy Lifestyle Factors on the Risk of Alzheimer’s Dementia: Findings from Two Prospective Cohort Studies , Alzheimer’s Association International Conference, Los Angeles, July 14, 2019; I. E. Jansen et al., “Genome-wide Meta-analysis Identifies Nature Genetics 5, no. 3 (2019): 404–413.
5 chronic inflammatory process precedes the onset of Alzheimer’s: P. Eikelenboom et al., “Whether, When and How Chronic Inflammation Increases the Risk of Developing Late-Onset Alzheimer’s Disease,” Alzheimer’s Research and Therapy 4, no. 3 (2012): 15, http://dx.doi.org/10.1186/alzrt118 .
6 Another cutting-edge treatment being investigated: Eikelenboom et al., “Whether, When and How Chronic Inflammation”; D. J. Marciani, “Development of an Effective Alzheimer’s Vaccine,” in Immunology , vol. 1, Immunotoxicology, Immunopathology, and Immunotherapy , ed. M. A. Hayat, pp. 149–169 (London: Elsevier, 2018).
7 baby rats that received a great deal of licking: M. J. Meaney and M. Szyf, “Environmental Programming of Stress Responses through DNA Methylation: Life at the Interface between a Dynamic Environment and a Fixed Genome,” Dialogues in Clinical Neuroscience 7, no. 2 (2005): 103–123.
9 happiest time of one’s life is eighty-two: Stone, A. A., Schwartz, J. E., Broderick, J. E., and Deaton, A. (2010). A snapshot of the age distribution of psychological well-being in the United States. Proceedings of the National Academy of Sciences, 107(22), 9985–9990.
1 If they survived these increased risks: S. E. Hampson, “Personality Development and Health,” in The Handbook of Personality Development , ed. D. McAdams, R. Shiner, and J. Tackett, pp. 489–502 (New York: Guilford Press, 2019).
2 “Lack of self-control may result in behaviors”: Hampson, “Personality Development and Health.”
3 Childhood personality traits: S. E. Hampson et al., “Lifetime Trauma, Personality Traits, and Health: A Pathway to Midlife Health Status,” Psychological Trauma: Theory, Research, Practice, and Policy 8, no. 4 (2016): 447–454, http://dx.doi.org/10.1037/tra0000137 .
4 The same childhood traits even predict life span: H. S. Friedman et al., “Does Childhood Personality Predict Longevity?,” Journal of Personality and Social Psychology 65, no. 1 (1993): 176–185, http://dx.doi.org/10.1037/0022-3514.65.1.176 .
5 people, even older adults, can meaningfully change: W. Bleidorn, “What Accounts for Personality Maturation in Early Adulthood?,” Current Directions in Psychological Science 24, no. 3 (2015): 245–252; G. W. Edmonds et al., “Personality Stability from Childhood to Midlife: Relating Teachers’ Assessments in Elementary School to Observer- and Self-Ratings 40 Years Later,” Journal of Research in Personality 47, no. 5 (2013): 505–513; N. W. Hudson and R. C. Fraley, “Volitional Personality Trait Change: Can People Choose to Change Their Personality Traits?,” Journal of Personality and Social Psychology 109, no. 3 (2015): 490–507.
6 people retain the capacity to change throughout their life span: N. Bayley, “The Life Span as a Frame of Reference in Psychological Research,” Vita Humana 6, no. 3 (1963): 125–139.
7 “Most developmental researchers”: P. B. Baltes and K. W. Schaie, “On Life-Span Developmental Research Paradigms: Retrospects and Prospects,” in Life-Span Developmental Psychology (Cambridge, MA: Academic Press, 1973), pp. 365–395.
8 the idea that people can change is the entire basis of modern psychotherapy: B. P. Chapman, S. Hampson, and J. Clarkin, “Personality-Informed Interventions for Healthy Aging: Conclusions from a National Institute on Aging Workgroup,” Developmental Psychology 50, no. 5 (2014): 1426–1441.
12 Skin color, weight, and attractiveness: L. A. Zebrowitz and J. M. Montepare, “Social Psychological Face Perception: Why Appearance Matters,” Social and Personality Psychology Compass 2, no. 3 (2008): 1497–1517; P. Belluck, “Yes, Looks Do Matter,” The New York Times , April 24, 2009, p. ST1.
13 male, nonwhite, poor, and younger suspects: W. Terrill and S. D. Mastrofski, “Situational and Officer-Based Determinants of Police Coercion,” Justice Quarterly 19, no. 2 (2002): 215–248.
14 actress Kristen Stewart: C. Gibson, “Scientists Have Discovered What Causes Resting Bitch Face,” The Washington Post , February 2, 2016, https://www.washingtonpost.com .
15 “individual differences that are of the most significance”: L. R. Goldberg, personal communication, 1994; see also L. R. Goldberg, “Language and Individual Differences: The Search for Universals in Personality Lexicons,” Review of Personality and Social Psychology 2, no. 1 (1981): 141–165.
16 “The more important an individual difference is”: Goldberg, “Language and Individual Differences.”
17 very little that is distinctive culturally: J. M. Murphy, “Psychiatric Labeling in Cross-Cultural Perspective,” Science 191, no. 4231 (1976): 1019–1028.
18 in English, there are 4,500 of them: G. W. Allport and H. S. Odbert, “Trait-Names: A Psycho-Lexical Study,” Psychological Monographs 47, no. 1 (1936): 1–171; J. S. Wiggins, Paradigms of Personality Assessment (New York: Guilford Press, 2003); L. R. Goldberg, personal communication, August 8, 2018.
19 One prominent scientist argued for twenty: L. R. Goldberg, “What the Hell Took So Long? Donald Fiske and the Big-Five Factor Structure,” in Personality Research, Methods, and Theory: A Festschrift Honoring Donald W. Fiske , ed. P. E. Shrout and S. K. Fiske, pp. 29–43 (Hillsdale, NJ: Erlbaum, 1995).
20 several others for two: L. R Goldberg, “The Structure of Phenotypic Personality Traits,” American Psychologist 48, no. 1 (1993): 26–34.
21 Openness to Experience + Intellect: G. Saucier, “Openness versus Intellect: Much Ado about Nothing?,” European Journal of Personality 6 (1992): 381–386.
22 EXTRAVERSION includes:Psychological Assessment 4, no. 1 (1992): 26.
23 People who score high on the Extraversion dimension: L. R. Goldberg, “A Broad-Bandwidth, Public Domain, Personality Inventory Measuring the Lower-Level Facets of Several Five-Factor Models,” in Personality Psychology in Europe , vol. 7, ed. I. Mervielde et al., pp. 7–28 (Tilburg, The Netherlands: Tilburg University Press, 1999); L. R. Goldberg et al., “The International Personality Item Pool and the Future of Public-Domain Personality Measures,” Journal of Research in Personality 40 (2006): 84–96.
24 People who score high on this dimension are quick to understand: Lew Goldberg notes that few if any large-scale lexical studies have found an “Openness” factor.
25 If you want to sound like a personality researcher: You may have seen these in other books presented as the OCEAN or CANOE model, which simply put the factors in a different order and renamed Emotional Stability as its opposite, Neuroticism.
26 all personality differences are biological: DeYoung, “Personality Neuroscience.”
27 Higher levels lead us toward aggressive behaviors: DeYoung, “Personality Neuroscience.”
28 such as a successful hunt: B. C. Trumble et al., “Successful Hunting Increases Testosterone and Cortisol in a Subsistence Population,” Proceedings of the Royal Society of London B: Biological Sciences 281, no. 1776 (2014): 20132876.
29 driving a fast car: G. Saad and J. G. Vongas, “The Effect of Conspicuous Consumption on Men’s Testosterone Levels,” Organizational Behavior and Human Decision Processes 110, no. 2 (2009): 80–92.
30 being in charge of a large number of people: S. M. Van Anders, J. Steiger, and K. L. Goldey, “Effects of Gendered Behavior on Testosterone in Women and Men,” Proceedings of the National Academy of Sciences 112, no. 45 (2015): 13805–13810.
31 Low levels of serotonin are associated with: DeYoung, “Personality Neuroscience.”
32 Alterations to the gene known as SLC6A4 : X. Gonda et al., “Association of the S Allele of the 5-HTTLPR with Neuroticism-Related Traits and Temperaments in a Psychiatrically Healthy Population,” European Archives of Psychiatry and Clinical Neuroscience 259, no. 2 (2009): 106–113.
33 Babies are born with certain predispositions: J. T. Nigg, “Temperament and Developmental Psychopathology,” Journal of Child Psychology and Psychiatry 47, nos. 3–4 (2006): 395–422.
34 Temperament and the young child’s early life experiences: M. K. Rothbart, “Temperament, Development, and Personality,” Psychological Science 16, no. 4 (2007): 20–26.
35 it is biologically based: M. I. Posner, M. K. Rothbart, and B. E. Sheese, “Attention Genes,” Developmental Science 10 (2007): 24–29.
36 Temperament is typically measured: H. E. Fisher et al., “Four Broad Temperament Dimensions: Description, Convergent Validation Correlations, and Comparison with the Big Five,” Frontiers in Psychology 6 (2015): 1098.
37 meta-analysis of ninety-two research papers: B. W. Roberts, K. E. Walton, and W. Viechtbauer, “Patterns of Mean-Level Change in Personality Traits across the Life Course: A Meta-Analysis of Longitudinal Studies,” Psychological Bulletin 132, no. 1 (2006): 1–25; Sarah Hampson adds this caveat after reading Chapter 1 : “I like the upbeat message that personality changes and we can change. I believe this, but I also have to acknowledge that our findings on the Hawaii project (childhood personality influences health outcomes 40 years later, independent of adult personality influences) are a challenge for this position. What can we do as adults if we were poorly controlled, unconscientious kids? Our long-term health may have been damaged by these early influences. At least, as adults, we can strive to be more conscientious and use this trait to take steps to address the health issues that may have originated in childhood (e.g., compensate by living a healthier
38 Older adults tend to be better at controlling impulses: B. W. Roberts and D. Mroczek, “Personality Trait Change in Adulthood,” Current Directions in Psychological Science 17, no. 1 (2008): 31–35.
39 men typically show increased emotional sensitivity: R. Helson, C. Jones, and V. S. Kwan, “Personality Change over 40 Years of Adulthood: Hierarchical Linear Modeling Analyses of Two Longitudinal Samples,” Journal of Personality and Social Psychology 83, no. 3 (2002): 752.
40 Openness increases around adolescence: Roberts, Walton, and Viechtbauer, “Patterns of Mean-Level Change.”
41 Agreeableness increases substantially: Helson, Jones, and Kwan, “Personality Change over 40 Years”; Roberts, Walton, and Viechtbauer, “Patterns of Mean-Level Change.”
42 They show increased Emotional Stability: Roberts and Mroczek, “Personality Trait Change in Adulthood”; W. Bleidorn, “What Accounts for Personality Maturation?”
43 a study of nearly 1 million individuals: Bleidorn, “What Accounts for Personality Maturation?”
44 Individuals appear to become more self-content in old age: Roberts, Walton, and Viechtbauer, “Patterns of Mean-Level Change in Personality Traits.”
45 Older adults are less likely to engage in risky: R. R. McCrae et al., “Age Differences in Personality across the Adult Life Span: Parallels in Five Cultures,” Developmental Psychology 35, no. 2 (1999): 466.
46 we can become our own autobiographers: D. P. McAdams, “The Psychological Self as Actor, Agent, and Author,” Perspectives on Psychological Science 8, no. 3 (2013): 272–295.
47 Julia “Hurricane” Hawkins: K. Peveto, “101-Year-Old Baton Rouge Runner Earns World Record, and a New Nickname, at National Senior Games,” The Advocate , July 2, 2017, https://www.theadvocate.com .
52 Conscientiousness has been linked to lower all-cause mortality: S. E. Hampson et al., “Childhood Conscientiousness Relates to Objectively Measured Adult Physical Health Four Decades Later,” Health Psychology 32, no. 8 (2013): 925.
53 To become more conscientious: Chapman, Hampson, and Clarkin, “Personality-Informed Interventions.”
54 Charles Koch, CEO: C. Koch, personal communication, July 22, 2017.
55 Overdiagnosis is common: H. G. Welch and W. C. Black, “Overdiagnosis in Cancer,” Journal of the National Cancer Institute 102 (2010): 605–613; H. G. Welch, L. Schwartz, and S. Woloshin, Overdiagnosed: Making People Sick in the Pursuit of Health (Boston: Beacon, 2011).
56 people who forced a smile: F. Strack, L. L. Martin, and S. Stepper, “Inhibiting and Facilitating Conditions of the Human Smile: A Nonobtrusive Test of the Facial Feedback Hypothesis,” Journal of Personality and Social Psychology 54 (1988): 768–777; T. L. Kraft and S. D. Pressman, “Grin and Bear It: The Influence of Manipulated Facial Expression on the Stress Response,” Psychological Science 23, no. 11 (2012): 1372–1378.
57 “Compassion is the key to happiness”: Thupten Jinpa Langri, personal communication, April 2, 2018.
58 He tries to avoid feeling anger, suspicion, and distrust: J. Oliver, “Tibetan Sovereignty Debate and Human Rights in Tibet,” Last Week Tonight with John Oliver , produced by J. Oliver, aired March 5, 2017, HBO.
60 studies since Bayley and Baltes: R. Helson, C. Jones, and V. S. Kwan, “Personality Change over 40 Years.”
61 Exposure to high levels of glucocorticoids: S. J. Lupien et al., “Increased Cortisol Levels and Impaired Cognition in Human Aging: Implication for Depression and Dementia in Later Life,” Reviews in the Neurosciences 10, no. 2 (1999): 117–140.
1 George Martin, the Beatles’ producer: G. Martin, personal communication, September 17, 1993.
2 The recognition that memory is not one thing: A. J. O. Dede and C. N. Smith, “The Functional and Structural Neuroanatomy of Systems Consolidation for Autobiographical and Semantic Memory,” in Behavioral Neuroscience of Learning and Memory, Current Topics in Behavioral Neurosciences , vol. 37, ed. R. E. Clark and S. Martin (Cham, Switzerland: Springer, 2016); M. Moscovitch et al., “Functional Neuroanatomy of Remote Episodic, Semantic and Spatial Memory: A Unified Account Based on Multiple Trace Theory,” Journal of Anatomy 207, no. 1 (2005): 35–66; B. Milner, S. Corkin, and H. L. Teuber, “Further Analysis of the Hippocampal Amnesic Syndrome: 14-Year Follow-Up Study of HM,” Neuropsychologia 6, no. 3 (1968): 215–234.
3 different parts of the brain hold semantic memories versus episodic ones: Dede and Smith, “Functional and Structural Neuroanatomy”; Moscovitch et al., “Functional Neuroanatomy.”
4 television images of an airplane crashing into the first tower: I wrote about this previously in D. J. Levitin, The Organized Mind (New York: Dutton, 2014).
5 Gazzaniga tells the story of a patient: M. S. Gazzaniga, Who’s in Charge: Free Will and the Science of the Brain (New York: Ecco, 2012).
6 conducted an experiment in 1991: D. J. Levitin, “Absolute Memory for Musical Pitch: Evidence from the Production of Learned Melodies,” Perception & Psychophysics 56, no. 4 (1994): 414–23.
7 contemporary version of the residue theory—multiple-trace theory: Journal of Experimental Psychology 88, no. 3 (1971): 297; D. L. Hintzman, “Judgments of Frequency and Recognition Memory in a Multiple-Trace Memory Model,” Psychological Review 95, no. 4 (1988): 528; S. D. Goldinger, “Echoes of Echoes? An Episodic Theory of Lexical Access,” Psychological Review 105, no. 2 (1998): 251.
8 The creation of multiple, related traces facilitates: D. L. Hintzman, “‘Schema Abstraction’ in a Multiple-Trace Memory Model,” Psychological Review 93, no. 4 (1986): 411.
9 this occurs in brain cells without having to involve the hippocampus: Moscovitch et al., “Functional Neuroanatomy”; B. R. Postle, “The Hippocampus, Memory, and Consciousness,” in The Neurology of Consciousness , 2nd ed., ed. S. Laureys, O. Gosseries, and G. Tononi (San Diego, CA: Elsevier, 2016).
10 if we need to remember something, we should draw it: J. D. Wammes, M. E. Meade, and M. A. Fernandes, “The Drawing Effect: Evidence for Reliable and Robust Memory Benefits in Free Recall,” Quarterly Journal of Experimental Psychology 69, no. 9 (2016): 1752–1776.
11 “I keep thinking of Dr. Spock”: J. Weinstein, personal communication, Brooklyn, NY, April 25, 2018.
12 cognitive prostheses: S. Kosslyn, personal communication, September 8, 2018.
13 “I remember in Dr. Zhivago ”: J. Mitchell, personal communication, September 9, 2012.
14 “You have a routine”: G. Shultz, personal communication, Stanford, CA, March 21, 2018.
15 mental checklist of five things: J. Kimball, personal communication, Los Angeles, CA, March 3, 2018.
16 Neuroscientist Sonia Lupien: S. Lupien, personal communication, Montreal, QC, March 13, 2019.
17 traditional form of memory testing: S. Sindi et al., “When We Test, Do We Stress? Impact of the Testing Environment on Cortisol Secretion and Memory Performance in Older Adults,” Psychoneuroendocrinology 38, no. 8 (2013): 1388–1396; S. Sindi et al., “Now You See It, Now You Don’t: Testing Environments Modulate the Association between Hippocampal Volume and Cortisol Levels in Young and Older Adults,” Hippocampus 24, no. 12 (2014): 1623–1632; in a more naturalistic memory context, younger and older adults did not differ in overall accuracy: D. Davis, N. Alea, and S. Bluck, “The Difference between Right and Wrong: Accuracy of Older and Younger Adults’ Story Recall,” International Journal of Environmental Research and Public Health 12, no. 9 (2015): 10861–10885; one study concluded that older adults were not more stressed by laboratory testing than younger, but they did not measure stress directly and did not collect cortisol levels: A. Ihle et al., “Adult Age Differences in Prospective Memory in the Laboratory: Are They Related to Higher Stress Levels in the Elderly?,” Frontiers in Human Neuroscience 8 (2014): 1021.
18 Uncorrected losses to vision and hearing: B. M. Ben-David, G. Malkin, and H. Erel, “Ageism and Neuropsychological Tests,” in Contemporary Perspectives on Ageism , ed. Liat Ayalon and Clemens Tesch-Römer, pp. 277–297 (Cham, Switzerland: Springer, 2018).
19 retrieval of words … can decline with age: M. A. Shafto et al., “On the Tip-of-the-Tongue: Neural Correlates of Increased Word-Finding Failures in Normal Aging,” Journal of Cognitive Neuroscience 19, no. 12 (2007): 2060–2070.
1 the Bible taught us the centrality of ethics: S. Innes, “Review of The Cambridge Introduction to Emmanuel Levinas by Michael Morgan,” Religious Studies 48, no. 4 (2012): 552–557, http://www.jstor.org/stable/23351460 .
2 Neural growth in the womb: L. K. Jones, “Neurophysiological Development across the Lifespan,” in Neurocounseling: Brain-Based Clinical Approaches , ed. T. A. Field, L. K. Jones, and L. A. Russell-Chapin (Alexandria, VA: John Wiley & Sons, 2017).
3 Why are humans at the top of the food chain?: I thank “Darpa” Dan Kaufman for this formulation. D. Kaufman, personal communication, July 14, 2018.
4 more than 1 million per minute at birth: Center on the Developing Child, “Five Numbers to Remember about Early Childhood Development,” brief, 2009, www.developingchild.harvard.edu .
5 by six months, up to 2 million new connections a minute: E. Santos and C. A. Noggle, “Synaptic Pruning,” in Encyclopedia of Child Behavior and Development , ed. S. Goldstein and J. A. Naglieri (Boston: Springer, 2011).
8 Some understandings appear to be hardwired: I’ve been careful to use the terms statistical inferencing and statistical analysis. Just how the brain learns complex things like language is a contentious issue. There are some who believe that the brain has a modular structure and that some of these modules are “hardwired,” a term you may see both in scientific articles and in popular books. Others believe that the brain has biological predispositions but that experience shapes those, and that “hardwired” is too strong a claim. Reasonable scientists are disagreeing. We’ll just have to wait until more experiments are conducted and more data come in.
10 blooming, buzzing confusion: W. James, The Principles of Psychology (London: MacMillan, 1890).
11 a condition called synesthesia: B. Brogaard, “Serotonergic Hyperactivity as a Potential Factor in Developmental, Acquired and Drug-Induced Synesthesia,” Frontiers in Human Neuroscience 7 (2013): 657.
12 the infant brain overwires: L. K. Low and H. J. Cheng, “Axon Pruning: An Essential Step Underlying the Developmental Plasticity of Neuronal Connections,” Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 361 (2006): 1531–1544.
13 axons and dendrites extend to more targets: Low and Cheng, “Axon Pruning.”
14 Some adult, late-onset mental disorders: Z. Petanjek et al., “Extraordinary Neoteny of Synaptic Spines in the Human Prefrontal Cortex,” Proceedings of the National Academy of Sciences 108, no. 32 (2011): 13281–13286.
16 pruning forces the brain to specialize: M. Gazzaniga, personal communication, July 15, 2018.
18 This skill is a precursor to mathematical ability: O. T. Giles et al., “Hitting the Target: Mathematical Attainment in Children Is Related to Interceptive-Timing Ability,” Psychological Science 29, no. 8 (2018): 1334–1345.
19 Cochlear implants: J. K. Niparko et al., “Spoken Language Development in Children following Cochlear Implantation,” Journal of the American Medical Association 303 (2010): 1498–1506; J. G. Nicholas and A. E. Geers, “Sensitivity of Expressive Linguistic Domains to Surgery Age and Audibility of Speech in Preschoolers with Cochlear Implants,” Cochlear Implants International 19, no. 1 (2018): 26–37.
20 it’s not sound that the brain needs to acquire the statistical underpinnings of language: M. L. Hall et al., “Auditory Access, Language Access, and Implicit Sequence Learning in Deaf Children,” Developmental Science 21, no. 3 (2018): e12575.
21 The term sensitive period refers to: A. K. Bhatara, E. M. Quintin, and D. J. Levitin, “Musical Ability and Developmental Disorders,” The Oxford Handbook of Intellectual Disability and Development (New York: Oxford University Press, 2012), 138.
22 having an alcoholic father: H. J. Lee et al., “Transgenerational Effects of Paternal Alcohol Exposure in Mouse Offspring,” Animal Cells and Systems 17, no. 6 (2013): 429–434; J. Day et al., “Influence of Paternal Preconception Exposures on Their Offspring: Through Epigenetics to Phenotype,” American Journal of Stem Cells 5, no. 1 (2016): 11.
24 sensory receptors in the fetus’s developing tongue: Neurons from the retina grow along a path until they find the visual cortex at the back of the brain, stopping first at a relay station, the lateral geniculate nucleus. Neurons also terminate in the superior colliculus, for the control of eye movements; at the pretectum, to control the dilation and constriction of the pupils; and at the suprachiasmatic nucleus, to help control diurnal rhythms and to regulate hormones in response to time of day, as indicated by sunlight. They are guided in part by genetic instructions.
25 Neuroplasticity provides this compensatory mechanism: M. Bedny, H. Richardson, and R. Saxe, “‘Visual’ Cortex Responds to Spoken Language in Blind Children,” Journal of Neuroscience 35, no. 33 (2015): 11674–11681; B. Röder et al., “Speech Processing Activates Visual Cortex in Congenitally Blind Humans,” European Journal of Neuroscience 16, no. 5 (2002): 930–936.
26 blocked the path from the retina to the visual cortex: M. Sur, P. E. Garraghty, and A. W. Roe, “Experimentally Induced Visual Projections into Auditory Thalamus and Cortex,” Science 242, no. 4884 (1988): 1437–1441; S. L. Pallas, A. W. Roe, and M. Sur, “Visual Projections Induced into the Auditory Pathway of Ferrets. I. Novel Inputs to Primary Auditory Cortex (AI) from the LP/Pulvinar Complex and the Topography of the MGN-AI Projection,” Journal of Comparative Neurology 298, no. 1 (1990): 50–68.
27 sensory integration can begin to fail: A. L. de Dieuleveult et al., “Effects of Aging in Multisensory Integration: A Systematic Review,” Frontiers in Aging Neuroscience 9 (2017): 80, http://dx.doi.org/10.3389/fnagi.2017.00080 .
28 A reduction in the ability to produce neurochemicals: A. Shimamura, Get SMART! Five Steps toward a Healthy Brain (Scotts Valley, CA: CreateSpace, 2017).
29 Dopamine levels fall about 10 percent: Postgraduate Medical Journal 82, no. 964 (2006): 84–88; R. Rutledge et al., “Risk Taking for Potential Reward Decreases across the Lifespan,” Current Biology 26, no. 12 (2016): 1634–1639.
30 alcohol consumption can lead to neuronal death: M. Kubota et al., “Alcohol Consumption and Frontal Lobe Shrinkage: Study of 1432 Non-Alcoholic Subjects,” Journal of Neurology, Neurosurgery and Psychiatry 71, no. 1 (2001): 104–106; X. Yang et al., “Cortical and Subcortical Gray Matter Shrinkage in Alcohol-Use Disorders: A Voxel-Based Meta-Analysis,” Neuroscience and Biobehavioral Reviews 66 (2016): 92–103.
31 5 percent per decade through age sixty: A. M. Hedman et al., “Human Brain Changes across the Life Span: A Review of 56 Longitudinal Magnetic Resonance Imaging Studies,” Human Brain Mapping 33, no. 8 (2012): 1987–2002.
32 decline speeding up after age seventy: Peters, “Ageing and the Brain.”
33 “one of the most significant problems in older adults”: Shimamura, Get SMART!.
35 Disruptions of this daydreaming mode: R. Buckner, J. Andrews-Hanna, D. Schacter, “The Brain’s Default Network: Anatomy, Function, and Relevance to Disease,” Annals of the New York Academy of Sciences 1124, no. 1 (2008): 1–38.
36 Mild cognitive impairment: S. Gauthier et al., “Mild Cognitive Impairment,” Lancet 367, no. 9518 (2006): 1262–1270.
37 leads to Alzheimer’s disease: Gauthier et al., “Mild Cognitive Impairment.”
38 other times it exists independently: R. C. Petersen, “Mild Cognitive Impairment,” Continuum: Lifelong Learning in Neurology 22, no. 2, Dementia (2016): 404.
39 systematic changes in the brain: B. C. M. Stephan et al., “The Neuropathological Profile of Mild Cognitive Impairment (MCI): A Systematic Review,” Molecular Psychiatry 17, no. 11 (2012): 1056.
40 no single neurophysiological profile: R. C. Petersen et al., “Mild Cognitive Impairment: A Concept in Evolution,” Journal of Internal Medicine 275, no. 3 (2014): 214–228.
41 able to classify individuals: L. Qian et al., “Intrinsic Frequency Specific Brain Networks for Identification of MCI Individuals Using Resting-State fMRI,” Neuroscience Letters 664 (2018): 7–14.
42 the concept of cognitive reserve: Y. Stern, “Cognitive Reserve in Ageing and Alzheimer’s Disease,” Lancet Neurology 11, no. 11 (2012): 1006–1012; Y. Stern, “Cognitive Reserve: Implications for Assessment and Intervention,” Folia Phoniatrica et Logopaedica 65, no. 2 (2013): 49–54; H. Amieva et al., “Compensatory Mechanisms in Higher-Educated Subjects with Alzheimer’s Disease: A Study of 20 Years of Cognitive Decline,” Brain 137, no. 4 (2014): 1167–1175.
43 One particular protein, called beta-amyloid: Shimamura, Get SMART!.
44 drugs that reduce amyloid buildup: P. Belluck, “Will We Ever Cure AD?,” The New York Times , November 19, 2018, p. D6.
45 chronic inflammatory processes: P. Eikelenboom and R. Veerhuis, “The Importance of Inflammatory Mechanisms for the Development of Alzheimer’s Disease,” Experimental Gerontology 34, no. 3 (1999): 453–461.
46 taking NSAIDs … before the expected onset of Alzheimer’s: Journal of Alzheimer’s Disease 54, no. 3 (2016): 853–857.
47 The APOE gene: N. Brouwers, K. Sleegers, and C. Van Broeckhoven, “Molecular Genetics of Alzheimer’s Disease: An Update,” Annals of Medicine 40, no. 8 (2008): 562–583; A. Pink et al., “Neuropsychiatric Symptoms, APOE ε4, and the Risk of Incident Dementia: A Population-Based Study,” Neurology 84, no. 9 (2015): 935–943.
48 the presence of the gene is protective: Y. Y. Lim, E. C. Mormino, and Alzheimer’s Disease Neuroimaging Initiative, “APOE Genotype and Early β-Amyloid Accumulation in Older Adults without Dementia,” Neurology 89, no. 10 (2017): 1028–1034.
50 The Lancet ’s expert panel: G. Livingston et al., “Dementia Prevention, Intervention, and Care,” Lancet 390, no. 10113 (2017): 2673–2734.
55 seven hundred new neurons per day: S. M. Ryan and Y. M. Nolan, “Neuroinflammation Negatively Affects Adult Hippocampal Neurogenesis and Cognition: Can Exercise Compensate?,” Neuroscience and Biobehavioral Reviews 61 (2016): 121–131.
56 hippocampus is estimated to have around 47 million neurons: O. Bergmann, K. L. Spalding, and J. Frisén, “Adult Neurogenesis in Humans,” Cold Spring Harbor Perspectives in Biology 7, no. 7 (2015): a018994.
57 hippocampal neurogenesis drops to undetectable levels in childhood: S. F. Sorrells et al., “Human Hippocampal Neurogenesis Drops Sharply in Children to Undetectable Levels in Adults,” Nature 555, no. 7696 (2018): 377.
58 preserved neurogenesis: M. Boldrini et al., “Human Hippocampal Neurogenesis Persists throughout Aging,” Cell Stem Cell 22, no. 4 (2018): 589–599.
59 resolve the contradiction: S. C. Danzer, “Adult Neurogenesis in the Human Brain: Paradise Lost?,” Epilepsy Currents 18, no. 5 (2018): 329–331; G. Kempermann et al., “Human Adult Neurogenesis: Evidence and Remaining Questions,” Cell Stem Cell 23, no. 1 (2018): 25–30.
60 Mari Kodama: M. Kodama, personal communication, December 25, 2016.
61 older adults can learn how to use computers: Innovation in Aging 1, no. 3 (2018): igy002; T. L. Mitzner et al., “Technology Adoption by Older Adults: Findings from the PRISM Trial,” Gerontologist 59, no. 1 (2018): 34–44.
63 one in six Americans with hearing loss wears hearing aids: W. Chien and F. R. Lin, “Prevalence of Hearing Aid Use among Older Adults in the United States,” Archives of Internal Medicine 172, no. 3 (2012): 292–293.
1 The lens of the eye is shaped: I. Kohler, “Experiments with Goggles,” Scientific American 206, no. 5 (1962): 62–73.
2 Perceptual completion emerges in infancy: S. P. Johnson and E. E. Hannon, “Perceptual Development,” Handbook of Child Psychology and Developmental Science 2 (2015): 63–112; L. G. Craton, “The Development of Perceptual Completion Abilities: Infants’ Perception of Stationary, Partially Occluded Objects,” Child Development 67, no. 3 (1996): 890–904; B. S. Hadad and R. Kimchi, “Perceptual Completion of Partly Occluded Contours during Childhood,” Journal of Experimental Child Psychology 167 (2018): 49–61.
3 he studied this using distorting glasses: H. E. F. von Helmholtz, Treatise on Physiological Optics , ed. and trans. J. P. C. Southall (1909; repr., New York: Dover, 1962).
4 adaptations produce changes in the brain: J. Luauté et al., “Dynamic Changes in Brain Activity during Prism Adaptation,” Journal of Neuroscience 29, no. 1 (2009): 169–178; Y. Rossetti et al., “Testing Cognition and Rehabilitation in Unilateral Neglect with Wedge Prism Adaptation: Multiple Interplays between Sensorimotor Adaptation and Spatial Cognition,” in Clinical Systems Neuroscience , ed. K. Kansaku, L. G. Cohen, and N. Birbaumer, pp. 359–381 (Tokyo: Springer, 2015).
5 the hippocampus, the seat of spatial maps: J. Luauté et al., “Functional Anatomy of the Therapeutic Effects of Prism Adaptation on Left Neglect,” Neurology 66, no. 12 (2006): 1859–1867; M. Lunven et al., “Anatomical Predictors of Successful Prism Adaptation in Chronic Visual Neglect,” Cortex (2018).
6 interactions between the visual and motor system: R. Held, “Plasticity in Sensory-Motor Systems,” Scientific American 213, no. 5 (1965): 84–97; J. Fernández-Ruiz and R. Díaz, “Prism Adaptation and Aftereffect: Specifying the Properties of a Procedural Memory System,” Learning and Memory 6, no. 1 (1999): 47–53.
7 But as few as three interactions can bootstrap: The system is sensitive to two separate parameters: the angle of displacement and the number of times that a motor adaptation must be made.
8 the Innsbruck experiments included a pair of inverting goggles: A video of the experiment can be seen here: “Erismann and Kohler inversion ‘upside-down’ goggles—Film 2,” posted by Perceiving Acting, April 10, 2013, https://www.youtube.com/watch?v=z1HYcN7f9N4 .
9 took the goggles off: Cortex 92 (2017): 222–232.
11 hemispatial neglect: A. R. Riestra and A. M. Barrett, “Rehabilitation of Spatial Neglect,” in Handbook of Clinical Neurology , vol. 110, ed. M. P. Barnes and D. C. Good, pp. 347–355 (Amsterdam: Elsevier, 2013).
12 A reliable way to treat hemispatial neglect: Y. Rossetti et al., “Prism Adaptation to a Rightward Optical Deviation Rehabilitates Left Hemispatial Neglect,” Nature 395, no. 6698 (1998): 166; F. Frassinetti et al., “Long-Lasting Amelioration of Visuospatial Neglect by Prism Adaptation,” Brain 125, no. 3 (2002): 608–623; N. Vaes et al., “Rehabilitation of Visuospatial Neglect by Prism Adaptation: Effects of a Mild Treatment Regime. A Randomised Controlled Trial,” Neuropsychological Rehabilitation 28, no. 6 (2018): 899–918.
13 “rubber hand illusion”: M. Botvinick and J. Cohen, “Rubber Hands ‘Feel’ Touch That Eyes See,” Nature 391 (1998): 756, http://dx.doi.org/10.1038/35784 ; A. Kalckert and H. H. Ehrsson, “The Onset Time of the Ownership Sensation in the Moving Rubber Hand Illusion,” Frontiers in Psychology 8 (2017): 344; M. Tsakiris, “My Body in the Brain: A Neurocognitive Model of Body-Ownership,” Neuropsychologia 48 (2010): 703–712, http://dx.doi.org/10.1016/j.neuropsychologia.2009.09.034 ; M. Tsakiris and P. Haggard, “The Rubber Hand Illusion Revisited: Visuotactile Integration and Self-Attribution,” Journal of Experimental Psychology: Human Perception and Performance 31 (2005): 80–91, http://dx.doi.org/10.1037/0096-1523.31.1.80 ; you can see videos of this at “The Rubber Hand Illusion—Horizon: Is Seeing Believing?—BBC Two,” posted by BBC, October 15, 2010, https://www.youtube.com/watch?v=sxwn1w7MJvk , and “Is That My Real Hand? Breakthrough,” posted by National Geographic, November 4, 2015, https://www.youtube.com/watch?v=DphlhmtGRqI .
14 In the enfacement illusion: M. Tsakiris, “Looking for Myself: Current Multisensory Input Alters Self-Face Recognition,” PLoS One 3 (2008): e4040, http://dx.doi.org/10.1371/journal.pone.0004040 ; M. Tsakiris, “The Multisensory Basis of the Self: From Body to Identity to Others,” Quarterly Journal of Experimental Psychology 70, no. 4 (2017): 597–609; M. P. Paladino et al., “Synchronous Multisensory Stimulation Blurs Self-Other Boundaries,” Psychological Science 21 (2010): 1202–1207, http://dx.doi.org/10.1177/0956797610379234 ; you can see a video of this at “Demo Enfacement Illusion Tsakiris October 2011,” posted by “manostsak,” February 13, 2018, https://www.youtube.com/watch?v=WO1MrUX0K3c .
15 your very sense of self is constructed: G. Porciello et al., “The ‘Enfacement’ Illusion: A Window on the Plasticity of the Self,” Cortex 104 (2018): 261–275.
16 This is what happened to John F. Kennedy Jr.: National Transportation Safety Board, NTSB ID: NYC99MA178: Accident occurred July 16, 1999, in Vineyard Haven, MA (Washington, DC: NTSB, 1999). The official report on the accident, by the National Transportation Safety Board, emphasizes that “illusions or false impressions occur when information provided by sensory organs is misinterpreted or inadequate … some illusions might lead to spatial disorientation or the inability to determine accurately the attitude or motion of the aircraft in relation to the earth’s surface.” For more information, see R. Gibb, B. Ercoline, and L. Scharff, “Spatial Disorientation: Decades of Pilot Fatalities,” Aviation, Space, and Environmental Medicine 82, no. 7 (2011): 717–724.
17 After pain is experienced in a localized part: Neuroscience Letters 361, nos. 1–3 (2004): 136–139; T. Weiss, “Plasticity and Cortical Reorganization Associated with Pain,” Zeitschrift für Psychologie (2016).
18 phantom limb pain: S. Aglioti, A. Bonazzi, and F. Cortese, “Phantom Lower Limb as a Perceptual Marker of Neural Plasticity in the Mature Human Brain,” Proceedings of the Royal Society of London. Series B: Biological Sciences 255, no. 1344 (1994): 273–278; L. Nikolajsen and K. F. Christensen, “Phantom Limb Pain,” in Nerves and Nerve Injuries , ed. R. Tubbs et al., pp. 23–34 (New York: Elsevier, 2015).
19 A different approach to phantom limb pain: E. L. Altschuler et al., “Rehabilitation of Hemiparesis after Stroke with a Mirror,” Lancet 353, no. 9169 (1999): 2035–2036; V. S. Ramachandran and D. Rogers-Ramachandran, “Phantom Limbs and Neural Plasticity,” Archives of Neurology 57, no. 3 (2000): 317–320; J. Barbin et al., “The Effects of Mirror Therapy on Pain and Motor Control of Phantom Limb in Amputees: A Systematic Review,” Annals of Physical and Rehabilitation Medicine 59, no. 4 (2016): 270–275.
20 surgical correction of presbyopia: R. S. Davidson et al., “Surgical Correction of Presbyopia,” Journal of Cataract & Refractive Surgery 42, no. 6 (2016): 920–930.
21 this kind of automatic categorization: D. E. Levari et al., “Prevalence-Induced Concept Change in Human Judgment,” Science 360, no. 6396 (2018): 1465–1467.
22 abstract judgments: Levari et al., “Prevalence-Induced Concept Change.”
24 Cataract surgery: National Eye Institute, “Facts about Cataracts.”
25 age-related deterioration in mitochondrial DNA: J. O. Pickles, “Mutation in Mitochondrial DNA as a Cause of Presbycusis,” Audiology and Neurotology 9, no. 1 (2004): 23–33; Y. Shen et al., “Cognitive Decline, Dementia, Alzheimer’s Disease and Presbycusis: Examination of the Possible Molecular Mechanism,” Frontiers in Neuroscience 12 (2018): 394.
26 This imbalance can lead to problems: V. Lobo et al., “Free Radicals, Antioxidants and Functional Foods: Impact on Human Health,” Pharmacognosy Reviews 4, no. 8 (2010): 118; A. Santo, H. Zhu, and Y. R. Li, “Free Radicals: From Health to Disease,” Reactive Oxygen Species 2, no. 4 (2016): 245–263.
27 Foods that are high in antioxidants: Lobo et al., “Free Radicals”; M. Serafini and I. Peluso, “Functional Foods for Health: The Interrelated Antioxidant and Anti-Inflammatory Role of Fruits, Vegetables, Herbs, Spices and Cocoa in Humans,” Current Pharmaceutical Design 22, no. 44 (2016): 6701–6715.
28 evidence for the effectiveness of antioxidant foods: E. A. Decker et al., “Hurdles in Predicting Antioxidant Efficacy in Oil-in-Water Emulsions,” Trends in Food Science and Technology 67 (2017): 183–194.
31 auditory hallucinations: T. G. Sanchez et al., “Musical Hallucination Associated with Hearing Loss,” Arquivos de Neuro-psiquiatria 69, no. 2B (2011): 395–400; M. M. J. Linszen et al., “Auditory Hallucinations in Adults with Hearing Impairment: A Large Prevalence Study,” Psychological Medicine 49, no. 1 (2019): 132–139.
33 Many experience emotional distress: J. Henry, K. Dennis, and M. Schechter, “Theoretical/Review Article—General Review of Tinnitus: Prevalence, Mechanisms, Effects, and Management,” Journal of Speech, Language, and Hearing Research 48, no. 5 (2005): 1204–1234; A. McCormack et al., “A Systematic Review of the Reporting of Tinnitus Prevalence and Severity,” Hearing Research 337 (2016): 70–79.
34 “The notion of peace and quiet”: Henry et al., “Theoretical/Review Article—General Review of Tinnitus,” p. 1207.
35 Tinnitus does appear to be occurring in the brain: A. L. Giraud et al., “A Selective Imaging of Tinnitus,” Neuroreport 10, no. 1 (1999): 1–5; N. Weisz et al., “Tinnitus Perception and Distress Is Related to Abnormal Spontaneous Brain Activity as Measured by Magnetoencephalography,” PLoS Medicine 2, no. 6 (2005): e153; A. B. Elgoyhen et al., “Tinnitus: Perspectives from Human Neuroimaging,” Nature Reviews Neuroscience 16, no. 10 (2015): 632.
36 results from homeostatic neural plasticity: M. Dominguez et al., “A Spiking Neuron Model of Cortical Correlates of Sensorineural Hearing Loss: Spontaneous Firing, Synchrony, and Tinnitus,” Neural Computation 18, no. 12 (2006): 2942–2958; R. Schaette and R. Kempter, “Development of Tinnitus-Related Neuronal Hyperactivity through Homeostatic Plasticity after Hearing Loss: A Computational Model,” European Journal of Neuroscience 23 (2006): 3124–3138; S. E. Shore, L. E. Roberts, and B. Langguth, “Maladaptive Plasticity in Tinnitus—Triggers, Mechanisms and Treatment,” Nature Reviews Neurology 12, no. 3 (2016): 150.
37 An experimental therapy for tinnitus: R. Schaette et al., “Acoustic Stimulation Treatments against Tinnitus Could Be Most Effective When Tinnitus Pitch Is within the Stimulated Frequency Range,” Hearing Research 269, nos. 1–2 (2010): 95–101; R. Schaette, “Mechanisms of Tinnitus,” in Annual Tinnitus Research Review , ed. D. Baguley and N. Wray, pp. 10–15 (Sheffield, UK: British Tinnitus Association, 2016).
38 As Atul Gawande writes: A. Gawande, Being Mortal: Medicine and What Matters in the End (New York: Metropolitan Books, 2014), p. 31.
39 Decreased sense of smell: R. L. Doty and V. Kamath, “The Influences of Age on Olfaction: A Review,” Frontiers in Psychology 5 (2014): 20; J. Seubert et al., “Prevalence and Correlates of Olfactory Dysfunction in Old Age: A Population-Based Study,” Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences 72, no. 8 (2017): 1072–1079.
41 taste helps us prepare the body: S. S. Schiffman, “Taste and Smell Losses in Normal Aging and Disease,” Journal of the American Medical Association 278, no. 16 (1997): 1357–1362; E. McGinley, “Supporting Older Patients with Nutrition and Hydration,” Journal of Community Nursing 31, no. 4 (2017).
42 a fifth taste, umami: Y. Zhang et al., “Coding of Sweet, Bitter, and Umami Tastes: Different Receptor Cells Sharing Similar Signaling Pathways,” Cell 112, no. 3 (2003): 293–301; K. Kurihara, “Umami the Fifth Basic Taste: History of Studies on Receptor Mechanisms and Role as a Food Flavor,” BioMed Research International (2015): article ID 189402.
43 Many older adults complain that food lacks flavor: J. L. Garrison and Z. A. Knight, “Linking Smell to Metabolism and Aging,” Science 358, no. 6364 Food for the Aging Population , ed. M. Raats, L. De Groot, and D. van Asselt, pp. 57–82 (New York: Elsevier, 2017); G. Sergi et al., “Taste Loss in the Elderly: Possible Implications for Dietary Habits,” Critical Reviews in Food Science and Nutrition 57, no. 17 (2017): 3684–3689; S. Schiffman and M. Pasternak, “Decreased Discrimination of Food Odors in the Elderly,” Journal of Gerontology 34 (1979): 73–79, http://dx.doi.org/10.1093/geronj/34.1.73 ; S. S. Schiffman, “Taste and Smell Losses with Age,” Boletín de la Asociación Médica de Puerto Rico 83 (1991): 411–414; S. S. Schiffman, J. Moss, and R. P. Erickson, “Thresholds of Food Odors in the Elderly,” Experimental Aging Research (1976): 389–398, http://dx.doi.org/10.1080/03610737608257997 ; S. S. Schiffman and J. Zervakis, “Taste and Smell Perception in the Elderly: Effect of Medication and Disease,” Advances in Food and Nutrition Research 44 (2002): 247–346, http://dx.doi.org/10.1016/S1043-4526(02)44006-5 .
44 The loss of flavor: J. M. Boyce and G. R. Shone, “Effects of Ageing on Smell and Taste,” Postgraduate Medical Journal 82, no. 966 (2006): 239–241; L. E. Spotten et al., “Subjective and Objective Taste and Smell Changes in Cancer,” Annals of Oncology 28, no. 5 (2017): 969–984; B. N. Landis, C. G. Konnerth, and T. Hummel, “A Study on the Frequency of Olfactory Dysfunction,” Laryngoscope 114, no. 10 (2004): 1764–1769.
45 reduced ability of older adults to identify foods: S. Schiffman, “Changes in Taste and Smell with Age: Psychophysical Aspects,” in Sensory Systems and Communication in the Elderly: Aging , vol. 10, ed. J. M. Ordy and K. Brizzee, pp. 227–246 (New York: Raven Press, 1979).
46 healing power of the outdoors: S. Grafton, personal communication, March 29, 2018.
1 Art Blakey: A. Blakey, quoted in the liner notes for Art Blakey Quintet, A Night at Birdland , vol. 3, Blue Note Records, compact disc / 10-inch LP, 1954.
2 infants from African countries: L. B. Karasik et al., “WEIRD Walking: Cross-Cultural Research on Motor Development,” Behavioral and Brain Sciences 33, nos. 2–3 (2010): 95–96. WEIRD stands for Western, educated, industrialized, rich, and democratic because, ironically, that subpopulation accounts for about 80 percent of what behavioral scientists know about human behavior, even though the subpopulation comprises less than 12 percent of the world population.
3 environmental toxins impair learning: R. D. Baker and F. R. Greer, “Diagnosis and Prevention of Iron Deficiency and Iron-Deficiency Anemia in Infants and Young Children (0–3 Years of Age),” Pediatrics 126, no. 5 (2010): 1040–1050; P. M. Gupta et al., “Iron, Anemia, and Iron Deficiency Anemia among Young Children in the United States,” Nutrients 8, no. 6 (2016): 330, http://dx.doi.org/10.3390/nu8060330 .
4 Learning doesn’t happen the same way: Committee on How People Learn II, How People Learn II: Learners, Contexts and Cultures (Washington, DC: National Academies Press, 2018), p. 21, free download at http://nap.edu/24783 .
5 David Krakauer: D. Krakauer, personal communication, July 19, 2019.
6 “school failure may be partly explained”: Committee on How People Learn II, How People Learn II.
7 acquisitional intelligence: Robert Sternberg wrote about the importance of knowledge acquisition in his triarchic theory of intelligence, although he did not consider it a separate type of intelligence as I do here; R. J. Sternberg, Beyond IQ: A Triarchic Theory of Intelligence (Cambridge: Cambridge University Press, 1985).
8 information overload: The Organized Mind: Thinking Straight in the Age of Information Overload (New York: Dutton, 2014).
9 or “social” intelligence: E. L. Thorndike, “The Measurement of Intelligence: Present Status,” Psychological Review 31 (1924): 219–252.
10 naturalistic (knowledge of nature): H. Gardner, “Reflections on Multiple Intelligences: Myths and Messages,” Phi Delta Kappan 77 (1995): 200–209.
11 Sternberg studied naturalistic intelligence: R. J. Sternberg et al., “The Relationship between Academic and Practical Intelligence: A Case Study in Kenya,” Intelligence 29, no. 5 (2001): 408.
12 The children performed very well: A typical question was as follows:
A small child in your family has homa. She has a sore throat, headache, and fever. She has been sick for 3 days. Which of the following five Yadh nyaluo (Luo herbal medicines) can treat homa?
Chamama. Take the leaf and fito (sniff medicine up the nose to sneeze out illness).
Kaladali. Take the leaves, drink, and fito.
Obuo. Take the leaves and fito.
Ogaka. Take the roots, pound, and drink.
Ahundo. Take the leaves and fito.
In this item, Options 1 and 2 represent common treatments for homa, Option 3 represents a rare treatment, Option 4 represents a treatment that is not used for homa, and Option 5 represents an imaginary (nonexistent) herb. Thus Options 1–3 were scored as correct answers. If Option 5 was chosen, a penalty of 3 points was applied.
To avoid ethnocentric bias, scoring was based on healers’ knowledge, not on what Westerners might believe to be the correct answers.
13 As Sternberg notes: Sternberg et al., “The Relationship between Academic and Practical Intelligence,” p. 414.
14 Dandelions can grow: M. Gazzaniga et al., Psychological Science , 3rd Canadian ed. (New York: W. W. Norton, 2010).
15 My favorite example of this: J. L. Adams, Conceptual Blockbusting: A Guide to Better Ideas (New York: W. W. Norton, 1980).
16 The standard solution to the nine dot puzzle:
How to Solve It , a great little book that has expanded the problemsolving skills of generations of students—and because of his infectious and easy writing style, he reaches even those who are math-phobic. G. Polya, How to Solve It: A New Aspect of Mathematical Method (Princeton, NJ: Princeton University Press, 2004).
17 “It’s just a party trick”: J. Mogil, personal communication, July 15, 2019.
18 The Mona Lisa : M. Lankford, Becoming Leonardo: An Exploded View of the Life of Leonardo da Vinci (Brooklyn, NY: Melville House, 2017).
19 the aging brain and reaction times: A. P. Shimamura et al., “Memory and Cognitive Abilities in Academic Professors: Evidence for Successful Aging,” Psychological Science 6 (1995): 271–277; A. P. Shimamura, Get SMART! Five Steps toward a Healthy Brain (Scotts Valley, CA: CreateSpace, 2017).
20 age-related decreases in blood flow: R. C. Gur et al., “Age and Regional Cerebral Blood Flow at Rest and during Cognitive Activity,” Archives of General Psychiatry 44 (1987): 617–621.
21 changes in the structure of cells: R. L. Buckner, “Memory and Executive Function in Aging and AD: Multiple Factors That Cause Decline and Reserve Factors That Compensate,” Neuron 44 (2004): 195–208.
22 low fluid intelligence in childhood: S. Aichele et al., “Fluid Intelligence Predicts Change in Depressive Symptoms in Later Life: The Lothian Birth Cohort 1936,” Psychological Science (2018): 1–12, http://dx.doi.org/10.1177/0956797618804501 .
23 Practical intelligence increases with age: Sternberg et al., “The Relationship between Academic and Practical Intelligence.”
24 Intelligent, adaptive behavior requires abstracting: S. L. Brincat et al., “Gradual Progression from Sensory to Task-Related Processing in Cerebral Cortex,” Proceedings of the National Academy of Sciences 115, no. 30 (2018): E7202—E7211.
25 abstraction involves a wide range of brain regions: Brincat et al., “Gradual Progression from Sensory to Task-Related Processing in Cerebral Cortex,” Proceedings of the National Academy of Sciences 115, no. 30 (2018): E7202–E7211.
26 tendency to form abstract representations: A. Susac et al., “Development of Abstract Mathematical Reasoning: The Case of Algebra,” Frontiers in Human Neuroscience 8 (2014): 679.
27 It isn’t until around sixteen or seventeen: Susac et al., “Development of Abstract Mathematical Reasoning.”
28 abstract thinking in other species: S. R. Howard et al., “Numerical Ordering of Zero in Honey Bees,” Science 360, no. 6393 (2018): 1124–1126; A. Nieder, “Honey Bees Zero In on the Empty Set,” Science 360, no. 6393 (2018): 1069–1070.
29 Diane Ackerman invented a game called Dingbats: D. Ackerman, One Hundred Names for Love (New York: W. W. Norton, 2011), pp. 82–83.
30 increased cortical thickness and gray-matter volume: S. Kühn et al., “The Importance of the Default Mode Network in Creativity—a Structural MRI Study,” Journal of Creative Behavior 48, no. 2 (2014): 152–163; R. E. Beaty et al., “Creativity and the Default Network: A Functional Connectivity Analysis of the Creative Brain at Rest,” Neuropsychologia 64 (2014): 92–98.
31 Aging is not accompanied by unavoidable cognitive decline: T. A. Salthouse, “The Processing-Speed Theory of Adult Age Differences in Cognition,” Psychological Review 103, no. 3 (1996): 403; T. A. Salthouse, T. M. Atkinson, and D. E. Berish, “Executive Functioning as a Potential Mediator of Age-Related Journal of Experimental Psychology: General 132, no. 4 (2003): 566; L. J. Whalley et al., “Cognitive Reserve and the Neurobiology of Cognitive Aging,” Ageing Research Reviews 3, no. 4 (2004): 369–382.
32 neuroprotective and neurorestorative capabilities: Whalley et al., “Cognitive Reserve.”
33 biological, pathological markers for Alzheimer’s disease: P. G. Ince, “Pathological Correlates of Late-Onset Dementia in a Multicenter Community-Based Population in England and Wales,” Lancet 357, no. 9251 (2001): 169–175.
34 Cognitive reserve can insulate against: Whalley et al., “Cognitive Reserve.”
35 occupational complexity: Whalley et al., “Cognitive Reserve”; K. Fujishiro et al., “The Role of Occupation in Explaining Cognitive Functioning in Later Life: Education and Occupational Complexity in a US National Sample of Black and White Men and Women,” Journals of Gerontology: Series B (2017): gbx112, https://doi.org/10.1093/geronb/gbx112 .
36 low educational attainment and low occupational complexity: S. Cullum et al., “Decline across Different Domains of Cognitive Function in Normal Ageing: Results of a Longitudinal Population-Based Study Using CAMCOG,” International Journal of Geriatric Psychiatry 15 (2000): 853–862; M. Zhang et al., “The Prevalence of Dementia and Alzheimer’s Disease in Shanghai, China: Impact of Age, Gender, and Education,” Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society 27, no. 4 (1990): 428–437; Y. Stern, “Cognitive Reserve in Ageing and Alzheimer’s Disease,” Lancet Neurology 11, no. 11 (2012): 1006–1012; E. A. Boots et al., “Occupational Complexity and Cognitive Reserve in a Middle-Aged Cohort at Risk for Alzheimer’s Disease,” Archives of Clinical Neuropsychology 30, no. 7 (2015): 634–642.
37 Karl Duncker: K. Duncker and L. S. Lees, “On Problem-Solving,” Psychological Monographs 58, no. 5 (1945): 1.
38 Duncker then proposed a problem: This problem has been used in several different versions and wordings, from Duncker’s original conception, to papers by Gick and Holyoak and entries in cognitive psychology texts. This formulation is my own amalgamation of those. Duncker and Lees, “On Problem-Solving”; M. L. Gick and K. J. Holyoak, “Schema Induction and Analogical Transfer,” Cognitive Psychology 15, no. 1 (1983): 1–38; M. L. Gick and K. J. Holyoak, “Analogical Problem Solving,” Cognitive Psychology 12, no. 3 (1980): 306–355.
39 What is wisdom?: E. E. Lee and D. V. Jeste, “Neurobiology of Wisdom,” in The Cambridge Handbook of Wisdom , ed. R. J. Sternberg and J. Glück (Cambridge, UK: Cambridge University Press, 2019).
40 Paul Baltes defined wisdom as: P. B. Baltes and J. Smith, “The Fascination of Wisdom: Its Nature, Ontogeny, and Function,” Perspectives on Psychological Science 3, no. 1 (2008): 56–64.
41 the development of wisdom: J. Glück, S. Bluck, and N. M. Weststrate, “More on the MORE Life Experience Model: What We Have Learned (So Far),” Journal of Value Inquiry (2018): 1–22.
42 King Solomon: In the biblical account, two women present themselves to the king, who acted as judge for the kingdom, both claiming to be the mother of a small baby. Solomon proposes that the baby be cut in half. One of the women agreed to the solution and the other begged him not to, and to instead give the baby to her rival. Solomon knew that the real mother’s love for the child would be borne out by his proposal and that only the real mother would object to the proposal.
43 Older adults show higher levels of emotional regulation: Science 336, no. 6081 (2012): 612–614.
44 experience-based decision making and conflict resolution: I. Grossmann et al., “Reasoning about Social Conflicts Improves into Old Age,” Proceedings of the National Academy of Sciences 107, no. 16 (2010): 7246–7250; D. A. Worthy et al., “With Age Comes Wisdom,” Psychological Science 22, no. 11 (2011): 1375–1380.
45 prosocial behaviors: J. N. Beadle et al., “Aging, Empathy, and Prosociality,” Journals of Gerontology, Series B: Psychological Sciences and Social Sciences 70, no. 2 (2015): 215–224.
46 subjective emotional well-being: L. L. Carstensen et al., “Emotional Experience Improves with Age: Evidence Based on over 10 Years of Experience Sampling,” Psychology and Aging 26, no. 1 (2011): 21–33.
47 self-reflection or insight: Brassen et al., “Don’t Look Back in Anger!”
48 favoring positive emotions: L. L. Carstensen and M. DeLiema, “The Positivity Effect: A Negativity Bias in Youth Fades with Age,” Current Opinion in Behavioral Sciences 19 (2018): 7–12.
49 greater ability to maintain positive relationships: K. S. Birditt, L. M. Jackey, and T. C. Antonucci, “Longitudinal Patterns of Negative Relationship Quality across Adulthood,” Journals of Gerontology, Series B: Psychological Sciences and Social Sciences 64, no. 1 (2009): 55–64.
50 Greater wisdom is also marked by: T. W. Meeks and D. V. Jeste, “Neurobiology of Wisdom,” Archives of General Psychiatry 66, no. 4 (2009): 355–365.
51 dopamine decreases with age: P. S. Goldman-Rakic and R. M. Brown, “Regional Changes of Monoamines in Cerebral Cortex and Subcortical Structures of Aging Rhesus Monkeys,” Neuroscience 6, no. 2 (1981): 177–187; L. Bäckman et al., “The Correlative Triad among Aging, Dopamine, and Cognition: Current Status and Future Prospects,” Neuroscience and Biobehavioral Reviews 30, no. 6 (2006): 791–807; V. Kaasinen et al., “Age-Related Dopamine D2/D3 Receptor Loss in Extrastriatal Regions of the Human Brain,” Neurobiology of Aging 21, no. 5 (2000): 683–688.
52 Precursors of wisdom: R. J. Sternberg, “Why Schools Should Teach for Wisdom: The Balance Theory of Wisdom in Educational Settings,” Educational Psychologist 36, no. 4 (2001): 227–245.
1 When Stevie sings: S. Wonder, Visions , from Inner Visions , Tamla, T326L.
2 When Joni sings the single word blue : I wrote about this previously in D. J. Levitin, “Inside the Theater of the Mind. Review of How Emotions Are Made by Lisa Feldman Barrett,” The Wall Street Journal , March 4, 2017, p. B5.
3 Emotions occur against: R. J. Davidson, “On Emotion, Mood, and Related Affective Constructs,” in The Nature of Emotion: Fundamental Questions , ed. P. Ekman and R. J. Davidson, pp. 51–55 (New York: Oxford University Press, 1994).
4 Emotion, motivation, reinforcement, and arousal: J. LeDoux, “Rethinking the Emotional Brain,” Neuron 73 (2002): 653–676.
5 biologist Frans de Waal: F. de Waal, Mama’s Last Hug (New York: W. W. Norton, 2019).
6 Our human survival strategies go back: R. M. Macnab and D. E. Koshland, “The Gradient-Sensing Mechanism in Bacterial Chemotaxis,” Proceedings of the National Academy of Sciences 69, no. 9 (1972): 2509–2512.
7 a neuropeptide called nematocin: S. W. Emmons, “The Mood of a Worm,” Science 338, no. 6106 (2012): 475–476; J. L. Garrison et al., “Oxytocin/Vasopressin-Related Science 338, no. 6106 (2012): 540–543.
8 Survival circuits, from worms to humans: LeDoux, “Rethinking the Emotional Brain.”
9 What we call emotions or feelings: LeDoux, “Rethinking the Emotional Brain.”
10 the rickety bridge experiment: D. G. Dutton and A. P. Aron, “Some Evidence for Heightened Sexual Attraction under Conditions of High Anxiety,” Journal of Personality and Social Psychology 30, no. 4 (1974): 510.
11 emotions can easily be misattributed: S. Schachter and J. Singer, “Cognitive, Social, and Physiological Determinants of Emotional State,” Psychological Review 69, no. 5 (1962): 379; G. L. White, S. Fishbein, and J. Rutsein, “Passionate Love and the Misattribution of Arousal,” Journal of Personality and Social Psychology 41, no. 1 (1981): 56.
12 there are emotions that dogs: I wrote about this previously in D. J. Levitin, “Brain Candy. Review of Human: The Science behind What Makes Us Unique , by M. Gazzaniga,” The New York Times Sunday Book Review , August 24, 2008, 5.
13 we should add spite to the list: K. Jensen, J. Call, and M. Tomasello, “Chimpanzees Are Vengeful but Not Spiteful,” Proceedings of the National Academy of Sciences 104, no. 32 (2007): 13046–13050.
14 Tagalog, which calls it kilig : T. Lomas, “Towards a Positive Cross-Cultural Lexicography: Enriching Our Emotional Landscape through 216 ‘Untranslatable’ Words Pertaining to Well-Being,” Journal of Positive Psychology 11, no. 5 (2016): 546–558, http://dx.doi.org/10.1080/17439760.2015.1127993 ; T. Lomas, “The Magic of Untranslatable Words,” Scientific American , July 12, 2016, https://www.scientificamerican.com/article/the-magic-of-untranslatable-words/?print=true .
15 As emotion researcher Lisa Feldman Barrett says: L. F. Barrett, How Emotions Are Made: The Secret Life of the Brain (Boston: Houghton Mifflin Harcourt, 2017).
16 Emotion differentiation: E. C. Nook et al., “The Nonlinear Development of Emotion Differentiation: Granular Emotional Experience Is Low in Adolescence,” Psychological Science 29, no. 8 (2018): 1346–1357.
17 gene-by-environment interactions: I’ve written about some of this previously in D. J. Levitin, “The Ultimate Brain Quest. Review of Connectome: How the Brain’s Wiring Makes Us Who We Are by Sebastian Seung,” The Wall Street Journal , February 4, 2012, C5–C6.
18 University of Montreal colleague Sonia Lupien: S. J. Lupien et al., “Beyond the Stress Concept: Allostatic Load—A Developmental Biological and Cognitive Perspective,” in Developmental Psychopathology , vol. 2, Developmental Neuroscience , ed. D. Cicchetti and D. J. Cohen, pp. 578–628 (Hoboken, NJ: John Wiley and Sons, 2015).
20 some of our physiological systems … require continual adjustment: P. Sterling, “Allostasis: A Model of Predictive Regulation,” Physiology and Behavior 106 (2012): 5–15; G. H. Ice and G. D. James, Measuring Stress in Humans: A Practical Guide for the Field (Cambridge: Cambridge University Press, 2007), p. 284.
21 stability through change is called allostasis : P. Sterling and J. Eyer, “Allostasis: A New Paradigm to Explain Arousal Pathology,” in Handbook of Life Stress, Cognition and Health , ed. S. Fisher and J. Reason, pp. 629–649 (Oxford, UK: John Wiley and Sons, 1988).
22 This in turn causes a dysregulation:
23 Your allostatic load can be calculated: A. Edes and D. E. Crews, “Allostatic Load and Biological Anthropology,” American Journal of Physical Anthropology 162 (2017): 44–70.
24 ways to reduce stress: H. Frumkin et al., “Nature Contact and Human Health: A Research Agenda,” Environmental Health Perspectives 125, no. 7 (2017): 075001; C. E. Hostinar and M. R. Gunnar, “Social Support Can Buffer against Stress and Shape Brain Activity,” AJOB Neuroscience 6, no. 3 (2015): 34–42; A. Linnemann et al., “Music Listening as a Means of Stress Reduction in Daily Life,” Psychoneuroendocrinology 60 (2015): 82–90.
25 Doing this is metabolically expensive: A. Danese and B. S. McEwen, “Adverse Childhood Experiences, Allostasis, Allostatic Load, and Age-Related Disease,” Physiology and Behavior 106, no. 1 (2012): 29–39; B. S. McEwen, “Allostasis and Allostatic Load: Implications for Neuropsychopharmacology,” Neuropsychopharmacology 22, no. 2 (2000): 108–124.
26 A stable fetal and early childhood: D. J. Barker, “Developmental Origins of Chronic Disease,” Public Health 126, no. 3 (2012): 185–189.
27 Increased allostatic load: T. Booth et al., “Association of Allostatic Load with Brain Structure and Cognitive Ability in Later Life,” Neurobiology of Aging 36 (2015): 1390–1399.
28 linked to a number of psychiatric conditions: G. Bizik et al., “Allostatic Load as a Tool for Monitoring Physiological Dysregulations and Comorbidities in Patients with Severe Mental Illnesses,” Harvard Review of Psychiatry 21 (2012): 296–313; R. W. Kobrosly et al., “Depressive Symptoms Are Associated with Allostatic Load among Community-Dwelling Older Adults,” Physiology and Behavior 123 (2014): 223–230; J. A. Stewart, “The Detrimental Effects of Allostasis: Allostatic Load as a Measure of Cumulative Stress,” Journal of Physiological Anthropology 25 (2006): 133–145.
29 normal age-related changes in structures that regulate allostasis: E. Zsoldos et al., “Allostatic Load as a Predictor of Grey Matter Volume and White Matter Integrity in Old Age: The Whitehall II MRI Study,” Scientific Reports 8, no. 1 (2018): 6411.
30 sleep disturbances to increases in load: R. P. Juster and B. S. McEwen, “Sleep and Chronic Stress: New Directions for Allostatic Load Research,” Sleep Medicine 16, no. 1 (2015): 7–8.
31 Reducing stress and increasing resilience: B. L. Ganzel, P. A. Morris, and E. Wethington, “Allostasis and the Human Brain: Integrating Models of Stress from the Social and Life Sciences,” Psychological Review 117, no. 1 (2010): 134; B. S. McEwen and P. J. Gianaros, “Stress- and Allostasis-Induced Brain Plasticity,” Annual Review of Medicine 62 (2011): 431–445; G. Tabibnia and D. Radecki, “Resilience Training That Can Change the Brain,” Consulting Psychology Journal: Practice and Research 70, no. 1 (2018): 59–88.
32 the same across continents: G. Y. Lim et al., “Prevalence of Depression in the Community from 30 Countries between 1994 and 2014,” Scientific Reports 8, no. 1 (2018): 2861; J. Wang et al., “Prevalence of Depression and Depressive Symptoms among Outpatients: A Systematic Review and Meta-analysis,” BMJ Open 7, no. 8 (2017): e017173, http://dx.doi.org/10.1136/BMJopen-2017-017173 ; D. J. Brody, L. A. Pratt, and J. P. Hughes, “Prevalence of Depression among Adults Aged 20 and Over: United States, 2013–2016” (Hyattsville, MD: NCHS Data Brief 303, National Center for Health Statistics, 2018), pp. 1–8.
33 antidepressant drugs tend to work only 20 percent: https://www.ncbi.nlm.nih.gov/books/NBK361016/ ; A. Cipriani et al., “Antidepressants Might Work for People with Major Depression: Where Do We Go from Here?,” Lancet Psychiatry 5, no. 6 (2018): 461–463.
34 After the procession, we met in his office: His Holiness the Dalai Lama, personal communication, Dharamsala, India, August 30, 2018.
38 Depression in old age is: U. Padayachey, S. Ramlall, and J. Chipps, “Depression in Older Adults: Prevalence and Risk Factors in a Primary Health Care Sample,” South African Family Practice 59, no. 2 (2017): 61–66.
39 the impact of the curtailment of daily activities: A. Fiske, J. L. Wetherell, and M. Gatz, “Depression in Older Adults,” Annual Review of Clinical Psychology 5 (2009): 363–389.
40 Insomnia, a hallmark of aging: K. L. Lichstein et al., “Insomnia in the Elderly,” Sleep Medicine Clinics 1, no. 2 (2006): 221–229.
41 understanding of the role of meaningful engagement: H. C. Hendrie et al., “The NIH Cognitive and Emotional Health Project: Report of the Critical Evaluation Study Committee,” Alzheimer’s and Dementia 2, no. 1 (2006): 12–32.
42 the presence of intimate others: R. J. Davidson et al., “Neural and Behavioral Substrates of Mood and Mood Regulation,” Biological Psychiatry 52, no. 6 (2002): 478–502; G. Gariepy, H. Honkaniemi, and A. Quesnel-Vallee, “Social Support and Protection from Depression: Systematic Review of Current Findings in Western Countries,” British Journal of Psychiatry 209, no. 4 (2016): 284–293.
43 “dopamine was the drunk”: J. Mogil, personal communication, July 16, 2019.
44 SSRIs should be the first-line pharmacological: J. Rodda, Z. Walker, and J. Carter, “Depression in Older Adults,” British Medical Journal 343, no. 8 (2011): d5219.
45 Low doses of methylphenidate: H. Lavretsky et al., “Combined Citalopram and Methylphenidate Improved Treatment Response Compared to Either Drug Alone in Geriatric Depression: A Randomized Double-Blind, Placebo-Controlled Trial,” American Journal of Psychiatry 172, no. 6 (2015): 561; T. A. Ketter et al., “Long-Term Safety and Efficacy of Armodafinil in Bipolar Depression: A 6-Month Open-Label Extension Study,” Journal of Affective Disorders 197 (2016): 51–57.
46 Psychotherapy can change the structure of the brain: K. N. Månsson et al., “Neuroplasticity in Response to Cognitive Behavior Therapy for Social Anxiety Disorder,” Translational Psychiatry 6, no. 2 (2016): e727; D. Collerton, “Psychotherapy and Brain Plasticity,” Frontiers in Psychology 4 (2013): 548.
47 talk therapy has proven its effectiveness: R. D. Lane et al., “Memory Reconsolidation, Emotional Arousal, and the Process of Change in Psychotherapy: New Insights from Brain Science,” Behavioral and Brain Sciences 38 (2015).
48 as effective as antidepressant drugs: Nature Reviews Neuroscience 9, no. 10 (2008): 788.
49 coping styles in depression: Davidson et al., “Neural and Behavioral Substrates.”
50 rumination … feels good: W. H. Frey II, Crying: The Mystery of Tears (Minneapolis, MN: Winston Press, 1985); R. Turner et al., “Effects of Emotion on Oxytocin, Prolactin, and ACTH in Women,” Stress 5, no. 4 (2002): 269–276.
51 The more effective strategy: S. Nolen-Hoeksema, “Responses to Depression and Their Effects on the Duration of the Depressive Episode,” Journal of Abnormal Psychology 100, no. 4 (1991): 569–582; S. Nolen-Hoeksema and J. Morrow, “Effects of Rumination and Distraction on Naturally Occurring Depressed Mood,” Cognition and Emotion 7, no. 6 (1993): 561–570.
52 the time of the month when women get cabin fever: N. M. Morris and J. R. Udry, “Variations in Pedometer Activity during the Menstrual Cycle,” Obstetrics and Gynecology 35, no. 2 (1970): 199–201; M. Haselton, Hormonal: The Hidden Intelligence of Hormones—How They Drive Desire, Shape Relationships, Influence Our Choices, and Make Us Wiser (Boston: Little, Brown, 2018).
53 Higher estrogen is: S. J. Stanton and O. C. Schultheiss, “Basal and Dynamic Relationships between Implicit Power Motivation and Estradiol in Women,” Hormones and Behavior 52, no. 5 (2007): 571–580; K. Lebron-Milad, B. M. Graham, and M. R. Milad, “Low Estradiol Levels: A Vulnerability Factor for the Development of Posttraumatic Stress Disorder,” Biological Psychiatry 72, no. 1 (2012): 6–7, http://dx.doi.org/10.1016/j.biopsych.2012.04.029 .
54 The increased progesterone production: M. Østensen, P. M. Villiger, and F. Förger, “Interaction of Pregnancy and Autoimmune Rheumatic Disease,” Autoimmunity Reviews 11, nos. 6–7 (2012): A437–A446.
55 Pregnant women who have had rheumatoid arthritis: J. Greenspan et al., “Studying Sex and Gender Differences in Pain and Analgesia: A Consensus Report,” Pain 132 (2007): S26–S45.
56 High progesterone leads women: M. L. Smith et al., “Facial Appearance Is a Cue to Oestrogen Levels in Women,” Proceedings of the Royal Society of London B: Biological Sciences 273, no. 1583 (2006): 135–140; D. S. Fleischman and D. M. Fessler, “Progesterone’s Effects on the Psychology of Disease Avoidance: Support for the Compensatory Behavioral Prophylaxis Hypothesis,” Hormones and Behavior 59, no. 2 (2011): 271–275.
57 Psychological scientist Martie Haselton writes: Haselton, Hormonal , p. 76.
58 Progesterone is associated with: O. C. Schultheiss, A. Dargel, and W. Rohde, “Implicit Motives and Gonadal Steroid Hormones: Effects of Menstrual Cycle Phase, Oral Contraceptive Use, and Relationship Status,” Hormones and Behavior 43, no. 2 (2003): 293–301.
59 progesterone promotes calmness: E. Timby et al., “Pharmacokinetic and Behavioral Effects of Allopregnanolone in Healthy Women,” Psychopharmacology 186, no. 3 (2006): 414; A. Smith et al., “Cycles of Risk: Associations between Menstrual Cycle and Suicidal Ideation among Women,” Personality and Individual Differences 74 (2015): 35–40.
60 testosterone appears to regulate: C. Eisenegger, J. Haushofer, and E. Fehr, “The Role of Testosterone in Social Interaction,” Trends in Cognitive Sciences 15, no. 6 (2011): 263–271.
61 risky activities, such as gambling: S. J. Stanton, S. H. Liening, and O. C. Schultheiss, “Testosterone Is Positively Associated with Risk Taking in the Iowa Hormones and Behavior 59, no. 2 (2011): 252–256; see also J. M. Coates and J. Herbert, “Endogenous Steroids and Financial Risk Taking on a London Trading Floor,” Proceedings of the National Academy of Sciences 105, no. 16 (2008): 6167–6172.
62 having sexual relations with multiple partners: S. M. van Anders, L. D. Hamilton, and N. V. Watson, “Multiple Partners Are Associated with Higher Testosterone in North American Men and Women,” Hormones and Behavior 51, no. 3 (2007): 454–459.
63 In “the smelly T-shirt study”: S. L. Miller, and J. K. Maner, “Scent of a Woman: Men’s Testosterone Responses to Olfactory Ovulation Cues,” Psychological Science 21, no. 2 (2010): 276–283.
64 increase after achieving public success: O. C. Schultheiss, K. L. Campbell, and D. C. McClelland, “Implicit Power Motivation Moderates Men’s Testosterone Responses to Imagined and Real Dominance Success,” Hormones and Behavior 36, no. 3 (1999): 234–241.
65 male finches sing more: M. Ritschard et al., “Enhanced Testosterone Levels Affect Singing Motivation but Not Song Structure and Amplitude in Bengalese Finches,” Physiology and Behavior 102, no. 1 (2011): 30–35.
66 aggressive behaviors increase testosterone: Eisenegger et al., “The Role of Testosterone in Social Interaction.”
67 The compulsory education: Committee on How People Learn II, How People Learn II: Learners, Contexts and Cultures (Washington, DC: National Academies Press, 2018), p. 21, free download at http://nap.edu/24783 .
68 Take Paul Simon: P. Simon, personal communication, New York, September 19, 2013.
70 Paul Simon again: P. Simon, personal communication, New York, March 4, 2009.
71 Two knowledge domains that are: Committee on How People Learn II, How People Learn II , p. 21.
72 Prior experience is a factor: P. L. Ackerman and M. E. Beier, “Determinants of Domain Knowledge and Independent Study Learning in an Adult Sample,” Journal of Educational Psychology 98, no. 2 (2006): 366–381; M. E. Beier and P. L. Ackerman, “Determinants of Health Knowledge: An Investigation of Age, Gender, Abilities, Personality, and Interests,” Journal of Personality and Social Psychology 84, no. 2 (2003): 439–448; M. E. Beier and P. L. Ackerman, “Age, Ability, and the Role of Prior Knowledge on the Acquisition of New Domain Knowledge: Promising Results in a Real-World Learning Environment,” Psychology and Aging 20, no. 2 (2005): 341–355, http://dx.doi.org/10.1037/0882-7974.20.2.341 ; M. E. Beier, C. K. Young, and A. J. Villado, “Job Knowledge: Its Definition, Development and Measurement,” in The Handbook of Industrial, Work, and Organization Psychology , ed. D. Ones et al. (Los Angeles, CA: Sage, 2018).
73 Physicians have an easier time comprehending: V. L. Patel, G. J. Groen, and C. H. Frederiksen, “Differences between Medical Students and Doctors in Memory for Clinical Cases,” Medical Education 20, no. 1 (1986): 3–9; see also B. L. Anderson-Montoya et al., “Running Memory for Clinical Handoffs: A Look at Active and Passive Processing,” Human Factors 59, no. 3 (2017): 393–406.
74 People who focus mainly on getting recognition: E. L. Deci and R. M. Ryan, Intrinsic Motivation and Self-Determination in Human Behavior (New York: Plenum Psychological Inquiry 11 (2000): 227–268; R. M. Ryan and E. L. Deci, Self-Determination Theory: Basic Psychological Needs in Motivation, Development, and Wellness (New York: Guilford Publications, 2017).
75 even geniuses work hard :Educational Leadership 68, no. 1 (2010): 16–20.
76 Dweck describes two kinds of mind-sets: C. S. Dweck, Mindset: The New Psychology of Success (New York: Penguin Random House, 2008).
77 People with a fixed mind-set: Some of these bullet points are from S. Levitin, Heart and Sell (Wayne, NJ: Career Press, 2017), p. 31.
78 Dweck counsels the following: C. Dweck, “Carol Dweck Revisits the Growth Mindset,” Education Week 35, no. 5 (2015): 20–24.
79 Older adults show increases in their motivation: Committee on How People Learn II, How People Learn II , p. 21; L. L. Carstensen, D. M. Isaacowitz, and S. T. Charles, “Taking Time Seriously: A Theory of Socioemotional Selectivity,” American Psychologist 54, no. 3 (1999): 165–181.
81 Tim Laddish (age seventy-seven), former senior assistant attorney general: T. Laddish, email communication, October 29, 2018.
82 But lottery winners tend not to be happy: P. Brickman, D. Coates, and R. Janoff-Bulman, “Lottery Winners and Accident Victims: Is Happiness Relative?,” Journal of Personality and Social Psychology 36, no. 8 (1978): 917.
83 But paraplegics and quadriplegics adapt: See also D. A. Schkade and D. Kahneman, “Does Living in California Make People Happy? A Focusing Illusion in Judgments of Life Satisfaction,” Psychological Science 9, no. 5 (1998): 340–346; D. Gilbert, Stumbling on Happiness (Toronto: Vintage Canada, 2009); S. Lyubomirsky, The Myths of Happiness: What Should Make You Happy, but Doesn’t, What Shouldn’t Make You Happy, but Does (New York: Penguin, 2014).
84 Vicente Fox: V. Fox, personal communication, Léon, Mexico, May 18, 2018.
1 “L’enfer, c’est les autres ”: I open with this quote because it is so well-known and rings true to many of us; we understand the desire to be free of the demands and irritating nature of others. But this is a misinterpretation of Sartre’s line. He did not actually mean that one is happier hiding in isolation. What he meant is that we cannot escape the judgments of others, their watchful eyes, the shame we feel in our flaws being revealed to them. The full quote, from the play No Exit , is:
All those eyes intent on me. Devouring me. What? Only two of you? I thought there were more; many more. So this is hell. I’d never have believed it. You remember all we were told about the torture-chambers, the fire and brimstone, the “burning marl.” Old wives’ tales! There’s no need for red-hot pokers. HELL IS OTHER PEOPLE!
P. Caws, “To Hell and Back: Sartre on (and in) Analysis with Freud,” Sartre Studies International 11, no. 1 (2005): 166–176. And Sartre himself said,
“Hell is other people” has always been misunderstood. It has been thought that what I meant by that was that our relations with other people are always
2 Loneliness is associated with early mortality: L. C. Hawkley and J. T. Cacioppo, “Loneliness Matters: A Theoretical and Empirical Review of Consequences and Mechanisms,” Annals of Behavioral Medicine 40, no. 2 (2010): 218–227.
3 It leads to inflammation: L. M. Jaremka et al., “Loneliness Promotes Inflammation during Acute Stress,” Psychological Science 24, no. 7 (2013): 1089–1097.
4 it negates the beneficial effects of exercise: A. M. Stranahan, D. Khalil, and E. Gould, “Social Isolation Delays the Positive Effects of Running on Adult Neurogenesis,” Nature Neuroscience 9, no. 4 (2006): 526.
6 If you are chronically lonely: J. Holt-Lunstad et al., “Loneliness and Social Isolation as Risk Factors for Mortality: A Meta-Analytic Review,” Perspectives on Psychological Science 10, no. 2 (2015): 227–237.
7 Government research in the UK: Holt-Lunstad et al., “Loneliness and Social Isolation.”
8 Harvard political scientist Robert Putnam: R. D. Putnam, “Bowling Alone: America’s Declining Social Capital,” in Culture and Politics , ed. L. Crothers and C. Lockhart, pp. 223–234 (New York: Palgrave Macmillan, 2000).
10 (getting “likes” can produce an addictive hit of dopamine): I previously wrote about this in D. J. Levitin, The Organized Mind (New York: Dutton, 2014).
11 Proper brain functioning depends on: M. Ankarcrona et al., “Glutamate-Induced Neuronal Death: A Succession of Necrosis or Apoptosis Depending on Mitochondrial Function,” Neuron 15, no. 4 (1995): 961–973; R. Sattler and M. Tymianski, “Molecular Mechanisms of Glutamate Receptor-Mediated Excitotoxic Neuronal Cell Death,” Molecular Neurobiology 24, nos. 1–3 (2001): 107–129.
12 MSG does not significantly change levels of glutamate: R. A. Hawkins, “The Blood-Brain Barrier and Glutamate,” American Journal of Clinical Nutrition 90, no. 3 (2009): 867S–874S; M. B. Bogdanov and R. J. Wurtman, “Effects of Systemic or Oral Ad Libitum Monosodium Glutamate Administration on Striatal Glutamate Release, as Measured Using Microdialysis in Freely Moving Rats,” Brain Research 660, no. 2 (1994): 337–340.
13 psychedelics such as LSD and psilocybin: F. X. Vollenweider and M. Kometer, “The Neurobiology of Psychedelic Drugs: Implications for the Treatment of Mood Disorders,” Nature Reviews Neuroscience 11, no. 9 (2010): 642.
14 and depression affect gene expression: Proceedings of the National Academy of Sciences 112, no. 49 (2015): 15142–15147.
15 Social isolation co-opts the fear: J. Rodriguez-Romaguera and G. D. Stuber, “Social Isolation Co-opts Fear and Aggression Circuits,” Cell 173, no. 5 (2018): 1071–1072.
16 After the threatening stimulus is removed: K. Asahina et al., “Tachykinin-Expressing Neurons Control Male-Specific Aggressive Arousal in Drosophila,” Cell 156, no. 1 (2014): 221–235.
17 It also shows up in studies of emotion: Y. Yang et al., “Neural Correlates of Proactive and Reactive Aggression in Adolescent Twins,” Aggressive Behavior 43, no. 3 (2017): 230–240.
18 Increases in putamen size are associated with higher aggression: Yang et al., “Neural Correlates.”
19 reductions in putamen size: L. W. De Jong et al., “Strongly Reduced Volumes of Putamen and Thalamus in Alzheimer’s Disease: An MRI Study,” Brain 131, no. 12 (2008): 3277–3285.
20 The putamen may also modulate social anxiety: F. Caravaggio et al., “Exploring Personality Traits Related to Dopamine D⅔ Receptor Availability in Striatal Subregions of Humans,” European Neuropsychopharmacology 26, no. 4 (2016): 644–652; A. Laakso et al., “Prediction of Detached Personality in Healthy Subjects by Low Dopamine Transporter Binding,” American Journal of Psychiatry 157, no. 2 (2000): 290–292.
21 He raised infant monkeys in isolation: H. F. Harlow and S. J. Suomi, “Social Recovery by Isolation-Reared Monkeys,” Proceedings of the National Academy of Sciences 68, no. 7 (1971): 1534–1538.
22 educational attainment has been associated with decreased allostatic load: Å. M. Hansen et al., “School Education, Physical Performance in Late Midlife and Allostatic Load: A Retrospective Cohort Study,” Journal of Epidemiology and Community Health 70 (2016): 748–754.
23 In 1915, Dr. Henry Chapin: H. D. Chapin, “Are Institutions for Infants Necessary?,” Journal of the American Medical Association 64, no. 1 (1915): 1–3.
25 Early family experience is key not just to socialization: K. L. Humphreys et al., “Foster Care Promotes Adaptive Functioning in Early Adolescence among Children Who Experienced Severe, Early Deprivation,” Journal of Child Psychology and Psychiatry 59, no. 7 (2018): 811–821.
27 rates of autism among children raised in Mexico: E. Fombonne et al., “Prevalence of Autism Spectrum Disorders in Guanajuato, Mexico: The Leon Survey,” Journal of Autism and Developmental Disorders 46, no. 5 (2016): 1669–1685.
29 social isolation in the fruit fly: Cell 156, no. 1 (2014): 221–235.
30 mRNA translation are highly similar: J. Shih, R. Hodge, and M. A. Andrade-Navarro, “Comparison of Inter- and Intraspecies Variation in Humans and Fruit Flies,” Genomics Data 3 (2015): 49–54.
31 Social isolation for two weeks: M. Zelikowsky et al., “The Neuropeptide Tac2 Controls a Distributed Brain State Induced by Chronic Social Isolation Stress,” Cell 173, no. 5 (2018): 1265–1279.
33 Directly stimulating the nucleus accumbens: V. Trezza et al., “Nucleus Accumbens μ-Opioid Receptors Mediate Social Reward,” Journal of Neuroscience 31, no. 17 (2011): 6362–6370.
34 Indirect stimulation, however, is possible in humans: Trezza et al., “Nucleus Accumbens μ-Opioid Receptors.”
35 loneliness can be reduced simply by listening to music: M. L. Chanda and D. J. Levitin, “The Neurochemistry of Music,” Trends in Cognitive Sciences 17, no. 4 (2013): 179–193; V. Menon and D. J. Levitin, “The Rewards of Music Listening: Response and Physiological Connectivity of the Mesolimbic System,” Neuroimage 28, no. 1 (2005): 175–184.
36 “therapeutic lag”: S. M. Wang et al., “Five Potential Therapeutic Agents as Antidepressants: A Brief Review and Future Directions,” Expert Review of Neurotherapeutics 15, no. 9 (2015): 1015–1029.
37 Cognitive behavioral therapy … was shown in a Norwegian study: H. M. Nordahl et al., “Paroxetine, Cognitive Therapy or Their Combination in the Treatment of Social Anxiety Disorder with and without Avoidant Personality Disorder: A Randomized Clinical Trial,” Psychotherapy and Psychosomatics 85, no. 6 (2016): 346–356.
38 learning to control lifestyle elements: L. C. Hawkley and J. T. Cacioppo, “Loneliness Matters: A Theoretical and Empirical Review of Consequences and Mechanisms,” Annals of Behavioral Medicine 40, no. 2 (2010): 218–227; S. Ni et al., “Effect of Gratitude on Loneliness of Chinese College Students: Social Support as a Mediator,” Social Behavior and Personality 43, no. 4 (2015): 559–566.
39 Those social benefits appear also to accrue: C. Lim and R. D. Putnam, “Religion, Social Networks, and Life Satisfaction,” American Sociological Review 75, no. 6 (2010): 914–933.
40 Paul Tang: Khullar, “How Social Isolation Is Killing Us.”
44 strategically and adaptively cultivating our social networks: Frontiers in Aging Neuroscience 7 (2015): 120.
45 In contrast, when constraints on time are perceived: The structure and ideas of this paragraph were influenced by Lim and Yu, “Aging and Wisdom.”
46 socioemotional selectivity theory: L. L. Carstensen and B. L. Fredrickson, “Influence of HIV Status and Age on Cognitive Representations of Others,” Health Psychology 17, no. 6 (1998): 494; L. L. Carstensen, D. M. Isaacowitz, and S. T. Charles, “Taking Time Seriously: A Theory of Socioemotional Selectivity,” American Psychologist 54, no. 3 (1999): 165; L. L. Carstensen, H. H. Fung, and S. T. Charles, “Socioemotional Selectivity Theory and the Regulation of Emotion in the Second Half of Life,” Motivation and Emotion 27, no. 2 (2003): 103–123; C. E. Löckenhoff and L. L. Carstensen, “Socioemotional Selectivity Theory, Aging, and Health: The Increasingly Delicate Balance between Regulating Emotions and Making Tough Choices,” Journal of Personality 72, no. 6 (2004): 1395–1424; L. L. Carstensen, “The Influence of a Sense of Time on Human Development,” Science 312, no. 5782 (2006): 1913–1915.
47 how we relate to the world: J. Heckhausen, C. Wrosch, and R. Schulz, “A Motivational Theory of Life-Span Development,” Psychological Review 117, no. 1 (2010): 32.
48 better emotional balance: Löckenhoff and Carstensen, “Socioemotional Selectivity Theory.”
49 less likely to experience negative thoughts as we age: T. Hedden and J. D. Gabrieli, “Insights into the Ageing Mind: A View from Cognitive Neuroscience,” Nature Reviews Neuroscience 5, no. 2 (2004): 87.
50 exert some control over our environment: L. A. Leotti, S. S. Iyengar, and K. N. Ochsner, “Born to Choose: The Origins and Value of the Need for Control,” Trends in Cognitive Sciences 14, no. 10 (2010): 457–463.
51 choice and responsibility in a nursing home: E. J. Langer and J. Rodin, “The Effects of Choice and Enhanced Personal Responsibility for the Aged: A Field Experiment in an Institutional Setting,” Journal of Personality and Social Psychology 34, no. 2 (1976): 191.
52 Albert Bandura … uses the terms agency and self-efficacy : A. Bandura and R. Wood, “Effect of Perceived Controllability and Performance Standards on Self-Regulation of Complex Decision Making,” Journal of Personality and Social Psychology 56, no. 5 (1989): 805.
53 great activity in the putamen when they choose : E. M. Tricomi, M. R. Delgado, and J. A. Fiez, “Modulation of Caudate Activity by Action Contingency,” Neuron 41, no. 2 (2004): 281–292; G. Coricelli et al., “Regret and Its Avoidance: A Neuroimaging Study of Choice Behavior,” Nature Neuroscience 8, no. 9 (2005): 1255.
54 Choosing … activates the brain’s reward system: Leotti, Iyengar, and Ochsner, “Born to Choose.”
55 friends and family play a critical role: R. M. Ryan et al., “The Significance of Autonomy and Autonomy Support in Psychological Development and Psychopathology,” in Developmental Psychopathology , vol. 1, Theory and Method , ed. D. Cicchetti and D. J. Cohen, pp. 795–849 (Hoboken, NJ: John Wiley and Sons, 2015).
58 pay more attention to the positive things in their lives: A. P. Shimamura, Get SMART! Five Steps toward a Healthy Brain (Scotts Valley, CA: CreateSpace, 2017).
59 Art Shimamura describes it this way: Shimamura, Get SMART! .
60 having a large social network: Shimamura, Get SMART! .
61 urgent need to identify lifestyle activities: N. D. Anderson et al., “The Benefits Associated with Volunteering among Seniors: A Critical Review and Recommendations for Future Research,” Psychological Bulletin 140, no. 6 (2014): 1505.
62 volunteering is associated with reduced symptoms of depression: Anderson et al., “The Benefits Associated with Volunteering.”
63 volunteering worldwide contributes: International Labour Organization, Manual on the Measurement of Volunteer Work (Geneva, Switzerland: International Labour Organization, 2011).
64 Volunteers in a controlled study showed improvements: M. C. Carlson et al., “Exploring the Effects of an ‘Everyday’ Activity Program on Executive Function and Memory in Older Adults: Experience Corps,” Gerontologist 48 (2008): 793–801.
65 Volunteering in management or committee roles: T. D. Windsor, K. J. Anstey, and B. Rodgers, “Volunteering and Psychological Well-Being among Young-Old Adults: How Much Is Too Much?,” Gerontologist 48, no. 1 (2008): 59–70.
1 It hurts when I do this: The subtitle of this chapter is from an old vaudeville joke. A man goes to his doctor, and, jerking his elbow hard and to the side, he says, “It hurts when I do this.” The doctor replies, “Don’t do that!”
2 Pain accounts for 80 percent of trips to the doctor in the United States: R. J. Gatchel et al., “The Biopsychosocial Approach to Chronic Pain: Scientific Advances and Future Directions,” Psychological Bulletin 133, no. 4 (2007): 581.
3 Anxiety has been shown to demonstrably increase pain: C. S. Lin, S. Y. Wu, and C. A. Yi, “Association between Anxiety and Pain in Dental Treatment: A Systematic Review and Meta-analysis,” Journal of Dental Research 96, no. 2 (2017): 153–162; M. Zhuo, “Neural Mechanisms Underlying Anxiety—Chronic Pain Interactions,” Trends in Neurosciences 39, no. 3 (2016): 136–145.
4 30 percent of the population is experiencing chronic pain: N. D. Volkow and A. T. McLellan, “Opioid Abuse in Chronic Pain—Misconceptions and Mitigation Strategies,” New England Journal of Medicine 374, no. 13 (2016): 1253–1263.
7 The costs of treating chronic pain: Journal of Pain 13, no. 8 (2012): 715–724.
8 the current opioid epidemic: N. D. Volkow and A. T. McLellan, “Opioid Abuse in Chronic Pain—Misconceptions and Mitigation Strategies,” New England Journal of Medicine 374, no. 13 (2016): 1253–1263.
9 paper published just after World War II: H. K. Beecher, “Pain in Men Wounded in Battle,” Annals of Surgery 123, no. 1 (1946): 96.
10 Pain also has an emotional, affective component: The observation that sensory and affective components of pain are distinguishable was the basis for Melzack and Wall’s (1965) paper, which launched the modern study of pain; R. Melzack and P. D. Wall, “Pain Mechanisms: A New Theory,” Science 150 (1965): 971–979; see also J. Katz and B. N. Rosenbloom, “The Golden Anniversary of Melzack and Wall’s Gate Control Theory of Pain: Celebrating 50 Years of Pain Research and Management,” Pain Research and Management 20, no. 6 (2015): 285–286.
11 “There was no dependable relation”: H. K. Beecher, “Relationship of Significance of Wound to Pain Experienced,” Journal of the American Medical Association 161, no. 17 (1956): 1609–1613.
12 the brain can override everything: Melzack and Wall, “Pain Mechanisms.”
13 McGill Pain Questionnaire: R. Melzack, “The McGill Pain Questionnaire from Description to Measurement,” Anesthesiology 103, no. 1 (2005): 199–202.
14 “the sensory components of pain and the feeling-related components”: R. D. Treede et al., “The Cortical Representation of Pain,” Pain 79, nos. 2–3 (1999): 105–111.
15 lower resolution for distinguishing touch in different parts of your body: There’s a separate cortical representation map for motor movements, also derived by Penfield, with a linear map of how muscles from head to toe are represented in the brain. The muscles of the face and pharynx take up about 40 percent of all your motor cortex, and the hands take up another 30 percent. That means that controlling the entire rest of your body gets only 30 percent of the cortex. That 70 percent allows us to speak, to gesture while we speak, and to play musical instruments. The 30 percent dedicated to the hands is what allows watchmakers and painters and other highly skilled professionals to pursue their work, and research shows that those areas become enlarged with more training and experience.
16 The different types of pain … map to different brain regions: M. C. Bushnell, M. Čeko, and L. A. Low, “Cognitive and Emotional Control of Pain and Its Disruption in Chronic Pain,” Nature Reviews Neuroscience 14, no. 7 (2013): 502.
17 cutaneous pain … and visceral pain … are experienced very differently: I. A. Strigo et al., “Psychophysical Analysis of Visceral and Cutaneous Pain in Human Subjects,” Pain 97, no. 3 (2002): 235–246. Subjects were subjected to heat pain on their chest, or a balloon was inflated in their esophagus. The esophageal balloon creates a discomfort similar to the endorectal balloon sometimes used in endoscopy. The cutaneous heat used was up to 46 degrees Celsius (115 degrees Fahrenheit), and the visceral pressure was up to 40 mmHg.
18 visceral pain is more difficult to localize: Strigo et al., “Psychophysical Analysis.”
19 This leads to a certain imprecision: F. Cervero and L. A. Connell, “Distribution of Somatic and Visceral Primary Afferent Fibres within the Thoracic Spinal Cord Journal of Comparative Neurology 230, no. 1 (1984): 88–98; F. Cervero and L. A. Connell, “Fine Afferent Fibers from Viscera Do Not Terminate in the Substantia Gelatinosa of the Thoracic Spinal Cord,” Brain Research 294, no. 2 (1984): 370–374.
20 Visceral pain in turn elicits greater activation: I. A. Strigo et al., “Differentiation of Visceral and Cutaneous Pain in the Human Brain,” Journal of Neurophysiology 89 (2003): 3294–3303.
21 Administration of ketamine: I. A. Strigo et al., “The Effects of Racemic Ketamine on Painful Stimulation of Skin and Viscera in Human Subjects,” Pain 113, no. 3 (2005): 255–264.
22 The anticipation of pain lights up: P. Raineville, “Brain Mechanisms of Pain Affect and Pain Modulation,” Current Opinion in Neurobiology 12 (2002): 195–204.
23 toddlers with HSAD/CIPA: L. Sztriha et al., “Congenital Insensitivity to Pain with Anhidrosis,” Pediatric Neurology 25, no. 1 (2001): 63–66.
24 Twenty percent of people with this disorder: S. Mardy et al., “Congenital Insensitivity to Pain with Anhidrosis (CIPA): Effect of TRKA (NTRK1) Missense Mutations on Autophosphorylation of the Receptor Tyrosine Kinase for Nerve Growth Factor,” Human Molecular Genetics 10, no. 3 (2001): 179–188.
26 Another type of HSAD: E. M. Nagasako, A. L. Oaklander, and R. H. Dworkin, “Congenital Insensitivity to Pain: An Update,” Pain 101, no. 3 (2003): 213–219.
27 reaction to pain typically follows a sequence: P. D. Wall, Pain: The Science of Suffering (New York: Columbia University Press, 2000).
28 acute, short-term pain has survival value: R. Y. Hwang et al., “Nociceptive Neurons Protect Drosophila Larvae from Parasitoid Wasps,” Current Biology 17, no. 24 (2007): 2105–2116; Nagasako et al., “Congenital Insensitivity to Pain.”
29 purpose of chronic pain: R. J. Crook et al., “Nociceptive Sensitization Reduces Predation Risk,” Current Biology 24, no. 10 (2014): 1121–1125.
30 “They responded more strongly to visual stimuli”: D. Netburn, “What Injured Squid Can Teach Us about Irritability and Pain,” Los Angeles Times , May 8, 2014.
31 humans in pain can be more attentive: L. Tiemann et al., “Behavioral and Neuronal Investigations of Hypervigilance in Patients with Fibromyalgia Syndrome,” PLoS One 7, no. 4 (2012): e35068.
32 culture defines what is acceptable: S. Linton, Understanding Pain for Better Clinical Practice: A Psychological Perspective , vol. 16 (New York: Elsevier Health Sciences, 2005), p. 15.
33 people of different ethnicities experience and communicate pain: R. Moore and I. Brodsgaard, “Cross-Cultural Investigations of Pain,” Epidemiology of Pain (1999): 53–80.
34 Parents may encourage a more stoic view: Linton, Understanding Pain , p. 14.
35 As psychological scientist Steven Linton says: Linton, Understanding Pain , p. 3.
36 the enormous success of placebos: D. D. Price, D. G. Finniss, and F. Benedetti, “A Comprehensive Review of the Placebo Effect: Recent Advances and Current Thought,” Annual Review of Psychology 59 (2008): 565–590.
37 a placebo was effective in 35 percent of patients: R. Dobrila-Dintinjana and A. Načinović-Duletić, “Placebo in the Treatment of Pain,” Collegium Antropologicum 35, no. 2 (2011): 319–323.
38 chronic knee osteoarthritis: PLoS Biology 14, no. 10 (2016): e1002570.
39 placebo effects in acupuncture: M. Cummings, “Modellvorhaben Akupunktur—a Summary of the ART, ARC and GERAC Trials,” Acupuncture in Medicine 27, no. 1 (2009): 26–30; K. Linde et al., “The Impact of Patient Expectations on Outcomes in Four Randomized Controlled Trials of Acupuncture in Patients with Chronic Pain,” Pain 128, no. 3 (2007): 264–271; D. C. Cherkin et al., “A Randomized Trial Comparing Acupuncture, Simulated Acupuncture, and Usual Care for Chronic Low Back Pain,” Archives of Internal Medicine 169, no. 9 (2009): 858–866.
40 the gene that confers red hair: J. S. Mogil et al., “Melanocortin-1 Receptor Gene Variants Affect Pain and μ-opioid Analgesia in Mice and Humans,” Journal of Medical Genetics 42, no. 7 (2005): 583–587.
41 response to stress and pain can be passed to infants: D. Francis et al., “Nongenomic Transmission across Generations of Maternal Behavior and Stress Responses in the Rat,” Science 286, no. 5442 (1999): 1155–1158.
42 Nobel Prize–winning psychologist Daniel Kahneman: D. Kahneman et al., “When More Pain Is Preferred to Less: Adding a Better End,” Psychological Science 4, no. 6 (1993): 401–405.
43 A central goal of modern medical practice: Linton, Understanding Pain , p. 14.
45 switch from oral to topical analgesics: T. J. Atkinson et al., “Medication Pain Management in the Elderly: Unique and Underutilized Analgesic Treatment Options,” Clinical Therapeutics 35, no. 11 (2013): 1669–1689.
46 The most used NSAID worldwide is diclofenac: B. R. Da Costa et al., “Effectiveness of Non-Steroidal Anti-Inflammatory Drugs for the Treatment of Pain in Knee and Hip Osteoarthritis: A Network Meta-Analysis,” Lancet 390, no. 10090 (2017): e21–e33.
47 The oral version of diclofenac: C. A. Heyneman, C. Lawless-Liday, and G. C. Wall, “Oral versus Topical NSAIDs in Rheumatic Diseases,” Drugs 60, no. 3 (2000): 555–574.
48 Yoga practice enlarges the insula: C. Villemure et al., “Insular Cortex Mediates Increased Pain Tolerance in Yoga Practitioners,” Cerebral Cortex 24, no. 10 (2013): 2732–2740. Several styles of yoga were studied: the practice of physical postures (asana in Sanskrit), breathing exercises (pranayama ), concentration exercises that focus and stabilize attention (dharana ), and meditation (dhyana ).
49 Mild exercise can reduce pain: M. H. Pitcher et al., “Modest Amounts of Voluntary Exercise Reduce Pain- and Stress-Related Outcomes in a Rat Model of Persistent Hind Limb Inflammation,” Journal of Pain 18, no. 6 (2017): 687–701.
50 “Exercise is the best analgesic”: J. Mogil, personal communication, July 20, 2019.
52 blocking substance P could relieve pain: R. Hill, “NK1 (Substance P) Receptor Antagonists—Why Are They Not Analgesic in Humans?,” Trends in Pharmacological Sciences 21, no. 7 (2000): 244–246.
53 regulating mood, anxiety, and stress: Amino Acids 31, no. 3 (2006): 251–272.
54 the growth of new neurons: S. W. Park et al., “Substance P Is a Promoter of Adult Neural Progenitor Cell Proliferation under Normal and Ischemic Conditions,” Journal of Neurosurgery 107, no. 3 (2007): 593–599.
55 wound healing, and the growth of new cells: T. W. Reid et al., “Stimulation of Epithelial Cell Growth by the Neuropeptide Substance P,” Journal of Cellular Biochemistry 52, no. 4 (1993): 476–485; S. M. Brown et al., “Neurotrophic and Anhidrotic Keratopathy Treated with Substance P and Insulinlike Growth Factor 1,” Archives of Ophthalmology 115, no. 7 (1997): 926–927.
56 Pain in one part of the skin can cause: V. Gangadharan and R. Kuner, “Pain Hypersensitivity Mechanisms at a Glance,” Disease Models and Mechanisms 6, no. 4 (2013): 889–895.
57 Allodynia can occur: A. Latremoliere and C. J. Woolf, “Central Sensitization: A Generator of Pain Hypersensitivity by Central Neural Plasticity,” Journal of Pain 10, no. 9 (2009): 895–926.
58 relief from notalgia paresthetica through exercise: A. B. Fleischer, T. J. Meade, and A. B. Fleischer, “Notalgia Paresthetica: Successful Treatment with Exercises,” Acta Dermato-venereologica 91, no. 3 (2011): 356–357.
59 distraction diminishes pain signals in the insula: M. C. Bushnell, M. Čeko, and L. A. Low, “Cognitive and Emotional Control of Pain and Its Disruption in Chronic Pain,” Nature Reviews Neuroscience 14, no. 7 (2013): 502.
60 Effective distraction while in pain: N. J. Stagg et al., “Regular Exercise Reverses Sensory Hypersensitivity in a Rat Neuropathic Pain Model: Role of Endogenous Opioids,” Anesthesiology 114, no. 4 (2011): 940–948.
61 Steven Linton describes the role of an enriched environment: Linton, Understanding Pain , p. 28.
62 This lowering of the general pain threshold: K. B. Jensen et al., “Evidence of Dysfunctional Pain Inhibition in Fibromyalgia Reflected in rACC during Provoked Pain,” Pain 144, nos. 1–2 (2009): 95–100; M. N. Baliki et al., “Chronic Pain and the Emotional Brain: Specific Brain Activity Associated with Spontaneous Fluctuations of Intensity of Chronic Back Pain,” Journal of Neuroscience 26, no. 47 (2006): 12165–12173.
63 Structural brain changes have been observed: K. D. Davis and M. Moayedi, “Central Mechanisms of Pain Revealed through Functional and Structural MRI,” Journal of Neuroimmune Pharmacology 8, no. 3 (2013): 518–534.
64 “The original Phase 2 study”: J. Mogil, personal communication, June 5, 2018.
65 The side effects of polypharmacy: M. C. S. Rodrigues and C. D. Oliveira, “Drug-Drug Interactions and Adverse Drug Reactions in Polypharmacy among Older Adults: An Integrative Review,” Revista Latino-Americana de Enfermagem (2016): 24.
66 primary cause of confusion: O. C. Gleason, “Delirium,” American Family Physician 67, no. 5 (2003): 1027–1034.
1 Faulty or misaligned internal clocks: A. A. Kondratova and R. V. Kondratov, “The Circadian Clock and Pathology of the Ageing Brain,” Nature Reviews Neuroscience 13, no. 5 (2012): 325.
1 Have you ever woken in the middle: This opening gambit was inspired by that used by U. Schibler and P. Sassone-Corsi, “A Web of Circadian Pacemakers,” Cell 111, no. 7 (2002): 919–922.
2 Circadian rhythms are: T. Roenneberg and M. Merrow, “The Circadian Clock and Human Health,” Current Biology 26, no. 10 (2016): R432–R443.
3 Biological clocks evolved early in evolutionary history: J. C. Dunlap and J. J. Loros, “Making Time: Conservation of Biological Clocks from Fungi to Animals,” Microbiology Spectrum 5, no. 3 (2017).
4 Clocks have also been found in a bread mold: R. Lehmann et al., “Morning and Evening Peaking Rhythmic Genes Are Regulated by Distinct Transcription Factors in Neurospora crassa ,” in Information and Communication Theory in Molecular Biology , ed. M. Bossert, Lecture Notes in Bioengineering (Cham, Switzerland: Springer, 2018).
5 In the aplysia, scientists have found: L. L. Moroz et al., “Neuronal Transcriptome of Aplysia: Neuronal Compartments and Circuitry,” Cell 127, no. 7 (2006): 1453–1467.
7 They also exert a large influence on aging: O. Froy, “Circadian Rhythms, Aging, and Life Span in Mammals,” Physiology 26, no. 4 (2011): 225–235; H. Li and E. Satinoff, “Fetal Tissue Containing the Suprachiasmatic Nucleus Restores Multiple Circadian Rhythms in Old Rats,” American Journal of Physiology—Regulatory, Integrative and Comparative Physiology 275, no. 6 (1998): R1735–R1744.
8 All cells in the brain and body: In humans, clocks are presumed to exist in every cell; they have been found in the adrenal glands, esophagus, lungs, liver, pancreas, spleen, thymus, skin, and brain.
9 Our SCN … is sensitive to inputs from the retina: S. B. S. Khalsa et al., “A Phase Response Curve to Single Bright Light Pulses in Human Subjects,” Journal of Physiology 549, no. 3 (2003): 945–952; K. N. Paul, T. B. Saafir, and G. Tosini, “The Role of Retinal Photoreceptors in the Regulation of Circadian Rhythms,” Reviews in Endocrine and Metabolic Disorders 10, no. 4 (2009): 271–278; J. M. Zeitzer et al., “Response of the Human Circadian System to Millisecond Flashes of Light,” PLoS One 6, no. 7 (2011): e22078; P. C. Zee and P. Manthena, “The Brain’s Master Circadian Clock: Implications and Opportunities for Therapy of Sleep Disorders,” Sleep Medicine Reviews 11, no. 1 (2007): 59–70.
10 The SCN communicates time-of-day information: C. Dibner and U. Schibler, “Circadian Timing of Metabolism in Animal Models and Humans,” Journal of Internal Medicine 277, no. 5 (2015): 513–527.
11 Tissues in the liver and pancreas regulate: S. Hood and S. Amir, “The Aging Clock: Circadian Rhythms and Later Life,” Journal of Clinical Investigation 127, no. 2 (2017): 437–446.
12 The timing of meals: G. Asher and P. Sassone-Corsi, “Time for Food: The Intimate Interplay between Nutrition, Metabolism, and the Circadian Clock,” Cell 161 (2015): 84–93.
13 SCN can regulate the microbiome: Asher and Sassone-Corsi, “Time for Food.”
14 Different chronotypes have a genetic: T. Roenneberg, “What Is Chronotype?,” Sleep and Biological Rhythms 10, no. 2 (2012): 75–76; T. Roenneberg, A. Wirz-Justice, and M. Merrow, “Life between Clocks: Daily Temporal Patterns of Human Chronotypes,” Journal of Biological Rhythms 18, no. 1 (2003): 80–90.
15 waking their body up before it is biologically ready: E. The New York Times , December 25, 2018, p. D1.
16 an experiment at the ThyssenKrupp steel factory: C. Vetter et al., “Aligning Work and Circadian Time in Shift Workers Improves Sleep and Reduces Circadian Disruption,” Current Biology 25, no. 7 (2015): 907–911.
17 Once their chronotypes were aligned: Laber-Warren, “Up for the Job?”
18 sleep deprivation is responsible for some of the worst industrial disasters: S. Horstmann et al., “Sleepiness-Related Accidents in Sleep Apnea Patients,” Sleep 23, no. 3 (2000): 383–392.
19 “Some must watch while some must sleep”: W. Shakespeare, The Tragedy of Hamlet , act 3, scene 2.
20 The sentinel hypothesis is: D. R. Samson et al., “Chronotype Variation Drives Night-Time Sentinel-like Behaviour in Hunter-Gatherers,” Proceedings of the Royal Society B: Biological Sciences 284, no. 1858 (2017): 20170967.
21 Chronotype is heritable: D. A. Kalmbach et al., “Genetic Basis of Chronotype in Humans: Insights from Three Landmark GWAS,” Sleep 40, no. 2 (2017).
22 researchers analyzed the genomes of seven hundred thousand Britons: S. E. Jones et al., “Genome-wide Association Analyses of Chronotype in 697,828 Individuals Provides Insights into Circadian Rhythms,” Nature Communications 10, no. 1 (2019): 343.
23 “poorly sleeping grandparent hypothesis”: Samson et al., “Chronotype Variation.”
24 The Hadza are a group of about twelve hundred people: F. Marlowe, The Hadza: Hunter-Gatherers of Tanzania (Berkeley: University of California Press, 2010).
25 signaling deficit is due to loss: S. Michel, G. D. Block, and J. H. Meijer, “The Aging Clock,” in Circadian Medicine , 1st ed., ed. C. S. Colwell, pp. 321–335 (Hoboken, NJ: John Wiley and Sons, 2015).
26 transplanting young tissue into the SCN of hamsters: M. W. Hurd and M. R. Ralph, “The Significance of Circadian Organization for Longevity in the Golden Hamster,” Journal of Biological Rhythms 13, no. 5 (1998): 430–436; H. Li and E. Satinoff, “Fetal Tissue Containing the Suprachiasmatic Nucleus Restores Multiple Circadian Rhythms in Old Rats,” American Journal of Physiology—Regulatory, Integrative and Comparative Physiology 275, no. 6 (1998): R1735–R1744.
27 rhythms of the genes PER1 and PER2 : Hood and Amir, “The Aging Clock.”
28 Postmortem studies of dementia patients’ brains: D. G. Harper et al., “Dorsomedial SCN Neuronal Subpopulations Subserve Different Functions in Human Dementia,” Brain 131, no. 6 (2008): 1609–1617; Michel et al., “The Aging Clock.”
29 Repetitive disturbances of the circadian rhythm: M. H. Smolensky et al., “Circadian Disruption: New Clinical Perspective of Disease Pathology and Basis for Chronotherapeutic Intervention,” Chronobiology International 33, no. 8 (2016): 1101–1119.
30 Sundowner’s syndrome: Michel et al., “The Aging Clock.”
31 time-zone shift: S. Forbes-Robertson et al., “Circadian Disruption and Remedial Interventions,” Sports Medicine 42, no. 3 (2012): 185–208.
32 Eating within two hours of bedtime: M. P. Mattson et al., “Meal Frequency and Timing in Health and Disease,” Proceedings of the National Academy of Sciences 111, no. 47 (2014): 16647–16653.
33 Alcohol is known to disrupt sleep cycles: C. B. Forsyth et al., “Circadian Rhythms, Alcohol and Gut Interactions,” Alcohol 49, no. 4 (2015): 389–398; G. R. Swanson et al., “Decreased Melatonin Secretion Is Associated with Increased Intestinal Permeability and Marker of Endotoxemia in Alcoholics,” American Journal 308, no. 12 (2015): G1004–G1011.
34 high-fat diets tend to advance the clock: K. Eckel-Mahan and P. Sassone-Corsi, “Metabolism and the Circadian Clock Converge,” Physiological Reviews 93, no. 1 (2013): 107–135; V. Leone et al., “Effects of Diurnal Variation of Gut Microbes and High-Fat Feeding on Host Circadian Clock Function and Metabolism,” Cell Host and Microbe 17, no. 5 (2015): 681–689; A. Zarrinpar et al., “Diet and Feeding Pattern Affect the Diurnal Dynamics of the Gut Microbiome,” Cell Metabolism 20, no. 6 (2014): 1006–1017.
35 Light therapy and melatonin treatments: Kondratova and Kondratov, “The Circadian Clock”; R. F. Riemersma-Van Der Lek et al., “Effect of Bright Light and Melatonin on Cognitive and Noncognitive Function in Elderly Residents of Group Care Facilities: A Randomized Controlled Trial,” Journal of the American Medical Association 299, no. 22 (2008): 2642–2655.
36 effective in people with Alzheimer’s: D. P. Cardinali, A. M. Furio, and L. I. Brusco, “Clinical Aspects of Melatonin Intervention in Alzheimer’s Disease Progression,” Current Neuropharmacology 8, no. 3 (2010): 218–227.
37 In lab studies, melatonin interacts with beta-amyloid protein: R. Hornedo-Ortega et al., “In Vitro Effects of Serotonin, Melatonin, and Other Related Indole Compounds on Amyloid-β Kinetics and Neuroprotection,” Molecular Nutrition and Food Research 62, no. 3 (2018): 1700383; M. Shukla et al., “Mechanisms of Melatonin in Alleviating Alzheimer’s Disease,” Current Neuropharmacology 15, no. 7 (2017): 1010–1031.
38 melatonin use in early-stage Alzheimer’s: A. de Jonghe et al., “Effectiveness of Melatonin Treatment on Circadian Rhythm Disturbances in Dementia. Are There Implications for Delirium? A Systematic Review,” International Journal of Geriatric Psychiatry 25, no. 12 (2010): 1201–1208.
39 noticeable individual differences in how melatonin: A. J. Lewy, “Circadian Misalignment in Mood Disturbances,” Current Psychiatry Reports 11, no. 6 (2009): 459; A. J. Lewy, “Clinical Implications of the Melatonin Phase Response Curve,” Journal of Clinical Endocrinology and Metabolism 95, no. 7 (2010): 3158–3160.
40 Sleep-medicine specialist Alfonso Padilla: A. Padilla, personal communication, August 26, 2019.
41 next most effective treatment: A. M. Schroeder et al., “Voluntary Scheduled Exercise Alters Diurnal Rhythms of Behaviour, Physiology and Gene Expression in Wild-Type and Vasoactive Intestinal Peptide-Deficient Mice,” Journal of Physiology 590, no. 23 (2012): 6213–6226; Y. Yamanaka et al., “Physical Exercise Accelerates Reentrainment of Human Sleep-Wake Cycle but Not of Plasma Melatonin Rhythm to 8-H Phase-Advanced Sleep Schedule,” American Journal of Physiology—Regulatory, Integrative and Comparative Physiology 298, nos. 3 (2009): R681–R691.
42 Caffeine is one of the most: J. W. Daly, J. Holmen, and B. B. Fredholm, “Is Caffeine Addictive? The Most Widely Used Psychoactive Substance in the World Affects Same Parts of the Brain as Cocaine,” Lakartidningen 95, nos. 51–52 (1998): 5878–5883.
43 caffeine interferes with the human circadian clock: M. Lazarus et al., “Adenosine and Sleep,” in Handbook of Experimental Pharmacology , ed. J. Barret (Berlin: Springer, 2017).
44 lengthen the daytime activity rhythm in fruit flies: T. M. Burke et al., “Effects of Caffeine on the Human Circadian Clock In Vivo and In Vitro,” Science Translational Medicine 7, no. 305 (2015): 305ra146.
45 The detrimental effects of caffeine on sleep: Clark
46 Using cultured cells in vitro: Burke et al., “Effects of Caffeine.”
47 elite athletes … chronotype: M. Lastella et al., “The Chronotype of Elite Athletes,” Journal of Human Kinetics 54, no. 1 (2016): 219–225.
48 Because chronotypes fall along a continuum: L. C. Roden, T. D. Rudner, and D. E. Rae, “Impact of Chronotype on Athletic Performance: Current Perspectives,” ChronoPhysiology and Therapy 7 (2017): 1–6; J. A. Vitale and A. Weydahl, “Chronotype, Physical Activity, and Sport Performance: A Systematic Review,” Sports Medicine 47, no. 9 (2017): 1859–1868.
49 An elite runner who: S. Forbes-Robertson et al., “Circadian Disruption and Remedial Interventions,” Sports Medicine 42, no. 3 (2012): 185–208.
50 affect performance in American football: J. Roy and G. Forest, “Greater Circadian Disadvantage during Evening Games for the National Basketball Association (NBA), National Hockey League (NHL) and National Football League (NFL) Teams Travelling Westward,” Journal of Sleep Research 27, no. 1 (2017): 86–89; A. Song, T. Severini, and R. Allada, “How Jet Lag Impairs Major League Baseball Performance,” Proceedings of the National Academy of Sciences 114, no. 6 (2017): 1407–1412.
51 decoupling can cause problems: Kondratova and Kondratov, “The Circadian Clock.”
1 tomatoes are good for you: S. Agarwal and A. V. Rao, “Tomato Lycopene and Its Role in Human Health and Chronic Diseases,” Canadian Medical Association Journal 163, no. 6 (2000): 739–744; A. V. Rao and L. G. Rao, “Carotenoids and Human Health,” Pharmacological Research 55, no. 3 (2007): 207–216.
2 The American Medical Association has admonished: J. C. Tilburt, M. Allyse, and F. W. Hafferty, “The Case of Dr. Oz: Ethics, Evidence, and Does Professional Self-Regulation Work?,” AMA Journal of Ethics 19, no. 2 (2017): 199–206.
3 their glucose metabolism: A. Astrup and M. F. Hjorth, “Low-Fat or Low Carb for Weight Loss? It Depends on Your Glucose Metabolism,” EBioMedicine 22 (2017): 20–21.
4 the activity of lipoprotein lipase: R. H. Eckel, ed., Obesity: Mechanisms and Clinical Management (Philadelphia: Lippincott Williams and Wilkins, 2003).
5 genetic factors: E. Topol, “The A.I. Diet,” The New York Times , March 3, 2019, p. SR1.
6 nutrigenomics promises to fill this gap: M. Müller and S. Kersten, “Nutrigenomics: Goals and Strategies,” Nature Reviews Genetics 4, no. 4 (2003): 315.
7 Stanford nutrition scientist Christopher Gardner: S. Ipaktchian, “Read This and Lose 50 Pounds,” Stanford Medicine Magazine , Fall 2007, http://sm.stanford.edu/archive/stanmed/2007fall/diet.html ; see also C. D. Gardner et al., “Comparison of the Atkins, Zone, Ornish, and LEARN Diets for Change in Weight and Related Risk Factors among Overweight Premenopausal Women: The A to Z Weight Loss Study: A Randomized Trial,” Journal of the American Medical Association 297, no. 9 (2007): 969–977.
8 People on a diet typically: R. H. Eckel, “The Dietary Approach to Obesity: Is It the Diet or the Disorder?,” Journal of the American Medical Association 293, no. 1 (2005): 96–97.
9 a research article that compared: Journal of the American Medical Association 293, no. 1 (2005): 43–53.
10 restricting dietary carbohydrates offers: C. B. Ebbeling et al., “Effects of a Low Carbohydrate Diet on Energy Expenditure during Weight Loss Maintenance: Randomized Trial,” British Medical Journal 363 (2018): k4583.
11 Kevin Hall, senior investigator: K. D. Hall and J. Guo, “Carbs versus Fat: Does It Really Matter for Maintaining Lost Weight?,” bioRxiv (2019): 476655.
13 he had to pay $2.5 million: S. Lerner, “When Medicine Is Murder,” The Village Voice , March 26, 2002.
14 20 percent of Indian-manufactured Ayurvedic: R. B. Phillips et al., “Lead, Mercury, and Arsenic in US- and Indian-manufactured Ayurvedic Medicines Sold via the Internet,” Journal of the American Medical Association 300, no. 8 (2008): 915–923; Centers for Disease Control and Prevention, “Lead Poisoning Associated with Ayurvedic Medications—Five States, 2000–2003,” Morbidity and Mortality Weekly Report 53, no. 26 (2004): 582–584.
18 a number of built-in antioxidant mechanisms: T. A. Polk, The Aging Brain (Chantilly, VA: The Great Courses, 2016); Khan Academy, “Introduction to Cellular Respiration and Redox,” n.d., https://www.khanacademy.org/science/biology/cellular-respiration-and-fermentation/intro-to-cellular-respiration/a/intro-to-cellular-respiration-and-redox ; R. Boumis, “What Is Being Oxidized and What Is Being Reduced in Cell Respiration?,” Sciencing , May 29, 2019, https://sciencing.com/being-oxidized-being-reduced-cell-respiration-17081.html . This excerpt from an article by Lobo et al. fills in some more detail:
The term [oxidative stress] is used to describe the condition of oxidative damage resulting when the critical balance between free radical generation and antioxidant defenses is unfavorable. Oxidative stress, arising as a result of an imbalance between free radical production and antioxidant defenses, is associated with damage to a wide range of molecular species including lipids, proteins, and nucleic acids. Short-term oxidative stress may occur in tissues injured by trauma, infection, heat injury, hypertoxia, toxins, and excessive exercise. These injured tissues produce increased radical generating enzymes (e.g., xanthine oxidase, lipogenase, cyclooxygenase), activation of phagocytes, release of free iron, copper ions, or a disruption of the electron transport chains of oxidative phosphorylation, producing excess ROS. The initiation, promotion, and progression of cancer, as well as the side-effects of radiation and chemotherapy, have been linked to the imbalance between ROS and the antioxidant defense system. ROS have been implicated in the
V. Lobo et al., “Free Radicals, Antioxidants and Functional Foods: Impact on Human Health,” Pharmacognosy Reviews 4, no. 8 (2010): 118.
19 free radicals accelerate the aging process: B. T. Ashok and R. Ali, “The Aging Paradox: Free Radical Theory of Aging,” Experimental Gerontology 34, no. 3 (1999): 293–303.
20 reduction of free radicals can delay aging: A lot of transgenic work shows that downregulating antioxidant enzymes doesn’t necessarily shorten life span. This is controversial, however.
21 no universal agreement among scientists: D. Han (associate professor of biopharmaceutical sciences at KGI), email communication, January 22, 2019.
22 substances that are often mentioned as antioxidants: J. King (Professor Emerita, University of California at Berkeley), email communication, January 21, 2019.
23 One recent meta-analysis found: U. Nurmatov, G. Devereux, and A. Sheikh, “Nutrients and Foods for the Primary Prevention of Asthma and Allergy: Systematic Review and Meta-Analysis,” Journal of Allergy and Clinical Immunology 127, no. 3 (2011): 724–733.
24 randomized controlled trials with a range of antioxidant supplements: A. M. Pisoschi and A. Pop, “The Role of Antioxidants in the Chemistry of Oxidative Stress: A Review,” European Journal of Medicinal Chemistry 97 (2015): 55–74.
25 no effect of antioxidant supplements on cardiovascular disease: S. K. Myung et al., “Efficacy of Vitamin and Antioxidant Supplements in Prevention of Cardiovascular Disease: Systematic Review and Meta-Analysis of Randomised Controlled Trials,” British Medical Journal 346 (2013): f10.
26 might be interfering with the immune system: Pisoschi and Pop, “The Role of Antioxidants.”
27 (For some subsets of the population with a really poor diet): D. Han, personal communication, February 25, 2019.
28 vitamins C and E: M. Ristow et al., “Antioxidants Prevent Health-Promoting Effects of Physical Exercise in Humans,” Proceedings of the National Academy of Sciences 106, no. 21 (2009): 8665–8670.
30 three hundred people have to take a statin: R. Chou et al., “Statins for Prevention of Cardiovascular Disease in Adults: Evidence Report and Systematic Review for the US Preventive Services Task Force,” Journal of the American Medical Association 316, no. 19 (2016): 2008–2024; A. Thompson and N. J. Temple, “The Case for Statins: Has It Really Been Made?,” Journal of the Royal Society of Medicine 97, no. 10 (2004): 461–464.
31 not all fats are created equal: Mayo Clinic Staff, “High Cholesterol.”
32 no association between the consumption of saturated fats and heart disease: R. Chowdhury et al., “Association of Dietary, Circulating, and Supplement Fatty Acids with Coronary Risk: A Systematic Review and Meta-Analysis,” Annals of Internal Medicine 160, no. 6 (2014): 398–406.
34 Diets high in omega-3 … reduce the risk of heart disease by 7 percent:
35 consumption of fats … is not the cause of heart disease: A. Malhotra, R. F. Redberg, and P. Meier, “Saturated Fat Does Not Clog the Arteries: Coronary Heart Disease Is a Chronic Inflammatory Condition, the Risk of Which Can Be Effectively Reduced from Healthy Lifestyle Interventions,” British Journal of Sports Medicine 51, no. 15 (2017): 1111–1112; M. M. Pinheiro and T. Wilson, “Dietary Fat: The Good, the Bad, and the Ugly,” in Nutrition Guide for Physicians and Related Healthcare Professionals , ed. N. J. Temple, T. Wilson, and G. A. Bray, pp. 241–247 (Cham: Humana Press, 2017).
37 A number of stressors mediate this reaction: R. J. Colman et al., “Dietary Restriction Delays Disease Onset and Mortality in Rhesus Monkeys,” Science 325 (2009): 201–204; W. Mair et al., “Demography of Dietary Restriction and Death in Drosophila,” Science 301 (2003): 1731–1733.
38 caloric restriction triggers a change in the metabolic response: C. Lee and V. Longo, “Dietary Restriction with and without Caloric Restriction for Healthy Aging,” F1000Research 5 (2016).
39 Molecular biologist Cynthia Kenyon explains: C. Kenyon, “The Genetics of Ageing,” Nature 464 (2010): 504–512.
40 (hyperinsulinemia) … obesity: N. M. Templeman et al., “A Causal Role for Hyperinsulinemia in Obesity,” Journal of Endocrinology 232, no. 3 (2017): R173–R183.
41 (hyperinsulinemia) … immune-system suppression: R. Marín-Juez et al., “Hyperinsulinemia Induces Insulin Resistance and Immune Suppression via Ptpn6/Shp1 in Zebrafish,” Journal of Endocrinology 222, no. 2 (2014): 229–241.
42 (hyperinsulinemia) … cardiac arrhythmias: L. Drimba et al., “The Role of Acute Hyperinsulinemia in the Development of Cardiac Arrhythmias,” Naunyn-Schmiedeberg’s Archives of Pharmacology 386, no. 5 (2013): 435–444.
43 Neuroscientist Mark Mattson: Mattson, “Why Fasting Bolsters Brain Power.”
44 insulin may play a role in developing: G. Bedse et al., “Aberrant Insulin Signaling in Alzheimer’s Disease: Current Knowledge,” Frontiers in Neuroscience 9 (2015): 204.
45 Metformin was further found to have a neuroprotective effect: J. M. Campbell et al., “Metformin Use Associated with Reduced Risk of Dementia in Patients with Diabetes: A Systematic Review and Meta-Analysis,” Journal of Alzheimer’s Disease 65, no. 4 (2018): 1225–1236.
46 A protocol for testing the hypothesis: V. M. Walker et al., “Can Commonly Prescribed Drugs Be Repurposed for the Prevention or Treatment of Alzheimer’s and Other Neurodegenerative Diseases? Protocol for an Observational Cohort Study in the UK Clinical Practice Research Datalink,” BMJ Open 6, no. 12 (2016): e012044; see also A. Gupta, B. Bisht, and C. S. Dey, “Peripheral Insulin-Sensitizer Drug Metformin Ameliorates Neuronal Insulin Resistance and Alzheimer’s-like Changes,” Neuropharmacology 60, no. 6 (2011): 910–920.
47 Mark Mattson does intermittent fasting: Mattson, “Why Fasting Bolsters Brain Power.”
48 Consuming olive oil: F. R. Pérez-López et al., “Effects of the Mediterranean Diet on Longevity and Age-Related Morbid Conditions,” Maturitas 64, no. 2 (2009): 67–79.
49 Cruciferous vegetables: As
G. Tse and G. D. Eslick, “Cruciferous Vegetables and Risk of Colorectal Neoplasms: A Systematic Review and Meta-Analysis,” Nutrition and Cancer 66, no. 1 (2014): 128–139.
R. W.-L. Ma and K. Chapman, “A Systematic Review of the Effect of Diet in Prostate Cancer Prevention and Treatment,” Journal of Human Nutrition and Dietetics 22, no. 3 (2009): 187–199.
M. Loef and H. Walach, “Fruit, Vegetables and Prevention of Cognitive Decline or Dementia: A Systematic Review of Cohort Studies,” Journal of Nutrition, Health and Aging 16, no. 7 (2012): 626–630.
J. D. Potter and K. Steinmetz, “Vegetables, Fruit and Phytoestrogens as Preventive Agents,” IARC Scientific Publications 139 (1996): 61–90.
H. Steinkellner et al., “Effects of Cruciferous Vegetables and Their Constituents on Drug Metabolizing Enzymes Involved in the Bioactivation of DNA-Reactive Dietary Carcinogens,” Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 480 (2001): 285–297.
H. H. Nguyen et al., “The Dietary Phytochemical Indole-3-Carbinol Is a Natural Elastase Enzymatic Inhibitor That Disrupts Cyclin E Protein Processing,” Proceedings of the National Academy of Sciences 105, no. 50 (2008): 19750–19755.
F. Fuentes, X. Paredes-Gonzalez, and A. N. T. Kong, “Dietary Glucosinolates Sulforaphane, Phenethyl Isothiocyanate, Indole-3-Carbinol/3, 3’-Diindolylmethane: Antioxidative Stress/Inflammation, Nrf2, Epigenetics/Epigenomics and in Vivo Cancer Chemopreventive Efficacy,” Current Pharmacology Reports 1, no. 3 (2015): 179–196.
K. J. Royston and T. O. Tollefsbol, “The Epigenetic Impact of Cruciferous Vegetables on Cancer Prevention,” Current Pharmacology Reports 1, no. 1 (2015): 46–51.
50 a current fad of taking omega-3 supplements: Grand View Research, “Omega 3 Supplement Market Analysis by Source (Fish Oil, Krill Oil), by Application (Infant Formula, Food and Beverages, Nutritional Supplements, Pharmaceutical, Animal Feed, Clinical Nutrition), and Segment Forecasts, 2018–2025,” May 2017, https://www.grandviewresearch.com/industry-analysis/omega-3-supplement-market ; Statista, “Global Omega-3 Supplement Market Size in 2016 and 2025 (in Billion US Dollars),” 2016, https://www.statista.com/statistics/758383/omega-3-supplement-market-size-worldwide/ .
51 A Cochrane systematic review: A. S. Abdelhamid et al., “Omega-3 Fatty Acids for the Primary and Secondary Prevention of Cardiovascular Disease,” Cochrane Database of Systematic Reviews 11 (2018).
54 no evidence that red wine influences: British Medical Journal 342 (2011): d636.
55 Moderate alcohol consumption: A. Artero et al., “The Impact of Moderate Wine Consumption on Health,” Maturitas 80, no. 1 (2015): 3–13.
56 Alcohol consumption increases risks: World Cancer Research Fund and American Institute for Cancer Research, Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective , vol. 1 (Washington, DC: American Institute for Cancer Research, 2007).
57 increases mortality in breast cancer survivors: L. Schwingshackl and G. Hoffmann, “Adherence to Mediterranean Diet and Risk of Cancer: An Updated Systematic Review and Meta-Analysis of Observational Studies,” Cancer Medicine 4, no. 12 (2015): 1933–1947.
58 insufficient evidence that resveratrol supplements: Pérez-López et al., “Effects of the Mediterranean Diet”; O. Vang et al., “What Is New for an Old Molecule? Systematic Review and Recommendations on the Use of Resveratrol,” PLoS One 6, no. 6 (2011): e19881.
59 another comprehensive review recommended it: J. M. Smoliga, J. A. Baur, and H. A. Hausenblas, “Resveratrol and Health—a Comprehensive Review of Human Clinical Trials,” Molecular Nutrition and Food Research 55, no. 8 (2011): 1129–1141.
60 Many cognitive and physical benefits are claimed: D. G. Loughrey et al., “The Impact of the Mediterranean Diet on the Cognitive Functioning of Healthy Older Adults: A Systematic Review and Meta-Analysis,” Advances in Nutrition 8, no. 4 (2017): 571–586.
61 Healthy diets that lower cholesterol: O. van de Rest et al., “Dietary Patterns, Cognitive Decline, and Dementia: A Systematic Review,” Advances in Nutrition 6, no. 2 (2015): 154–168.
62 Older adults absorb protein less effectively: J. Brody, “Muscle Loss in Aging Can Be Reversed,” The New York Times , September 4, 2018, p. D5.
64 The most effective proteins for older adults: Brody, “Muscle Loss in Aging.”
66 leucine toxicity: R. Elango et al., “Determination of the Tolerable Upper Intake Level of Leucine in Acute Dietary Studies in Young Men,” American Journal of Clinical Nutrition 96, no. 4 (2012): 759–767; A. G. Wessels et al., “High Leucine Diets Stimulate Cerebral Branched-Chain Amino Acid Degradation and Modify Serotonin and Ketone Body Concentrations in a Pig Model,” PLoS One 11, no. 3 (2016): e0150376; M. Yudkoff et al., “Brain Amino Acid Requirements and Toxicity: The Example of Leucine,” Journal of Nutrition 135, no. 6 (2005): 1531S–1538S.
67 current thinking is that soy is beneficial: M. Messina, “Soy and Health Update: Evaluation of the Clinical and Epidemiologic Literature,” Nutrients 8, no. 12 (2016): 754.
68 second leading killer of children under four: E. Disaster Medicine and Public Health Preparedness 7, no. 6 (2013): 547–548.
69 eighth leading cause of death: C. Troeger et al., “Estimates of the Global, Regional, and National Morbidity, Mortality, and Aetiologies of Diarrhoea in 195 Countries: A Systematic Analysis for the Global Burden of Disease Study 2016,” Lancet Infectious Diseases 18, no. 11 (2018): 1211–1228; C. Trinh and K. Prabhakar, “Diarrheal Diseases in the Elderly,” Clinics in Geriatric Medicine 23, no. 4 (2007): 833–856.
70 Alcohol is also a culprit: E. P. Dolhun (MD), personal communication, February 21, 2017.
71 the greatest risk for dehydration: D. R. Thomas et al., “Understanding Clinical Dehydration and Its Treatment,” Journal of the American Medical Directors Association 9, no. 5 (2008): 292–301.
73 Avoid bread or dried fruit: Dolhun, personal communication.
74 oral rehydration solutions: Unfortunately, many of the ORS products have a bad taste, which causes the people who need them not to drink them; others are loaded with refined sugar to improve the taste, which is counterproductive. I recommend DripDrop, developed by a colleague of mine, Eduardo Dolhun, a Mayo Clinic–trained doctor who regularly performs humanitarian missions to Third World countries and treats dehydration using his product. I have no financial interest in the company, nor do I benefit from your purchasing of this product. See a list of references here: Eduardo P. Dolhun, Oral rehydration composition, US Patent 8,557,301, filed July 1, 2011, and issued October 15, 2013, https://patentimages.storage.googleapis.com/bd/54/5b/cd03de0b6f973c/US8557301.pdf .
75 Constipation is one of the most common: D. Gandell et al., “Treatment of Constipation in Older People,” CMAJ 185, no. 8 (2013): 663–670.
76 constipation led to changes in gene expression: Y. Li et al., “Hippocampal Gene Expression Profiling in a Rat Model of Functional Constipation Reveals Abnormal Expression Genes Associated with Cognitive Function,” Neuroscience Letters 675 (2018): 103–109.
77 chronic constipation and cognitive impairment: Y. M. I. Kazem et al., “Constipation, Oxidative Stress in Obese Patients and Their Impact on Cognitive Functions and Mood, the Role of Diet Modification and Foeniculum vulgare Supplementation,” Journal of Biological Sciences 17, no. 7 (2017): 312–319; R. T. Wang and Y. Li, “Analysis of Cognitive Function of Old People with Functional Constipation,” Journal of Harbin Medical University 6 (2011): 603–605.
79 SCN (suprachiasmatic nucleus in the hypothalamus) can regulate the microbiome: G. Asher and P. Sassone-Corsi, “Time for Food: The Intimate Interplay between Nutrition, Metabolism, and the Circadian Clock,” Cell 161 (2015): 84–93.
80 90 percent of the serotonin in the body resides in the gut: A. Evrensel and M. E. Ceylan, “The Gut-Brain Axis: The Missing Link in Depression,” Clinical Psychopharmacology and Neuroscience 13, no. 3 (2015): 239; Y. E. Borre et al., “Microbiota Trends in Molecular Medicine 20, no. 9 (2014): 509–518.
81 Lactobacillus acidophilus increases the expression of the natural cannabinoid:Lactobacillus acidophilus Modulates Intestinal Pain and Induces Opioid and Cannabinoid Receptors,” Nature Medicine 13, no. 1 (2007): 35.
82 Gut bacteria have been linked to mental well-being: M. Valles-Colomer et al., “The Neuroactive Potential of the Human Gut Microbiota in Quality of Life and Depression,” Nature Microbiology 1 (2019).
83 John Cryan calls bacteria: T. G. Dinan and J. F. Cryan, “Melancholy Microbes: A Link between Gut Microbiota and Depression?,” Neurogastroenterology and Motility , no. 25 (2013): 713–19.
84 composition of the gut microbiome: Borre et al., “Microbiota and Neurodevelopmental Windows.”
85 Rats separated from their mothers: Evrensel and Ceylan, “The Gut-Brain Axis”; J. F. Cryan and T. G. Dinan, “Mind-Altering Microorganisms: The Impact of the Gut Microbiota on Brain and Behaviour,” Nature Reviews Neuroscience 13, no. 10 (2012): 701.
86 The full extent of gut-brain interactions: Cryan and Dinan, “Mind-Altering Microorganisms”; E. G. Severance et al., “Discordant Patterns of Bacterial Translocation Markers and Implications for Innate Immune Imbalances in Schizophrenia,” Schizophrenia Research 148, nos. 1–3 (2013): 130–137; A. I. Petra et al., “Gut-Microbiota-Brain Axis and Its Effect on Neuropsychiatric Disorders with Suspected Immune Dysregulation,” Clinical Therapeutics 37, no. 5 (2015): 984–995; F. Dickerson, E. Severance, and R. Yolken, “The Microbiome, Immunity, and Schizophrenia and Bipolar Disorder,” Brain, Behavior, and Immunity 62 (2017): 46–52.
87 an imbalanced microbiome: Borre et al., “Microbiota and Neurodevelopmental Windows.”
88 increasing iron absorption: M. Hoppe et al., “Probiotic Strain Lactobacillus plantarum 299v Increases Iron Absorption from an Iron-Supplemented Fruit Drink: A Double-Isotope Cross-Over Single-Blind Study in Women of Reproductive Age,” British Journal of Nutrition 114, no. 8 (2015): 1195–1202.
89 protecting against pesticide absorption: M. Trinder et al., “Probiotic Lactobacilli: A Potential Prophylactic Treatment for Reducing Pesticide Absorption in Humans and Wildlife,” Beneficial Microbes 6, no. 6 (2015): 841–847.
90 distribution of fat around the body: M. Zarrati et al., “Effects of Probiotic Yogurt on Fat Distribution and Gene Expression of Proinflammatory Factors in Peripheral Blood Mononuclear Cells in Overweight and Obese People with or without Weight-Loss Diet,” Journal of the American College of Nutrition 33, no. 6 (2014): 417–425.
91 treatments for irritable bowel syndrome: Y. Zhang et al., “Effects of Probiotic Type, Dose and Treatment Duration on Irritable Bowel Syndrome Diagnosed by Rome III Criteria: A Meta-analysis,” BMC Gastroenterology 16, no. 1 (2016): 62.
92 Bifidobacterium infantis , can alleviate depression:Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in Rats and Human Subjects,” British Journal of Nutrition 105, no. 5 (2011): 755–764.
93 Lactobacillus helveticus and Bifidobacterium longum can reduce cortisol levels:
94 a probiotic mixture containing Bifidobacterium lactis : European Journal of Neuroscience 41, no. 2 (2015): 264–274.
95 Kefir, yogurt, and other fermented milk: K. Tillisch et al., “Consumption of Fermented Milk Product with Probiotic Modulates Brain Activity,” Gastroenterology 144, no. 7 (2013): 1394–1401.
96 eating more fiber promotes gut health: A. Reynolds et al., “Carbohydrate Quality and Human Health: A Series of Systematic Reviews and Meta-Analyses,” Lancet 393, no. 10170 (2019): 434–445.
97 The distinct microbiome of the elderly: M. J. Claesson et al., “Gut Microbiota Composition Correlates with Diet and Health in the Elderly,” Nature 488, no. 7410 (2012): 178; Cryan and Dinan, “Mind-Altering Microorganisms.”
98 Microbiomic balance: Borre et al., “Microbiota and Neurodevelopmental Windows.”
99 loss of diverse community-associated microbiota: Claesson et al., “Gut Microbiota Composition Correlates with Diet and Health in the Elderly.”
101 probiotics function best: C. C. Dodoo et al., “Use of a Water-Based Probiotic to Treat Common Gut Pathogens,” International Journal of Pharmaceutics 556 (2019): 136–141; M. Fredua-Agyeman and S. Gaisford, “Comparative Survival of Commercial Probiotic Formulations: Tests in Biorelevant Gastric Fluids and Real-Time Measurements using Microcalorimetry,” Beneficial Microbes 6, no. 1 (2014): 141–151.
102 It’s difficult to be an informed consumer: Y. Ringel, E. M. Quigley, and H. C. Lin, “Using Probiotics in Gastrointestinal Disorders,” American Journal of Gastroenterology Supplements 1, no. 1 (2012): 34.
105 the Dannon Company settled: GI Society: Canadian Society of Intestinal Research, “Lawsuit Settled: Dannon Yogurt Didn’t Measure Up to Its Claims,” November 16, 2016, https://www.badgut.org/information-centre/a-z-digestive-topics/dannon-lawsuit-settled/ . An additional class-action suit not mentioned in the text settled for $8.25 million in 2017 against GT’s Kombucha found the brand had up to 2.5 percent alcohol, similar to low-alcohol beers. The suit also charged that GT’s Kombucha contained more than the 2 grams of sugar per 8-ounce serving noted on the nutrition label. M. Caballero, “Judge Approves $8.25 Million Settlement in GT’s Kombucha and Whole Foods Suit,” BevNet News, February 3, 2017, https://www.bevnet.com/news/2017/judge-approves-8-25-million-settlement-gts-kombucha-whole-foods-suit .
106 products that are known to be effective: https://www.symprove.com/ , and Visbiome, available from https://www.visbiome.com/ . I have no financial stake in these companies and I do not benefit from your buying these products.
107 Even less is known about prebiotics: D. Charalampopoulos and R. A. Rastall, “Prebiotics in Foods,” Current Opinion in Biotechnology 23, no. 2 (2012): 187–191.
108 Food molecules are known to protect probiotics: B. M. Corcoran et al., “Survival of Probiotic Lactobacilli in Acidic Environments Is Enhanced in the Presence of Metabolizable Sugars,” Applied and Environmental Microbiology 71, no. 6 (2005): 3060–3067.
109 Dozens of foods act as prebiotics: M. Lyte et al., “Resistant Starch Alters the Microbiota-Gut Brain Axis: Implications for Dietary Modulation of Behavior,” PLoS One 11, no. 1 (2016): e0146406; A. Gunenc, C. Alswiti, and F. Hosseinian, “Wheat Bran Dietary Fiber: Promising Source of Prebiotics with Antioxidant Potential,” Journal of Food Research 6, no. 2 (2017): 1; F. M. N. A. Aida et al., “Mushroom as a Potential Source of Prebiotics: A Review,” Trends in Food Science and Technology 20, nos. 11–12 (2009): 567–575; M. de Jesus Raposo, A. de Morais, and R. de Morais, “Emergent Sources of Prebiotics: Seaweeds and Microalgae,” Marine Drugs 14, no. 2 (2016): 27.
110 fecal microbiota transplantation … for treating a range of diseases: G. J. Bakker and M. Nieuwdorp, “Fecal Microbiota Transplantation: Therapeutic Potential for a Multitude of Diseases beyond Clostridium difficile ,” Microbiology Spectrum 5, no. 4 (2017); J. F. Petrosino, “The Microbiome in Precision Medicine: The Way Forward,” Genome Medicine 10, no. 1 (2018): 12.
111 The technique has had mixed results: S. Paramsothy et al., “Faecal Microbiota Transplantation for Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis,” Journal of Crohn’s and Colitis 11, no. 10 (2017): 1180–1199.
112 cardiovascular disease, stroke, cancer, and diabetes: H. Eyre et al., “Preventing Cancer, Cardiovascular Disease, and Diabetes: A Common Agenda for the American Cancer Society, the American Diabetes Association, and the American Heart Association,” Circulation 109, no. 25 (2004): 3244–3255.
113 health among hunter-gatherer societies: A. O’Connor, “The Hunt for an Optimal Diet,” The New York Times , December 25, 2018, D4; H. Pontzer, B. M. Wood, and D. A. Raichlen, “Hunter-Gatherers as Models in Public Health,” Obesity Reviews 19 (2018): 24–35.
114 he fed them ultra-processed foods: K. Hall et al., “Ultra-Processed Diets Cause Excess Calorie Intake and Weight Gain: An Independent Randomized Controlled Trial of Ad Libitum Food Intake,” Cell Metabolism 30 (2019): 67–77.
115 intuitive eating: N. Van Dyke and E. J. Drinkwater, “Relationships between Intuitive Eating and Health Indicators: Literature Review,” Public Health Nutrition 17, no. 8 (2014): 1757–1766.
117 The cycle of repeatedly dieting and failing: K. Buchanan and J. Sheffield, “Why Do Diets Fail? An Exploration of Dieters’ Experiences Using Thematic Analysis,” Journal of Health Psychology 22, no. 7 (2017): 906–915.
118 four additional principles of intuitive dieting: Van Dyke and Drinkwater, “Relationships between Intuitive Eating.”
119 binge eating: Current Psychology 37, no. 4 (2018): 924–933.
1 “I can’t speak for two geniuses”: S. Grafton, email communication, December 21, 2018.
2 the brain is a giant problem-solving device: I previously wrote about this in D. J. Levitin, The Organized Mind (New York: Dutton, 2014); see also D. C. Dennett, “The Cultural Evolution of Words and Other Thinking Tools,” in Evolution: The Molecular Landscape , ed. B. Stillman, D. Stewart, and J. Witkowski, Cold Spring Harbor Symposia on Quantitative Biology , vol. 74, pp. 435–441 (Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 2009); and P. MacCready, “An Ambivalent Luddite at a Technological Feast,” Designfax, August 1999, http://maccready.library.caltech.edu/islandora/object/pbm%3A27832#page/1/mode/2up .
3 memory is enhanced by physical activity: P. D. Loprinzi, M. K. Edwards, and E. Frith, “Potential Avenues for Exercise to Activate Episodic Memory-Related Pathways: A Narrative Review,” European Journal of Neuroscience 46, no. 5 (2017): 2067–2077.
4 embodied cognition: A. Setti and A. M. Borghi, “Embodied Cognition over the Lifespan: Theoretical Issues and Implications for Applied Settings,” Frontiers in Psychology 9 (2018): 550. Scott Grafton advises, “We need to be careful and explicit about what we mean by embodied cognition. It has been hijacked by some psychologists into a kind of woo woo explanandum for cosmic oneness with the senses, like J. J. Gibson on acid.
The term arises from Rodney Brooks, a roboticist who made the case that it is really stupid from an engineering perspective to put all the control elements of a sense and respond system in a central CPU. You want some stuff to get done out in the periphery to free up the central control unit (i.e., the brain). Another clear example with nerves is the Sherrington reflex (knee jerk reflex), which involves just the spinal cord. These are layered loops, each adding function. The first two don’t need a cortex at all. In other words, embodied cognition is putting intelligence and control out in the body. (Grafton, email communication.)
5 movement is inextricably bound with knowledge: D. Krakauer, personal communication, July 19, 2019.
6 embodied, ecologically and genetically embedded social agents: A. Linson et al., “The Active Inference Approach to Ecological Perception: General Information Dynamics for Natural and Artificial Embodied Cognition,” Frontiers in Robotics and AI 5 (2018): 21.
7 The body influences the mind: C. R. Madan and A. Singhal, “Using Actions to Enhance Memory: Effects of Enactment, Gestures, and Exercise on Human Memory,” Frontiers in Psychology 3 (2012): 507.
8 exercise had a significant beneficial effect on memory: P. D. Loprinzi et al., “Experimental Effects of Exercise on Memory Function among Mild Cognitive Impairment: Systematic Review and Meta-Analysis,” Physician and Sportsmedicine (2018): 1–6.
9 risk is increased by atrophy of the hippocampus: Loprinzi et al., “Experimental Effects.”
10 Aging is an irreversible: Frontiers in Aging Neuroscience 8 (2016): 57.
11 onset of walking triggers neurochemical activity: A. M. Glenberg and J. Hayes, “Contribution of Embodiment to Solving the Riddle of Infantile Amnesia,” Frontiers in Psychology 7 (2016): 10.
12 The central role that the hippocampus: M. C. Costello and E. K. Bloesch, “Are Older Adults Less Embodied? A Review of Age Effects through the Lens of Embodied Cognition,” Frontiers in Psychology 8 (2017): 267.
13 cognitive and perceptual abilities are not a static: B. Hommel and A. Kibele, “Down with Retirement: Implications of Embodied Cognition for Healthy Aging,” Frontiers in Psychology 7 (2016): 1184.
14 three kinds of bodily changes: Hommel and Kibele, “Down with Retirement.”
17 Interacting with the world also enhances creativity: C. Y. Kuo and Y. Y. Yeh, “Sensorimotor-Conceptual Integration in Free Walking Enhances Divergent Thinking for Young and Older Adults,” Frontiers in Psychology 7 (2016): 1580.
18 physical activity increases the effectiveness of astrocytes: Tsai et al., “Exercise Counteracts Aging-Related Memory Impairment.”
19 hippocampus grows seven hundred new neurons per day: S. M. Ryan and Y. M. Nolan, “Neuroinflammation Negatively Affects Adult Hippocampal Neurogenesis and Cognition: Can Exercise Compensate?,” Neuroscience and Biobehavioral Reviews 61 (2016): 121–131.
20 increase hippocampal neurogenesis: Ryan and Nolan, “Neuroinflammation Negatively Affects.”
21 “improvement in memory for human adults”: Ryan and Nolan, “Neuroinflammation Negatively Affects.”
22 prime the brain with increased blood flow: A. Shimamura, Get SMART! Five Steps toward a Healthy Brain (Scotts Valley, CA: CreateSpace, 2017).
23 aerobic activity:ACSM’s Guidelines for Exercise Testing and Prescription (Philadelphia: Lippincott Williams and Wilkins, 2013).
24 Anaerobic activity can help to build: H. Patel et al., “Aerobic vs Anaerobic Exercise Training Effects on the Cardiovascular System,” World Journal of Cardiology 9, no. 2 (2017): 134.
25 Sarcopenia is the loss of muscle tissue: J. Brody, “Muscle Loss in Aging Can Be Reversed,” The New York Times , September 4, 2018, p. D5.
26 significantly increased their leg strength and muscle mass: W. R. Frontera et al., “Strength Conditioning in Older Men: Skeletal Muscle Hypertrophy and Improved Function,” Journal of Applied Physiology 64, no. 3 (1988): 1038–1044.
27 significant improvements in frail nursing home residents: M. A. Fiatarone et al., “High-Intensity Strength Training in Nonagenarians: Effects on Skeletal Muscle,” Journal of the American Medical Association 263, no. 22 (1990): 3029–3034.
28 Adults aged sixty to seventy-nine years who engaged in indoor aerobic: S. J. Colcombe et al., “Aerobic Exercise Training Increases Brain Volume in Aging Journals of Gerontology Series A: Biological Sciences and Medical Sciences 61, no. 11 (2006): 1166–1170.
30 reducing the risk of heart attack: J. M. Letnes et al., “Peak Oxygen Uptake and Incident Coronary Heart Disease in a Healthy Population: The HUNT Fitness Study,” European Heart Journal (2018).
31 “a bit more is probably better”: “Making 2019 Happier,” The Week , January 11, 2019, p. 16.
32 Time-efficient workouts: J. S. Thum et al., “High-Intensity Interval Training Elicits Higher Enjoyment Than Moderate Intensity Continuous Exercise,” PLoS One 12, no. 1 (2017): e0166299.
33 having sex before an athletic competition: L. M. Valenti et al., “Effect of Sexual Intercourse on Lower Extremity Muscle Force in Strength-Trained Men,” Journal of Sexual Medicine 15, no. 6 (2018): 888–893.
35 barely measurable amount of physical activity: K. Suwabe et al., “Rapid Stimulation of Human Dentate Gyrus Function with Acute Mild Exercise,” Proceedings of the National Academy of Sciences 115, no. 41 (2018): 10487–10492; A. Wahid et al., “Quantifying the Association between Physical Activity and Cardiovascular Disease and Diabetes: A Systematic Review and Meta-Analysis,” Journal of the American Heart Association 5, no. 9 (2016): e002495; see also P. Siddarth et al., “Sedentary Behavior Associated with Reduced Medial Temporal Lobe Thickness in Middle-Aged and Older Adults,” PLoS One 13, no. 4 (2018): e0195549.
36 single bout of light physical movement: Suwabe et al., “Rapid Stimulation.”
37 benefits show up immediately: S. B. Chapman et al., “Shorter Term Aerobic Exercise Improves Brain, Cognition, and Cardiovascular Fitness in Aging,” Frontiers in Aging Neuroscience 5 (2013): 75.
39 virtues of walking for neurocognitive health: R. A. Friedman, “Standing Can Make You Smarter,” The New York Times , April 19, 2018, p. A31.
1 chemicals in the brain that lead us to feel sleepy: M. Lazarus et al., “Adenosine and Sleep,” in Handbook of Experimental Pharmacology , J. Barrett, ed. (Berlin: Springer, 2017).
2 ideas for songs came to him during sleep: P. Doyle, “The Last Word: Billy Joel on Self-Doubt, Trump and Finally Becoming Cool,” Rolling Stone , June 14, 2017.
3 Thomas Edison viewed sleep: The New York Times Sunday Book Review , October 15, 2017, p. BR16.
4 twenty others preceded Edison’s: R. Friedel and P. Israel, Edison’s Electric Light: The Art of Invention , rev. ed. (Baltimore, MD: Johns Hopkins University Press, 2010), pp. 29–31.
5 putting off sleep: M. Walker, Why We Sleep: Unlocking the Power of Sleep and Dreams (New York: Scribner, 2017). And this line summarizing the book comes from Kamp, “Nighty Night.”
6 fewer than five hours of sleep: R. Cooke, “‘Sleep Should Be Prescribed’: What Those Late Nights Out Could Be Costing You,” The Guardian , September 24, 2017.
7 They tend to get less sleep: Walker, Why We Sleep.
8 adults sleep less than seven hours: Cooke, “‘Sleep Should Be Prescribed.’”
9 The Roman poet Ovid: Ovid, Metamorphoseon libri (Metamorphoses ) (AD 8).
10 Sleep-deprived people: S. S. Yoo et al., “The Human Emotional Brain without Sleep—a Prefrontal Amygdala Disconnect,” Current Biology 17, no. 20 (2007): R877–R878.
11 Cerebrospinal fluid circulates: L. Xie et al., “Sleep Drives Metabolite Clearance from the Adult Brain,” Science 342, no. 6156 (2013): 373–377.
12 A U-shaped distribution: J. Fang et al., “Association of Sleep Duration and Hypertension among US Adults Varies by Age and Sex,” American Journal of Hypertension 25, no. 3 (2012): 335–341.
13 sleep duration of less than six hours: D. J. Gottlieb et al., “Association of Sleep Time with Diabetes Mellitus and Impaired Glucose Tolerance,” Archives of Internal Medicine 165, no. 8 (2005): 863–867.
14 Poor sleep duration or quality: A. J. Clark et al., “Impaired Sleep and Allostatic Load: Cross-Sectional Results from the Danish Copenhagen Aging and Midlife Biobank,” Sleep Medicine 15, no. 12 (2014): 1571–1578; R. P. Juster and B. S. McEwen, “Sleep and Chronic Stress: New Directions for Allostatic Load Research,” Sleep Medicine 16, no. 1 (2015): 7–8.
15 areas most impacted by sleep deprivation: E. Shokri-Kojori et al., “β-Amyloid Accumulation in the Human Brain after One Night of Sleep Deprivation,” Proceedings of the National Academy of Sciences 115, no. 17 (2018): 4483–4488.
16 We sleep in roughly ninety-minute cycles: E. van Der Helm and M. P. Walker, “Overnight Therapy? The Role of Sleep in Emotional Brain Processing,” Psychological Bulletin 135, no. 5 (2009): 731.
17 Charles Dickens wondered: C. Dickens, Night Walks (New York: Penguin Classics, 1860).
18 The sleep medication Ambien: C. M. Paradis, L. A. Siegel, and S. B. Kleinman, “Two Cases of Zolpidem-Associated Homicide,” Primary Care Companion for CNS Disorders 14, no. 4 (2012).
19 brain during non-REM sleep: Cooke, “‘Sleep Should Be Prescribed.’”
20 Acetylcholine levels drop during non-REM: This paragraph is from D. J. Levitin, The Organized Mind: Thinking Straight in the Age of Information Overload (New York: Dutton, 2014); M. Sarter and J. P. Bruno, “Cortical Cholinergic Inputs Mediating Arousal, Attentional Processing and Dreaming: Differential Afferent Regulation of the Basal Forebrain by Telencephalic and Brainstem Afferents,” Neuroscience 95, no. 4 (1999): 933–952.
21 memory can be impaired for several days: X. De Jaeger et al., “Decreased Acetylcholine Release Delays the Consolidation of Object Recognition Memory,” Behavioural Brain Research 221, no. 2 (2011): 424–429; E. J. Wamsley et al., “Dreaming of a Learning Task Is Associated with Enhanced Sleep-Dependent Memory Consolidation,” Current Biology 20, no. 9 (2010): 850–855.
22 More than 40 percent of people over sixty-five: S. Drechsler et al., “With Mouse Age Comes Wisdom: A Review and Suggestions of Relevant Mouse Models for Age-Related Conditions,” Mechanisms of Ageing and Development 160 (2016): 54–68.
23 the essential slow-wave sleep stage: S. Farajnia et al., “Aging of the Suprachiasmatic Clock,” Neuroscientist 20, no. 1 (2014): 44–55.
24 Sleep disturbance causes memory loss: Drechsler et al., “With Mouse Age Comes Wisdom.”
25 sleep requirements remain the same as we age: M. A. Lluch, T. Lloret, and P. V. Llorca, “Aging and Sleep, and Vice Versa,” Approaches to Aging Control 16 (2012): 17–21.
26 naps are associated with a decreased: See, for example, A. Naska et al., “Siesta in Healthy Adults and Coronary Mortality in the General Population,” Archives of Internal Medicine 167, no. 3 (2007): 296–301.
27 the past one hundred years of industrialization: Walker, Why We Sleep.
28 obstructive sleep apnea: L. Barateau et al., “Hypersomnolence, Hypersomnia, and Mood Disorders,” Current Psychiatry Reports 19, no. 2 (2017): 13.
29 hypersomnia and depression: Barateau et al., “Hypersomnolence.”
30 Treatment for hypersomnia: K. Gleason and W. V. McCall, “Current Concepts in the Diagnosis and Treatment of Sleep Disorders in the Elderly,” Current Psychiatry Reports 17, no. 6 (2015): 45.
31 Menopausal symptoms last seven and a half years: N. E. Avis et al., “Duration of Menopausal Vasomotor Symptoms over the Menopause Transition,” JAMA Internal Medicine 175, no. 4 (2015): 531–539.
32 vasomotor symptoms can be a direct cause of sleep disturbance: M. Bruyneel, “Sleep Disturbances in Menopausal Women: Aetiology and Practical Aspects,” Maturitas 81, no. 3 (2015): 406–409; L. Lampio et al., “Predictors of Sleep Disturbance in Menopausal Transition,” Maturitas 94 (2016): 137–142.
33 A meta-analysis of more than fifteen thousand women: D. Cintron et al., “Efficacy of Menopausal Hormone Therapy on Sleep Quality: Systematic Review and Meta-Analysis,” Endocrine 55, no. 3 (2017): 702–711.
34 Sonia Lupien: S. Lupien, email communication, December 5, 2018.
35 “Women’s Health Initiative [WHI] study”: Writing Group for the Women’s Health Initiative Investigators, “Risks and Benefits of Estrogen plus Progestin in Healthy Postmenopausal Women: Principal Results from the Women’s Health Initiative Randomized Controlled Trial,” Journal of the American Medical Association 288, no. 3 (2002): 321–333.
36 A review of where we are at: R. A. Lobo, “Where Are We 10 Years after the Women’s Health Initiative?,” Journal of Clinical Endocrinology and Metabolism 98, no. 5 (2013): 1771–1780.
37 reductions in androgens: A. Vermeulen, “Andropause,” Maturitas 34, no. 1 (2000): 5–15; A. M. Matsumoto, “Andropause: Clinical Implications of the Decline in Serum Testosterone Levels with Aging in Men,” Journals of Gerontology Series A: Biological Sciences and Medical Sciences 57, no. 2 (2002): M76–M99.
38 testosterone administration: Vermeulen, “Andropause.”
39 most men over the age of seventy-five: Journal of Urology 143, no. 4 (1990): 742–746.
40 genetics plays a role in caffeine metabolism: A. Yang, A. A. Palmer, and H. de Wit, “Genetics of Caffeine Consumption and Responses to Caffeine,” Psychopharmacology 211, no. 3 (2010): 245–257.
41 Caffeine breaks down in the body: T. Roehrs and T. Roth, “Caffeine: Sleep and Daytime Sleepiness,” Sleep Medicine Reviews 12, no. 2 (2008): 153–162.
42 adenosine receptors in the brain: E. Murillo-Rodriguez et al., “Anandamide Enhances Extracellular Levels of Adenosine and Induces Sleep: An In Vivo Microdialysis Study,” Sleep 26, no. 8 (2003): 943–947.
43 reduces total sleep time and quality: I. Clark and H. P. Landolt, “Coffee, Caffeine, and Sleep: A Systematic Review of Epidemiological Studies and Randomized Controlled Trials,” Sleep Medicine Reviews 31 (2017): 70–78.
44 reduce melatonin secretion: L. Shilo et al., “The Effects of Coffee Consumption on Sleep and Melatonin Secretion,” Sleep Medicine 3, no. 3 (2002): 271–273.
45 Caffeine also shortens stage 3 and 4: Roehrs and Roth, “Caffeine.”
46 caffeine blocks adenosine receptors and attenuates delta waves: H. P. Landolt, “Caffeine, the Circadian Clock, and Sleep,” Science 349, no. 6254 (2015): 1289–1289.
47 cues your body normally uses: J. Snel and M. M. Lorist, “Effects of Caffeine on Sleep and Cognition,” in Human Sleep and Cognition Part II: Clinical and Applied Research, Progress in Brain Research , vol. 190, ed. H. P. A. Van Dongen and G. A., Kerkhof, pp. 105–117 (Amsterdam: Elsevier, 2011).
48 In the retina: T. Jiang et al., “Protective Effects of Melatonin on Retinal Inflammation and Oxidative Stress in Experimental Diabetic Retinopathy,” Oxidative Medicine and Cellular Longevity (2016).
49 In bone marrow: F. Yang et al., “Melatonin Protects Bone Marrow Mesenchymal Stem Cells against Iron Overload–Induced Aberrant Differentiation and Senescence,” Journal of Pineal Research 63, no. 3 (2017): e12422.
50 In the gastrointestinal tract: Z. Xin et al., “Melatonin as a Treatment for Gastrointestinal Cancer: A Review,” Journal of Pineal Research 58, no. 4 (2015): 375–387.
51 reflux esophagitis, peptic ulcers: N. T. de Talamoni et al., “Melatonin, Gastrointestinal Protection, and Oxidative Stress,” in Gastrointestinal Tissue , ed. J. Gracia-Sancho and J. Salvadó, pp. 317–325 (Cambridge, MA: Academic Press, 2017).
52 components of photosynthesis: V. Martinez et al., “Tolerance to Stress Combination in Tomato Plants: New Insights in the Protective Role of Melatonin,” Molecules 23, no. 3 (2018): 535.
53 timed use of melatonin supplements: T. I. Morgenthaler et al., “Practice Parameters for the Clinical Evaluation and Treatment of Circadian Rhythm Sleep Disorders,” Sleep 30, no. 11 (2007): 1445–1459.
55 Melatonin levels in the blood are highest: G. Chechile, “Melatonin and Cancer,” Approaches to Aging Control 17 (2012): 33–47.
56 protective effects against many cancers: Chechile, “Melatonin and Cancer.”
57 write a quick to-do list: M. K. Scullin et al., “The Effects of Bedtime Writing on Difficulty Falling Asleep: A Polysomnographic Study Comparing To-Do Lists and Completed Activity Lists,” Journal of Experimental Psychology: General 147, no. 1 (2018): 139.
1 Jeanne Calment of France: Recently there have been challenges to the claim of 122 years, but I don’t think this changes our understanding of longevity in humans. There are other cases of people who lived nearly as long, such as 119-year-old Sarah Knauss. See N. Zak, “Evidence That Jeanne Calment Died in 1934—Not 1997,” Rejuvenation Research 22, no. 1 (2019): 3–12; J. Daly, “Was the World’s Oldest Person Ever Actually Her 99-Year-Old Daughter?,” Smithsonian , January 2, 2019, https://www.smithsonianmag.com/smart-news/study-questions-age-worlds-oldest-woman-180971153/ .
3 the gene, EGR : A. R. Gehrke et al., “Acoel Genome Reveals the Regulatory Landscape of Whole-Body Regeneration,” Science 363, no. 6432 (2019): eaau6173.
4 the tail … could regenerate a new brain: T. Shomrat and M. Levin, “An Automated Training Paradigm Reveals Long-Term Memory in Planarians and Its Persistence through Head Regeneration,” Journal of Experimental Biology 216, no. 20 (2013): 3799–3810. Their work was based on earlier work by K. Agata and Y. Umesono: “Brain Regeneration from Pluripotent Stem Cells in Planarian,” Philosophical Transactions of the Royal Society B: Biological Sciences 363, no. 1500 (2008): 2071–2078, and others.
5 telomerase also repairs cancer cells: W. C. Hahn et al., “Inhibition of Telomerase Limits the Growth of Human Cancer Cells,” Nature Medicine 5, no. 10 (1999): 1164.
6 Tardigrades can survive: S. J. McInnes and P. J. A. Pugh, “Tardigrade Biogeography,” in Water Bears: The Biology of Tardigrades , ed. R. O. Schill, pp. 115–129 (Cham, Switzerland: Springer, 2018).
7 unusual type of protein (IDP): T. C. Boothby et al., “Tardigrades Use Intrinsically Disordered Proteins to Survive Desiccation,” Molecular Cell 65, no. 6 (2017): 975–984; Boothby made an educational video about the tardigrade: R. Cans, director, “Meet the Tardigrade, the Toughest Animal on Earth,” TEDEd, March 21, 2017, http://ed.ted.com/lessons/meet-the-tardigrade-the-toughest-animal-on-earth-thomas-boothby .
8 maximum life span of humans is fixed: X. Dong, B. Milholland, and J. Vijg, “Evidence for a Limit to Human Lifespan,” Nature 538, no. 7624 (2016): 257.
11 Two McGill biologists, Bryan Hughes and Siegfried Hekimi: B. G. Hughes, and S. Hekimi, “Many Possible Lifespan Trajectories,” Nature 546, no. 7660 (2017): E8.
13 Olshansky … disagrees:
14 analysis of thousands of elderly Italians: E. Barbi et al., “The Plateau of Human Mortality: Demography of Longevity Pioneers,” Science 360, no. 6396 (2018): 1459–1461.
15 Hekimi, who was not involved in the study: C. Zimmer, “What Is the Limit of Our Life Span?,” The New York Times , July 3, 2018, p. D3.
16 “Current understanding of the biology of aging”: M. P. Rozing, T. B. Kirkwood, and R. G. Westendorp, “Is There Evidence for a Limit to Human Lifespan?,” Nature 546, no. 7660 (2017): E11.
17 Most people living in the blue zones: D. Buettner and S. Skemp, “Blue Zones: Lessons from the World’s Longest Lived,” American Journal of Lifestyle Medicine 10, no. 5 (2016): 318–321; M. Poulain, A. Herm, and G. Pes, “The Blue Zones: Areas of Exceptional Longevity around the World,” Vienna Yearbook of Population Research 11, no. 1 (2013): 87.
18 longevity data from 400 million people: J. G. Ruby et al., “Estimates of the Heritability of Human Longevity Are Substantially Inflated Due to Assortative Mating,” Genetics 210, no. 3 (2018): 1109–1124.
19 What makes it look like longevity runs in families: M. Molteni, “The Key to Long Life Has Little to Do with ‘Good Genes,’” Wired , November 6, 2018.
20 variant of the APOE gene: S. Ryu et al., “Genetic Landscape of APOE in Human Longevity Revealed by High-Throughput Sequencing,” Mechanisms of Ageing and Development 155 (2016): 7–9.
21 FOXO in humans: R. Martins, G. J. Lithgow, and W. Link, “Long Live FOXO: Unraveling the Role of FOXO Proteins in Aging and Longevity,” Aging Cell 15, no. 2 (2016): 196–207.
22 double the life span of the worm: Kenyon did this indirectly, by manipulating insulin-like signaling upstream of FOXO.
24 “I tried caloric restriction”: C. Kenyon, personal communication, February 28, 2016.
25 removing part of the worms’ gonadal systems: H. Hsin and C. Kenyon, “Signals from the Reproductive System Regulate the Lifespan of C. elegans ,” Nature 399, no. 6734 (1999): 362.
26 castrated men tend to live an average of fourteen years longer: J. B. Hamilton and G. E. Mestler, “Mortality and Survival: Comparison of Eunuchs with Intact Men and Women in a Mentally Retarded Population,” Journal of Gerontology 24, no. 4 (1969): 395–411.
27 involves something more than testosterone: M. Gámez-del-Estal et al., “Epigenetic Effect of Testosterone in the Behavior of C. elegans. A Clue to Explain Androgen-Dependent Autistic Traits?,” Frontiers in Cellular Neuroscience 8 (2014): 69.
28 egg is swept clean of age-damaged, deformed proteins: K. A. Bohnert and C. Kenyon, “A Lysosomal Switch Triggers Proteostasis Renewal in the Immortal C. elegans Germ Lineage,” Nature 551, no. 7682 (2017): 629; C. Zimmer, “Young Again: How Mating Turns Back Time,” The New York Times , November 22, 2017, p. D3.
29 gene mutations and other interventions that increase longevity: C. Kenyon, “The Genetics of Ageing,” Nature (2010): 464, 504–512.
30 (the Hayflick limit): L. Hayflick, “Human Cells and Aging,” Scientific American 218, no. 3 (1968): 32–37.
32 role played by the telomeres: Alexey Olovnikov, a Russian biologist, came up with an analogy having to do with a subway train and a tunnel, but I have never been able to follow the logic of it, nor to visualize what he was talking about. A. M. Olovnikov, “Telomeres, Telomerase, and Aging: Origin of the Theory,” Experimental Gerontology 31, no. 4 (1996): 443–448.
33 people with short telomeres die younger: M. Armanios and E. H. Blackburn, “The Telomere Syndromes,” Nature Reviews Genetics 13, no. 10 (2012): 693.
34 childhood Conscientiousness predicts telomere length: G. W. Edmonds, H. C. Côté, and S. E. Hampson, “Childhood Conscientiousness and Leukocyte Telomere Length 40 Years Later in Adult Women—Preliminary Findings of a Prospective Association,” PLoS One 10, no. 7 (2015): e0134077.
35 Exercise is associated with increased telomere length: N. C. Arsenis et al., “Physical Activity and Telomere Length: Impact of Aging and Potential Mechanisms of Action,” Oncotarget 8, no. 27 (2017): 45008; E. Puterman et al., “The Power of Exercise: Buffering the Effect of Chronic Stress on Telomere Length,” PLoS One 5, no. 5 (2010): e10837; J. H. Kim et al., “Habitual Physical Exercise Has Beneficial Effects on Telomere Length in Postmenopausal Women,” Menopause 19, no. 10 (2012): 1109–1115.
36 A diet of whole foods: J. Y. Lee et al., “Association between Dietary Patterns in the Remote Past and Telomere Length,” European Journal of Clinical Nutrition 69, no. 9 (2015): 1048; N. Rafie et al., “Dietary Patterns, Food Groups and Telomere Length: A Systematic Review of Current Studies,” European Journal of Clinical Nutrition 71, no. 2 (2017): 151; A. M. Fretts et al., “Processed Meat, but Not Unprocessed Red Meat, Is Inversely Associated with Leukocyte Telomere Length in the Strong Heart Family Study,” Journal of Nutrition 146, no. 10 (2016): 2013–2018.
37 Neighborhoods with low social cohesion: S. Y. Gebreab et al., “Perceived Neighborhood Problems Are Associated with Shorter Telomere Length in African American Women,” Psychoneuroendocrinology 69 (2016): 90–97; B. L. Needham et al., “Neighborhood Characteristics and Leukocyte Telomere Length: The Multi-Ethnic Study of Atherosclerosis,” Health and Place 28 (2014): 167–172.
38 hormesis: T. G. Son, S. Camandola, and M. P. Mattson, “Hormetic Dietary Phytochemicals,” Neuromolecular Medicine 10, no. 4 (2008): 236.
39 long-term, chronic stress: E. Blackburn and E. Epel, The Telomere Effect: A Revolutionary Approach to Living Younger, Healthier, Longer (New York: Hachette, 2017).
40 healthful challenge response: Blackburn and Epel, The Telomere Effect.
41 Mindfulness meditation: N. S. Schutte and J. M. Malouff, “A Meta-Analytic Review of the Effects of Mindfulness Meditation on Telomerase Activity,” Psychoneuroendocrinology 42 (2014): 45–48; M. Alda et al., “Zen Meditation, Length of Telomeres, and the Role of Experiential Avoidance and Compassion,” Mindfulness 7, no. 3 (2016): 651–659; E. A. Hoge et al., “Loving-Kindness Meditation Practice Associated with Longer Telomeres in Women,” Brain, Behavior, and Immunity 32 (2013): 159–163.
42 “telomere dysfunction turns into pain”: J. Mogil, “What’s Wrong with Animal Models of Pain?,” The Opioid Crisis and the Future of Addiction and Pain Therapeutics: Opportunities, Tools, and Technologies Symposium, Washington, DC, February 2019, video, at 30:35: https://videocast.nih.gov/summary.asp?Live=31408&bhcp=1 .
43 study of more than twenty-six thousand people: ScienceDaily , April 3, 2017, www.sciencedaily.com/releases/2017/04/170403083123.htm ; J. M. Yuan et al., “A Prospective Assessment for Telomere Length in Relation to Risk of Cancer in the Singapore Chinese Health Study,” AACR Annual Meeting, Washington, DC, April 2017.
44 study of 9,127 patients and thirty-one cancer types: F. P. Barthel et al., “Systematic Analysis of Telomere Length and Somatic Alterations in 31 Cancer Types,” Nature Genetics 49, no. 3 (2017): 349. See also P. C. Haycock et al., “Association between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study,” JAMA Oncology 3, no. 5 (2017): 636–651.
45 In their book The Telomere Effect : Blackburn and Epel, The Telomere Effect.
46 Siegfried Hekimi concurs: S. Hekimi, personal communication, March 26, 2019.
48 telomere shortening evolved as an anticancer adaptation: J. W. Shay, “Role of Telomeres and Telomerase in Aging and Cancer,” Cancer Discovery 6, no. 6 (2016): 584–593.
50 paper coauthored by Leonard Hayflick: S. J. Olshansky, L. Hayflick, and B. A. Carnes, “No Truth to the Fountain of Youth,” Scientific American 286, no. 6 (2002): 92–95.
51 extending life span artificially is still out of reach: S. J. Olshansky, “Is Life Extension Today a Faustian Bargain?,” Frontiers in Medicine 4 (2017): 215.
53 people who famously tried to live forever: P. Kennedy, “No Magic Pill Will Get You to 100,” The New York Times , March 9, 2018, p. SR1.
55 clearance of these zombie cells: D. J. Baker et al., “Clearance of p16 Ink4a-Positive Senescent Cells Delays Ageing-Associated Disorders,” Nature 479, no. 7372 (2011): 232.
56 Removing the senescent cells: M. Scudellari, “To Stay Young, Kill Zombie Cells,” Nature 550, no. 7677 (2017): 448–450.
57 Subsequent work in mice: M. J. Schafer et al., “Cellular Senescence Mediates Fibrotic Pulmonary Disease,” Nature Communications 8 (2017): 14532; O. H. Jeon et al., “Local Clearance of Senescent Cells Attenuates the Development of Post-Traumatic Osteoarthritis and Creates a Pro-Regenerative Environment,” Nature Medicine 23, no. 6 (2017): 775; D. J. Baker et al., “Naturally Occurring p16 Ink4a-Positive Cells Shorten Healthy Lifespan,” Nature 530, no. 7589 (2016): 184.
58 It can also prevent memory loss: Nature 562, no. 7728 (2018): 578.
59 fourteen different senolytics: Scudellari, “To Stay Young, Kill Zombie Cells.”
60 molecular biologist Nathaniel David: Scudellari, “To Stay Young, Kill Zombie Cells.”
62 “Everything looks good in mice”: Quoted in Corbyn, “Want to Live for Ever?”
63 “The immune system doesn’t know”: J. Allison, personal communication, July 28, 2018.
64 “Unleashing the immune system”: Allison, personal communication.
65 80 percent of patients die: F. S. Hodi et al., “Two-Year Overall Survival Rates from a Randomised Phase 2 Trial Evaluating the Combination of Nivolumab and Ipilimumab versus Ipilimumab Alone in Patients with Advanced Melanoma,” Lancet Oncology 17, no. 11 (2016): 1558.
66 self-propagating prion form: A. Aoyagi et al., “Aβ and Tau Prion-Like Activities Decline with Longevity in the Alzheimer’s Disease Human Brain,” Science Translational Medicine 11, no. 490 (2019): eaat8462.
67 Prusiner told me: S. Prusiner, personal communication, September 12, 2019.
68 DeGrado adds: B. DeGrado, personal communication, September 11, 2019.
71 To solve the various problems of aging: H. Warner et al., “Science Fact and the SENS Agenda: What Can We Reasonably Expect from Ageing Research?,” EMBO Reports 6, no. 11 (2005): 1006–1008.
72 inconsistent with what we know about mitochondria: A. Kowald and T. B. Kirkwood, “Evolution of the Mitochondrial Fusion-Fission Cycle and Its Role in Aging,” Proceedings of the National Academy of Sciences 108, no. 25 (2011): 10237–10242.
73 plethora of unknown variables: M. Kyriazis, “The Impracticality of Biomedical Rejuvenation Therapies: Translational and Pharmacological Barriers,” Rejuvenation Research 17, no. 4 (2014): 390–396.
74 A consortium of twenty-eight scientists: Warner et al., “Science Fact and the SENS Agenda.
75 On the Horizon: N. Barzilai, “An Update on Anti-Aging Drug Trials,” Innovation in Aging 2, suppl. 1 (2018): 544.
76 rapamycin … in mice … can extend life by 25 percent: D. E. Harrison et al., “Rapamycin Fed Late in Life Extends Lifespan in Genetically Heterogeneous Mice,” Nature 460, no. 7253 (2009): 392.
77 weekly doses of rapamycin increased immune function: J. B. Mannick et al., “mTOR Inhibition Improves Immune Function in the Elderly,” Science Translational Medicine 6, no. 268 (2014): 268ra179.
78 metformin … to combat aging: Rejuvenation Research 20, no. 3 (2017): 173–182; M. G. Novelle et al., “Metformin: A Hopeful Promise in Aging Research,” Cold Spring Harbor Perspectives in Medicine 6, no. 3 (2016): a025932.
80 NAD+ regulates cellular metabolism: Y. Aman et al., “Therapeutic Potential of Boosting NAD+ in Aging and Age-Related Diseases,” Translational Medicine of Aging (2018); S. I. Imai and L. Guarente, “NAD+ and Sirtuins in Aging and Disease,” Trends in Cell Biology 24, no. 8 (2014): 464–471.
82 After just a week of supplementation: J. Li et al., “A Conserved NAD+ Binding Pocket That Regulates Protein-Protein Interactions During Aging,” Science 355, no. 6331 (2017): 1312–1317.
83 a sixty-year-old human looks like a twenty-year-old: S. Dutta and P. Sengupta, “Men and Mice: Relating Their Ages,” Life Sciences 152 (2016): 244–248.
84 combination of two NAD+ precursors, NR and PT: R. W. Dellinger et al., “Repeat Dose NRPT (Nicotinamide Riboside and Pterostilbene) Increases NAD+ Levels in Humans Safely and Sustainably: A Randomized, Double-Blind, Placebo-Controlled Study,” NPJ Aging and Mechanisms of Disease 3, no. 1 (2017): 17.
85 1,000 mg per day of NR: C. R. Martens et al., “Chronic Nicotinamide Riboside Supplementation Is Well-Tolerated and Elevates NAD+ in Healthy Middle-Aged and Older Adults,” Nature Communications 9, no. 1 (2018): 1286.
88 “I have tested the NMN”: D. Sinclair, personal communication, March 19, 2019.
89 The Mexican axolotl: S. Nowoshilow et al., “The Axolotl Genome and the Evolution of Key Tissue Formation Regulators,” Nature 554, no. 7690 (2018): 50.
90 In one species, it doubled life span: M. Lucanic et al., “Impact of Genetic Background and Experimental Reproducibility on Identifying Chemical Compounds with Robust Longevity Effects,” Nature Communications 8 (2017): 14256.
91 As Richard Klausner, CEO of Lyell Immunopharma, says: R. Klausner, In Favor of Science: The Importance and Impact of Scientific Research , Minerva Schools at KGI (San Francisco: Consequent, 2019).
92 Centenarians live longer than ever: P. B. Baltes and J. Smith, “New Frontiers in the Future of Aging: From Successful Aging of the Young Old to the Dilemmas of the Fourth Age,” Gerontology 49, no. 2 (2003): 123–135.
93 Richard Overton: S. Sault, “If You Ask Richard Overton the Secret to Longevity, He’ll Tell You God and Cigars Are the Answer,” Texas Hill Country , June 15, 2017, https://texashillcountry.com/richard-overton-the-secret-to-longevity/ ; B. Meyer, “At 112, America’s Oldest Man Has the Secret to a Long Life: ‘Just Keep Dallas News , May 10, 2017, https://www.dallasnews.com/life/better-living/2018/05/10/americas-oldest-man-still-kicking-smoking-nears-112-secret-dont-die .
1 spend time doing sudoku: M. Melby-Lervåg and C. Hulme, “Is Working Memory Training Effective? A Meta-Analytic Review,” Developmental Psychology 49, no. 2 (2013): 270.
4 Neurocore, backed by US education secretary Betsy DeVos: E. L. Green, “Brain-Function Firm Backed by DeVos Misled in Ads,” The New York Times , June 27, 2018, p. B3.
5 (brain changes in response to the training): D. J. Simons et al., “Do ‘Brain-Training’ Programs Work?,” Psychological Science in the Public Interest 17, no. 3 (2016): 103–186.
6 analyzed 132 papers cited by … brain-training companies: Simons et al., “Do ‘Brain-Training’ Programs Work?”
7 Simons and his colleagues concluded: Simons et al., “Do ‘Brain-Training’ Programs Work?”
8 Art Shimamura counsels: A. Shimamura, Get SMART! Five Steps toward a Healthy Brain (Scotts Valley, CA: CreateSpace, 2017).
9 A PCE or implant that can improve memory: B. Carey, “A Memory Jolt Raises Hopes,” The New York Times , February 13, 2018, p. D1.
10 Neuroscientist Michael Gazzaniga imagines: M. S. Gazzaniga, Human: The Science behind What Makes Your Brain Unique (New York: Harper Perennial, 2008). I wrote about this previously in D. J. Levitin, “Brain Candy,” The New York Times , August 22, 2008, p. BR9.
11 Ethicists have begun to grapple: A. D. Mohamed, “Neuroethical Issues in Pharmacological Cognitive Enhancement,” Wiley Interdisciplinary Reviews: Cognitive Science 5, no. 5 (2014): 533–549; H. Maslen, N. Faulmüller, and J. Savulescu, “Pharmacological Cognitive Enhancement—How Neuroscientific Research Could Advance Ethical Debate,” Frontiers in Systems Neuroscience 8 (2014): 107.
13 Members of the US Bioethics Commission write: A. L. Allen and N. K. Strand, “Cognitive Enhancement and Beyond: Recommendations from the Bioethics Commission,” Trends in Cognitive Sciences 19, no. 10 (2015): 549–551.
14 mixed results as to whether Adderall: Drug and Alcohol Dependence 178 (2017): 302–309.
15 impair creativity: M. J. Farah et al., “When We Enhance Cognition with Adderall, Do We Sacrifice Creativity? A Preliminary Study,” Psychopharmacology 202, nos. 1–3 (2009): 541–547.
16 modafinil … adenosine receptor antagonist: P. Gerrard and R. Malcolm, “Mechanisms of Modafinil: A Review of Current Research,” Neuropsychiatric Disease and Treatment 3, no. 3 (2007): 349.
17 increase motivation and promote wakefulness: M. J. Farah, “The Unknowns of Cognitive Enhancement,” Science 350, no. 6259 (2015): 379–380.
18 modafinil consistently enhanced attention: R. M. Battleday and A.-K. Brem, “Modafinil for Cognitive Neuroenhancement in Healthy Non-Sleep-Deprived Subjects: A Systematic Review,” European Neuropsychopharmacology 25 (2015): 1865–1881.
19 a reduction in creativity: A. D. Mohamed, “The Effects of Modafinil on Convergent and Divergent Thinking of Creativity: A Randomized Controlled Trial,” Journal of Creative Behavior 50, no. 4 (2014): 252–267.
20 modafinil … led to cognitive slowing: A. D. Mohamed and C. R. Lewis, “Modafinil Increases the Latency of Response in the Hayling Sentence Completion Test in Healthy Volunteers: A Randomised Controlled Trial,” PLoS One 9, no. 11 (2014): e110639.
21 loss of dopamine receptor neurons: L. Bäckman et al., “The Correlative Triad among Aging, Dopamine, and Cognition: Current Status and Future Prospects,” Neuroscience and Biobehavioral Reviews 30, no. 6 (2006): 791–807.
22 5 and 35 percent report having used it: T. E. Wilens et al., “Misuse and Diversion of Stimulants Prescribed for ADHD: A Systematic Review of the Literature,” Journal of the American Academy of Child and Adolescent Psychiatry 47, no. 1 (2008): 21–31.
23 nicotine … tends to reduce stress: I. Smith, “Psychostimulants and Artistic, Musical, and Literary Creativity,” in The Neuropsychiatric Complications of Stimulant Abuse , International Review of Neurobiology, vol. 120, ed. P. Taba, A. Lees, and K. Sikk, pp. 301–326 (Waltham, MA: Academic Press, 2015); S. J. Heishman, B. A. Kleykamp, and E. G. Singleton, “Meta-Analysis of the Acute Effects of Nicotine and Smoking on Human Performance,” Psychopharmacology 210, no. 4 (2010): 453–469.
24 deactivating areas of the default mode: B. Hahn et al., “Nicotine Enhances Visuospatial Attention by Deactivating Areas of the Resting Brain Default Network,” Journal of Neuroscience 27, no. 13 (2007): 3477–3489.
25 treatment for late-life depression: J. A. Gandelman, P. Newhouse, and W. D. Taylor, “Nicotine and Networks: Potential for Enhancement of Mood and Cognition in Late-Life Depression,” Neuroscience and Biobehavioral Reviews 84 (2018): 289–298.
26 neuroprotective effects: G. E. Barreto, A. Iarkov, and V. E. Moran, “Beneficial Effects of Nicotine, Cotinine and Its Metabolites as Potential Agents for Parkinson’s Disease,” Frontiers in Aging Neuroscience 6 (2015): 340; M. Kolahdouzan and M. J. Hamadeh, “The Neuroprotective Effects of Caffeine in Neurodegenerative Diseases,” CNS Neuroscience and Therapeutics 23, no. 4 (2017): 272–290.
28 tolcapone, a nonstimulant dopamine promoter: Neuropsychopharmacology 32, no. 5 (2007): 1011.
29 liver injury attributed to tolcapone: N. Borges, “Tolcapone-Related Liver Dysfunction,” Drug Safety 26, no. 11 (2003): 743–747.
30 pramipexole (Mirapex, Mirapexin, Sifrol): J. Micallef et al., “Antiparkinsonian Drug-Induced Sleepiness: A Double-Blind Placebo-Controlled Study of L-Dopa, Bromocriptine and Pramipexole in Healthy Subjects,” British Journal of Clinical Pharmacology 67, no. 3 (2009): 333–340; D. A. Pizzagalli et al., “Single Dose of a Dopamine Agonist Impairs Reinforcement Learning in Humans: Behavioral Evidence from a Laboratory-Based Measure of Reward Responsiveness,” Psychopharmacology 196, no. 2 (2008): 221–232.
31 doctor’s instructions to the girl: D. Hamilton, personal communication, June 8, 2019.
32 early and incomplete evidence that rivastigmine: A. Ströhle et al., “Drug and Exercise Treatment of Alzheimer Disease and Mild Cognitive Impairment: A Systematic Review and Meta-Analysis of Effects on Cognition in Randomized Controlled Trials,” American Journal of Geriatric Psychiatry 23, no. 12 (2015): 1234–1249; J. T. O’Brien et al., “Clinical Practice with Anti-Dementia Drugs: A Revised (Third) Consensus Statement from the British Association for Psychopharmacology,” Journal of Psychopharmacology 31, no. 2 (2017): 147–168.
33 glutamate-induced excitotoxicity: B. M. Altevogt, M. Davis, and D. E. Pankevich, eds., Glutamate-Related Biomarkers in Drug Development for Disorders of the Nervous System: Workshop Summary (Washington, DC: National Academies Press, 2011).
34 difference between rivastigmine and memantine: C. Quintana, personal communication, May 21, 2018.
35 combination therapy using the two drugs: P. L. Santaguida, T. A. Shamliyan, and D. R. Goldmann, “Cholinesterase Inhibitors and Memantine in Adults with Alzheimer Disease,” American Journal of Medicine 129, no. 10 (2016): 1044–1047.
36 inflammation is due to hormone deprivation: C. M. Gameiro, F. Romão, and C. Castelo-Branco, “Menopause and Aging: Changes in the Immune System—A Review,” Maturitas 67, no. 4 (2010): 316–320; C. Castelo-Branco and I. Soveral, “The Immune System and Aging: A Review,” Gynecological Endocrinology 30, no. 1 (2014): 16–22.
37 cognitive stimulation therapy: A. Spector et al., “Efficacy of an Evidence-Based Cognitive Stimulation Therapy Programme for People with Dementia: Randomised Controlled Trial,” British Journal of Psychiatry 183, no. 3 (2003): 248–254; J. D. Huntley et al., “Do Cognitive Interventions Improve General Cognition in Dementia? A Meta-Analysis and Meta-Regression,” BMJ Open 5, no. 4 (2015): e005247.
38 supplements for which manufacturers declare age-defying: J. Birks and J. G. Evans, “Ginkgo Biloba for Cognitive Impairment and Dementia,” Cochrane Database of Systematic Reviews 1 (2009); J. Geng et al., “Ginseng for Cognition,” Cochrane Database of Systematic Reviews 12 (2010); P. E. Gold, L. Cahill, and G. L. Wenk, “Ginkgo Biloba: A Cognitive Enhancer?,” Psychological Science in the Public Interest 3, no. 1 (2002): 2–11; A. W. Rutjes et al., “Vitamin and Mineral Supplementation for Maintaining Cognitive Function in Cognitively Healthy People in Mid and Late Life,” Cochrane Database of Systematic Reviews 12 (2018); Q. Yuan et al., “Effects of Ginkgo Biloba on Dementia: An Overview of Systematic Reviews,” Journal of Ethnopharmacology 195 (2017): 1–9.
40 necessary for the production of myelin: G. Scalabrino, “The Multi-Faceted Basis of Vitamin B12 (Cobalamin) Neurotrophism in Adult Central Nervous System: Lessons Learned from Its Deficiency,” Progress in Neurobiology 88, no. 3 (2009): 203–220.
41 homocysteine hypothesis: D. Kennedy, “B Vitamins and the Brain: Mechanisms, Dose and Efficacy—A Review,” Nutrients 8, no. 2 (2016): 68.
42 Vitamin B12 deficiency: J. L. Reay, M. A. Smith, and L. M. Riby, “B Vitamins and Cognitive Performance in Older Adults,” ISRN Nutrition 2013 (2013).
43 no association between B12 supplementation: R. Malouf and A. A. Sastre, “Vitamin B12 for Cognition,” Cochrane Database of Systematic Reviews 3 (2003).
44 B12 was indeed effective at lowering homocysteine: D. M. Zhang et al., “Efficacy of Vitamin B Supplementation on Cognition in Elderly Patients with Cognitive-Related Diseases: A Systematic Review and Meta-Analysis,” Journal of Geriatric Psychiatry and Neurology 30, no. 1 (2017): 50–59.
45 B12 supplementation led to significant memory improvement: R. L. Kane et al., “Interventions to Prevent Age-Related Cognitive Decline, Mild Cognitive Impairment, and Clinical Alzheimer’s-Type Dementia,” Comparative Effectiveness Reviews 188 (2017).
46 strongest effect being in those with higher homocysteine levels: G. Douaud et al., “Preventing Alzheimer’s Disease-Related Gray Matter Atrophy by B-Vitamin Treatment,” Proceedings of the National Academy of Sciences 110, no. 23 (2013): 9523–9528.
47 Taking B12 supplementation does not cause any harm: B. Bistrian, “Should I Stop Taking These Vitamins?,” Harvard Health Letter , May 2010.
49 Mushrooms are a mixture of proteins: E. Ulziijargal and J. L. Mau, “Nutrient Compositions of Culinary-Medicinal Mushroom Fruiting Bodies and Mycelia,” International Journal of Medicinal Mushrooms 13, no. 4 (2011).
50 Hericium erinaceus polysaccharides … increases levels of acetylcholine:Hericium erinaceus on Amyloid β (25-35) Peptide-Induced Learning and Memory Deficits in Mice,” Biomedical Research 32, no. 1 (2011): 67–72.
51 HEP also has neuroprotective and neuroregenerative qualities: K. Mori et al., “Improving Effects of the Mushroom Yamabushitake (Hericium erinaceus ) on Mild Cognitive Impairment: A Double-Blind Placebo-Controlled Clinical Trial,” Phytotherapy Research 23, no. 3 (2009): 367–372.
52 it reduces depression and anxiety: M. Nagano et al., “Reduction of Depression and Anxiety by 4 Weeks Hericium erinaceus Intake,” Biomedical Research 31, no. 4 (2010): 231–237.
53 Ganoderma lucidum :Ganoderma lucidum Improves Cancer-Related Fatigue in Breast Cancer Patients Undergoing Endocrine Therapy: A Pilot Clinical Trial,” Evidence-Based Complementary and Alternative Medicine 2012 (2012).
54 neuroprotective effects on the hippocampus: Y. Zhou et al., “Neuroprotective Effect of Preadministration with Ganoderma lucidum Spore on Rat Hippocampus,” Experimental and Toxicologic Pathology 64, nos. 7–8 (2012): 673–680.
55 promotes cognitive function in mouse models of AD: Ganoderma lucidum Promote Cognitive Function and Neural Progenitor Proliferation in Mouse Model of Alzheimer’s Disease,” Stem Cell Reports 8, no. 1 (2017): 84–94.
56 anti-inflammatory properties: W. B. Stavinoha, “Status of Ganoderma lucidum in United States: Ganoderma lucidum as an Anti-Inflammatory Agent,” in Proceedings of the 1st International Symposium on Ganoderma Lucidum in Japan , pp. 17–18 (2008).
57 reduces oxidative stress: W. J. Li et al., “Ganoderma atrum Polysaccharide Attenuates Oxidative Stress Induced by D-Galactose in Mouse Brain,” Life Sciences 88, nos. 15–16 (2011): 713–718.
58 seven hundred adults aged sixty and over in Singapore: L. Feng et al., “The Association between Mushroom Consumption and Mild Cognitive Impairment: A Community-Based Cross-Sectional Study in Singapore,” Journal of Alzheimer’s Disease 68 (2019): 197–203.
59 Bacopa monnieri :Bacopa monnieri and Leersia oryzoides on Soil and Water Chemistry,” Ecohydrology: Ecosystems, Land and Water Process Interactions, Ecohydrogeomorphology 2, no. 3 (2009): 279–286.
60 improve higher-order cognitive processes: C. Stough et al., “The Chronic Effects of an Extract of Bacopa monniera (Brahmi) on Cognitive Function in Healthy Human Subjects,” Psychopharmacology 156, no. 4 (2001): 481–484.
61 significant effect on retaining new information: S. Roodenrys et al., “Chronic Effects of Brahmi (Bacopa monnieri ) on Human Memory,” Neuropsychopharmacology 27, no. 2 (2002): 279.
62 regulating tryptophan hydroxylase and serotonin transporter expression: P. D. Charles et al., “Bacopa monniera Leaf Extract Up-Regulates Tryptophan Hydroxylase (TPH2) and Serotonin Transporter (SERT) Expression: Implications in Memory Formation,” Journal of Ethnopharmacology 134, no. 1 (2011): 55–61.
63 “elastic thinking”: L. Mlodinow, Elastic: Flexible Thinking in a Time of Change (New York: Pantheon, 2018).
66 “among the safest drugs we know of”: D. Nutt, Drugs without the Hot Air: Minimising the Harms of Legal and Illegal Drugs (Cambridge: UIT Cambridge, 2012), p. 254.
67 Brian Wilson: S. Belli, “A Psychobiographical Analysis of Brian Douglas Wilson: Creativity, Drugs, and Models of Schizophrenic and Affective Disorders,” Personality and Individual Differences 46, no. 8 (2009): 809–819. See also D. H. Linszen, P. M. Dingemans, and M. E. Lenior, “Cannabis Abuse and the Course of Recent-Onset Schizophrenic Disorders,” Archives of General Psychiatry 51, no. 4 (1994): 273–279.
69 An ideal dose: J. Fadiman and S. Korb, “Microdosing Psychedelics,” in Advances in Psychedelic Medicine: State-of-the-Art Therapeutic Applications , ed. M. J. Winkelman and B. Sessa, p. 323 (Westport, CT: Praeger, 2019).
70 Microdosers scored lower: T. Anderson et al., “Microdosing Psychedelics: Personality, Mental Health, and Creativity Differences in Microdosers,” Psychopharmacology (2018): 1–10; P. S. Hendricks et al., “Classic Psychedelic Use Is Associated with Reduced Psychological Distress and Suicidality in the United States Adult Population,” Journal of Psychopharmacology 29, no. 3 (2015): 280–288.
71 Regular low doses of THC: A. Bilkei-Gorzo et al., “A Chronic Low Dose of Δ 9-Tetrahydrocannabinol (THC) Restores Cognitive Function in Old Mice,” Nature Medicine 23, no. 6 (2017): 782.
72 Cochlear implants: J. Saliba et al., “Functional Near-Infrared Spectroscopy for Neuroimaging in Cochlear Implant Recipients,” Hearing Research 338 (2016): 64–75.
73 Cochlear implants … six hundred thousand people: A. P. Sanderson et al., “Exploiting Routine Clinical Measures to Inform Strategies for Better Hearing Performance in Cochlear Implant Users,” Frontiers in Neuroscience 12 (2019).
74 neural implants … Parkinson’s: J. M. Bronstein et al., “Deep Brain Stimulation for Parkinson Disease: An Expert Consensus and Review of Key Issues,” Archives of Neurology 68, no. 2 (2011): 165.
75 neural implants … depression: A. M. Lozano et al., “Subcallosal Cingulate Gyrus Deep Brain Stimulation for Treatment-Resistant Depression,” Biological Psychiatry 64, no. 6 (2008): 461–467.
76 neural implant that increased memory encoding: Y. Ezzyat et al., “Closed-Loop Stimulation of Temporal Cortex Rescues Functional Networks and Improves Memory,” Nature Communications 9, no. 1 (2018): 365.
77 “jostling the system”: Quoted in B. Carey, “‘Pacemaker’ for the Brain Can Help Memory, Study Finds,” The New York Times , April 21, 2017, p. A19.
78 Kahana thinks that future research: B. Carey, “A Brain Implant Improved Memory, Scientists Report,” The New York Times , February 7, 2018, p. A17.
80 Samantha Payne, COO of OpenBionics: Quoted in R. Godwin, “We Will Get Regular Body Upgrades: What Will Humans Look Like in 100 Years?,” The Guardian , September 22, 2018.
81 A neural implant … paralyzed right arm: C. E. Bouton et al., “Restoring Cortical Control of Functional Movement in a Human with Quadriplegia,” Nature 533, no. 7602 (2016): 247.
83 Zoltan Istvan is a controversial figure: Z. Istvan, “I Just Got a Computer Chip Implanted in My Hand—and the Rest of the World Won’t Be Far Behind,” Business Insider , September 25, 2015.
84 Neil Harbisson, had an antenna installed: S. Jeffries, “Neil Harbisson: The World’s First Cyborg Artist,” The Guardian , May 6, 2014. To be clear, Harbisson is not able to browse the Internet with his brain or to receive video images displayed on some sort of mind-screen. People with Bluetooth can send and receive auditory https://www.cnet.com/news/cyborg-interview-hear-colors-with-antenna-in-your-skull/ .
85 The technology exists for these: A. Mandavilli, “A Patch Uses Sweat to Get a Read on Your Body’s Toil,” The New York Times , January 21, 2019, p. B3.
87 Meditation reduces activity within the default mode network: J. A. Brewer et al., “Meditation Experience Is Associated with Differences in Default Mode Network Activity and Connectivity,” Proceedings of the National Academy of Sciences 108, no. 50 (2011): 20254–20259; K. A. Garrison et al., “Meditation Leads to Reduced Default Mode Network Activity beyond an Active Task,” Cognitive, Affective, and Behavioral Neuroscience 15, no. 3 (2015): 712–720.
88 anti-inflammatory effect by reducing cytokines: J. D. Creswell et al., “Alterations in Resting-State Functional Connectivity Link Mindfulness Meditation with Reduced Interleukin-6: A Randomized Controlled Trial,” Biological Psychiatry 80, no. 1 (2016): 53–61.
89 Long-term meditators show structural changes: J. H. Jang et al., “Increased Default Mode Network Connectivity Associated with Meditation,” Neuroscience Letters 487, no. 3 (2011): 358–362; S. W. Lazar et al., “Meditation Experience Is Associated with Increased Cortical Thickness,” Neuroreport 16, no. 17 (2005): 1893; R. E. Wells et al., “Meditation’s Impact on Default Mode Network and Hippocampus in Mild Cognitive Impairment: A Pilot Study,” Neuroscience Letters 556 (2013): 15–19; K. C. Fox et al., “Is Meditation Associated with Altered Brain Structure? A Systematic Review and Meta-Analysis of Morphometric Neuroimaging in Meditation Practitioners,” Neuroscience and Biobehavioral Reviews 43 (2014): 48–73.
90 Even brief meditation reduces fatigue: F. Zeidan et al., “Mindfulness Meditation Improves Cognition: Evidence of Brief Mental Training,” Consciousness and Cognition 19, no. 2 (2010): 597–605.
91 benefits persist even after meditation: M. A. Cohn and B. L. Fredrickson, “In Search of Durable Positive Psychology Interventions: Predictors and Consequences of Long-Term Positive Behavior Change,” Journal of Positive Psychology 5, no. 5 (2010): 355–366.
92 lower levels of cortisol: M. A. Rosenkranz et al., “Reduced Stress and Inflammatory Responsiveness in Experienced Meditators Compared to a Matched Healthy Control Group,” Psychoneuroendocrinology 68 (2016): 117–125.
93 benefits show up after as little as four weeks: E. Walsh, T. Eisenlohr-Moul, and R. Baer, “Brief Mindfulness Training Reduces Salivary IL-6 and TNF-α in Young Women with Depressive Symptomatology,” Journal of Consulting and Clinical Psychology 84, no. 10 (2016): 887.
94 downregulation of inflammatory genes: P. Kaliman et al., “Rapid Changes in Histone Deacetylases and Inflammatory Gene Expression in Expert Meditators,” Psychoneuroendocrinology 40 (2014): 96–107.
95 meditation seems to have epigenetic effects: J. A. Dusek et al., “Genomic Counter-Stress Changes Induced by the Relaxation Response,” PLoS One 3, no. 7 (2008): e2576; H. Lavretsky et al., “A Pilot Study of Yogic Meditation for Family Dementia Caregivers with Depressive Symptoms: Effects on Mental Health, Cognition, and International Journal of Geriatric Psychiatry 28, no. 1 (2013): 57–65; E. Luders et al., “The Unique Brain Anatomy of Meditation Practitioners: Alterations in Cortical Gyrification,” Frontiers in Human Neuroscience 6, (2012): 34.
96 lower those levels and decrease feelings of loneliness: J. D. Creswell et al., “Mindfulness-Based Stress Reduction Training Reduces Loneliness and Pro-Inflammatory Gene Expression in Older Adults: A Small Randomized Controlled Trial,” Brain, Behavior, and Immunity 26, no. 7 (2012): 1095–1101.
97 associated with increased telomerase: N. S. Schutte and J. M. Malouff, “A Meta-Analytic Review of the Effects of Mindfulness Meditation on Telomerase Activity,” Psychoneuroendocrinology 42 (2014): 45–48; T. L. Jacobs et al., “Intensive Meditation Training, Immune Cell Telomerase Activity, and Psychological Mediators,” Psychoneuroendocrinology 36, no. 5 (2011): 664–681.
98 mild cognitive impairment and early-stage Alzheimer’s, meditation: J. Russell-Williams et al., “Mindfulness and Meditation: Treating Cognitive Impairment and Reducing Stress in Dementia,” Reviews in the Neurosciences 29, no. 7 (2018): 791–804.
1 David Bradley: Quoted in N. Narboe, ed., Aging: An Apprenticeship (Portland, OR: Red Notebook Press), p. 80.
2 Philosopher David Velleman suggests: D. Velleman, “Well-Being and Time,” Pacific Philosophical Quarterly 72, no. 1 (1991): 48–77.
3 prefer the life that takes the upward trend: M. Slote, Goods and Virtues (New York: Oxford University Press, 1983).
4 additional years of lower quality: E. Diener, D. Wirtz, and S. Oishi, “End Effects of Rated Life Quality: The James Dean Effect,” Psychological Science 12, no. 2 (2001): 124–131.
5 We’re sensitive to the timing of events: See also J. Glasgow, “The Shape of a Life and the Value of Loss and Gain,” Philosophical Studies 162, no. 3 (2013): 665–682.
7 healthy life expectancy (HALE): H. S. Friedman and M. L. Kern, “Personality, Well-Being and Health,” Annual Reviews of Psychology 65 (2014): 719–742.
8 This holds true across seventy-two countries: D. G. Blanchflower and A. J. Oswald, “Is Well-Being U-Shaped over the Life Cycle?,” Social Science and Medicine 66, no. 8 (2008): 1733–1749.
9 the middle-aged dip: Pink is summarizing an argument made by social scientist Hannes Schwandt. D. H. Pink, When: The Scientific Secrets of Perfect Timing (New York: Penguin Press, 2019).
10 The positivity bias: L. L. Carstensen and M. DeLiema, “The Positivity Effect: A Negativity Bias in Youth Fades with Age,” Current Opinion in Behavioral Sciences 19 (2018): 7–12.
11 two areas associated with selective attention: M. Mather, “The Affective Neuroscience of Aging,” Annual Review of Psychology 67 (2016): 213–238; L. K. Sasse et al., “Selective Control of Attention Supports the Positivity Effect in Aging,” PLoS One 9, no. 8 (2014): e104180.
12 Sonny Rollins: S. Rollins, personal communication, June 2018.
13 Most quaily of life indexes: http://www.economist.com/media/pdf/QUALITY_OF_LIFE.pdf ; European Union European Commission, “Quality of Life Indicators,” 2013, https://ec.europa.eu/eurostat/statistics-explained/index.php/Quality_of_life_indicators ; P. Haslam, J. Schafer, and P. Beaudet, eds., Introduction to International Development: Approaches, Actors, and Issues , 2nd ed. (Don Mills: Oxford University Press, 2012); D. Kahneman and A. B. Krueger, “Developments in the Measurement of Subjective Well-Being,” Journal of Economic Perspectives 20, no. 1 (2006): 3–24; United Nations Development Program, Human Development Report , 2013, http://hdr.undp.org/en/statistics/hdi/ . I thank my McGill honors students Lauren Guttman, Jane Stocks, and Noa Yaakoba-Zohar for bringing these issues and papers to my attention.
14 For people from collectivist and holistic societies: M. J. Hornsey et al., “How Much Is Enough in a Perfect World? Cultural Variation in Ideal Levels of Happiness, Pleasure, Freedom, Health, Self-Esteem, Longevity, and Intelligence,” Psychological Science 29, no. 9 (2018): 1393–1404. See also Y. Uchida and S. Kitayama, “Happiness and Unhappiness in East and West: Themes and Variations,” Emotion 9 (2009): 441–456.
15 The World Happiness Report :The Washington Post , March 21, 2019.
16 comedian Jimmy Kimmel: Quoted in Chiu, “Americans Are the Unhappiest.”
17 Jean Twenge: Quoted in Chiu, “Americans Are the Unhappiest.”
18 spate of addictions: J. M. Twenge and W. K. Campbell, “Associations between Screen Time and Lower Psychological Well-Being among Children and Adolescents: Evidence from a Population-Based Study,” Preventive Medicine Reports 12, no. 271 (2018).
19 blame overuse of digital devices: Chiu, “Americans Are the Unhappiest.”
21 A bigger predictor than cholesterol: Waldinger, “What Makes a Good Life?”
24 George Vaillant, who directed the study for three decades: Quoted in Shenk, “What Makes Us Happy?”
26 As Vaillant notes: Vaillant, “The Importance of Relationships.”
28 satisfied with their spouses have increased longevity: An increase of one standard deviation in spousal satisfaction was correlated with a 13 percent reduction in Psychological Science (2019): 0956797619835147.
29 Lamont Dozier: L. Dozier, personal communication, July 26, 2018.
30 Too much time spent with no purpose: M. A. Killingsworth and D. T. Gilbert, “A Wandering Mind Is an Unhappy Mind,” Science 330, no. 6006 (2010): 932.
31 25 and 40 percent of people who retire reenter: N. Maestas, “Back to Work Expectations and Realizations of Work after Retirement,” Journal of Human Resources 45, no. 3 (2010): 718–748; A. Mergenthaler et al., “The Changing Nature of (Un-)Retirement in Germany: Living Conditions, Activities and Life Phases of Older Adults in Transition” (working paper); L. G. Platts et al., “Returns to Work after Retirement: A Prospective Study of Unretirement in the United Kingdom,” Ageing and Society 39, no. 3 (2019): 439–464; R. Kanabar, “Unretirement in England: An Empirical Perspective” (discussion paper, Department of Economics and Related Studies, University of York, 2012).
32 Harvard economist Nicole Maestas says: Quoted in P. Span, “When Retirement Doesn’t Quite Work Out,” The New York Times , April 3, 2018, p. D5.
38 intergenerational choir: P. B. Harris and C. A. Caporella, “Making a University Community More Dementia Friendly through Participation in an Intergenerational Choir,” Dementia (2018): 1471301217752209.
40 volunteers felt a greater sense of accomplishment: M. C. Carlson et al., “Impact of the Baltimore Experience Corps Trial on Cortical and Hippocampal Volumes,” Alzheimer’s and Dementia 11, no. 11 (2015): 1340–1348.
41 As Anaïs Nin observed: C. A. Dingle, Memorable Quotations: French Writers of the Past (iUniverse, 2000), p. 126.
42 South African writer J. M. Coetzee: J. M. Coetzee, Disgrace (New York: Viking, 1999).
43 nonpersonal care: S. Duffy and T. H. Lee, “In-Person Health Care as Option B,” New England Journal of Medicine 378, no. 2 (2018): 104–106.
44 increased continuity of care: D. J. P. Gray et al., “Continuity of Care with Doctors—A Matter of Life and Death? A Systematic Review of Continuity of Care and Mortality,” BMJ Open 8, no. 6 (2018): e021161.
46 Dr. Eduardo Dolhun … ideal doctor-patient relationship: E. Dolhun, personal communication, July 9, 2013.
47 specialization tends to divide: R. Yeravdekar, V. R. Yeravdekar, and M. A. Tutakne, “Family Physicians: Importance and Relevance,” Journal of the Indian Medical Association 110, no. 7 (2012): 490–493.
49 patient-centered medical home: G. L. Jackson et al., “The Patient-Centered Medical Home: A Systematic Review,” Annals of Internal Medicine 158, no. 3 (2013): 169–178; Patient-Centered Primary Care Collaborative, “Defining the Medical Home,” https://www.pcpcc.org/about/medical-home ; K. C. Stange et al., “Defining and Measuring the Patient-Centered Medical Home,” Journal of General Internal Medicine 25, no. 6 (2010): 601–612; The Commonwealth Fund, “Primary Care: Our First Line of Defense,” June 12, 2013, https://www.commonwealthfund.org/publications/publication/2013/jun/primary-care-our-first-line-defense .
50 Dr. Gordon Caldwell: G. Caldwell, personal communication, March 27, 2019.
52 Argentum … “Assisted Living”: Argentum, “Senior Living Innovation Series: Memory Care” (white paper, 2016). Full disclosure: Argentum paid me to speak at their annual meeting, but I wrote this section before they invited me, and the invitation did not influence my decision to include them in this book.
55 HospitalInspections.org :The New York Times , August 22, 2016, p. A3.
58 an advance medical directive for dementia: P. Span, “One Day Your Mind May Fade. But You Can Plan Ahead,” The New York Times , January 23, 2018, p. D5; Dr. Gaster’s advance directive is available here: Advance Directive for Dementia, https://dementia-directive.org/ .
59 Gaster underscores the uniqueness of dementia: B. Gaster, E. B. Larson, and J. R. Curtis, “Advance Directives for Dementia: Meeting a Unique Challenge,” Journal of the American Medical Association 318, no. 22 (2017): 2175–2176.
60 says Gloria Steinem: G. Steinem, “Into the Seventies,” in Aging: An Apprenticeship , ed. N. Narboe, p. 177 (Portland, OR: Red Notebook Press, 2017).
63 Aversive experiences … nature: Environment and Behavior 50, no. 6 (2018): 599–625.
64 Patients who experienced VR scenes of nature: Tanja-Dijkstra et al., “The Soothing Sea.”
65 natural sounds: T. O. Iyendo, “Exploring the Effect of Sound and Music on Health in Hospital Settings: A Narrative Review,” International Journal of Nursing Studies 63 (2016): 82–100.
68 The TriPoint Medical Center: J. Ference, “Nature’s Calming Influence,” Health Facilities Management 23, no. 7 (2010): 44.
69 Rachel Clarke: R. Clarke, “In Life’s Last Moments, Open a Window,” The New York Times , September 9, 2018, p. SR7.
71 The playwright Dennis Potter: Quoted in J. Rockwell, “Dennis Potter’s Last Interview, on ‘Nowness’ and His Work,” The New York Times , June 12, 1994, p. 2002030.
73 A study from the Karolinska Institute: L. Fratiglioni et al., “Influence of Social Network on Occurrence of Dementia: A Community-Based Longitudinal Study,” Lancet 355, no. 9212 (2000): 1315–1319.
74 Gratitude: S. Ni et al., “Effect of Gratitude on Loneliness of Chinese College Students: Social Support as a Mediator,” Social Behavior and Personality 43, no. 4 (2015): 559–566.
75 Placido Domingo: Quoted in J. Barone, “Placido Domingo Nears the Unthinkable,” The New York Times , August 23, 2018, p. C1.
76 T. Boone Pickens: As told to Camille Sweeney in Lapham, “Old Masters.”
77 Individual strivings for accomplishment: H. S. Friedman and M. L. Kern, “Personality, Well-Being, and Health,” Annual Reviews of Psychology 65 (2014): 719–742.
79 three-quarters of the people over seventy-five: G. Vradenburg, personal communication, March 28, 2019. Vradenburg is the CEO of USAgainstAlzheimer’s.
80 Gloria Steinem: G. Steinem, Boston Speaker Series: Gloria Steinem , Boston Speakers Series, Boston, MA, January 9, 2019.