NOTES

PROLOGUE: THE MOUSE STUDY THAT ROARED

 

2 published that day by the journal: J. A. Baur et al., “Resveratrol improves health and survival of mice on a high-calorie diet,” Nature 444 (2006): 337- 42.

 

1: THE WILD OLD WICKED MYSTERY OF AGING

 

7 The “strange second puberty”: See D. Wyndham, “Versemaking and Lovemaking—W. B. Yeats’ ‘Strange Second Puberty’: Norman Haire and the Steinach Rejuvenation Operation,” Journal of the History of the Behavioral Sciences 39 (2003): 25-50; and Brenda Maddox, Yeats’s Ghosts: The Secret Life of W. B. Yeats (New York: HarperCollins, 1999), 277-81.

7 he enthused to his publisher: As cited in Ann Saddlemyer, Becoming George: The Life of Mrs. W. B. Yeats (Oxford: Oxford University Press, 2002), 476.

7 he wrote fifty poems: See Wyndham, “Versemaking and Lovemaking—W. B. Yeats’ ‘Strange Second Puberty’: Norman Haire and the Steinach Rejuvenation Operation,” Journal of the History of the Behavioral Sciences.

8 elicited ridicule: Ibid.

8 Sigmund Freud: See A. Kahn, “Regaining Lost Youth: The Controversial and Colorful Beginnings of Hormone Replacement Therapy in Aging,” Journals of Gerontology: Biological Sciences 60A (2005): 142-47; and C. Sengoopta, “ ‘Dr. Steinach coming to make old young!’: sex glands, vasectomy and the quest for rejuvenation in the roaring twenties,” Endeavour 27 (2003): 122-26.

8 inspired stranger things: Ibid.

10 Peter Medawar: Biographical material on Medawar was drawn from his autobiography, Peter Medawar, Memoir of a Thinking Radish (Oxford & New York: Oxford University Press, 1986), and a memoir by Medawar’s wife, Jean Medawar, A Very Decided Preference: Life with Peter Medawar (New York & London: W. W. Norton & Co., 1990).

11 Haldane’s approval: See B. Charlesworth, “John Maynard Smith: January 6, 1920- April 19, 2004,” Genetics 168 (2004): 1105- 9.

11 gave pride of place: Peter Medawar, The Uniqueness of the Individual (New York: Basic Books, 1957).

11 the blind watchmaker: Richard Dawkins, The Blind Watchmaker: Why the Evidence of Evolution Reveals a Universe Without Design (New York: W. W. Norton & Co., 1987).

12 a certain morbid fascination: See Robert Arking, Biology of Aging: Observations and Principles, 2nd ed. (Sunderland, MA: Sinauer Associates, 1998).

12 cadre of brilliant evolutionary thinkers: See Mark Ridley, Evolution, 3rd ed. (Oxford: Blackwell Publishing, 2004), 14-19.

12 Alex Comfort: See Claire Rayner, “Alex Comfort: Dazzling intellectual whose prolific output of novels, poetry and philosophy remains overshadowed by a sex manual,” Guardian, March 28, 2000.

12 Austad has suggested: Steven N. Austad, Why We Age: What Science Is Discovering about the Body’s Journey through Life (New York: John Wiley & Sons, 1997), 98.

14 E. Ray Lankester: E. Ray Lankester, On Comparative Longevity in Man and the Lower Animals (London: Macmillan & Co., 1870).

14 350-pound, 19-foot pike: Ibid., 57.

14 negligible senescence: See Caleb E. Finch, Longevity, Senescence, and the Genome (Chicago: University of Chicago Press, 1994), 134 and 206-36. See also John C. Guerin’s Web site on negligible senescence at http://www.agelessanimals.org/.

14 Ming the Clam: Richard Alleyne, “Clam, 405, is oldest animal ever,” The Daily Telegraph, October 31, 2007.

14 bowhead whales: James Meek, “The old man of the sea,” Guardian, November 17, 2000. See also J. C. George et al., “Age and growth estimates of bowhead whales (Balaena mysticetus) via aspartic acid racemization,” Canadian Journal of Zoology 77 (1999): 571-80.

15 pine named Methuselah: Finch, Longevity, Senescence, and the Genome, 229.

15 George C. Williams has pointed out: G. C. Williams, “Pleiotropy, natural selection, and the evolution of senescence,” Evolution 11 (1957): 398-411.

15 fact that Darwin himself: See B. Charlesworth, “Fisher, Medawar, Hamilton and the Evolution of Aging,” Genetics 156 (2000): 927-31.

15 vestiges of their dead ideas: See L. A. Gavrilov and N. S. Gavrilova, “Evolutionary Theories of Aging and Longevity,” The Scientific World 2 (2002): 339-56.

15 In a note he jotted: As quoted in Finch, Longevity, Senescence, and the Genome, 669-70.

16 August Weismann: See “August Freidrich Leopold Weismann,” Encyclopedia of World Biography, 2nd ed. (Farmington Hills, MI: Gale Group, 1997).

16 Echoing Wallace: August Weismann, “The Duration of Life,” Essays Upon Heredity and Kindred Biological Problems (Oxford: Clarendon Press, 1891).

16 young biologists of the day: See Gavrilov and Gavrilova, “Evolutionary Theories of Aging and Longevity,” The Scientific World.

16 lost his early enthusiasm: See Michael R. Rose, Evolutionary Biology of Aging (New York: Oxford University Press, 1991), 6-7.

16 theorists on gerontology’s fringe: See, for example, J. T. Bowles, “Shattered: Medawar’s test tubes and their enduring legacy of chaos,” Journal of Medical Hypotheses 54 (2000): 326-39.

16 highlighted the blunder: Medawar, “Old Age and Natural Death,” The Uniqueness of the Individual, 3.

17 his alternative theory: Medawar, “An Unsolved Problem of Biology,” The Uniqueness of the Individual, 43-48.

18 Robert Arking neatly put it: Arking, Biology of Aging: Observations and Principles, 112.

18 public talk at the: See John Brockman, “George C. Williams: A Package of Information,” The Third Culture: Beyond the Scientific Revolution (New York: Simon & Schuster, 1995).

18 Echoing Weismann: See R. G. Winther, “An obstacle to unification in biological social science: Formal and compositional styles of science,” Graduate Journal of Social Science 2 (2005).

19 a 1966 book: George C. Williams, Adaptation and Natural Selection: A Critique of Some Current Evolutionary Thought (Princeton, NJ: Princeton University Press, 1966).

19 a 1957 paper: Williams, “Pleiotropy, natural selection, and the evolution of senescence,” Evolution.

19 The son of a banker: Personal communication, Doris Williams.

20 Emerson “was all in favor of death”: See Brockman, “George C. Williams: A Package of Information,” The Third Culture: Beyond the Scientific Revolution.

20 Emerson was no lightweight: E. O. Wilson and C. D. Michener, “Alfred Edwards Emerson,” Biographical Memoirs, vol. 53 (Washington, DC: National Academies Press, 1982): 159-77.

20 1871 book: Charles Darwin, The Descent of Man, and Selection in Relation to Sex (London: John Murray, 1871).

20 Quaker-inspired pacifism: See R. Tobey, “Political Context of Scientific Thought,” Reviews in American History 22 (1994): 277-82.

21 essence of Williams’s theory: Williams, “Pleiotropy, natural selection, and the evolution of senescence,” Evolution.

22 “I predict that no human”: Ibid.

23 “this conclusion banishes”: Ibid.

23 February evening in 1977: Biographical details on Kirkwood were drawn from Tom Kirkwood, Time of Our Lives: The Science of Human Aging (New York: Oxford University Press, 1999). See also T. B. L. Kirkwood, “Evolution of ageing,” Nature 270 (1977): 301-4.

24 Kirkwood and a colleague, Robin Holliday: T. B. Kirkwood and R. Holliday, “The evolution of ageing and longevity,” Proceedings of the Royal Society B: Biological Sciences 205 (1979): 531-46. See also T. B. L. Kirkwood and M. R. Rose, “Evolution of Senescence: late survival sacrificed for reproduction,” Philosophical Transactions of the Royal Society B: Biological Sciences 332 (1991): 15-24.

25 landmark study in the late 1970s: See Rose, The Long Tomorrow: How Advances in Evolutionary Biology Can Help Us Postpone Aging (New York: Oxford University Press, 2005), 39-45.

25 Writing about it later: Ibid.

26 “scientific porn”: See “Pieces of the Puzzle: An Interview with Leonid A. Gavrilov, Ph.D.,” Journal of Anti-Aging Medicine 5 (2002): 255-63.

26 Looking into the future: Medawar, Memoir of a Thinking Radish, 197-98.

 

CHAPTER 2: RADICALS RISE UP

 

27 drugs he’d invented: S. Melov et. al., “Extension of life-span with superoxide dismutase/catalase mimetics,” Science 289 (2000): 1567-69.

27 trained in his native France: Lewis D. Solomon, The Quest for Human Longevity (New Brunswick, NJ: Transaction Publishers, 2006): 61-71.

28 we buy it: See “300% Growth in Antioxidant Food and Drink Products in Five Years as Consumers Fight Age,” NewswireToday, July 27, 2007.

29 press release: Press release jointly issued by Eukarion and the Buck Institute, “First Successful Use of Drugs to Extend Life Span,” August 2000.

29 media loved it: See “Worm has turned in anti-aging fight,” Belfast Telegraph, September 1, 2000; Mark Henderson, “Humble worm holds secret of eternal youth,” The Times (London), September 1, 2000; Grace Mclean, “Worms could help us all to wriggle out of old age,” Daily Record (Glasgow), September 1, 2000; Laura Johannes, “Worm Study May Aid Research on Aging,” Wall Street Journal, Section B, September 1, 2000; Ellen Licking, “Longer Life—For Worms,” BusinessWeek, September 11, 2000.

29 Canadian radio talk show: Personal communication, Bernard Malfroy.

30 interview with the British newspaper: James Meek, “New drug for longer life,” Guardian (London), June 30, 2001: 1.

30 nematodes get old: See online article by B. M. Zuckerman and S. Himmelhock, “Nematodes as models to study aging,” http://www.wormbase.org.

31 Denham Harman: Biographical details on Harman drawn from personal communication, Denham Harman; and from K. Kitani and G. O. Ivy, “I thought, thought, thought for four months in vain and suddenly the idea came—an interview with Denham and Helen Harman,” Biogerontology 4 (2003): 401-12.

32 a Russian scientist: See “Bogomolets & the Longer Life,” Time, June 17, 1946.

33 free radical: For more on free radicals, see Nick Lane, Oxygen: The Molecule That Made the World (Oxford: Oxford University Press, 2002).

34 led by Rebeca Gerschman: R. Gerschman et al., “Oxygen Poisoning and X-irradiation: A Mechanism in Common,” Science 119 (1954): 623-26.

34 Barry Commoner: B. Commoner et al., “Free radicals in biological materials,” Nature 174 (1954): 689-91.

35 molecules as ephemeral: See K. J. A. Davies and W. A. Pryor, “The evolution of Free Radical Biology & Medicine: A 20-year history,” Free Radical Biology & Medicine 39 (2005): 1263-64.

35 In 1956 Harman first presented: D. Harman, “Aging: A theory based on free radical and radiation chemistry,” Journals of Gerontology 11 (1956): 298-300.

36 blue-green protein: See I. Fridovich, “The trail to superoxide dismutase,” Protein Science 7 (1998): 2688-90.

36 “children with a new toy”: Ibid.

36 impossibly fast rate: See Lane, Oxygen: The MoleculeThat Made the World, 201.

36 it became clear: See Fridovich, “The trail to superoxide dismutase,” Protein Science.

36 like tiny dragons, spit superoxide: Ibid.

37 feeding antioxidants: See D. Harman, “Free radical theory of aging: dietary implications,” American Journal of Clinical Nutrition 25 (1972): 839-43.

37 Comfort reported: A. Comfort et. al., “Effect of ethoxyquin on the longevity of C3H mice,” Nature 229 (1971): 254-55.

37 large daily doses: Medawar, Memoir of a Thinking Radish, 201. 37 data were mixed: See Harman, “Free radical theory of aging: dietary implications,” American Journal of Clinical Nutrition.

38 Harman acknowledged: Kitani and Ivy, “I thought, thought, thought for four months in vain and suddenly the idea came—an interview with Denham and Helen Harman,” Biogerontology.

39 may well age faster: See S. N. Austad and D. M. Kristan, “Are mice calorically restricted in nature?” Aging Cell 2 (2003): 201-7.

39 second big idea: D. Harman, “The biologic clock: the mitochondria?” Journal of the American Geriatrics Society 20 (1972): 145-47; and Harman, “The aging process,” Proceedings of the National Academy of Sciences (hereafter, PNAS) 78 (1981): 7124-28.

40 theory was later honed: See T. Ozawa, “Mitochondrial DNA Mutations and Age,” in Towards Prolongation of the Healthy Lifespan: Practical Approaches to Intervention, ed. D. Harman, R. Holliday, and M. Meydani (New York: New York Academy of Sciences, 1998).

40 Ozawa and colleagues: M. K. Hayakawa et al., “Age-related extensive fragmentation of mitochondrial DNA into minicircles,” Biochemical and Biophysical Research Communications 226 (1996): 369-77.

40 Stadtman: E. R. Stadtman, “Protein Oxidation and Aging,” Science 257 (1991): 1220-24.

41 Other biotechs were riding: See Aeolus form S-1 filed with the SEC on June 7, 2007; Christopher Tritto, “Say Goodbye to Metaphore,” St. Louis Business Journal, December 16, 2005; and http://juvenon.com/.

41 idea didn’t pan out: B. J. Day, “Catalytic antioxidants: a radical approach to new therapeutics,” Drug Discovery Today 9 (2004): 557-66.

41 seed idea for Eukarion’s: Personal communication, Bernard Malfroy.

43 Catch-22 problem: Personal communication, Bernard Malfroy; and “Modex Announces Licensing Agreement with Eukarion for a Small Molecule to Treat Radiation-Induced Skin Damage,” Business Wire, October 5, 2001.

43 compounds failed: A. C. Bayne and R. S. Sohal, “Effects of superoxide dismutase/catalase mimetics on life span and oxidative stress resistance in the housefly, Musca domestica,” Free Radical Biology & Medicine 32 (2002): 1229- 34; and M. Keaney and D. Gems, “No increase in lifespan in Caenorhabditis elegans upon treatment with the superoxide dismutase mimetic EUK-8,” Free Radical Biology & Medicine 34 (2003): 277-82.

43 encouraging data: S. R. Doctrow et al., “Salen manganese complexes: Multifunctional catalytic antioxidants protective in models for neurodegenerative diseases of aging,” in ACS Symposium Series (Washington, DC: American Chemical Society, 2005): 319-47.

43 2003 mouse study: R. Liu et al., “Reversal of age-related learning deficits and brain oxidative stress in mice with superoxide dismutase/catalase mimetics,” PNAS 100 (2003): 8526-31.

44 early April 2002: Personal communication, Bernard Malfroy.

44 Boston Business Journal: “Australian firm snaps up Eukarion,” Boston Business Journal, December 17, 2004.

44 deal also included: Personal communication, Bernard Malfroy.

45 drug candidate failed: See Christopher Tritto, “Say Goodbye to Metaphore,” St. Louis Business Journal, December 16, 2005; and “ActivBiotics’ Intellectual Property Assets, Including Drug Product Candidates, Sold for $3.5 Million,” PRNewswire, April 2, 2008.

45 Aeolus: Aeolus press release, 2007.

45 controversy ignited: See L. Pauling, “Evolution and the Need for Ascorbic Acid,” PNAS 67 (1970): 1643-48; L. Pauling, “Are Recommended Daily Allowances for Vitamin C Adequate?” PNAS 71 (1974): 4442-46; and Lane, Oxygen: The Molecule That Made the World, 171-93.

47 abet free radical damage: See B. Halliwell, “Vitamin C: antioxidant or pro-oxidant in vivo?” Free Radical Research 25 (1996): 439-54.

47 iron plus vitamin C: See A. E. Fisher and D. P. Naughton, “Iron supplements: the quick fix with long-term consequences,” Nutrition Journal 3 (2004): 2; and A. E. Fisher and D. P. Naughton, “Vitamin C contributes to inflammation via radical generating mechanisms: a cautionary note,” Medical Hypotheses 61 (2003): 657-60.

47 large doses of vitamin C: M. Khassaf et al., “Effect of vitamin C supplements on antioxidant defence and stress proteins in human lymphocytes and skeletal muscle,” Journal of Physiology 549 (part 2, 2003): 645-52.

47 cited such interference: G. Bjelakovic et al., “Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention,” Journal of the American Medical Association 297 (2007): 842-57.

48 four major clinical studies: See E. Guallar et al., “An Editorial Update: Annus horribilis for Vitamin E,” Annals of Internal Medicine 143 (2005): 143- 45.

49 Big Idea, Version 3.0: See J. H. Chen et al., “DNA damage, cellular senescence and organismal ageing: causal or correlative?” Nucleic Acids Research 35 (2007): 7417-28; K. C. Kregel and H. J. Zhang, “An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations,” American Journal of Physiology, Regulatory, Integrative and Comparative Physiology 292 (2007): R18-36; and Caleb E. Finch, The Biology of Human Longevity: Inflammation, Nutrition, and Aging in the Evolution of Lifespans (Burlington, MA: Academic Press, 2007).

50 picture is murkier: See S. E. Schriner et al., “Extension of murine life span by overexpression of catalase targeted to mitochondria,” Science 308 (2005): 1909-11; and Y. C. Jan et al., “Overexpression of Mn Superoxide Dismutase Does Not Increase Life Span in Mice,” Journals of Gerontology Series A, July 24, 2009.

 

3: HAGRID’S BAT AND THE SABER-TOOTHED SAUSAGE

 

52 finding made it: A. J. Podlutsky et al., “A New Field Record for Bat Longevity,” Journals of Gerontology 60A (2005): 1366-68.

52 the longevity quotient: S. N. Austad and K. E. Fischer, “Mammalian Aging, Metabolism, and Ecology: Evidence from the Bats and Marsupials,” Journals of Gerontology 46 (1991): B47-53.

52 fit the usual pattern: See Austad, Why We Age, 85; and R. Buffenstein, “Negligible senescence in the longest living rodent, the naked mole-rat: insights from a successfully aging species,” Journal of Comparative Physiology B 178 (2008): 439-45.

53 more interesting explanation: Williams, “Pleiotropy, natural selection, and the evolution of senescence,” Evolution.

54 133 species of bats: See A. K. Brunet-Rossinni and S. N. Austad, “Aging studies on bats: a review,” Biogerontology 5 (2004): 211-22.

54 best predictor of long life span: G. S. Wilkinson and J. M. South, “Life history, ecology and longevity in bats,” Aging Cell 1 (2002): 124-31.

57 tracking opossums: S. N. Austad, “Retarded senescence in an insular population of Virgina opossums,” Journal of Zoology 229 (1993): 695-708.

59 theory also handily explained: J. Miquel et al., “Effects of temperature on the life span, vitality and fine structure of Drosophila melanogaster,” Mechanisms of Ageing and Development 5 (1976): 347-70.

59 Max Rubner: See Austad, Why We Age, 72-73.

59 cells of a rhinoceros: See A. J. Hulbert and P. L. Else, “Membranes and the setting of energy demand,” Journal of Experimental Biology 208 (2005): 1593- 99.

59 Raymond Pearl: See Austad, Why We Age, 76-78.

60 honeybees were forced: T. J. Wolf and P. Schmid-Hempel, “Extra loads and foraging lifespan in honeybee workers,” Journal of Animal Ecology 58 (1989): 943-54.

60 Austad and a colleague highlighted: Austad and Fischer, “Mammalian Aging, Metabolism, and Ecology: Evidence from the Bats and Marsupials,” Journals of Gerontology.

61 In 1980, researchers reported: J. M. Tolmasoff et al., “Superoxide dismutase: Correlation with life-span and specific metabolic rate in primate species,” PNAS 77 (1980): 2777-81.

61 study led by Rajindar Sohal: R. S. Sohal et al., “Relationship between antioxidant defenses and longevity in different mammalian species,” Mechanisms of Ageing and Development 3 (1990): 217-27.

61 research by Gustavo Barja: M. Lopez-Torres et al., “Maximum life span in vertebrates: Relationship with liver antioxidant enzymes, glutathione system, ascobate, urate, sensitivity to peroxidation, true malondialdehyde, in vivo H2O2, and basal and maximum aerobic capacity,” Mechanisms of Ageing and Development 70 (1993): 177-99.

62 Checking it out: H. H. Ku et al., “Relationship between mitochondrial superoxide and hydrogen peroxide production and longevity of mammalian species,” Free Radical Biology & Medicine 15 (1993): 621-27; and G. Barja et al., “Low mitochondrial free radical production per unit O2 consumption can explain the simultaneous presence of longevity and high aerobic metabolic rate in birds,” Free Radical Research 21 (1994): 317-27.

62 little brown bats: A. K. Brunet-Rossinni, “Reduced free radical production and extreme longevity in the little brown bat (Myotis lucifugus) versus two non-flying mammals,” Mechanisms of Ageing and Development 125 (2004): 11- 20.

62 free- tailed bats: Brunet-Rossinni and Austad, “Aging studies on bats: a review,” Biogerontology.

62 huge amounts of sugar: D. J. Keegan, “Aspects of the assimilation of sugars by Rousettus aegyptiacus,” Comparative Biochemistry and Physiology Part A 58 (1977): 349-52.

64 Mole-rats were introduced: See J. M. Jarvis and P. W. Sherman, “Heterocephalus glaber,” Mammalian Species 706 (2002): 1-9.

64 remained little-studied: Personal communication, Rochelle Buffenstein.

64 Alexander theorized: Elizabeth Pennisi, “Not just another pretty face—naked mole rat,” Discover, March 1986.

64 went public with the idea: J. U. M. Jarvis, “Eusociality in a mammal: cooperative breeding in naked mole-rat colonies,” Science 212 (1981): 571-73.

64 up to three hundred NMRs: Jarvis and Sherman, “Heterocephalus glaber,” Mammalian Species.

66 “Milton the Mole-Rat”: Personal communication, Rochelle Buffenstein.

66 the senior consort: R. Buffenstein and J. U. M. Jarvis, “The Naked Mole Rat—A New Record for the Oldest Living Rodent,” Science of Aging Knowledge Environment, no. 21 (2002).

66 NMRs basically don’t age: T. P. O’Connor et al., “Prolonged longevity in naked mole-rats: Age-related changes in metabolism, body composition and gastrointestinal function,” Comparative Biochemistry and Physiology Part A 133 (2002): 835- 42.

67 no more likely to die: R. Buffenstein, “Negligible senescence in the longest living rodent, the naked mole-rat: insights from a successfully aging species,” Journal of Comparative Physiology B 178 (2008): 439-45.

67 in 2008 she proposed: Ibid.

67 social- insect queens: See J. D. Parker et al., “Decreased expression of Cu-Zn superoxide dismutase 1 in ants with extreme lifespan,” PNAS 101 (2004): 3486-89.

68 mystery deepened: O’Connor et al., “Prolonged longevity in naked mole-rats: Age-related changes in metabolism, body composition and gastrointestinal function,” Comparative Biochemistry and Physiology.

68 glutathione peroxidase: B. Andziak et al., “Antioxidants do not explain the disparate longevity between mice and the longest-living rodent, the naked mole-rat,” Mechanisms of Ageing and Development 126 (2005): 1206- 12.

68 NMRs’ heart mitochondria: A. J. Lambert et al., “Low rates of hydrogen peroxide production by isolated heart mitochondria associate with long maximum lifespan in vertebrate homeotherms,” Aging Cell 6 (2007): 607-18.

68 riddled with free radical: B. Andziak et al., “High oxidative damage levels in the longest- living rodent, the naked mole-rat,” Aging Cell 5 (2006): 463-71.

69 NMRs operate at: O’Connor et al., “Prolonged longevity in naked mole-rats: Age-related changes in metabolism, body composition and gastrointestinal function,” Comparative Biochemistry and Physiology.

69 low fasting blood sugar: R. Buffenstein and M. Pinto, “Endocrine function in naturally long-living small mammals,” Molecular and Cellular Endocrinology (2008), in press.

69 Egyptian fruit bats’: See Brunet-Rossinni and Austad, “Aging studies on bats: a review,” Biogerontology.

69 vampire bats’: M. B. Freitas et al., ”Effects of short-term fasting on energy reserves of vampire bats (Desmodus rotundus),” Comparative Biochemistry and Physiology B 140 (2005): 59-62.

69 Baltimore Longitudinal Study of Aging: G. S. Roth et al., “Biomarkers of caloric restriction may predict longevity in humans,” Science 297 (2002): 811.

69 shoot up by 500 percent: Personal communication, Rochelle Buffenstein.

69 Bats can rev: Brunet-Rossinni and Austad, “Aging studies on bats: a review,” Biogerontology.

70 doses of hydrogen peroxide: N. Labinskyy et al., “Comparison of endothelial function, superoxide and hydrogen peroxide production, and vascular oxidative stress resistance between the longest-living rodent, the naked mole-rat, and mice,” American Journal of Physiology—Heart and Circulatory Physiology 291 (2006): H2698-704.

70 cells from little brown bats: J. M. Harper et al., “Skin-derived fibroblasts from long-lived species are resistant to some, but not all, lethal stresses and to the mitochondrial inhibitor rotenone,” Aging Cell 6 (2006): 1-13.

70 analyzed lipids: A. J. Hulbert et al., “Oxidation-resistant membrane phospholipids can explain longevity differences among the longest-living rodents and similar-sized mice,” Journals of Gerontology Series A 61 (2006): 1009-18.

70 “membrane pacemaker” hypothesis: A. J. Hulbert, “Life, death and membrane bilayers,” Journal of Experimental Biology 206 (2003): 2302-11.

71 Chaudhuri’s assay: A. Pierce et al., “A novel approach for screening the proteome for changes in protein conformation,” Biochemistry 45 (2006): 3077-85.

71 proteins from NMRs’ liver cells: V. I. Perez et al., “Protein stability and resistance to oxidative stress are determinants of longevity in the longest-living rodent, the naked mole-rat,” PNAS 106 (2009): 3059-64.

71 Proteins from long-lived bats: A. B. Salmon et al., “The long lifespan of two bat species is correlated with resistance to protein oxidation and enhanced protein homeostasis,” Journal of the American Federation of Societies for Experimental Biology, February 24, 2009.

71 implanting a gene: C. J. Cretekos et al., “Regulatory divergence modifies limb length between mammals,” Genes & Development 22 (2008): 141-51.

 

4: THE GENES THAT COULDN’T BE

 

73 great minds: C. Cerf and V. Navasky, The Experts Speak: The Definitive Compendium of Authoritative Misinformation (New York: Pantheon Books, 1984).

74 Highlighting this point: S. J. Olshansky et al., “In search of Methuselah: estimating the upper limits to human longevity,” Science 250 (1990): 634- 40.

74 One estimate: Rose, The Long Tomorrow: How Advances in Evolutionary Biology Can Help Us Postpone Aging, 97.

74 A more formidable number: G. M. Martin, “Genetic syndromes in man with potential relevance to the pathobiology of aging,” Birth Defects: Original Articles Series 14 (1978): 5-39.

76 history of nematode research: Andrew Brown, In the Beginning Was the Worm (New York: Columbia University, 2003).

76 fanciers have found it: See D. R. Denver et al., “Phylogenetics in Caenorhabditis elegans: An Analysis of Divergence and Outcrossing,” Molecular Biology and Evolution 20 (2003): 393-400.

76 strolled into his garden: See Howard Ferris’s Web site at the University of California at Davis, http://plpnemweb.ucdavis.edu.

77 telescoping life span: See T. E. Johnson, “Subfield History: Caenorhabditis elegans as a System for Analysis of the Genetics of Aging,” Science of Aging Knowledge Environment, August 28, 2002.

77 appeared in Nature: M. Klass and D. Hirsh, “Non-ageing developmental variant of Caenorhabditis elegans,” Nature 260 (1976): 523-25.

78 In 1983, he reported: M. R. Klass, “A method for the isolation of longevity mutants in the nematode Caenorhabditis elegans and initial results,” Mechanisms of Ageing and Development 22 (1983): 279-86.

79 Johnson had gotten interested: Personal communication, Tom Johnson.

81 paper was accepted: D. B. Friedman and T. E. Johnson, “A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility,” Genetics 118 (1988): 75-86.

82 study finally appeared: T. E. Johnson, “Increased life-span of age-1 mutants in Caenorhabditis elegans and lower Gompertz rate of aging,” Science 249 (1990): 4908-12.

82 there was little excitement: Personal communication, Gary Ruvkun.

83 report boldly concluded: C. Kenyon et al., “A C. elegans mutant that lives twice as long as wild type,” Nature 366 (1993): 404-5.

83 Scientific American Frontiers: Alda’s interview in 2000 with Kenyon is at http://www.pbs.org/saf/transcripts/transcript1003.htm.

84 A bookish polymath: Biographical details on Kenyon were drawn from personal communication; Alex Crevar, “As the Worm Turns,” Georgia Magazine, 2004; and Stephen S. Hall, Merchants of Immortality: Chasing the Dream of Human Life Extension (Boston: Houghton Mifflin Company, 2003).

85 They publicized the finding: Worm Breeder’s Gazette, vol. 12, no. 3, June 15, 1992.

85 a gene called daf-23: S. Gottlieb and G. Ruvkun, “Daf-2, daf-16 and daf-23: genetically interacting genes controlling Dauer formation in Caenorhabditis elegans,” Genetics 137 (1994): 107-20.

85 researcher James Thomas: Personal communication, Gary Ruvkun.

86 A tall, droll, avuncular man: Biographical details on Gary Ruvkun drawn from personal communication, Gary Ruvkun; and Ingfei Chen, “The Drifter,” Science of Aging Knowledge Environment, October 23, 2003.

87 his lab sifted: J. Z. Morris et al., “A phosphatidylinositol-2-OH kinase family member regulation longevity and diapause in Caenorhabditis elegans,” Nature 382 (1996): 536-39.

87 mom-wowing gerontogene discovery: K. D. Kimura et al., “daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans,” Science 277 (1997): 942-46.

88 Japanese study: H. Kim et. al., “Detection of mutations in the insulin receptor gene in patients with insulin resistance by analysis of single-stranded conformational polymorphisms,” Diabetologia 35 (1992): 261-66.

88 record would later show: S. Ogg et al., “The Forkhead transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans,” Nature 389 (1997): 994-99; and K. Lin et al., “daf-16: An HNF-2/forkhead family member that can function to double the life-span of Caenorhabditis elegans,” Science 278 (1997): 1319-22.

89 the Rome of aging genes: See S. S. Lee et al., “DAF-16 target genes that control C. elegans life-span and metabolism,” Science 300 (2003): 644-47.

89 a gene, dubbed “methuselah”: Y. J. Lin et al., “Extended life-span and stress resistance in the Drosophila mutant Methuselah,” Science 282 (1998): 943- 46.

89 Leonard Hayflick: L. Hayflick, “‘Anti- Aging’ Is an Oxymoron,” Journals of Gerontology, Series A 59 (2004): 573-78.

90 one of the subtexts: See L. Partridge and D. Gems, “Beyond the evolutionary theory of ageing, from functional genomics to evo-gero,” Trends in Ecology and Evolution 21 (2006): 334-40.

90 a 2000 study: D. W. Walker et al., “Evolution of lifespan in C. elegans,” Nature 405 (2000): 296-97.

91 among the first to shed light: J. R. Vanfleteren, “Oxidative stress and ageing in Caenorhabditis elegans,” Biochemistry Journal 292 (1993): 605-8; and P. L. Larsen, “Aging and resistance to oxidative damage in Caenorhabditis elegans,” PNAS 90 (1993): 8905-9.

91 resistant to heat stress: G. J. Lithgow et al., “Thermotolerance of a long-lived mutant of Caenorhabditis elegans,” Journals of Gerontology: Biological Sciences 49 (1994): B270-76.

92 worms’ smell and taste: J. Apfeld and C. Kenyon, “Regulation of lifespan by sensory perception in Caenorhabditis elegans,” Nature 402 (1999): 804- 9.

92 GenoPlex lasted: Personal communication, Tom Johnson.

 

5: THE REALLY STRANGE THING ABOUT DWARFS

 

94 a Buddhist priest: Mitosi Tokuda, “An Eighteenth Century Japanese GuideBook on Mouse-Breeding,” Journal of Heredity 26 (1935): 481-84.

95 rage for “fancy” mice: For details on the history of lab mice, see Lee M. Silver, Mouse Genetics: Concepts and Applications (Oxford: Oxford University Press, 1995); Terri Peterson Smith, “Mouse Work,” Invention and Technology 23 (Summer 2007); and Herbert C. Morse’s historical perspective on the lab mouse at http://www.informatics.jax.org.

96 The Snell dwarf: G. D. Snell, “Dwarf, A New Mendelian Recessive Character of the House Mouse,” PNAS 15 (1929): 733-34.

96 obituary in the New York Times: “Obituary; Gen. Tom Thumb,” New York Times, July 18, 1883, 8.

97 In 1972, a study: N. Fabris et al., “Lymphocytes, Hormones and Ageing,” Nature 240 (1972): 557-59.

97 The first blow: R. Silberberg, “Articular Aging and osteoarthrosis in dwarf mice,” Pathology & Microbiology (Basel) 38 (1972): 417-30.

97 The following year: J. G. M. Shire, “Growth Hormone and Premature Ageing,” Nature 245 (1973): 215-16.

98 In 1976, Gary Schneider: G. B. Schneider, “Immunological competence in Snell-Bagg pituitary dwarf mice: response to the contact-sensitizing agent oxazolone,” American Journal of Anatomy 145 (1976): 371-93.

98 published in a now-defunct: Personal communication, Andrzej Bartke.

98 Studies in rats: See A. V. Everitt et al., “The effects of hypophysectomy and continuous food restriction, begun at ages 70 and 400 days, on collagen aging, proteinuria, incidence of pathology and longevity in the male rat,” Mechanisms of Ageing and Development 12 (1980): 161-72.

99 chapter of a 1990 book: D. E. Harrison, Genetic Effects on Aging II (Caldwell, NJ: The Telford Press, 1990): 435-56.

100 Bartke began investigating: Personal communication, Andrzej Bartke.

100 abnormally rapid brain aging: R. W. Steger et al., “Premature ageing in transgenic mice expressing different growth hormone genes,” Journal of Reproduction and Fertility (supp.) 46 (1993): 61-75.

100 German scientists reported: R. Wanke et al., “The GH transgenic mouse as an experimental model for growth research: clinical and pathological studies,” Hormone Research 3 (1992): 74-87.

101 A native of Poland: Biographical details on Bartke drawn from Ingfei Chen, “The Mouse That Roared,” Science of Aging Knowledge Environment, 2003; and personal communication, Andrzej Bartke.

102 Schaible had glanced down: Personal communication, Robert Schaible.

103 study published by the New England Journal: D. Rudman et al., “Effects of Human Growth Hormone in Men Over 60 Years Old,” New England Journal of Medicine 323 (1990): 1-6.

103 postdocs in Bartke’s lab: Personal communication, Holly Brown-Borg.

104 a spectacular 50 percent longer: H. M. Brown-Borg et al., “Dwarf mice and the ageing process,” Nature 384 (1996): 33.

104 Bartke’s heart sank: Personal communication, Andrzej Bartke.

105 Flurkey’s new study: Personal communication, Kevin Flurkey.

106 Prop-1: M. W. Sornson et al., “Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism,” Nature 384 (1996): 327-33.

107 stunted, mutant mice: K. T. Coschigano et al., “Assessment of growth parameters and life span of GHR/BP gene-disrupted mice,” Endocrinology 141 (2000): 2608-13; K. Flurkey et al., “Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production,” PNAS 98 (2001): 6736-41.

107 age with amazing grace: B. A. Kinney et al., “Evidence that age-induced decline in memory retention is delayed in growth hormone resistant GH-R-KO (Laron) mice,” Physiology and Behavior 72 (2001): 653-60; and B. A. Kinney et al., “Evidence that Ames dwarf mice age differently from their normal siblings in behavioral and learning and memory parameters,” Hormones and Behavior 39 (2001): 277-84.

107 defenses are unusually robust: H. M. Brown-Borg, “Hormonal regulation of longevity in mammals,” Ageing Research Reviews 6 (2007): 28-45.

107 fad came under fire: See “Are Claims for Growth Hormone Bulked Up?” Harvard Health Letter 24 (April 1999): 1-3; and J. Takala et al., “Increased Mortality Associated with Growth Hormone Treatment in Critically Ill Adults,” New England Journal of Medicine 341 (1999): 785-92.

107 best obituary: See Rich Miller’s home page at http://www- personal.umich.edu.

108 jointly investigated patterns: I. Dozmorov et al., “Array-based expression analysis of mouse liver genes: effect of age and of the longevity mutant Prop1df,” Journals of Gerontology Series A 56 (2001): B72-80.

108 much- cited essay: R. A. Miller, “Kleemeier award lecture: are there genes for aging?,” Journals of Geronotology Series A 54A (1999): B297-307.

109 played a leading role: See R. A. Miller et al., “Big mice die young: early life body weight predicts longevity in genetically heterogeneous mice,” Aging Cell 1 (2002): 22-29.

109 led by Norman Wolf: B. J. Deeb and N. S. Wolf, “Studying Longevity and morbidity in giant and small breeds of dogs,” Veterinary Medicine (supp.) 89 (1994): 702-13.

110 dwarf fruit flies: M. Tatar et al., “A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function,” Science 292 (2001): 107-10; and D. J. Clancy et al., “Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein,” Science 292 (2001): 104-6.

110 professional baseball players: See T. T. Samaras and L. H. Storms, “Impact of height and weight on life span,” Bulletin of the World Health Organization 70 (1992): 259-67.

110 prone to various cancers: See G. D. Batty et al., “Adult height in relation to mortality from 14 cancer sites in men in London (UK): evidence from the original Whitehall study,” Annals of Oncology 17 (2006): 157-66.

110 shorter men: See F. Kee et al., “Short Stature and Heart Disease: Nature or Nurture?” International Journal of Epidemiology 26 (1997): 748-56.

110 Laron syndrome: Z. Laron, “Laron Syndrome (Primary Growth Hormone Resistance or Insensitivity): The Personal Experience 1958-2003,” Journal of Clinical Endocrinology & Metabolism 89 (2004): 1031- 44.

110 “little people of Krk”: V. Saftic et al., “Mendelian Diseases and Conditions in Croatian Island Populations: Historic Records and New Insights,” Croatian Medical Journal 47 (2006): 543-52.

110 Munchkins: See http://www.kansasoz.com/munchkins; and Dan Barry, “No Ordinary Coroner, No Ordinary Life,” New York Times, February 18, 2007.

111 animals with low growth hormone: See H. M. Brown-Borg, “Hormonal regulation of longevity in animals,” Ageing Research Reviews, 2007.

112 lived 26 percent longer: M. Holzenberger et al., “IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice,” Nature 421 (2003): 182- 87.

112 mice with low brain levels: L. Kapeler et al., “Brain IGF-1 Receptors Control Mammalian Growth and Lifespan through a Neuroendocrine Mechanism,” PLoS Biology 6 (2008).

112 deleterious effects on learning and memory: See W. E. Sonntag et al., “Growth hormone and IGF-I modulate local cerebral glucose utilization and ATP levels in a model of adult-onset growth hormone deficiency,” American Journal of Physiology—Endocrinology and Metabolism. 291 (2006): E604-10.

112 extended the life spans of mice by 18 percent: M. Bluher et al., “Extended longevity in mice lacking the insulin receptor in adipose tissue,” Science 299 (2003): 572- 74.

113 quashed hopes: See Robert Arking, Biology of Aging, 332-33.

113 Mouse 11C: Personal communication, Andrzej Bartke; and “Time runs out for world’s oldest mouse,” Southern Illinois University press release, January 15, 2003.

 

6: THAT OLD MAGIC

 

115 Loren Reid: Biographical details on Loren Reid drawn from personal communication; and Loren Reid, Hurry Home Wednesday: Growing Up in a Small Missouri Town, 1905-1921 (Columbia, MO: University of Missouri Press, 1978).

117 famous longevity illusionist: See Austad, Why We Age: What Science Is Discovering about the Body’s Journey through Life, 1-2; and Westminster Abbey on Parr at http://www.westminster-abbey.org.

118 bitingly skeptical tome: William J. Thoms, Human Longevity: Its Facts and Fictions (London: John Murray, Albermarle Street, 1873).

118 ran a cover story: See B. J. Willcox et al., “Secrets of Healthy Aging and Longevity from Exceptional Survivors around the Globe: Lessons from Octogenarians to Supercentenarians,” Journals of Gerontology Series A 63 (2008): 1181-85; and A. Leaf, “Every day is a gift when you are over 100,” National Geographic, January 1973: 92-119.

118 rigorous studies on centenarians: See Willcox et al., “Secrets of Healthy Aging and Longevity from Exceptional Survivors around the Globe: Lessons from Octogenarians to Supercentenarians,” Journals of Gerontology Series A.

118 number of centenarians: Thomas J. Perls, Margery Hutter Silver, with John F. Lauerman, Living to 100: Lessons in Living to Your Maximum Potential at Any Age (New York: Basic Books, 1999), 10.

118 According to the Census Bureau: See http://www.census.gov; and Carl Bialik, “Living to 100 May Be Easier Than Counting Those Who’ve Made It,” Wall Street Journal, April 11, 2008.

119 Death rates of old people: R. Rau et al., “Continued Reductions in Mortality at Advanced Ages,” Population and Development Review 34 (2008): 747- 68.

119 Between 1950 and 2002: Ibid.

119 reductions in childhood infections: See C. E. Finch and E. M. Crimmins, “Inflammatory exposure and historical changes in human life-spans,” Science 305 (2004): 1736- 39.

119 before the U.S. Senate: Vaupel’s testimony can be found at http://sageke.sciencemag.org.

119 one British bookmaker: Miles Brignall and Patrick Collinson, “William Hill slashes odds on living to 100,” Guardian, April 28, 2007.

119 British writer Ronald Blythe: Ronald Blythe, The View in Winter: Reflections on Old Age (New York: Harcourt Brace Jovanovich, 1979).

120 Aristotle portrayed: The Oxford Book of Aging, ed. Thomas R. Cole and Mary G. Winkler (Oxford: Oxford University Press, 1994): 23-26.

120 historian Gerald Gruman: G. J. Gruman, “A History of Ideas about the Prolongation of Life: The Evolution of Prolongevity Hypothesis to 1800,” Transactions of the American Philosophical Society 56 (1966): 1-102.

120 the Roman poet Lucretius: Ibid.

120 Roman statesman Cicero: Ibid.

121 black humor: The Oxford Book of Aging, 68.

121 Francis Bacon: Ibid., 34-35.

121 Schopenhauer: Ibid., 41.

121 physician George Miller Beard: Thomas R. Cole, The Journey of Life: A Cultural History of Aging in America (Cambridge, UK: Cambridge University Press, 1992): 163-67.

121 novelist Anthony Trollope: Ibid., 168-70.

122 physician William Osler: Ibid., 170-74.

122 revisionist leader on aging: See Gruman, “A History of Ideas About the Prolongation of Life: The Evolution of Prolongevity Hypothesis to 1800,” Transactions of the American Philosophical Society; Luigi Cornaro, Discourses on a Sober and Temperate Life: Translated from the Italian Original (London: Benjamin White, 1768); and the biographical sketch of Cornaro at http://www.boglewood.com/cornaro/xb26.html.

124 Benjamin Franklin speculated: See Gruman, “A History of Ideas About the Prolongation of Life: The Evolution of Prolongevity Hypothesis to 1800,” Transactions of the American Philosophical Society.

124 Marquis de Condorcet: Ibid.

124 economist’s seminal work: Ibid.

125 apologists and their opponents: See L. Kass, “L’Chaim and Its Limits: Why Not Immortality,” First Things 113 (2001): 17-24.

125 modern Malthusians: See James H. Schulz and Robert H. Binstock, Aging Nation: The Economics and Politics of Growing Older in America (Baltimore: Johns Hopkins University Press, 2006).

125 remarkable statistics: J. Evert et al., “Morbidity profiles of centenarians: survivors, delayers, and escapers,” Journals of Gerontology Series A 58 (2003): 232-37.

125 In another study: S. L. Andersen et al., “Cancer in the oldest old,” Mechanisms of Ageing and Development 126 (2005): 263-67.

125 escaped major diseases: Perls, Silver, and Lauerman, Living to 100, 109.

125 don’t need to enter assisted- living: D. C. Willcox et al., “Life at the extreme limit: phenotypic characteristics of supercentenarians in Okinawa,” Journals of Gerontology Series A 63 (2008): 1201-8.

126 The upshot, says Perls: Perls, Silver, and Lauerman, Living to 100, 18.

126 nearly two-thirds of 34: M. H. Silver et al., “Cognitive functional status of age-confirmed centenarians in a population-based study,” Journals of Gerontology Series B 56 (2001): 134-40.

126 A Danish team reported: K. Andersen- Ranberg et al., “Healthy centenarians do not exist, but autonomous centenarians do: a population-based study of morbidity among Danish centenarians,” Journal of the American Geriatrics Society 49 (2001): 900-908.

126 Baltimore Longitudinal Study: See http://www.grc.nia.nih.gov.

126 “successful aging movement”: See J. W. Rowe and R. L. Kahn, “Human aging: usual and successful,” Science 237 (1987): 143-49.

127 Satchel Paige: Quoted in Schulz and Binstock, Aging Nation, 180.

127 study on Danish twins: A. M. Herskind et al., “The heritability of human longevity: a population-based study of 2872 Danish twin pairs born 1870- 1900,” Human Genetics 97 (1996): 319-23.

127 Nir Barzilai: Personal communication, Nir Barzilai.

127 New England study’s subjects: Perls, Silver, and Lauerman, Living to 100, 59.

128 none is obese: Ibid., 71.

128 Scanning local newspapers: Perls, Silver, and Lauerman, Living to 100, 130.

128 Some gerontologists dismissed: Ibid.

129 telltale analysis: T. T. Perls et al., “Life-long sustained mortality advantage of siblings of centenarians,” PNAS 99 (2002): 8442-47.

129 Two years later, Barzilai: G. Altzmon et al., “Clinical phenotype of families with longevity,” Journal of the American Geriatrics Society 52 (2004): 274-77.

129 first one was identified: F. Schachter et al., “Genetic associations with human longevity at the APOE and ACE loci,” Nature Genetics 6 (1994): 29-32.

130 Perls developed a passion: See Henry Chesbrough, “Centagenetix: Building a Business Model for Genetic Longevity,” Harvard Business School case study, 2001.

130 won a $150,000 grant: Ibid.

130 stretch of DNA on chromosome 4: A. Puca et al., “A genome-wide scan for linkage to human exceptional longevity identifies a locus on chromosome 4,” PNAS 98 (2001): 10505-8.

131 Forming the company: See Chesbrough, “Centagenetix: Building a Business Model for Genetic Longevity,” Harvard Business School case study.

131 Perls and colleagues reported: B. J. Geesaman et al., “Haplotype-based identification of a microsomal transfer protein marker associated with the human lifespan,” PNAS 100 (2003): 14115-20.

131 Danish and German teams: L. Bathum et al., “No evidence for an association between extreme longevity and Microsomal Transfer Protein polymorphisms in a longitudinal study of 1651 nonagenarians,” European Journal of Human Genetics 13 (2005): 1154-58; and A. Nebel et al., “No association between microsomal triglyceride transfer protein (MTP) haplotype and longevity in humans,” PNAS 102 (2005): 7906-9.

131 By 2008 similar doubts: See K. Christensen et al., “The quest for genetic determinants of human longevity: challenges and insights,” Nature Reviews Genetics 7 (2006): 436-48.

132 Barzilai has led the way: See http://www.aecom.yu.edu.

133 high levels of HDL: Claudia Dreifus, “A Conversation with Nir Barzilai: It’s Not the Yogurt; Looking for Longevity Genes,” New York Times, February 24, 2004.

133 protein called CETP: See G. M. Martin et al., “Genetic Determinants of Human Health Span and Life Span: Progress and New Opportunities,” PLoS Genetics 3 (2007): 1121- 30.

133 intriguing links: Y. Suh et al., “Functionally significant insulin-like growth factor I receptor mutations in centenarians,” PNAS 105 (2008): 3438- 42.

133 gene called FOXO3a: B. J. Willcox et al., “FOXO3A gentotype is strongly associated with human longevity,” PNAS 105 (2008): 13987- 92.

134 apologists warn: See Kass, “L’Chaim and Its Limits: Why Not Immortality,” First Things.

134 Tithonus: See Gruman, “A History of Ideas about the Prolongation of Life: The Evolution of Prolongevity Hypothesis to 1800,” Transactions of the American Philosophical Society.

135 cast doubt: J. F. Fries, “Aging, Natural Death, and the Compression of Morbidity,” New England Journal of Medicine 303 (1980): 130-35.

136 chronically disabled dropped: K. G. Manton et al., “Change in chronic disability from 1982 to 2004/2005 as measured by long-term changes in function and health in the U.S. elderly population,” PNAS 103 (2006): 18374- 79.

136 review of disability: G. Lafortune, G. Balestat, and the Disability Study Expert Group Members, 2007, “Trends in Severe Disability among Elderly People: Assessing the Evidence in 12 OECD Countries and Future Implications,” OECD Health Working Papers No. 26, OECD.

137 Fries has helped compile: See J. F. Fries, “Frailty, Heart Disease, and Stroke: The Compression of Morbidity Paradigm,” American Journal of Preventive Medicine 29 (2005): 164-68.

137 Americans over eighty-five rose: Manton et al., “Change in chronic disability from 1982 to 2004/2005 as measured by long-term changes in function and health in the U.S. elderly population,” PNAS.

137 Perls has reported: See V. Mor and T. T. Perls, “Measuring Functional Decline in Population Aging in a Changing World and an Evolving Biology,” Journals of Gerontology Series A 59 (2004): M609-11.

137 prevalence of such illnesses: See E. M. Crimmins, “Trends in the health of the elderly,” Annual Review of Public Health 25 (2004): 79-98.

 

7: CRACKING THE LIFE-SPAN BARRIER

 

140 his initial report: C. M. McCay and M. F. Crowell, “Prolonging the Life Span,” Scientific Monthly 39 (1934): 405-14.

140 few researchers who did study: See E. J. Masoro, “Subfield History: Calorie Restriction, Slowing Aging, and Extending Life,” Science of Aging Knowledge Environment, February 26, 2003.

140 drugs that mimic CR’s effects: See, for example, J. A. Baur et al., “Resveratrol improves health and survival of mice on a high-calorie diet,” Nature 444 (2006): 337-42; R. Strong et al., “Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice,” Aging Cell 7 (2008): 641-50; and V. Wanke et al., “Caffeine extends yeast lifespan by targeting TORC1,” Molecular Microbiology 69 (2008): 277-85.

140 In 2005, the RAND: D. P. Goldman et al., “Consequences of Health Trends and Medical Innovation for the Future Elderly,” at http://content.healthaffairs.org.

141 Born in 1898: Biographical details on McCay drawn from J. K. Loosli, “Clive Maine McCay (1898-1967)—a biographical sketch,” Journal of Nutrition 103 (1973): 1-10; and W. Shurtleff and A. Aoyagi, “Clive and Jeanette McCay, and The New York State Emergency Food Commission: Work with Soy,” Soyinfo Center, unpublished manuscript.

142 known for landmark studies: T. B. Osborne et al., “The effect of retardation of growth upon the breeding period and duration of life in rats,” Science 45 (1917): 294-95; and T. B. Osborne and L. B. Mendel, “The Resumption of Growth after Long Continued Failure to Grow,” Journal of Biological Chemistry 23 (1915): 439-54.

142 McCay asked his mentor: Loosli, “Clive Maine McCay (1898-1967)—a biographical sketch,” 4.

142 fish on a low-protein: C. M. McCay et al., “Growth Rates of Brook Trout Reared upon Purified Rations,” Journal of Nutrition 1 (1929), 233.

143 Cornaro’s meager diet: C. M. McCay, “Effect of Restricted Feeding upon Aging and Chronic Diseases in Rats and Dogs,” American Journal of Public Health 37 (1947): 521-28.

143 immunologist Carlo Moreschi: Ibid., 523.

143 Peyton Rous: P. Rous, “The influence of diet on transplant and spontaneous tumors,” Journal of Experimental Medicine 20 (1914): 433-51.

143 fast-growing mice live longer: T. B. Robertson and L. A. Ray, “On the growth of relatively long lived compared with that of relatively short lived animals,” Journal of Biological Chemistry 42 (1920), 71-107.

143 Buffon theorized: McCay, Crowell, “Prolonging the Life Span,” 410.

143 Researchers exploded it: R. Weindruch and R. L. Walford, “Dietary restriction in mice beginning at 1 year of age: effects on lifespan and spontaneous cancer incidence,” Science 215 (1982): 1415-18.

143 McCay got a lot right: C. M. McCay et al., “The Effect of Retarded Growth upon the Length of Life Span and upon the Ultimate Body Size,” Journal of Nutrition 10 (1935): 63-79.

143 food-restricted females died: Ibid., 70.

144 male data were as clear: Ibid., 71.

144 the following decade: See C. M. McCay et al., “Experimental Prolongation of the Life Span,” Bulletin of the New York Academy of Medicine 32 (1956): 91-101; and McCay, “Effect of Restricted Feeding upon Aging and Chronic Diseases in Rats and Dogs.”

144 1940s and after: See McCay, “Effect of Restricted Feeding upon Aging and Chronic Diseases in Rats and Dogs”; and Loosli, “Clive Maine McCay (1898-1967)—a biographical sketch.”

146 life expectancy would climb: J. R. Speakman and C. Hambly, “Starving for Life: What Animal Studies Can and Cannot Tell Us about the Use of Caloric Restriction to Prolong Human Lifespan,” Journal of Nutrition 137 (2007): 1078- 86.

146 group of prominent gerontologists: S. J. Olshansky et al., “The Longevity Dividend,” The Scientist 20 (March 2006), 28.

146 Mediterranean fruit flies: J. R. Carey et al., “Life history response of Mediterranean fruit flies to dietary restriction,” Aging Cell 1 (2002): 140-48.

146 mice called DBA/2: Finch, The Biology of Human Longevity, 227.

146 list of CR responders: E. J. Masoro, “Dietary restriction-induced life extension: a broadly based biological phenomenon,” Biogerontology 7 (2006): 153-55.

146 methionine: See R. A. Miller et al., “Methionine- deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-1 and insuline levels, and increases hepatocyte MIF levels and stress resistance,” Aging Cell 4 (2005): 119-25.

147 51 percent of elderly female: R. T. Bronson and R. D. Lipman, “Reduction in Rate of Occurrence of Age Related Lesions in Dietary Restricted Laboratory Mice,” Growth, Development and Aging 55 (1991): 169-84.

147 suppress tumors: Finch, The Biology of Human Longevity, 185.

147 McCay reported: McCay, “Effect of Restricted Feeding upon Aging and Chronic Diseases in Rats and Dogs,” 525.

147 representative rat study: P. H. Duffy et al., “The effects of different levels of dietary restriction on non-neoplastic diseases in male Sprague-Dawley rats,” Aging Clinical and Experimental Research 16 (2004): 68-78.

147 members of the Calorie Restriction Society: T. E. Meyer et al., “Long-term caloric restriction ameliorates the decline in diastolic function in humans,” Journal of the American College of Cardiology 47 (2006): 398-402.

147 One of CR’s most important: Finch, The Biology of Human Longevity, 198.

147 keeps back overzealous: G. Fernandes et al., “Influence of diet on survival of mice,” PNAS 73 (1976): 1279-83.

147 immune-system weakening: Finch, The Biology of Human Longevity, 192-97.

147 rodent version of Alzheimer’s disease: Ibid., 219.

148 look much younger: McCay et al., “Experimental Prolongation of the Life Span,” 96.

148 hearing acuity: S. Someya et al., “Caloric restriction suppresses apoptotic cell death in the mammalian cochlean and leads to prevention of presbycusis,” Neurobiology of Aging 28 (2007): 1613-22.

148 loss of muscle: R. J. Colman et al., “Attenuation of sarcopenia by dietary restriction in rhesus monkeys,” Journals of Gerontology Series A. 63 (2008): 556-59.

148 a fourth of rodents on: C. R. Finch, The Biology of Human Longevity, 185.

149 drops in blood sugar: Ibid., 186.

149 described the mysterious deaths: “Seek Key to Anti-aging in Calorie Cutback,” Wall Street Journal, October 30, 2006, 1.

150 St. Louis study: See David Stipp, “Live a Lot Longer,” Fortune, June 5, 1999, 144-60.

150 much more interesting phenomenon: A. R. Heydari et al., “Expression of Heat Shock Protein 70 Is Altered by Age and Diet at the Level of Transcription,” Molecular and Cellular Biology 13 (1993): 2909-18.

151 Johnson and colleagues postulated: G. Lithgow et al., “Thermotolerance and extended life-span conferred by single-gene mutations and induced by thermal stress,” PNAS 92 (1995): 7540-44.

151 If you’re a mouse: Fernandes et al., “Influence of diet on survival of mice,” PNAS.

151 If you’re a rat: Duffy et al., “The effects of different levels of dietary restriction on non-neoplastic diseases in male Sprague-Dawley rats,” Aging Clinical and Experimental Research.

151 Masoro . . . strengthened: E. J. Masoro, “Hormesis and the anti-aging effect of dietary restriction,” Experimental Gerontology 33 (1998): 61-66.

152 hormesis was an esteemed concept: See E. J. Calabrese and L. A. Baldwin, “Chemical hormesis: its historical foundations as a biological hypothesis,” Human & Experimental Toxicology 19 (2000): 2-31; and David Stipp, “A Little Poison Can Be Good for You,” Fortune, May 28, 2003.

153 benefits of consuming lots of vegetables: See D. Gems and L. Partridge, “Stress-Response Hormesis and Aging: “That Which Does Not Kill Us Makes Us Stronger,” Cell Metabolism 7 (2008): 200-203.

153 have made a compelling case: See S. Rattan, “Applying hormesis in aging research and therapy,” Human & Experimental Toxicology 20 (2001): 281-86.

153 Hormesis isn’t all: E. J. Masoro, “Caloric restriction-induced life extension of rats and mice: A critique of proposed mechanisms,” Biochimica et Biophysica Acta (2009): 1-9.

153 “starvation response”: D. E. Harrison and J. R. Archer, “Natural selection for extended longevity from food restriction,” Growth Development and Aging 52 (1988): 65; and R. Holliday, “Food, reproduction and longevity—is the extended lifespan of calorie-restricted animals an evolutionary adaptation?” Bioessays 10 (1989): 125-27.

154 alternative theory: Personal communication, Steven Austad.

154 run themselves to death: See Finch, The Biology of Human Longevity, 230; and A. A. van Elburg et al., “Nurse evaluation of hyperactivity in anorexia nervosa: a comparative study,” European Eating Disorders Review 15 (2007): 425-29.

155 normal mice on CR and long- lived dwarf mice: V. D. Longo and C. E. Finch, “Evolutionary medicine: from dwarf model systems to healthy centenarians?” Science 299 (2003): 1343- 46.

155 low insulin and body temperature: G. S. Roth et al., “Biomarkers of caloric restriction may predict longevity in humans,” Science 297 (2002): 811.

155 Different methods of restricting: E. L. Greer and A. Brunet, “Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in C. elegans,” Aging Cell 8 (2009): 113-27.

155 already-long lives: M. M. Masternak et al., “Divergent effects of calorie restriction on gene expression in normal and long-lived mice,” Journals of Gerontology Series A 59 (2004): 784-88.

156 CR’s well-known downsides: See http://www.calorierestriction.org; E. M. Gardner, “Caloric restriction decreases survival of aged mice in response to primary influenza infection,” Journals of Gerontology Series A (2005): 688-94; and B. W. Ritz et al., “Energy restriction impairs natural killer cell function and increases the severity of influenza infection in young adult male C57BL/6 mice,” Journal of Nutrition 138 (2008): 2269- 75.

156 driven to cannibalism: McCay, “Effect of Restricted Feeding upon Aging and Chronic Diseases in Rats and Dogs,” 524.

156 including relentless hunger: Speakman and Hambly, “Starving for Life: What Animal Studies Can and Cannot Tell Us about the Use of Caloric Restriction to Prolong Human Lifespan,” 1081.

157 Leonard Hayflick, for example: Leonard Hayflick, How and Why We Age (New York: Ballantine Books, 1994), 277- 95.

157 Austad has found: See S. N. Austad and D. M. Kristan, “Are mice calorically restricted in nature?” Aging Cell 2 (2003): 201-7; and J. M. Harper et al., “Does caloric restriction extend life in wild mice?” Aging Cell 5 (2006): 441- 49.

157 pessimists’ best shot: See E. Le Bourg, “Dietary Restriction would probably not increase longevity in human beings and other species able to leave unsuitable environments,” Biogerontology 7 (2006): 149-52; R. Holliday, “Food, fertility and longevity,” Biogerontology 7 (2006): 139- 41; D. P. Shanley and T. B. L. Kirkwood, “Caloric restriction does not enhance longevity in all species and is unlikely to do so in humans,” Biogerontology 7 (2006): 165- 68; and J. P. Phelan and M. R. Rose, “Caloric restriction increases longevity substantially only when the reaction norm is steep,” Biogerontology 7 (2006): 161-64.

157 Optimists counter: See Masoro, “Dietary restriction-induced life extension: a broadly based biological phenomenon.”

157 case for optimism: See R. Weindruch, “Will dietary restriction work in primates?” Biogerontology 7 (2006): 169-71; and D. K. Ingram et al., “The potential for dietary restriction to increase longevity in humans: extrapolation from monkey studies,” Biogerontology 7 (2006): 143-48.

158 Weindruch’s group made a splash: R. J. Colman et al., “Caloric restriction delays disease onset and mortality in rhesus monkeys,” Science 325 (2009): 201- 4.

158 Correlates of slowed aging: See Meyer et al., “Long-term caloric restriction ameliorates the decline in diastolic function in humans”; and L. K. Heilbronn et al., “Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial,” Journal of the American Medical Association 295 (2006): 1539- 48.

159 Roy Walford: Biographical details on Walford drawn from Thomas H. Maugh II, “Obituary: Roy Walford,” 79; Eccentric UCLA Scientist Touted Food Restriction,” Los Angeles Times, May 1, 2004; and Gary Taubes, “Staying Alive,” Discover, February 2000.

159 Richard Miller points out: Personal communication, Richard Miller.

159 biosphereans’ hormonal: R. L. Walford et al., “Calorie Restriction in Biosphere 2: Alterations in Physiologic, Hematologic, Hormonal, and Biochemical Parameters in Humans Restricted for a 2-Year Period,” Journals of Gerontology Series A 57 (2002): B211-24.

160 longest-living 1 percent of Okinawans: D. C. Willcox et al., “Caloric restriction and human longevity: What can we learn from the Okinawans?” Biogerontology 7 (2006): 173-77.

161 Okinawans also appear: See Okinawa Centenarian Study Web site at http://www.okicent.org.

 

8: THE GREAT FREE LUNCH

 

162 first significant attempt: Personal communications, Donald Ingram and George Roth; and George S. Roth, The Truth About Aging: Can We Really Live Longer and Healthier? (Port Orchard, WA: Windstorm Creative, 2005).

163 2- deoxy-D- glucose: See M. Rezek and E. A. Kroeger, “Glucose Antimetabolites and Hunger,” Journal of Nutrition 106 (1976): 143- 57.

163 2DG’s physiological effects: See D. K. Ingram et al., “Calorie restriction mimetics: an emerging research field,” Aging Cell 5 (2006): 97-108; and M. A. Lane et al., “2-Deoxy-D- Glucose Feeding in Rats Mimics Physiologic Effects of Calorie Restriction,” Journal of Anti-Aging Medicine 1 (1998): 327-37.

163 who’d taken 2DG: Roth, The Truth About Aging, 171.

164 initial finding: Ibid., 170.

164 study’s overall results: Lane et al., “2-Deoxy- D- Glucose Feeding in Rats Mimics Physiologic Effects of Calorie Restriction,” Journal of Anti-Aging Medicine.

165 seemed that the medical world’s: D. K. Ingram et al., “Calorie restriction mimetics: an emerging research field,” Aging Cell; and W. Duan and M. P. Mattson, “Dietary restriction and 2- deoxyglucose administration improve behavioral outcome and reduce degeneration of dopaminergic neurons in models of Parkinson’s disease,” Journal of Neuroscience Research 57 (1999): 195-206.

165 “the millennium experiment”: Roth, The Truth About Aging, 177.

165 “began to kill rats”: Ibid., 177.

166 in 2009 Roth disclosed: See Janet Raloff, “Coming: Ersatz calorie restriction; Avocados may hold a key to longer, better health,” Science News, April 20, 2009.

168 share two telltale traits: G. S. Roth et al., “Biomarkers of caloric restriction may predict longevity in humans,” Science 297 (2002): 811.

169 raise some knotty issues: See R. A. Miller et al., “Interpretation, design, and analysis of gene array expression experiments,” Journals of Gerontology Series A 56 (2001): B52-57.

169 chips have very intriguing things: See C. K. Lee et al., “Transcriptional profiles associated with aging and middle age- onset caloric restriction in mouse hearts,” PNAS 99 (2002): 14988- 93; C. K. Lee et al., “Gene-expression profile of the ageing brain in mice,” Nature Genetics 25 (2000): 294-97; J. M. Dhahbi et al., “Temporal linkage between the phenotypic and genomic responses to caloric restriction,” PNAS 101 (2004): 5524-29; S. X. Cao et al., “Genomic profiling of short- and long-term caloric restriction effects in the liver of aging mice,” PNAS 98 (2001): 10630-35; and S. R. Spindler, “Use of microarray biomarkers to identify longevity therapeutics,” Aging Cell 5 (2006): 39-50.

169 changes in mere weeks: See S. R. Spindler, “Use of microarray biomarkers to identify longevity therapeutics,” Aging Cell.

169 repair preexisting damage: Ibid.

169 metformin is remarkably good: J. M. Dhahbi et al., “Identification of potential caloric restriction mimetics by microarray profiling,” Physiological Genomics 23 (2005): 343-50.

169 French lilac: L. A .Witters, “The Blooming of the French Lilac,” Journal of Clinical Investigation 108 (2001): 1105-7.

170 increase their average life span by 23 percent: V. M. Dilman and V. N. Anisimov, “Effect of treatment with phenformin, diphenylhydantoin or L-dopa on life span and tumour incidence in C2H/Sn mice,” Gerontology 26 (1980): 241-46.

170 The Russians’ 2008 report: V. N. Anisimov et al., “Metformin slows down aging and extends life span of female SHR mice,” Cell Cycle 7 (2008): 2769- 73.

171 enthusiasts are already blogging: See http://www.lef.org.

172 Guarente’s career: Biographical details on Guarente drawn from Lenny Guarente, Ageless Quest: One Scientist’s Search for Genes That Prolong Youth (Cold Spring Harbor, NY: Cold Spring Harbor Press, 2003); and from personal communication, Lenny Guarente.

173 bud off daughter cells: See R. Mortimer and J. Johnson, “Life span of individual yeast cells,” Nature 183 (1959): 1751- 52; and K. J. Bitterman et al., “Longevity Regulation in Saccharomyces cerevisiae: Linking Metabolism, Genome Stability, and Heterochromatin,” Microbiology and Molecular Biology Reviews 67 (2003): 376- 99.

176 doubly serendipitous: See B. K. Kennedy et al., “Mutation in the Silencing Gene SIR4 Can Delay Aging in S. cerevisiae,” Cell 80 (1995): 485- 96.

176 variant of a previously identified: Ibid.

177 Sinclair met Guarente: Personal communication, David Sinclair.

178 one of Sinclair’s first acts: Guarente, Ageless Quest, 35.

178 Sinclair flipped open: Personal communication, David Sinclair.

178 form little circles: D. A. Sinclair and L. Guarente, “Extrachromosomal rDNA Circles—A Cause of Aging in Yeast,” Cell 91 (1997): 1033- 42.

179 singled out SIR2: M. Kaeberlein et al., “The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms,” Genes & Development 13 (1999): 2570- 80.

179 rivals had stolen: Guarente, Ageless Quest, 49- 52.

180 Imai had shown: S. Imai et al., “Transcriptional silencing and longevity protein Sir2 is an NAD- dependent histone deacetylase,” Nature 403 (2000): 295- 300.

181 Michael West: See David Stipp, “The Hunt for the Youth Pill: From Cell-Immortalizing Drugs to Cloned Organs, Biotech Finds New Ways to Fight Against Time’s Toll,” Fortune, October 11, 1999.

181 Guarente found evidence in yeast: Guarente, Ageless Quest, 41.

182 Geron deemphasized: See Stipp, “The Hunt for the Youth Pill: From Cell-Immortalizing Drugs to Cloned Organs, Biotech Finds New Ways to Fight Against Time’s Toll,” Fortune.

182 mice age and die: See S. Kim et al., “Telomeres, aging and cancer: In search of a happy ending,” Oncogene 21 (2002): 503- 11.

182 Spanish scientists reported: A. Tomas-Loba et al., “Telomerase Reverse Transcriptase Delays Aging in Cancer-Resistant Mice,” Cell 135 (2008): 609- 22.

182 centenarians carry variants of the telomerase gene: G. Atzmon et al., “Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians,” PNAS (epub, December 4, 2009).

182 Su- Ju Lin: S. J. Lin et al., “Requirement of NAD and SIR2 for life-span extension by caloric restriction in Saccharomyces cerevisiae,” Science 289 (2000): 2126- 28.

183 Heidi Tissenbaum: H. A. Tissenbaum and L. Guarente, “Increased dosage of a sir- 2 gene extends lifespan in Caenorhabditis elegans,” Nature 410 (2001): 227- 30.

183 Guarente and Kenyon coauthored: L. Guarente and C. Kenyon, “Genetic pathways that regulate ageing in model organisms,” Nature 408 (2000): 255- 62.

183 resonant chord with Jonathan Fleming: Guarente, Ageless Quest, 115-24.

184 start-up gained momentum: See Solomon, The Quest for Human Longevity, 95-112.

184 Elixir’s merger with Centagenetix: Ibid.

184 ran a lengthy feature: James Burnett, “Take This Pill and Live Forever,” Boston, April 2003.

 

9: RED WINE’S ENIGMATIC DIRTY DRUG

 

185 from whose life: Biographical details drawn from personal communication, David Sinclair.

186 questioned his former mentor’s: See J. Couzin, “Aging research’s family feud,” Science 303 (2004): 1276-79.

186 splash by identifying resveratrol: K. T. Howitz et al., “Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan,” Nature 425 (2003): 191-96.

187 told Science magazine: See Couzin, “Aging research’s family feud,” Science.

187 Harvard Medical School: See http://hms.harvard.edu.

187 Its first step: Personal communication, David Sinclair.

188 piceatannol and quercetin: See Howitz et al., “Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan,” Nature.

189 First isolated in 1940: See J. A. Baur and D. A. Sinclair, “Therapeutic potential of resveratrol: the in vivo evidence,” Nature Reviews 5 (2006): 493-506.

189 food scientists suggested: E. H. Siemann and L. L. Creasy, “Concentration of the phytoalexin resveratrol in wine,” American Journal of Enology and Viticulture 43 (1992): 49-52.

189 popular news show: See Hilary Abramson, “The Flip Side of French Drinking,” The Marin Institute (Winter 2000).

189 proposed a sounder theory: M. Jan et al., “Cancer chemopreventive activity of resveratrol, a natural product derived from grapes,” Science 275 (1997): 218-20.

189 rose at an exponential rate: See Baur and Sinclair, “Therapeutic potential of resveratrol: the in vivo evidence,” Nature Reviews.

189 carrying it out himself: Personal communication, David Sinclair.

190 Nature published the study: Howitz et al., “Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan,” Nature.

191 Sinclair proved himself: See Mary Carmichael, “Chemical Wowie,” Newsweek, September 1, 2003, 9; Stephen Smith, “In Lab, Seeking Secret of Youth Chemical Abundant in Red Wine Appears to Slow Aging in Study,” Boston Globe, August 25, 2003, A2; and “Better red than dead, study finds,” Daily Telegraph, August 26, 2003, 5.

191 Bill Sardi: See Bill Sardi, The Red Wine Pill: The Miracle of Resveratrol (San Dimas, CA: Here and Now Books, 2004).

191 Sardi briefly enlisted: See Couzin, “Aging research’s family feud,” Science.

192 resveratrol promiscuously consorts: See Baur and Sinclair, “Therapeutic potential of resveratrol: the in vivo evidence,” Nature Reviews.

193 cast doubt on some of the Guarente lab’s: Personal communication, Matt Kaeberlein.

193 a 2005 paper coauthored: M. Kaeberlein et al., “Substrate-specific activation of sirtuins by resveratrol,” Journal of Biology and Chemistry 280 (2005): 17038-45.

194 a similar study: M. T. Borra et al., “Mechanism of human SIRT1 activation by resveratrol,” Journal of Biology and Chemistry 280 (2005): 17187-95.

194 critiques went way beyond: See M. Kaeberlein et al., “Sir2-independent life span extension by calorie restriction in yeast,” PLoS Biology 2 (2004): E296; and M. Kaeberlein and B. K. Kennedy, “Large-scale identification in yeast of conserved ageing genes,” Mechanisms of Ageing and Development 126 (2005): 17-21.

195 fruit flies and nematodes: J. G. Wood et al., “Sirtuin activators mimic caloric restriction and delay ageing in metazoans,” Nature 430 (2004): 686-89.

195 is absent in mice: D. Chen et al., “Increase in activity during calorie restriction requires Sirt1,” Science 310 (2005): 1641.

195 The MIT group also reported: F. Picard et al., “Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma,” Nature 429 (2004): 771-76.

195 A collaborative study: J. Luo et al., “Negative control of p53 by Sir2alpha promotes cell survival under stress,” Cell 107 (2001): 137-48.

195 helps prevent neurons: T. Araki et al., “Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration,” Science 305 (2004): 1010- 13.

195 SIRT1 in the heart cells: R. R. Alcendor et al., “Sirt1 regulations aging and resistance to oxidative stress in the heart,” Circulation Research 100 (2007): 1512-21.

195 Molecular details: A. Brunet et al., “Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase,” Science 303 (2004): 2011-15.

196 SIRT1 inhibits p53: See L. Guarente, “Calorie restriction and SIR2 genes—towards a mechanism,” Mechanisms of Ageing and Development. 126 (2005): 923-28.

196 induce cells’ resistance to stress: S. D. Westerheide et al., “Stress-inducible regulation of heat shock factor 1 by the Deacetylase SIRT1,” Science 323 (2009): 1063-66.

196 Kaeberlein didn’t take: See I. Chen, “Rookie rising,” Science of Aging Knowledge Environment, December 18, 2002.

197 By 2006, the two sides: See J. Rine, “Twists in the tale of the aging yeast,” Science 310 (2005): 1124-25.

197 turquoise killifish: D. R. Valenzano et al., “Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate,” Current Biology 16 (2006): 296-300.

198 man named Tom LoGiudice: Personal communication, David Sinclair.

200 the study’s initial findings: J. A. Baur et al., “Resveratrol improves health and survival of mice on a high-calorie diet,” Nature 444 (2006): 337-42.

200 New York Times headlined: Nicholas Wade, “Red Wine Holds Answer. Check Dosage,” New York Times, November 2, 2006.

201 Sirtris was already making fast progress: See J. C. Milne et al., “Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes,” Nature 450 (2007): 712-16.

202 French team’s data: M. Lagouge et al., “Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC- 1alpha,” Cell 127 (2006): 1109-22.

202 PGC-1- alpha: See J. T. Rodgers et al., “Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1,” Nature 434 (2005): 113-18.

 

10: RAPAMYCIN AND THE TALE OF TOR

 

204 resveratrol did not extend: K. J. Pearson et al., “Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span,” Cell Metabolism 8 (2008): 157-68.

205 jointly reported in Nature: D. E Harrison et al., “Rapamycin fed late in life extends lifespan in genetically heterogeneous mice,” Nature 460 (2009): 392-95.

205 lives were actually shortened: M. J. Forster et al., “Genotype and age influence the effect of caloric intake on mortality in mice,” Federation of American Societies for Experimental Biology Journal 17 (2003): 690-92.

205 veterans had little hope: See, for example, W. Sansom, “HSC scientists discover mice live longer with rapamycin,” University of Texas Health Science Center news release, July 13, 2009.

205 It began in 1964: See Barry D. Kahan, “Discoverer of the treasure from a barren island: Suren Sehgal (10 February 1932 to 21 January 2003),” Transplantion 76 (2003): 623-24.

206 Selman Waksman: See http://waksman.rutgers.edu.

206 there is now evidence: C. Mlot, “Antibiotics in nature: beyond biological warfare,” Science 324 (2009): 1637- 39.

207 isolated an antifungal compound: See Kahan, “Discoverer of the treasure from a barren island: Suren Sehgal (10 February 1932 to 21 January 2003),” Transplantion.

207 antitumor effects: S. Huang et al., “Rapamycins: Mechanism of Action and Cellular Resistance,” Cancer Biology & Therapy 2 (2003): 222-32.

207 Hall’s group discovered: J. Heitman et al., “Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast,” Science 23 (1991): 905-9.

207 worms, flies, mammals, and even plants: See J. L. Crespo and M. N. Hall, “Elucidating TOR Signaling and Rapamycin Action: Lessons from Saccharomyces cerevisiae,” Microbiology & Molecular Biology Reviews 66 (2002): 579-91.

207 By 2000 it had become clear: Ibid.

207 Japanese scientists discovered: See T. Noda and Y. Ohsumi, “Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast,” Journal of Biology and Chemistry 273 (1998): 3963-66.

207 boost cells’ defenses: See Crespo and Hall, “Elucidating TOR Signaling and Rapamycin Action: Lessons from Saccharomyces cerevisiae,” Microbiology & Molecular Biology Reviews.

207 especially intriguing discovery: Ibid.

208 Sharp got interested: Personal communication, Dave Sharp.

208 study with Andrzej Bartke: Z. D. Sharp and A. Bartke, “Evidence for down-regulation of phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR)- dependent translation regulatory signaling pathways in Ames dwarf mice,” Journals of Gerontology Series A 60 (2005): 293-300.

209 suppressing TOR in nematodes: T. Vellai et al., “Influence of TOR kinase on lifespan in C. elegans,” Nature 426 (2003): 620.

209 turning down TOR in fruit flies: P. Kapahi et al., “Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway,” Current Biology 14 (2004): 885-90.

209 loud wake-up call: M. Kaeberlein et al., “Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients,” Science 310 (2005): 1193-96.

209 Topping TOR’s to-do list: See Crespo and Hall, “Elucidating TOR Signaling and Rapamycin Action: Lessons from Saccharomyces cerevisiae,” Microbiology & Molecular Biology Reviews; and M. Hansen et al., “Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans,” Aging Cell 6 (2007): 95-110.

210 A number of chemical weapons: Personal communication, Gary Ruvkun.

210 another benefit of scaling back: See T. Vellai, “Autophagy genes and ageing,” Cell Death and Differentiation 16 (2009): 94-102.

210 proteins can form toxic aggregates: See W. E. Balch et al., “Adapting proteostasis for disease intervention,” Science 319 (2008): 916-19.

210 Stimulating autophagy: See Vellai, “Autophagy genes and ageing,” Cell Death and Differentiation.

211 mammals rely on autophagy: A. Kuma et al., “The role of autophagy during the early neonatal starvation period,” Nature 432 (2004): 1032-36.

211 he formally proposed: Personal communication, Dave Sharp.

211 ITP itself dates: Personal communication, Donald Ingram.

212 the ITP launches: See R. A. Miller et al., “An aging interventions testing program: study design and interim report,” Aging Cell 6 (2007): 565-75.

212 first round: R. Strong et al., “Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice,” Aging Cell 7 (2008): 641-50.

212 both inhibit TOR: Personal communication, Randy Strong.

213 Before testing rapamycin: Ibid.

213 stuff worked like magic: Harrison et al., “Rapamycin fed late in life extends lifespan in genetically heterogeneous mice,” Nature.

214 for starters, rapamycin can lower: See M. V. Blagosklonny, “An anti-aging drug today: from senescence- promoting genes to anti-aging pill,” Drug Discovery Today 12 (2007): 218-24; M. N. Stanfel et al., “The TOR pathway comes of age,” Biochimica et Biophysica Acta, (June 15, 2009); and M. Kaeberlein and B. K. Kennedy, “Protein translation, 2008,” Aging Cell 7 (2008): 777-82.

215 hinder formation of new neuronal: See B. Raught et al., “The target of rapamycin (TOR) proteins,” PNAS 98 (2001): 7037- 44.

215 cholesterol and triglycerides: See B. D. Kahan, “Fifteen years of clinical studies and clinical practice in renal transplantation: reviewing outcomes with de novo use of sirolimus in combination with cyclosporine,” Transplantation Proceedings 40 (2008): S17-20.

215 clinical studies with rapamycin: Ibid.

215 rapamycin can ward off cancer: See D. A. Guertin and D. M. Sabatini, “Defining the role of mTOR in cancer,” Cancer Cell 12 (2007): 9-22.

215 proteins that the AIDS virus: See A. Heredia et al., “Rapamycin causes down-regulation of CCR5 and accumulation of anti-HIV Ð-chemokines: An approach to suppress R5 strains of HIV-1,” PNAS 100 (2003): 10411-16.

216 “memory T-cells”: K. Araki et al., “mTOR regulates memory CD8 T-cell differentiation,” Nature (June 21, 2009).

216 a 2004 cancer study: E. Raymond et al., “Safety and Pharmacokinetics of Escalated Doses of Weekly Intravenous Infusion of CCI-779, A Novel mTOR Inhibitor, in Patients with Cancer,” Journal of Clinical Oncology 22 (2004): 2336-47.

216 seventy-six heart patients: A. E. Rodriguez et al., “Role of oral rapamycin to prevent restenosis in patients with de novo lesions undergoing coronary stenting: results of the Argentina single centre study (ORAR trial),” Heart 91 (2005): 1433-37.

216 CR itself might be characterized: See Finch, The Biology of Human Longevity, 190-92.

217 TOR-regulated enzyme, called S6K1: C. Selman et al., “Ribosomal protein S6 kinase 1 signaling regulates mammalian life span,” Science 326 (2009): 140-44.

217 stimulation of AMPK: C. Canto et al., “AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity,” Nature 458 (2009): 1056-60.

217 resveratrol’s gene-activity fingerprint: J. L. Barger et al., “A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice,” PLoS One 3 (2008): 2264.

217 mice implanted with extra SIRT1: See L. Bordone et al., “SIRT1 transgenic mice show phenotypes resembling calorie restriction,” Aging Cell 6 (2007): 759-67; and A. S. Banks et al., “SirT1 gain of function increases energy efficiency and prevents diabetes in mice,” Cell Metabolism 8 (2008): 333- 41.

217 2007 study by Linda Partridge: T. M. Bass et al., “Effects of resveratrol on lifespan in Drosophila melanogaster and Caenorhabditis elegans,” Mechanisms of Ageing and Development 128 (2007): 546-52.

218 test-tube studies in late 2009 and early 2010: D. Beher et al., “Resveratrol is not a direct activator of SIRT1 enzyme activity,” Chemical Biology and Drug Design 74 (2009): 619-24; M. Pacholec et al., “SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1,” Journal of Biological Chemistry (epub: January 8, 2010).

218 reduce the chronic, low-level inflammation: See S. Lavu et al., “Sirtuins—novel therapeutic targets to treat age-associated diseases,” Nature Reviews Drug Discovery 7 (2008): 841-53.

218 compelling cardiac benefits: See J. L. Barger et al., “Short-term consumption of a resveratrol-containing nutraceutical mixture mimics gene expression of long-term caloric restriction in mouse heart,” Experimental Gerontology 43 (2008): 859-66.

218 overlapping modes of action: See O. Medvedik et al., “MSN2 and MSN4 Link Calorie Restriction and TOR to Sirtuin-Mediated Lifespan Extension in Sacccharomyces cerevisiae,” PLoS Biology 5 (2007): 2330-41; I. H. Lee et al., “A role for the NAD- dependent deacetylase Sirt1 in the regulation of autophagy,” PNAS 105 (2008): 3374-79; and Blagosklonny, “An anti-aging drug today: from senescence-promoting genes to anti-aging pill,” Drug Discovery Today.

218 compound is remarkably benign: See, for example, L. D. Williams et al., “Safety studies conducted on high-purity trans-resveratrol in experimental animals,” Food and Chemical Toxicology (epub, June 6, 2009).

219 One notable risk: See, for example, E. J. Kim and S. J. Um, “SIRT1: roles in aging and cancer,” Biochemistry and Molecular Biology Reports 41 (2008): 751-56.

219 resveratrol fights cancer: See G. Boily et al., “SirT1-null mice develop tumors at normal rates but are poorly protected by resveratrol,” Oncogene (2009), epub ahead of print; R. Firestein et al., “The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth,” PLoS One 3 (2008): e2020; R. H. Wang et al., “Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis,” Molecular Cell 32 (2008): 11-20; and Lavu et al., “Sirtuins—novel therapeutic targets to treat age-associated diseases,” Nature Reviews Drug Discovery.

219 SIRT1’s anti-aging magic: P. Oberdoerffer et al., “SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging,” Cell 135 (2008): 907-18.

220 resveratrol is found in many foods: See Joseph Maroon, The Longevity Factor: How Resveratrol and Red Wine Activate Genes for a Longer and Healthier Life (New York: Atria Books, 2009).

220 For a rapamycinlike jolt: See V. Wanke et al., “Caffeine extends yeast lifespan by targeting TORC1,” Molecular Microbiology 69 (2008): 277-85.

220 studies suggesting that aspirin: See, for example, Z. Guo et al., “Aspirin Inhibits Serine Phosphorylation of Insulin Receptor Substate 1 in Tumor Necrosis Factor-treated Cells through Targeting Multiple Serine Kinases,” Journal of Biology and Chemistry 278 (2003): 24944-50.

220 Richard Miller has observed: R. A. Miller, “Extending life: scientific prospects and political obstacles,” Milbank Quarterly 80 (2002): 155-74.

 

11: SIRTRIS, MASTER VOYAGER OF THE VORTEX

 

222 Westphal had begun the year: Unless otherwise noted, the information in this chapter was drawn from reporting I did as a frequent visitor at Sirtris between 2005 and 2008.

223 article in the Wall Street Journal: David Hamilton, “Biotech Start-Ups Increasingly Opt for a Sale to Drug Firms over an IPO,” Wall Street Journal, July 13, 2006, C1.

224 a quiet, bookish youngster: Personal communications, Heiner and Frauke Westphal.

231 a whopping $113.5 million: Sirtris Pharmaceuticals initial public offering prospectus, May 8, 2007, 45.

236 licensed exclusive rights: “Sirtris Licenses Fundamental Patent from Guarente Lab at MIT: SIRT1 Activation Has Therapeutic Potential for Lipid Disorders,” Sirtris Pharmaceuticals press release, October 11, 2007.

236 scores of diabetes patients: See “Sirtris Announces Clinical Results from Phase 1 Trials of SRT501, a Sirtuin Therapeutic, Company Initiates Phase 1b Study in Type 2 Diabetes Patients,” Sirtris Pharmaceuticals press release, October 4, 2006.

237 Nature paper appeared: J. C. Milne et al., “Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes,” Nature 450 (2007): 712-16.

238 Auwerx chimed in: J. N.Feige et al., “Specific SIRT1 Activation Mimics Low Energy Levels and Protects against Diet-Induced Metabolic Disorders by Enhancing Fat Oxidation,” Cell Metabolism 8 (2008): 347-58.

238 a group at Pfizer reported: M. Pacholec, “SIRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1,” Journal of Biological Chemistry.

238 sirtuins have very complex functions: See S. Lavu et al., “Sirtuins—novel therapeutic targets to treat age-associated diseases,” Nature Reviews 7 (2008): 841-53; H. Yamamoto et al., “Sirtuin Functions in Health and Disease,” Molecular Endocrinology 21 (2007): 1745-55; M. C. Haigis and L. P. Guarente, “Mammalian sirtuins—emerging roles in physiology, aging, and calorie restriction,” Genes & Development 20 (2006): 2913-21; and W. C. Hallows et al., “Ure(k)a! Sirtuins Regulate Mitochondria,” Cell 137 (2009): 404-6.

240 study linking Avandia: S. E. Nissen and K. Wolski, “Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes,” New England Journal of Medicine 356 (2007): 2457-71.

240 data on the issue: See “The Rosiglitazone Story—Lessons from an FDA Advisory Committee Meeting,” New England Journal of Medicine 357 (2007): 844.

241 Avandia’s sales plunged: See Elena Berton, “Falling Avandia Sales Hit GlaxoSmithKline,” Dow Jones Newswire, February 7, 2008.

241 cost of developing a drug: A. J. J. Wood, “A Proposal for Radical Changes in the Drug-Approval Process,” New England Journal of Medicine 355 (2006): 618-23.

241 As Witty commented: See T. Stuart and J. Weber, “GSK’s Acquisition of Sirtris: Independence or Integration,” Harvard Business School Case Study N9- 809-026, April 13, 2009.

243 Elixir withdrew a planned IPO: See Roxanne Palmer, “Elixir Raises $12 million, Says Drug Trial Could Lead to Novartis Purchase,” xconomy.com, May 19, 2009.

 

12: THE GEORGE BURNS SCENARIO

 

245 self-reported happiness: See S. T. Charles and L. L. Carstensen, “Emotion Regulation and Aging,” in Handbook of Emotion Regulation, ed. J. J. Gross (New York: Guilford Press, 2007).

246 Thomas Lynch: Thomas Lynch, “Why Buy More Time?” New York Times, March 14, 1999.

246 a kind of apologist manifesto: L. R. Kass, “L’Chaim and Its Limits: Why Not Immortality?” First Things 113 (2001): 17- 24.

246 council mirrored Kass’s views: The President’s Council on Bioethics, “Beyond Therapy: Biotechnology and the Pursuit of Happiness,” October 2003.

247 “engineered negligible senescence”: See http://www.sens.org.

248 Kass wrote: Kass, “L’Chaim and Its Limits: Why Not Immortality?” First Things.

249 British bioethicist John Harris: J. Harris, “Immortal ethics,” Annals of the New York Academy of Sciences 1019 (2004): 527-34.

249 birthrates across the world are falling: See, for example, Stewart Brand, Whole Earth Discipline: An Ecopragmatist Manifesto (New York: Viking, 2009), 60-61.

250 New Republic heavy-handedly put it: H. Fairlie, “Talkin’ ’Bout My Generation,” New Republic, March 28, 1988, 19-22.

250 “Seniors suck the marrow”: As cited by James H. Schulz and Robert H. Binstock, Aging Nation: The Economics and Politics of Growing Older in America (Baltimore: Johns Hopkins University Press, 2006), 13.

250 allied to lobbyists for insurance companies: Ibid., 10-18.

250 older voters: Ibid., 205.

251 voted for Barack Obama: See 2008 CNN exit poll results at http://edition.cnn.com/ELECTION/2008/results/polls.main.

251 Kevin Murphy and Robert Topel: K. M. Murphy and R. H. Topel, “The Value of Health and Longevity,” Journal of Political Economy 114 (2006): 871-904.

251 longer life boosts productivity: D. E. Bloom and D. Canning, “The health and wealth of nations,” Science 287 (2000): 1207-9.

252 seminal 1957 paper: Williams, “Pleiotropy, natural selection, and the evolution of senescence,” Evolution.

252 average life span before the dawn: Robert N. Butler, The Longevity Revolution: The Benefits and Challenges of Living a Long Life (New York: PublicAffairs, 2008), 4.

252 even in the Stone Age: See R. D. Lee, “Intergenerational Relations and the Elderly,” Between Zeus and the Salmon: The Biodemography of Longevity (Washington, DC: National Academy Press, 1997).

252 “grandmother hypothesis”: See A. R. Rogers, “Economics and the evolution of life histories,” PNAS 100 (2003): 9114-15, and K. Hawkes, “The Grandmother Effect,” Nature 428 (2004): 128-29.

253 Female pilot whales: See J. R. Carey and C. Gruenfelder, “Population Biology of the Elderly,” and S. A. Austad, “Postreproductive Survival,” both in Between Zeus and the Salmon.

253 “Nurse bees”: G. V. Amdam and R. E. Page, “Intergenerational transfers may have decoupled physiological and chronological age in a eusocial insect,” Ageing Research Reviews 4 (2005): 398-408.

253 intergenerational transfers: R. D. Lee, “Rethinking the evolutionary theory of aging: Transfers, not births, shape senescence in social species,” PNAS 100 (2003): 9637-42.

254 “aged dependency ratio”: See Schulz and Binstock, Aging Nation, 32-35.

254 “support burden” in the United States will actually be smaller: Ibid.

254 solvent until 2037: See Social Security Board of Trustees annual report, at www.socialsecurity.gov/OACT/TR/2009/.

254 modest changes: Butler, The Longevity Revolution, 270-77.

255 average retirement age: See M. Gendell and J. S. Siegel, “Trends in retirement age by sex, 1950-2005,” Monthly Labor Review 115 (1992): 22-30.

255 labor force participation rates: Clare Ansberry, “Elderly Emerge as a New Class of Workers—and the Jobless,” Wall Street Journal, February 23, 2009.

255 employers regard the penalties: Schulz and Binstock, Aging Nation, 159.

255 refute the standard bad rap: See Butler, The Longevity Revolution, 245-47.

255 mentally and physically active: See Schulz and Binstock, Aging Nation, 168.

256 more than half cited poor health: Ibid., 154.

256 too frail to do ordinary work: As cited in Butler, The Longevity Revolution, 474.

256 By 2017 it will account for: Will Dunham, “Health care spending surge seen in next decade,” Reuters, February 26, 2008.

256 Robert Fogel has written: As cited in Butler, The Longevity Revolution, 29.

256 Medicare spending between 1994 and 2004: K. G. Manton et al., “Longterm economic growth stimulus of human capital preservation in the elderly,” PNAS 106 (2009): 21080- 85.

257 widening use of costly new medical: See Schulz and Binstock, Aging Nation, 192-98.

257 In Japan: Ibid., 191.

257 improved management of cardiovascular: See K. G. Manton et al., “Labor force participation and human capital increases in an aging population and implications for U.S. research investment,” PNAS 104 (2007): 10802-7.

257 spent more than $100 billion: Gina Kolata, “Advances Elusive in the Drive to Cure Cancer,” New York Times, April 24, 2009.

257 Alzheimer’s prevalence: See “Alzheimer’s Disease Facts and Figures, 2007,” Alzheimer’s Association, at http://www.alz.org.

258 the number of obese Americans: “Obese Americans now outweigh the merely overweight,” Reuters, January 9, 2009.

258 Health-care costs for obese adults: Roni Caryn Rabin, “Obese Americans Spend Far More on Health Care,” New York Times, July 28, 2009.

258 greatly elevated risk of dementia: Shirley S. Wang, “Study Ties Belly Fat to Dementia,” Wall Street Journal, March 27, 2008.

258 an astounding 86 percent of U.S. adults: Y. Wang et al., “Will All Americans Become Overweight or Obese? Estimating the Progression and Cost of the U.S. Obesity Epidemic,” Obesity 16 (2008): 2323-30.

258 lowball overweight’s health fallout: See “Body-mass index and cause-specific mortality in 900,000 adults: collaborative analyses of 57 prospective studies,” The Lancet 373 (2009): 1083-96; and K. F. Adams et al., “Overweight, Obesity, and Mortality in a Large Prospective Cohort of Persons 50 to 71 Years Old,” New England Journal of Medicine 355 (2006): 763-78.

259 In China: Shirley S. Wang, “Obesity in China Becoming More Common,” Wall Street Journal, July 8, 2008.

259 U.S. children are overweight: J. A. Skelton et al., “Prevalence and Trends of Severe Obesity among US Children and Adolescents,” Academic Pediatrics, June 26, 2009, epub ahead of print; J. L. Baker et al., “Childhood Obesity—The Shape of Things to Come,” New England Journal of Medicine 357 (2007): 2325; E. M. Urbina et al., “Youth with obesity and obesity-related type 2 diabetes mellitus demonstrate abnormalities in carotid structure and function,” Circulation 119 (2009): 2913-19.

259 overweight children viewed as normal: Ron Winslow, “Overweight and Overlooked: A Hidden Heart Risk for Kids,” Wall Street Journal, April 24, 2007.

259 dismaying prediction: S. J. Olshansky et al., “A Potential Decline in Life Expectancy in the United States in the 21st Century,” New England Journal of Medicine 352 (2005): 1138-45.

262 “longevity dividend”: S. J. Olshansky et al., “In Pursuit of the Longevity Dividend,” The Scientist 20 (2006): 28-36.

262 landmark 2005 study: D. P. Goldman et al., “Consequences of Health Trends and Medical Innovation for the Future Elderly,” at http://content.healthaffairs.org.

263 Richard Miller notes: R. A. Miller, “Genetic Approaches to the Study of Aging,” Journal of the American Geriatrics Society 53 (2005): 5284-86.