Aging is a great scientific mystery. For 4 decades, I have been fascinated by the possibility of a general theory addressing genomic mechanisms in the continuum of development and aging in health and disease. While a Yale undergraduate in Biophysics, I was fortunate to be mentored by Carl Woese, who suggested that if I wanted to tackle a really new problem in little-trodden scientific territory, I should think about aging: “It is even more mysterious than development.” About 5 years later as a graduate student at “the Rockefeller,” I began work on neuroendocrine aspects of aging guided by Alfred Mirsky (McEwen, 1992). Mirsky was a major conceptualizer of differential gene expression in cell differentiation and development, including postnatal growth and maturation. Eric Davidson and Bruce McEwen, prior Mirsky students, were also key debaters in developing my thoughts on aging.
In writing my PhD thesis, I tried to read everything published on biological and medical aspects of aging up to 1969. I chanced across two remarkable articles by Hardin B. Jones (Jones, 1956, 1959). These papers, rarely cited at that time or since, showed the importance of cohort analyses to understanding aging. James Tanner also noted cohort effects in growth and puberty during the last 150 years (Tanner, 1962). Some readers of my thesis thought my attentions had strayed from my experiments by the emphasis I gave them:
Tanner suspects that puberty occurs earlier because of decreased exposure to disease in childhood. Jones analyses has actually shown that the mortality of cohorts as children can be used to predict the mortality of these same cohorts as adults. If both conclusions prove true, there may be a common site of action of the environment on the organ systems governing the length of mature life. (Finch, 1969, p. 11.)
I was also was fortunate to learn some pathology as a graduate student at the Rockefeller by two masters of “in-the-gross” necropsy, Robert Leader and John Nelson, who taught me first-hand to use tweezers and scalpel and to see clues to pathology from the texture and color of tissues and fluids. “Old” John Nelson’s vast experience in rodent pathology helped me understand McCay’s observations that caloric restriction suppressed chronic lung disease (Chapter 3). Peyton Rous made a chilling comment after my thesis lecture (to the effect of): “Finch, I don’t see why you are wasting your time on a subject like aging—everyone knows aging is only about vascular disease and cancer.” Rous may yet be proved right, but to no chagrin in view of the thriving subject that has emerged and that may give a broad understanding of shared processes in many aspects of aging.
During the past 35 years, my research has remained focused on brain mechanisms in aging. The turn toward inflammation began with molecular studies of Alzheimer disease about 15 years ago. My lab and others discovered that inflammatory mechanisms were activated in Alzheimer disease (AD). Moreover, we showed that some glial inflammatory changes in AD also occur to lesser degrees during normal aging and can be detected before midlife. Furthermore, caloric restriction, which increases rodent life span, also retarded brain inflammatory changes. During this same decade, it became clear that vascular disease also involves slow inflammatory processes and that anti-inflammatory drugs reduce the risk of heart disease and possibly of Alzheimer disease as well. In the last 5 years, I have developed a major collaboration with Eileen Crimmins, a USC demographer whose work also showed the importance of inflammation in human health. Our papers address the questions of 4 decades back and have given the rationale for a new set of animal models being developed in collaboration with my close colleagues Todd Morgan and Valter Longo. Inflammation–diet interactions could explain the recent evolution of human longevity with caveats of its future potential.
My inquiry necessarily leads to a broad range of evidence usually not considered “on the same page” by highly focused researchers of specific diseases. The examples illustrate key points and cannot be comprehensive. I will try to indicate the level of certainty in evidence being considered and not try to explain “too much.”