The not-so-close relationship between biological aging and age-associated pathologies in humans.

Abstract

HERE is no denying a close relationship between the aging process and age-associated diseases. What distinguishes Robin Holliday’s view from mine is the answer to the question, ‘‘How close is it?’’ Contrary to Robin Holliday’s position, I believe that the two phenomena are distinct in that an advancing aging process simply increases vulnerability to age-associated diseases or to pathology. The distinction between aging and age-associated diseases is based, not on a dictionary definition, but on several practical observations: Unlike any disease, age changes (a) occur in every animal that reaches a fixed size in adulthood, (b) cross virtually all species barriers, (c) occur in all members of a species only after the age of reproductive maturation, (d) occur in all animals removed from the wild and protected by humans even when that species probably has not experienced aging for thousands or even millions of years, (e) do not appear before reproductive maturation, (f) occur in virtually all animate or inanimate matter, and (g) have the same molecular etiology in both animate and inanimate objects. The distinction between the aging process and its associated diseases might also be appreciated by speculating on the insights into the aging process that might be gained when some, or all, age-associated diseases are resolved as causes of death. In my view, the resolution of age-associated diseases will advance our knowledge of the fundamental aging process to the same extent as the resolution of pediatric-associated diseases, such as poliomyelitis, acute lymphocytic leukemia, Wilms’ tumors, and iron-deficiency anemia, advanced our fund of knowledge about the biology of human development. That is, with the resolution of each, no advance in our understanding of human development occurred at all. For example, about a half century ago, the leading cause ofdeathin oldage waspneumonia,often called ‘‘the old man’s friend’’ (with its sexist overtones). Pneumonia is no longer one of the three leading causes of death in old age but its resolution did not advance our knowledge of the biology of aging at all. Similarly, the resolution of any age-associated disease, like the resolution of any disease associated with development, will tell us little if anything about the fundamental biology of the aging process. I agree with Robin Holliday’s assertion that, ‘‘during aging there are innumerable documented changes at the cell, tissue, and organ level.’’ Also, I concur with the many age changes that he lists that appear at all levels of complexity. Furthermore, I have no disagreement with the examples that he gives of ‘‘cellular damage, and repair of this damage, or cell renewal.’’ He describes such abnormalities as the profound effect of the loss of blood vessel elasticity, abnormalities of lipid metabolism, formation of blood clots, and that ‘‘The heart is a very efficient pump, but it cannot be expected to last indefinitely.’’ All of these changes are manifestations of the aging process and precursors of pathology. The heart ‘‘cannot be expected to last indefinitely,’’ nor can any other organ, not because of the initial appearance of pathology but because of the initial appearance of the aging process. None of these pathologies ordinarily occur in youth because young cells, unlike old cells, do not increase vulnerability to these pathologies. The aging process simply increases the vulnerability to disease or pathology. The energetics of the molecules that compose the cells (and their products) in all organs have been selected to maintain their fidelity only until reproductive maturation, after which time the energy costs are too great to maintain molecular fidelity indefinitely because there is no benefit to species survival (1‐3). The fact that quick deaths occur after reproductive success in rare ‘‘big bang’’ animal species like the Pacific salmon does benefit species’ survival by having the corpses of postreproductive animals contribute to the food chain necessary for the survival of their offspring. However, this process in ‘‘big bang’’ animals is driven genetically and is therefore different from the stochastically driven aging process. It is not obligatory for death to be preceded by an aging process. The energy cost of evolving a system that will shut down all metabolic processes immediately after reproductive success is too great to pay when it does not benefit the species. Thus, normal metabolism continues beyond the time of reproductive success, incurring random losses in molecular fidelity that leads to greater vulnerability in feral animals to predation, accident, or, in the case of humans and the animals we choose to protect, pathology (1,3). In the example that Robin Holliday gives of the heart that ‘‘cannot be expected to last indefinitely’’ and whose structures ‘‘deteriorate,’’ he makes my point precisely