The Journals
of Gerontology Series A: Biological Sciences and Medical Sciences 59:B547-B550 (2004)
Debates
The Not-So-Close Relationship Between Biological
Aging and Age-Associated Pathologies in Humans
Department of Anatomy,
Correspondence: Address correspondence to
Leonard Hayflick, PhD, Professor of Anatomy,
Department of Anatomy,
THERE 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 of death in old age was pneumonia, 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 because he appears to support my contention that the initiating events leading to the functional failure of the heart (and other organs) is not pathology but the aging process that increases vulnerability to subsequent pathology. He lends further support to my contention that the loss of molecular fidelity precedes pathology by citing many excellent examples of age-dependent posttranscriptional molecular modifications in the eye, brain, and in the etiology of cancer, all of which are expressions of the aging process, and that increase vulnerability in those molecules to further modifications that become the precursors of frank pathology.
Robin Holliday seems to provide the greatest evidence against his
position that the aging process and age-associated diseases are not
"distinct" and that they have "considerable overlap" by
stating that, "In the context of carcinogenesis, it is worth noting
that the examination of the structure, properties, and behavior of a
particular type of neoplasm may well tell us nothing about aging,
but the prior events which eventually gave rise to the tumour are very likely to do so." The "prior
events," which I assume to mean the aging process, are what
increases vulnerability to subsequent events that have come to be
labeled age-associated diseases or pathology.
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ONE CAUSE |
Robin Holliday and I are also in substantial agreement in our belief
that there is not one cause of the aging process. However, there is
a semantic trap lurking here in respect to the definition of
"one cause." In the sense that there is no single specific event
that occurs in a single molecule or class of molecules that triggers
all subsequent aging events, we are in agreement. However, there is
a single cause of the aging process in the sense that there is a
single unifying concept that underlies virtually all theories of
aging. It is not unlike the physicists much-sought-after
"Theory of Everything." It might be called, "The
Theory of Everything Old."
The concept is based on the definition of biological aging that I have given previously (1,3,4). Aging in biological systems is a stochastic process that occurs systemically after reproductive maturity in animals that reach a fixed size in adulthood and is caused by the escalating loss of molecular fidelity that ultimately exceeds repair capacity thus increasing vulnerability to pathology or age-associated diseases.
The fundamental cause of this molecular disorder is rooted in the intrinsic instability of most complex biological molecules whose precise three-dimensional folded structures must be maintained with precise accuracy in order to function. These instabilities have been described for decades and are associated with the energetics of, for example, hydrogen bonds, covalent bonds, and van der Waals forces.
As Robin Holliday states, there is a catalog of other thermodynamic forces that lead to molecular infidelity. These include covalent modifications such as glycation, age-related conformational alterations, aggregation and precipitation, amyloid formation, changes in protein degradation and synthesis rates, and nuclear and mitochondrial DNA damage and alterations. The molecular disorder that defines biological aging might occur passively by increasing decrements in the energy necessary to maintain molecular fidelity or actively through, for example, the action of reactive oxygen species (ROS).
Robin Holliday asserts "It could not be said that the cross-linking of collagen is the same as the postsynthetic changes in the crystallin of the lens, or that the accumulation of AGEs is related to the ROS damage that may produce deletions in mitochondrial DNA." On the contrary, the unifying concept that embraces all of these changes is loss of molecular fidelity regardless of its cause or specific energetic state. The loss of molecular fidelity is clearly expressed differently in different molecules, as I have described above, but the underlying and unifying concept is the generality of their loss of fidelity no matter what energetic change characterizes that loss. No one will disagree with Robin Holliday's assertion that "[t]he damage from wear and tear in joints leading to osteoarthritis could hardly be related to the formation of amyloid plaques in the brain." However, the unifying concept that is the common denominator to these and all other age changes is, again, the loss of molecular fidelity.
Most complex biological molecules are constantly renewed in order to replace preexisting forms whose energetics will only permit short lives or to replace and dispose of molecules that have incurred errors and may be harmful. Thus, the complex mechanisms that drive turnover, repair, quality control, and waste disposal also have evolved to guarantee that their molecules will retain functional capacity long enough for their possessor to reach reproductive success. The anabolic mechanisms that govern molecular turnover, repair, quality control, and disposal are themselves composed of complex molecules that will suffer the same fate, as will their substrate molecules and for the same reasons.
Thus, biological processes, through natural selection, have evolved molecules with energetics that maintain fidelity, and that of their subsequent copies, with energy levels sufficient to permit them to function long enough so that most of their possessors will reach reproductive success. After reproductive success, the random loss of molecular fidelity continues to escalate and, for many molecules, soon exceeds repair and turnover capacity. Then the manifestations of age changes at higher levels of organization become expressed and vulnerability to pathology increases.
Thus, the stochastic processes that lead to molecular disorder represent the genesis of age changes as repair processes gradually become overwhelmed after reproductive maturity. That is not to say that many of these stochastic processes do not occur prior to sexual maturation. They undoubtedly do. However, repair processes must be capable of managing these losses in molecular fidelity with such efficiency that reproductive success is reached by most members of a species, otherwise the species would vanish. The aging of living things caused by molecular disorder is not unlike the aging of everything else in the universe including the universe itself. It follows, then, that age changes are not governed by genes but that the determinants of longevity are (1,3).
Robin Holliday also addresses the issue of the causes of species life span differences in which he states, "The evolutionary forces that result in the increase or decrease in life span must be acting on all processes of aging," and, "... increased longevity can evolve by increasing the stability of cellular components, and also by improving repair and replacement mechanisms. These include defense against damaging agents such as ROS, or toxic chemicals in the diet; better recognition and breakdown of abnormal proteins, and more efficient DNA repair, and other mechanisms."
I am in complete agreement with this concept, although, rather than
just hinting at the difference between longevity determinants and
the aging process, I would have preferred that Robin Holliday would
have described those differences head on. It would be useful to have
his understanding of this critical distinction. In my view, the
distinction between the aging process and the process that
determines longevity is not fully appreciated by many, including
some biogerontologists. Failure to understand this
distinction, like the failure to distinguish between the aging
process and age-associated diseases, has muddled much of the
thinking in the field of biogerontology. Together,
these failures have not only produced spurious scientific conclusions
but they have resulted in research and health policy decisions that
are not based on fact. It is for this reason that I will define
those differences and indicate why they are important.
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THE DETERMINANTS
OF LONGEVITY |
The principle difference between the aging process and the process of
longevity determination is that the former is stochastically driven
and the latter, indirectly, is driven by the genome (1).
Potential longevity is determined by the energetics of molecules present at the time of reproductive maturation. It is these molecules, and the machinery involved in their turnover, maintenance, and repair, that are the substrate molecules that then undergo the aging process. The determinants of the fidelity of all molecules present at reproductive maturity are, of course, governed by the genome but the stochastically driven aging process acts subsequently to perturb that fidelity.
In respect to species' life span differences that Robin Holliday addresses, survival depends on a sufficient number of members living long enough to reproduce and, if necessary, to raise progeny to independence. The verity of this premise is self-evident because if animals are unable to reach sexual maturity, the species will vanish.
The best way to ensure survival to reproductive success is for natural selection to favor animals that have greater physiological reserve in vital organs. Indeed, it is well known that in adult humans, for example, there is an extraordinary physiological reserve in major organs such as the lungs, kidneys, and liver.
In a harsh environment, animals whose vital systems have a large over-capacity are better able to survive. That is, animals that have superior physiological capacity and survival skills have evolved greater reserve capacity in their vital systems. They may have a more efficient healing process, faster sensory responses, or greater strength or speed to avoid predation or natural disasters, find food, and survive disease, accidents, and environmental extremes. The favored animals will have developed redundant capacity, or greater physiological reserve, thus increasing chances for survival to reproductive success.
The state of molecular energetics that determines excess physiological capacity or redundancy present at the time of reproductive maturation is the indirect determinant of longevity. It is these molecules that then succumb to the aging process.
Living well beyond reproductive success incurs an increasing loss of molecular fidelity, which characterizes the aging process and does not benefit species survival. Thus, the youthful and largely successful responses to the constant forces of natural selection diminish after reproductive maturation. Nature does not squander energy by providing complex vital molecules with levels of stability that significantly exceed what is necessary for the animals that they form to reach reproductive success. For the survival of any species, energy is better spent on directly ensuring reproductive success by increasing physiological redundancy than it is for increasing individual longevity. However, the excess physiological capacity possessed by animals at the time of reproductive success indirectly permits them to survive beyond sexual maturation. Longevity determination therefore is an entirely different process than aging and is independent of the aging process. One might think of aging as the process that, after reproductive maturity, results in the disorder of preexisting molecules that produced the mature individual and that determined that individual's level of physiological reserve.
Because life occurs in an open system, the molecular disorder that
results in the aging of living systems cannot be thought of,
strictly, as a result of The Second Law of Thermodynamics,
that is, increasing entropy. However, the analogy of the aging
process to increasing entropy is, nevertheless, apt because the
aging of living things intrinsically incapable of perfect repair is
not unlike the aging of everything else in the universe.
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CONCLUSION
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Both Robin Holliday and I are in complete agreement with the view
that geriatric medicine is a discipline distinct from biogerontology.
I have argued further that because most physicians believe, almost
approaching the level of a mantra, that the greatest risk factor for
age-associated diseases is the aging process, why then is support
for the study of the greatest risk factor microscopic compared to the
support available for geriatric medicine (1,3,4)?
What is singularly important, and what Robin Holliday also
recognizes, is that a better understanding of the aging process
could result in the discovery of a common cause for all of the
leading causes of death in old age. Thus, the essential question
that is rarely posed and, consequently, on which research is rarely
done, is "Why are old cells more vulnerable to pathology than
young cells?"
The difference in views between that of Robin Holliday and myself can best be expressed as quantitative rather than qualitative. Where he sees an overlap between the aging process and age-associated diseases, I see a rather sharper line of demarcation. My view is based on the belief that the same list of age changes pointed out by Robin Holliday to be unassociated with pathology (e.g., gray hair, wrinkled skin, and presbyopia) are not pathologies and are easily understood not to be diseases (1,3,4). It is probable that the same losses in molecular fidelity that underlie these obvious phenotypic age changes produce less obvious changes when they occur at levels other than that of the hair, skin, or eyes. Decrements in neuromuscular coordination, running speed, grip strength, and reaction time, to name a few, also are not known to be precursors of pathology. However, when similar losses in molecular fidelity occur in the cells or cell products in vital organs, then vulnerability to life-threatening pathology becomes increasingly probable.
However, Robin Holliday makes several statements that appear to contradict his belief that there is an overlap between the processes of aging and age-associated diseases. He writes: "The example of loss of muscular strength is part of normal aging, but the decline in bone strength is osteoporosis, clearly understood to be an abnormal condition, if not a disease," and, "... it is worth noting that the examination of the structure, properties, and behavior of a particular type of neoplasm may well tell us nothing about aging, but the prior events that eventually gave rise to the tumor are very likely to do so." He further suggests that there is no overlap by writing: "The gradual loss of accommodation of the lens of the eye is not a disease, although it is treated by providing spectacles" and that "... the wear and tear of teeth with age is not regarded as pathological ..." He also writes: "In summary, we can say that the treatment of age-associated disease in humans is part of medical practice and geriatrics, and it is not gerontology ..."
In his defense, it is likely that we will never know what structural changes
in the energetics of a molecule, defined as an age
change, then becomes by a further subtle change in energetics to be the genesis of a pathological
process. If, for example, the loss or formation of one cross-link or
covalent bond will someday be proven to be the etiology of an age
change, it may or may not be possible to characterize a cascade of
those changes as pathology.
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Footnotes |
Decision Editor: James R. Smith, PhD
Received for publication
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References |
- Hayflick
L. Aging, longevity determination and disease. In: Rosenthal RA, Zenilman ME, Katlic MR, eds.
Principles and Practice of Geriatric Surgery.