Review Volume 4, Issue 12 pp 861—877
Answering the ultimate question “What is the Proximal Cause of Aging?”
- 1 Department of Cell Stress Biology, Roswell Park Cancer Institute, BLSC, L3-312, Elm and Carlton Streets, Buffalo, NY 14263, USA
Received: December 20, 2012 Accepted: December 29, 2012 Published: December 30, 2012https://doi.org/10.18632/aging.100525
How to Cite
Recent discoveries suggest that aging is neither driven by accumulation of molecular damage of any cause, nor by random damage of any kind. Some predictions of a new theory, quasi-programmed hyperfunction, have already been confirmed and a clinically-available drug slows aging and delays diseases in animals. The relationship between diseases and aging becomes easily apparent. Yet, the essence of aging turns out to be so startling that the theory cannot be instantly accepted and any possible arguments are raised for its disposal. I discuss that these arguments actually support a new theory. Are any questions remaining? And might accumulation of molecular damage still play a peculiar role in aging?
It is commonly believed that aging is caused by random accumulation of molecular damage due to failure of maintenance, because repair is costly [1, 2]. As emphasized by Kirkwood, “the aging process is caused by the gradual buildup of a huge number of individually tiny faults - some damage to a DNA strand here, a deranged protein molecule there, and so on” . The view is very logical, intuitive and simple. As argued recently , the scholastic philosopher William of Ockham would surely have liked it. Yet, the damage/repair theory leads to incorrect predictions and to bizarre paradoxes [4, 5]. Also, the free radical version of this theory has not been confirmed [6-15]. After all, William of Ockham lived before Galileo. Now we know that a theory must make correct predictions and be useful, rather than just be elegant.
What if aging is not caused by accumulation of molecular damage? What if random accumulation of molecular damage is irrelevant to aging? Then the cause of molecular damage is not really important. What if aging does not start from day one. In fact, the mortality rate is lower in 10-years old children than in infants. So the period of growth is hardly aging. But when developmental growth is finished, growth-signaling pathways may continue to run on inertia (Fig. 1). Where would that lead the soma?
Figure 1. Aging as a quasi-program of development. When development is finished cellular normal functions become excessive (hyperfunctions). They lead to diseases. Development is strictly programmed and therefore is precise (one line), whereas aging is not (a continuation of developmental program or quasi-program), and so age-related diseases (ADR) occur at different age.
The hyperfunction theory
In cell culture, when actual proliferation is blocked, then still active growth-signaling and nutrient-sensing pathways such as the TOR (Target of Rapamycin) pathway cause senescence [16-27]. TOR can convert quiescent cells into senescent cells without any involvement of molecular damage [28-36]. The TOR pathway is involved in yeast and organismal aging from worm to mammals [37-53] as well as in age-related disease in mammals [54-65]. The same pathway, which drives developmental growth, later drives aging and its associated diseases. As discussed in detail previously [54, 66], aging is of course not a program, but it is a quasi-program, a useless and unintentional continuation (or run on) of developmental programs. Similarly, cellular senescence is a continuation of cellular growth [36, 67, 68]. In brief, over-stimulation leads to increased functions. Such functions include secretion by fibroblasts, contraction by arterial smooth muscle cells (SMC), aggregation by platelets, bone resorption by osteoclasts, lipogeneisis by fat cells, glycogenesis by liver cells, inflammation by neutrophils, phagocytosis by macrophages and so on and so one. Also, overstimulation may render cell signal resistance due to feedback block of signaling pathways. In turn, hyperfunction coupled with signal-resistance causes loss of homeostasis, diseases, organ damage and eventually death of the organism . For example, taken together, hyperfunctions of arterial smooth muscle cells, macrophages, hepatocytes, fat cells, blood platelets, neurons and glial cells, fibroblasts, beta-cells cause organ hypertrophy and fibrosis, atherosclerosis and hypertension (and their complications such as stroke and infarction), osteoporosis and (as complication, born rupture), age-related blindness, gangrenes, renal and heart failure and even cancer. There is no ARD that cannot be linked to initial cellular hyperfunction, in part, driven by mTOR . The senescence-associated secretory phenotype (SASP) [69- 73] is a characteristic hyperfunction of fibroblasts (and some other cells) caused by hyper-mitogenic stimulation of arrested cells [74, 35]. Chronic inflammation, a classic example of hyperfunction, is associated with aging and age-related diseases [75- 82]. Even telomere shortening [83-93] can also be viewed as a consequence of hyperfunction insofar as it is promoted by hyper-proliferation, and perhaps, therefore, is associated with accelerated age-related diseases (ARD). Although loss of functions is often in terminal aging, loss of function always results from initial hyperfunction (and no another example could be found . This is also applicable to simple multicellular organisms such as Drosophila and C. Elegans [94, 95].
Given that cellular hyperfunction is one of the main characteristics of aging, David Gems, Yila de la Guardia and Linda Partridge suggested a short name “hyperfunction theory” [94, 95], which I will use here.
Many predictions of the hyperfunction theory have already been confirmed . Pro-aging signal-transduction pathways and potential anti-aging agents that target them have been revealed, including several existing drugs such as rapamycin and metformin . Moreover, inhibition of hyperfunction in downstream processes regulated by aging pathways, e.g. attenuation of protein synthesis, extends lifespan [98-100]. Intriguingly, some anti-hypertensive drugs “calm down” hyper-functional signaling-pathways, simultaneously preventing other age-related diseases such as cancer (see for references ). Examples include inhibitors of beta-adrenergic [101-103] as well as of angiotensin II signaling [104, 105], which are both linked to mTOR signaling . Metformin, an anti-diabetic drug, which indirectly inhibits the mTOR pathway, decreases cancer incidence, prevents premature menopause and increases lifespan in rodents [107-112]. Rapamycin not only delays typical age-related diseases in animal models but also extends life span in mice [113-119]. Thus, there exists the opportunity to extend both health span and lifespan in our life time [120, 121].
The molecular damage theory dies hard
But what about the molecular damage? It was assumed that molecular damage contributes to aging because it accumulates with time. Well, over time you may accumulate money in your bank account. However, neither accumulation of molecular damage nor accumulation of money is a cause of your aging. Yes, molecular damage must accumulate. But although molecular damage accumulates, it does not necessarily limit lifespan, particularly if other causes limit life span. By analogy, if everyone died from accidents, starvation and infection early in life, then aging and age-related diseases (such as obesity and atherosclerosis) would not even be known. By the same token, “aging” due to molecular damage will not manifest itself, if aging due to hyperfunction invariably limits life span . Notably, as a marker of hyperfunction in senescent cells, DNA damage response-signaling pathways can be hyper-activated even without DNA damage [123-126].
The hyperfunction theory suggests that repair of molecular damage is important for long life, exactly because it is harmful from day one. But the importance of any process for viability does not imply its role in aging. For example, although DNA replication is important, it (or its abnormalities) does not drive aging. Nonetheless, with a few exceptions, most gerontologists cannot let go of the damage accumulation theory, historically the dominant paradigm in the field. This outlook is superbly expressed by Piotr Zimniak, who argues that the molecular damage theory cannot be replaced by the hyperfunction theory  He has briefly summarized the hyperfunction theory in figures 1 A (here figure 1A). First, I will extend figure 2 from A to B (Fig. 2 A,B) in part because the terms “loss of homeostasis” and “age-related diseases” are manifestations of aging either according to molecular-damage or to hyperfunction theories, retrospectively. “Loss of homeostasis” and “age-related diseases” are not alternatives, but instead overlapping terms, almost synonyms, closely related phenomena.
Figure 2. The hyperfunction theory: three representations. (A) The simplest model. Cause-effect relationship between TOR-driven hyperfunction and death via age-related diseases (diseases). For diseases, we mean age-related diseases (ADR). (B) Extended model. Diseases include initial loss of homeostasis and systemic hyperfunction (an increase in blood pressure and glucose) leading to organ damage like stroke, menopause and diabetes. Cellular hyperfunctions (e.g. hyper-secretion) can be viewed as cellular aging. (C) Unification of the hyper-function theory. Since cellular aging is cellular hyperfunction, it can be unified with systemic hyperfinction. In brief, aging = hyperfunction. Loss of homeostasis, decline and organ damage, which can be unified as ADR (age-related DISEASES).
Normal and hyper-functions
Hyper-functions result from the continuation (or running on) of normal functions. For example, blood pressure rises from birth to adulthood. This developmental program increases robustness by assuring optimal blood pressure. But its continuation (hyperfunction) leads to hypertension. As another example, at puberty in girls, a carefully-regulated increase of estrogen and gonadotropin levels switch on the reproduction (program, function). A continuation of the same process (quasi-program, hyperfunction) progressively impairs fertility after 30 (Fig. 2) and eventually culminates in ovarian failure and menopause [128, 134, 135]. Then, levels of estrogens drop (decline), accelerating osteoporosis. Menopause is a typical age-related disease . It is not called a disease simply because it happens in all women (Fig. 3). Actually, it does not: some women die before menopause. Just 300 years ago most women died before menopause. Menopause is a quasi-programmed disease . Menopause is particularly program-like, because it happens relatively early in life, when quasi-program (hyperfunction) is still very directional, a precise continuation of the developmental program for reproduction.
I need to emphasize that hyper-function is not always an increased function. It may be unneeded normal function like growth and apoptosis. In analogy, a car that is driving at 65 pmh at small parking lot is “hyperfunctional”, even if at the highway, this speed isr normal. Similarly, the TOR activity that is constantly and chronically at the level of rapidly dividing cells, (“proliferating cell” level) is gerogeni in resting postmitotic cells.
From hyperfunction/hypertrophy to decline/atrophy
There are diverse mechanisms of secondary atrophy during aging.
Quasi-programmed (hyperfunction-driven) apoptosis. In this case, atrophy is secondary to signal resistance due to mTOR overactivation. For example, in insulin-secreting beta-cells overactivated by nutrients and insulin, mTOR causes cellular hypertrophy/hyperplasia/hyperfunction and secondary insensitivity to IGF-1 and deactivation of Akt, leading to beta-cell death [130, 175, 176]. mTOR-dependent hyperfunction and hypertrophy of beta-cells, may eventually culminate in cell loss and decline of function [177, 178]. Similar quasi-programmed apoptosis could be observed in the muscle, the immune system and subcutaneous adipocytes. Apoptosis is programmed in development but quasi-programmed in aging. Also, strong hyper-mitogenic drive can force post-mitotic neurons into the cell cycle leading to apoptosis in Alzheimer disease [179-184]. Importantly, cellular senescence is associated with both hyper-mitogenic drive and death in mitosis, explaining this phenomenon .
Poor wound-healing could be due to signal resistance secondary to cellular aging and hyperglycemia .
Common atrophy is secondary not to aging itself but to age-related diseases. This is disease-driven atrophy, the end point of some diseases. This is so far away from initial cause that it is completely unrelated to aging and is mTOR-independent. Let me provide two examples. Atherosclerosis of the femoral artery can cause not only atrophy but even gangrene of the feet. Atrophy is very common in ischemia due to atherosclerosis. As another example, hip fracture in an elderly person often leads to prolonged immobilization. Muscle atrophy is secondary to immobilization, which is secondary to the broken hip, which is secondary to osteoporosis, which is secondary to hyperfunction of osteoclasts… and so on. This is disease-driven atrophy. Atrophy is common because it is secondary to diseases. This further supports the thesis that there is no healthy aging (healthy aging is no aging or very slow aging).
Argument 5: When cellular hyperfunction causes atrophy, there must be molecular mechanisms such as interaction of ligand with receptor, protein aggregation and so on. More specifically, the critic claims that “an overproduced ligand may over stimulate or desensitize a receptor”  For example, an overproduced ligand may over stimulate or desensitize a receptor, and an overabundant protein may aggregate and interfere with intracellular trafficking, or co-precipitate with and thus withdraw essential cell constituents. First, this is still an example of hyper-function. Importantly, rapamycin alleviates toxicity of different aggregate-prone proteins  and decreases aggregate-prone proteins [196-200]Second, this is not molecular damage but signal transduction. In contrast, the molecular damage theory is about life long accumulation (!) of random (!) molecular damage due to failure of repair/maintenance (!). As emphasized by Kirkwood, “the aging process is caused by the gradual buildup of a huge number of individually tiny faults - some damage to a DNA strand here, a deranged protein molecule there, and so on” .
If we redefine “signal transduction” as “accumulation of random molecular damage due to failure of maintenance”, then yes, this is a cause of aging and age-related diseases. Then driven by mTOR, “molecular damage” (formerly, signal transduction) includes protein phosphorylation as well as protein synthesis, inhibition of autophagy and caspase activation. But this is hyperfunction, not failure of maintenance. Phosphorylation of S6K by mTOR, modification of NF-kB or dephosphorylation of Akt, for instance, are not molecular damage. This is signal transduction. Exactly the same signal transduction is involved in development, cell growth, differentiation and apoptosis. These are normal functions. Since the same molecular events are involved in development and developmental growth, this would lead to the reductio ad absurdum that development is caused by damage. More plausibly, their (developmental functions) continuation gives rise to quasi-programmed hyperfunction. These normal functions and hyperfunctions can be inhibited by signal transduction inhibitors including rapamycin.
Life long accumulation of molecular damage is irrelevant to aging. Aging (hyper-function of signaling pathway) causes damage and this damage is organ/system/organismal damage (not molecular damage). Hyperfunction of liver cells, for instance, after several decades, contributes to brain damage via stroke.
Healthy death in molecular damage theory
As commonly depicted , aging (loss of homeostasis), caused by molecular damage, in turn causes death via two independent ways (Fig. 4A). The first way is via an increased susceptibility to diseases. The second way is directly without any diseases, and is the true aging mechanism, according the molecular damage theory. This is incorrect. Consider young healthy constructor worker fall to death from the storm (Yes, this is “healthy” death but not from aging). Another example. The fall from the height of 100 year old person is due to either age-related Parkinson's disease or due to infarction. This is not death from healthy aging. This is death due to an age-related disease.
As we discussed, death from aging is death from diseases (natural causes) (Figs. 5,6). Even the oldest people do not die from healthy aging. There is no such medical diagnosis as healthy death or death from asymptomatic accumulation of molecular damage. Of course, we can consider “loss of homeostasis” broadly, including severe deviations of homeostasis or diseases. But then there is no other “disease pathway” anyway. Regardless of the causes of aging, the causes of death and the path from “loss of homeostasis” to death are well known. In all theories of aging, this must be identical because this is a medical fact (Fig. 5). There is no death directly from healthy aging (of healthy loss of homeostasis). This is a part of the same path (Fig. 5). So, shift from A to B (Fig. 4), exactly as in figure 2 B.
Figure 5. Harmonizing two theories for direct comparison. The causes of molecular damage are mostly unknown and also irrelevant.
Now the question is how accumulation of molecular damage drives each age-related diseases (Figs. 5, 6). For example, how accumulation of molecular damage causes insulin resistance, hypertension and obesity. There is no obvious answer.
Is TOR-driven hyperfunction true aging?
Is it true aging? Or is it just a process related to disease and mortality ? No, it is genuine aging. Not only because it determines mortality (a hallmark of aging is an exponential increase in mortality rate) but also because mTOR-dependent hyperfunctions, signal-resistance, hypertrophy, hypermitogenic drive coupled with loss of regenerative potential are markers of cellular senescence. Cellular senescence can be caused by mTOR activation in cell culture. Although by arresting cell cycle, DNA damage response (DDR) creates conditions for senescence (if mTOR is active), the accumulation of molecular damage itself does not cause senescence in cell culture [35, 36]. In contrast, accumulation of molecular damage contributes to cancer cell immortality . Thus TOR-driven hyperfunction links cellular aging to age-related diseases and organismal aging, defined as an increase of the probability of death.
Do any questions remain unanswered?
Although we have answered most of the issues relating to the damage/maintenance vs hyperfunction debate raised by P. Zimniak (one is left for the conclusion), it may seem that many more unanswered questions remain. Yet, some of them have been answered previously (see PubMed “Blagosklonny” and related references within) and others will be answered in forthcoming articles. The evolutionary aspects, the links between development and aging, pro-aging and anti-aging genes, common signaling pathways that drive aging, cellular senescence and diseases such as cancer have been extensively discussed. According to the hyperfunction theory, aging and its manifestations are never programmed: even menopause and the death of Pacific Salmon are not programmed. Both are excellent examples of quasi-program, a non-adoptive, aimless, harmful continuation of a reproductive program.
Also, as already discussed, lifespan is determined not only by the aging process but also by aging-tolerance, an ability to tolerate disease of aging and their complications. As a matter of fact, almost all medical interventions (including by-pass surgery and teeth proteases) increase aging tolerance rather than slow down aging. When needed, natural selection may favor anatomical and molecular adaptations such as collateral blood vessels and heat shock proteins, for example. Thus extra coronary arteries would increase lifespan despite age-related atherosclerosis, hypertension and thrombosis. Aging-tolerance is a concept that can solve some mysteries of aging. Many potential questions that might be asked are purely medical. Their answers can be found in medical textbooks.
There are a few questions that are difficult to answer now: What TOR-independent pathways contribute to hyperfunctional aging? For example, sirtuins, FOXO, AMPK and IGF-1 can all be linked to the mTOR networks [201-206]. What about JNK [158, 207-209] and NF-kB , [162, 211, 212]? Are these pathways TOR-independent? And what are crucial downstream effectors of TOR that control aging? It seems that rapamycin should be used in intermittent fashion, perhaps in combinations with e.g. metformin, lipid-lowering drugs, and beta-blockers and angiotens together with dietary restriction and physical exercise. But what are the exact doses and schedules maximize positive and minimize negative effects? What would be the causes of death if TOR-driven aging were suppressed? Hyperfunction driven by run on of other pathways? Accumulation of molecular damage? Mitochondrial expansion? Other types of unknown aging? Would anti-oxidants become useful for that types of aging? And what are the pathological manifestations of accumulation of random molecular damage?
What TOR-independent pathways contribute to hyperfunctional aging? For example, sirtuins, FOXO, AMPK and IGF-1 can all be linked to the mTOR networks [201-206]. What about JNK [158, 207-209] and NF-kB , [162, 211, 212]? Are these pathways TOR-independent? And what are crucial downstream effectors of TOR that control aging?
It seems that rapamycin should be used in intermittent fashion, perhaps in combinations with e.g. metformin, lipid-lowering drugs, and beta-blockers and angiotens together with dietary restriction and physical exercise. But what are the exact doses and schedules maximize positive and minimize negative effects?
What would be the causes of death if TOR-driven aging were suppressed? Hyperfunction driven by run on of other pathways? Accumulation of molecular damage? Mitochondrial expansion? Other types of unknown aging? Would anti-oxidants become useful for that types of aging? And what are the pathological manifestations of accumulation of random molecular damage?
The peculiar role of molecular damage
Repair of random molecular damage is so important that cumulative damage does not reach a deadly threshold during the lifetime. In progeria , fitness is low from day one. There is a very strong natural selection for repair and maintenance. In contrast, mTOR-driven functions are essential early in life and there is a very strong selection for robust mTOR-dependent functions, even if their continuation (hyperfunctions) are harmful in old age. Still, we cannot exclude contribution of molecular damage to some symptoms of aging (Fig.7). This is simply unknown. May it decrease aging-tolerance [127, 214]? This is a fascinating question to answer.
A peculiar case is cancer. Accumulation of damage does not make a cancer cell fragile, arguing against the molecular damage theory, but instead via rounds of selection and proliferation which create robust cells that damage the organism. Notably, such selection of random mutations culminates in non-random activation of the mTOR pathway . Activation of the PI3K/mTOR pathway is the most common alteration (and therapeutic target) in cancer [215-227]. Also, hyper-activation of the DNA damage response, involving TOR-like kinases, may contribute to hyperfunction. Therefore, molecular damage and autonomous activation of damage-sensing signal-transduction pathways may contribute to hyperfunction, not vice versa.
The last argument for molecular damage theory
The last argument by Zimniak is: “Hyperfunction is one of several sources of molecular damage, on equal footing with reactive metabolites, toxicants, ROS, electrophiles, stochastic events, and many others” . This argument will not be discussed all over again. Not only because hyper-functions are not a source of accumulation of molecular damage. But mostly because the starting point of this article is that the theory of molecular damage did not fit numerous observation, made incorrect predictions, did not contribute to medical advances, and did not lead to any practical application. As philosophers teach us, the theory cannot be wrong (or right), but it can be useless.
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