Research Article: Answering the ultimate question “What is the Proximal Cause of Aging?”

Date Published: December 30, 2012

Publisher: Impact Journals LLC

Author(s): Mikhail V. Blagosklonny.



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?

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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 [54]. 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 [54]. 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 [54]. This is also applicable to simple multicellular organisms such as Drosophila and C. Elegans [94, 95].

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 [122]. Notably, as a marker of hyperfunction in senescent cells, DNA damage response-signaling pathways can be hyper-activated even without DNA damage [123-126].

Cellular hyper-function (and secondary signal resistance) must cause loss of homeostasis and, eventually, organ damage and death. Loss of homeostasis encompasses pre-diseases (e.g., glucose intolerance or insulin-resistance), syndromes such as metabolic and diseases such as hypertension, obesity, diabetes, atherosclerosis, renal and cardiac failure and so on. Obesity, hypertension, hyperlipidemia, hyperglycemia, hyperinsulinemia, hyperprolactinemia (and other hypers) are all systemic hyperfunctions, measurable by standard medical methods. They are systemic manifestations of cellular hyperfunction. Such systemic hyperfunctions also constitute loss of homeostasis.

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 [136]. 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 [128]. 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.

Any theory of aging (regardless of the cause of aging) must be in agreement with the following medical facts:
The incidence of age-related diseases (ARD) increases exponentially with age in parallel with death rate. This is not co-incidental but rather reflects the fact that ARD cause death. If an individual does not die from one disease (e.g., cancer), he/she will eventually die from another (e.g., stroke and myocardial infarction). Of course, small organisms, which even lack the heart have different ARD, which would be better studied, if these small animals “complain to their “doctors”.Aging kills via diseases. In fact, no one has ever died without a cause. And “natural causes” always denotes disease. In very elderly people, the diagnosis of “death from natural causes” means many competing causes (diseases) simultaneously. Death from natural causes simply excludes death from suicide and homicide. But there is no such medical diagnosis as “death from accumulation of molecular damage”. This “nonexistent diagnosis” is simply not needed because one or several deadly diseases can be always (always) found (unless homicide). Even sudden cardiac death usually results from myocardial fibrillation (archetypical hyper-function of electrical myocytes andventricular hypertrophy).

Due to extensive biomedical research, humans are the most studied animal. No one dies from “healthy aging”, without a cause: either natural causes such as disease or homicide/suicide. Similar, all mammals die from age-related diseases (ARD), albeit their frequencies vary dramatically. This could be expected given a quasi-programmed nature of aging and ARD. If one disease occurs earlier than other diseases, it will mask all other diseases. Likewise, Pacific Salmon die from quasi-programmed ADR, namely massive organ damage, resulting from continuation of the reproductive program. This is a particular clear example of quasi-programmed hyperfunction [142]. It is often stated that all Pacific Salmon die from aging/ADR, and therefore that this is a program. Not true. Only 1-2% Pacific Salmon die from ADR, all others die earlier from accidental causes, which must be expected in the wild [142], (see figure 3 in ref.[4]).

There are diverse mechanisms of secondary atrophy during aging.

As commonly depicted [3], 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.

Is it true aging? Or is it just a process related to disease and mortality [3]? 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 [122]. Thus TOR-driven hyperfunction links cellular aging to age-related diseases and organismal aging, defined as an increase of the probability of death.

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.

Repair of random molecular damage is so important that cumulative damage does not reach a deadly threshold during the lifetime. In progeria [213], 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.

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” [3]. 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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