Research Article: Hormesis does not make sense except in the light of TOR-driven aging

Date Published: November 12, 2011

Publisher: Impact Journals LLC

Author(s): Mikhail V. Blagosklonny.



Weak stresses (including weak oxidative stress, cytostatic agents, heat shock, hypoxia, calorie restriction) may extend lifespan. Known as hormesis, this is the most controversial notion in gerontology. For one, it is believed that aging is caused by accumulation of molecular damage. If so, hormetic stresses (by causing damage) must shorten lifespan. To solve the paradox, it was suggested that, by activating repair, hormetic stresses eventually decrease damage. Similarly, Baron Munchausen escaped from a swamp by pulling himself up by his own hair. Instead, I discuss that aging is not caused by accumulation of molecular damage. Although molecular damage accumulates, organisms do not live long enough to age from this accumulation. Instead, aging is driven by overactivated signal-transduction pathways including the TOR (Target of Rapamycin) pathway. A diverse group of hormetic conditions can be divided into two groups. “Hormesis A” inhibits the TOR pathway. “Hormesis B” increases aging-tolerance, defined as the ability to survive catastrophic complications of aging. Hormesis A includes calorie restriction, resveratrol, rapamycin, p53-inducing agents and, in part, physical exercise, heat shock and hypoxia. Hormesis B includes ischemic preconditioning and, in part, physical exercise, heat shock, hypoxia and medical interventions.

Partial Text

It is believed that aging is a decline, deterioration due to accumulation of random molecular and cellular damage caused by free radicals, radiation, stresses, pathogens, toxins, carcinogens, mistakes in replication/translation, protein misfolding and even mechanical forces. If aging is caused by damage, then damaging stresses would accelerate aging (Figure 1A). However, mild stresses (including oxidative stress) can extend life span in different species [1-30].

First, it is paradoxical to decrease damage by causing damage (Figure 1B). There is no similar example in medicine. If one wishes to prevent stroke due to high blood pressure, one needs to decrease blood pressure not to increase it. Examples are endless including weight control to prevent diabetes and quitting smoking to prevent lung cancer. No one will advocate “mild and repeated” smoking to prevent lung cancer even though it might activate the defenses. The simple reason is that DNA damage is actually involved in cancer initiation. But even cancer-promoting damage is not random: mutations activate growth-promoting pathways including PI3K/mTOR, the most universal alteration in cancer [42-45]. And cancer-initiating damage does not cause cellular decline (in contrast, cancer cells are very robust and hyper-functional), is not sufficient to cause cancer, requiring rounds of cell replication, selection [46, 47] and organismal aging [48]. By slowing down aging, CR and rapamycin delay cancer (without affecting mutations). The notion that aging promotes cancer is beyond the topic of this article and cannot be discussed here. The point here is that since DNA damage contributes to cancer, no one will suggest hormetic smoking or radioactivity (at any doses) to delay cancer. In analogy, if damaging hormesis may delay aging, aging cannot be possibly be caused by damage.

If aging is driven by damage, then damage must accelerate aging. If hormesis induces damage and slows down aging, then aging is not driven by damage. So a straightforward explanation is that aging is not caused by accumulation of molecular damage [36]. It was predicted “that five years from now, current opponents will take the TOR-centric model for granted, which then will become new dogma (ironically)” [35].

The nutrient-sensing TOR pathway is activated by insulin, growth factors and nutrients (Figure 2). In turn, it increases protein synthesis, stimulates ribosomal biogenesis and cell mass growth (causing cell hypertrophy), inhibits autophagy, induces accumulation of aggregation-prone proteins, increases growth factors (GF) secretion and causes resistance to GF and insulin [69-79].

Life span can be extended by either (a) slowing down aging and (b) by increasing aging tolerance, defined as the ability to survive complications (catastrophes) of aging [36].

Hormetic stresses include two groups of agents that (a) slow down aging by inhibiting the TOR pathway and (b) increase aging tolerance, without affecting the aging process (Figure 2). We will call them hormesis A and hormesis B. Examples of hormesis A are calorie restricttion, rapamycin, resveratrol and p53-inducing agents. Examples of hormesis B are adaptive preconditioning to ischemia and coronary bypass. Heat shock, hypoxia and physical exercise belong to both groups.

Plants, microorganisms and sea animals produce toxic agents that inhibit or damage microtubules, DNA and many other vital targets. Due to their toxicity, some of them are used as anti-cancer drugs, although nature did not created them for that purpose. Nature of course created these poisons to hurt predators and competitors [125, 126]. Similarly, rapamycin is an antifungal antibiotic produced by bacteria. TOR stimulates growth in response to nutrients. Therefore, soil bacteria produce rapamycin to inhibit yeast growth. While inhibiting TOR-dependent growth, rapamycin slows down TOR-dependent aging in older yeast [93, 94]. Given that cancer (like aging) is “a form of growth”, the mTOR pathway is activated in cancer. And, although not created for that purpose by nature, inhibitors of mTOR are used as anticancer agents [42, 43, 127, 128]. I wish to emphasize again that bacteria produce rapamycin neither as a medicine for longevity nor as an anticancer drug, but as an antifungal antibiotic. Simply the same signaling pathways that are involved in growth also are involved in cancer and aging [88]. Growth suppressants may suppress aging because aging is a continuation of growth, driven by the same TOR/S6K pathway [129]. To extend lifespan, they either should inhibit the TOR pathway or increase aging tolerance (Figure 2).

DNA damage induces p53, which is known to inhibit mTOR pathway both upstream and downstream of mTOR [187-197]. Induction of p53 by nutlin-3a can suppress senescent phenotype or suppress conversion of quiescence into senescence [197-200]. The gero-suppressive effect is evident only when p53 is capable to inhibit mTOR [198, 201]. In certain conditions, p53 may act as an anti-aging agent [202-207].

Hormesis B extends life span by increasing aging tolerance. Mild stresses prepare organism to catastrophes caused by diseases of aging. Examples of catastrophes include stroke and myocardial ischemia. The occlusion of a cerebral artery for 60 min (injurious ischemia) damages the brain. The occlusion of the same cerebral artery for 15 min (preconditioning) protects from the damage caused by injurious ischemia [208]. Similarly, severe myocardial ischemia causes irreversible injury. Mild ischemia protects the heart from severe ischemia. Similarly, by inducing HSPs, heat shock may protect the myocardium from severe ischemia. Repeated, transient ischemic episodes or heat shock augment the ischemic tolerance of affected myocardium. Upregulation of immediate early genes and heat shock genes plays an important role in myocardial adaptation to acute ischemic stress [209]. Also, hormetic stresses can cause growth of collateral arteries. This coronary collateral function can preserve ischemic myocardium [210].

The hypothesis that aging is NOT driven by accumulation of random damage allows us to explain hormesis. Type A hormesis antagonizes the TOR pathway (Figure 2). Hormesis B causes stresses including damaging stresses. Since aging is not caused by damage, this does not contribute to aging but instead may cause aging-tolerance, thus protecting organisms from lethal consequences of aging-induced catastrophes.





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