Molecular damage in cancer: an argument for mTOR-driven aging.

Despite common belief, accumulation of molecular damage does not play a key role in aging. Still, cancer (an age-related disease) is initiated by molecular damage. Cancer and aging share a lot in common including the activation of the TOR pathway. But the role of molecular damage distinguishes cancer and aging. Furthermore, an analysis of the role of both damage and aging in cancer argues against “a decline, caused by accumulation of molecular damage” as a cause of aging. I also discuss how random molecular damage, via rounds of multiplication and selection, brings about non-random hallmarks of cancer.


INTRODUCTION
Aging is defined as a decline caused by accumulation of all sorts of damage, in particular, molecular damage. This statement seemed so obvious that it was not questioned. Yet several lines of evidence rule out molecular damage as a cause of aging [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]. Yes, of course, molecular damage accumulates over time. But this accumulation is not sufficient to cause organismal death. Eventually it would. But the organism does not live long enough, because another cause terminates life first [8]. This cause is aging, a continuation of developmental growth.
Definitely, developmental growth is not driven by accumulation of molecular damage, although molecular damage accumulates. Similarly, aging is not driven by damage.

Damage in cancer
Damage causes activate oncogenes and de-activate tumor suppressors due to genetic mutations, epigenetic alterations and microRNAs dysregulation . Even according to alternative theories, cancer is caused by damage too [58]. So damage is involved in cancer. There are some exceptions, mostly related to embryonic cells. Also, in theory, extra-genetic alterations such as stable activation of oncogenic pathways via positive feedback loops can contribute to malignant phenotype [59]. Finally, positive feedback loops could be established between cancer and normal cells [59][60][61]. But in general molecular damage is a key factor in cancer origin. In agreement, cancer is associated with genetic instability [59, 62-69].

Damage is not sufficient to cause cancer
However, molecular damage is not sufficient either to cause cancer or to hurt organism. This damage is multiplied billions of times via cell replication. Also, cells with random mutations undergo non-random selection ( Figure 1).

Multiplication and selection
A 1 cm tumor contains 10 9 (1 billion) cells. Therefore, damage does not passively accumulate but is actively multiplied. Cells undergo clonal selection, analogous to Darwinian selection [70, 97-100]. Importantly, most mutations are so called "passenger" mutations that remain random and useless [72,79,80,101]. But nevertheless they do not decrease cell vitality.
One additional explanation is that chronic overactivation of mTOR renders normal cells irresponsive to growth factors [157]. (In fact, mTOR/S6K renders cells resistant to insulin and growth factors [158,159]). Then, cancer cells, which are growth signal-independent, acquire selective advantage. In theory, by restoring responsiveness of normal cells to mitogenic signals, treatment with rapamycin can eliminate selective advantage for cancer cells. It was predicted that rapamycin can restore responsiveness of aging cells [157]. In fact, mTOR may cause exhaustion of the proliferative potential of stem cells and, in some studies, rapamycin improved the responsiveness of aging stem cells and immune cells [160][161][162][163]. As an example, activation of mTOR promoted leukemia-initiated cells, while depleting normal hematopoietic stem cell. Rapamycin not only depleted leukaemia-initiating cells but also restored normal stem cell function [160,164]. Thus decreased proliferative potential of normal cells is associated with selective advantage to cancer cells.

Oncogenic transformation and gerogenic conversion
There are non-mutually exclusive ways to depict oncogenic transformation, as complementary activation/ disabling of signaling pathways [88, [217][218][219][220][221][222][223][224][225]. Here to compare cancer with aging, I view oncogenic transformation as (a) activation of growth-promoting pathways such as mTOR and (b) loss of cell cycle control. Growth promoting pathways can drive either growth or aging, whereas avoidance of cell cycle arrest precludes aging (Fig. 1). In quiescent cells, activation of growth-promoting pathways (such as mTOR) converts quiescence into senescence, a process named gerogenic conversion or geroconversion [226,227]. In proliferating cells, mTOR is fully activated. Induction of cell cycle arrest, without inhibition of mTOR causes gerogenic conversion too. When cell cycle is arrested, growth-promoting pathways drive hypertrophy and aging instead of growth. The difference between quiescence and senescence was recently discussed in detail [227]. Cellular hyper-functions and feedback signal resistance are manifestations of cellular senescence/aging that lead to age-related diseases [227]. These hallmarks result from excessive activation of signaling pathways not from accumulation of damage.

Why aging is not caused by accumulation of damage
To harbor the active mTOR pathway, cancer cells undergo multiple rounds of selection. In other words, numerous random mutations are selected for non-random activation of mTOR. In contrast it is resting non-dividing cells such as liver, muscle, fat, connective tissue, neurons www.impactaging.com that undergo aging (geroconversion) in the organism. Not only levels of molecular damage are low in normal cells, but also there is no amplification and selection. So random damage hardly can cause non-random activation of mTOR. Noteworthy, calorie restriction (CR) inhibits mTOR. Even short-term CR suppresses cellular senescence in the organism [228,229].

Extragenetic activation of mTOR in aging
mTOR pathway is activated by growth factors, hormones, mitogens, pro-inflammatory cytokines and other secretory molecules and nutrients. Cells can overactivate each other, via positive feedback loops. For example in the liver and fat, hyper-active mTOR causes insulin-resistance, which in turn leads to activation mTOR in beta-cells, which produce insulin. Insulin further activates mTOR in the liver and fat.

Cancer prevention and therapy
Prevention of DNA damage can decrease cancer incidence. For example, non-smoking prevents smoking-induced cancer. Also, cancer can be prevented by decelerating the aging process by calorie restriction and rapamycin. Both calorie restriction and rapamycin delay cancer. Although rapalogs can directly affect cancer cells, rapalogs are only modestly effective as anti-cancer therapy [168,261,262], compared with their dramatic preventive effects. In any case, cancer can be prevented without decreasing levels of molecular damage. Furthermore, DNA damaging drugs are cornerstone of cancer therapy. And these drugs are also carcinogens, because anti-cancer and carcinogenic effects are two sides of the same coin [103].

CONCLUSION
Although molecular damage is typically necessary for cancer initiation, this damage limits life span not because of cellular decline but because of cellular robustness. Damage undergoes multiplication and selection. Aging by itself is a selective force that favors cancer probably because aging cells are signal resistant, thus providing selective advantage to cells that by-pass the need in mitogenic signals. In addition to nonrandom selection for oncogenic mutations, cancer cells accumulate even higher levels of random "passenger" mutations. Despite that cancer cells are robust. It must be expected that a lower rate of DNA damage in normal cells cannot cause cellular decline. Yes, molecular damage accumulates but is not a driving force for aging. Aging would occur in the absence of any molecular damage. On the other hand, yes, molecular damage is involved in something like cancer that can limit lifespan in mammals to some extend. Noteworthy, worms and flies do not die from cancer. Still they undergo PI3K/TOR-dependent aging [263][264][265][266][267][268][269].
As already discussed, if quasi-programmed TOR-driven aging would be eliminated, thus extending lifespan, then accumulation of molecular damage would become life-limiting [10]. In any case, in mammals, cellular aging (characterized by cellular overactivation, hyperfunction and secondary signal resistance) can cause diseases, which lead to organ damage. And cancer, an age-related disease, is not an exception: it kills not because cancer cells fail due to decline but because these cells damage organs. Perhaps, cancer is not the only one damage-related disease among agingdependent conditions. But a subtle interference of molecular damage with TOR-driven aging will be a topic for another article, which will discuss the intricate relationship between non-random organ damage and random molecular damage.

CONFLICT OF INTERESTS STATEMENT
The author of this manuscript has no conflict of interest to declare.