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

Date Published: December 31, 2011

Publisher: Impact Journals LLC

Author(s): Mikhail V. Blagosklonny.

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Abstract

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.

Partial Text

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 [1-15]. 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.

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 non-random 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 [263-269].

 

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