The Tumor Suppression Theory of Aging

While they cannot explain aging as a whole, single cause theories of aging can be useful tools to frame discussion and investigation aimed at better understanding aging and its evolution. The theory presented here is aging viewed through the lens of cancer, two entwined processes. Aging is viewed as largely a consequence of tumor suppression mechanisms that evolved to keep cancer at a low enough incidence for successful selection and continuation of the species. Cancer and evolution are themselves in a dynamic, competing equilibrium. Evolution requires a certain minimal rate of spontaneous mutation, while cancer thrives on those mutations; the higher the rate, the higher the risk of cancer. An ever more complex arms race results, eventually resulting in the varied pace of mutation and aging, types of tumor suppression mechanisms, and incidence of cancer found across diverse species today.

Single cause theories of aging remain important in aging research. One obvious reason for this is the need for simplification. Another reason is the necessity to at least break up the aging process into potentially treatable parts, even if no single treatment can be expected to do much. Somatic mutations have long been proposed as a cause of aging and genomic instability is one of the four primary hallmarks of aging. The tumor suppression theory of aging outlined here differs from previous theories in that clonal expansion and malignancy is proposed as the relevant consequence of somatic mutation and that impairment, loss of cellular function, or cell death as a consequence of somatic mutation is largely irrelevant. To counter the tumorigenic potential of clonally expanding cells, we have evolved tumor suppression mechanisms that remove or limit proliferation of stem cells. Accumulating senescent cells and loss of capacity for self-renewal and repair eventually cause the phenotypes we experience in very old age.

Obesity and caloric restriction accelerate and decelerate aging due to their effect on cell proliferation, during which most mutations arise. Most phenotypes of aging are merely tumor-suppressive mechanisms that evolved to limit malignant growth, the dominant age-related cause of death in early and middle life.

Cancer limits life span for most long-lived mammals, a phenomenon known as Peto's paradox. Its conservation across species demonstrates that mutation is a fundamental but hard limit on mammalian longevity. Cell senescence and apoptosis and differentiation induced by oncogenes, telomere shortening, or DNA damage evolved as a second line of defense to limit the tumorigenic potential of clonally expanding cells, but accumulating senescent cells, senescence-associated secretory phenotypes and stem cell exhaustion eventually cause tissue dysfunction and the majority, if not most, phenotypes of aging.

If the tumor suppression theory of aging would be correct, the only way to retard human aging would be a reduction of somatic mutation. Preventing aging would be the same as preventing cancer. Unfortunately, reduction or prevention of somatic mutation is something that remains thoroughly out of reach of current medical technology. The problem of aging will probably defy the assault of human ingenuity for some time to come.

In the meantime, removal of senescent cells seems to offer a reasonable chance of alleviating many phenotypes of very old age. Cell senescence is antagonistically pleiotropic, and accumulation of senescent cells probably an evolutionary accident brought about by the unforeseen increase in average human life expectancy. Together with a second antagonistically pleiotropic phenomenon, the age-related emergence of systemic and excessive chronic sterile inflammation, these two phenomena might be mutually reinforcing evolutionary accidents responsible for many of the pathogenic processes promoting the irreversible functional decline of very old age. Even though they do not prevent aging per se, in terms of looking at realistic strategies for increasing human health span, these two processes are, compared to the primary prevention of mutation, probably lower hanging fruit and offer plentiful possibilities in postponing the dreaded symptoms of old age.



Why didn't the human genome just add extra copies of p53? It works for elephants. Why all of the complex anti-cancer mechanisms instead?

Posted by: Carl White at November 4th, 2021 6:18 PM

Interesting idea could be to add extra p53 copies to mice and see effects

Posted by: Robert Read at November 5th, 2021 3:46 AM

Thank you for introducing my work. Please also have a look at the 'trashing' of caloric restriction,
"Rodent diet aids and the fallacy of caloric restriction" (,
the first part of the paper appearing in the same issue.
I'd like to hear any opinion Alexander M. Wolf

Posted by: Alexander M. Wolf at November 20th, 2021 12:39 PM
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