User:Alexander M. Wolf/sandbox

= Tumor suppression theory of aging = The tumor suppression theory of aging is a mechanistic theory of aging that proposes aging to be mostly the consequence of tumor-suppressive mechanisms that evolved to limit the tumorigenic potential of clonally expanding cells. A variation of the somatic mutation theory of aging, oncogenic mutations and clonal expansion, but not functional impairment, are postulated as the most relevant consequence of somatic mutations. Accumulating senescent cells, senescence-associated secretory phenotypes and stem cell exhaustion eventually cause tissue dysfunction and the majority, if not most, phenotypes of aging.

Background and history
The theory, first mentioned in, evolved out of an analysis of the effects of obesity and caloric restriction on cell proliferation and aging and was published in the journal "Mechanisms of Ageing and Development" in December 2021.

Principles
Somatic mutation is postulated to cause cancer and, indirectly, aging. Only mutations causing aberrant proliferation and clonal expansion are seen as important, functional impairment is seen as mostly irrelevant. Most phenotypes of aging are suggested to be the product of tumor suppressive mechanisms that include cell senescence, telomere shortening, apoptosis and (oncogene-induced) differentiation. These together cause stem cell exhaustion and the typical signs of ageing such as functional decline and repair deficiency. Cancer and aging are postulated to be the consequence of too much and too little (capacity for) self-renewal. The limits on cell self-renewal that evolved to suppress cancer eventually cause the phenotype of ageing in late life.

Mechanisms
Cancer is caused by oncogenic mutations in somatic cells. Mutations arise predominantly during cell division. The pace of cell division is postulated to determine not only cancer risk (as shown by Tomasetti ), but also the pace of ageing, as it is the primary determinant of the rate of somatic mutation accumulation. In an accompanying paper, it is proposed that caloric restriction, and several caloric restriction mimetics including resveratrol, NAD supplementation, rapamycin and metformin as well, increase life span mostly through inducing weight loss and the associated reduction in the detrimental effects of obesity and increased proliferative signalling. It is concluded that obesity accelerates and caloric restriction decelerates aging through their effects on cell proliferation rate, which is driven by excess nutrient intake and the resulting obesity.

Cancer driven by somatic mutation is seen as an important limit on mammalian longevity, which was largely confirmed in an unrelated publication a month later. Peto’s paradox, the observation that cancer risk is independent of animal size and longevity is taken as proof that “mutation is a fundamental and hard limit on mammalian longevity”. It is also argued that cancer must have been the dominant age-related cause of death for humans in their primitive, prehistoric environment.

Aging is thought to be the consequence of mechanisms that evolved because it was beneficial overall to limit the replicative potential of individual cells in order to suppress tumorigenesis. Aging is therefore a case of antagonistic pleiotropy, aging being the trade-off of tumor suppression. Because mutations are “invisible” to the cell itself, tumor-suppressive mechanisms are triggered by replication itself. The purpose of many hallmarks of aging, such as telomere shortening and cell senescence, is tumor suppression. DNA damage caused by oncogene-induced hyper-replication is seen as another important driver of tumor-suppressive cell senescence. Cell senescence causes, together with apoptosis and differentiation, the exhaustion of stem cell pools, another hallmark of aging. In old age, cell senescence and growth arrest become so widespread that the detrimental effects of limiting self-renewal become more and more apparent, manifesting as aging.

Novelty
The most important novelty of the tumor suppression theory of aging is that oncogenic mutations are seen as the only type of somatic mutation relevant for ageing. Previously, somatic mutations were almost exclusively seen as a form of damage, leading, like other damage, to a loss of function (with the exception of cancer). But despite considerable advance in DNA sequencing, there is still little evidence for a meaningful age-related functional decline as a consequence of somatic mutation. The tumor suppression theory of aging sides with Aubrey de Grey, who in 2007 suggested that because cancer is so lethal, somatic mutations have to be prevented to such an extent that they may never accumulate to the magnitude necessary to result in a pathogenic effect other than cancer. Because somatic mutation occurs almost exclusively during cell division, the rate of cell division in stem cell compartments is proposed to determine the rate of human aging.