Understanding the molecular mechanisms of normal aging is a prerequisite to significantly increase human health span. Caloric restriction (CR), which delays aging in most animal models, serves as a yardstick to evaluate interventions extending life span. However, mice given unlimited access to food suffer severe obesity and benefits from CR might be through reducing obesity-associated mortality. Health gains from CR depend on the control mice being gluttonous enough and less obese mouse strains benefit far less from CR. Most pharmacologic interventions reported to mimic CR and increase life span in mice, including resveratrol, rapamycin, nicotinamide mononucleotide and metformin, also reduce mouse body weight. In primates, CR does not delay aging unless the control group is eating enough to suffer from obesity-related disease. Human survival peaks at a BMI achievable without CR. CR mimetics are just diet aids and CR should not be regarded as increasing longevity in healthy weight individuals. Instead, I propose the tumor suppression theory of aging: most phenotypes of aging are the consequence of tumor-suppressive cell senescence that has evolved to limit the tumorigenic potential of clonally expanding cells. A variant of the somatic mutation theory of aging, oncogenic mutations and clonal expansion (opposed to functional impairment) are postulated as the most relevant consequence of somatic mutations. Irreversible cell cycle arrest, accumulating senescent cells, the senescence-associated secretory phenotype and subsequent stem cell depletion eventually cause tissue dysfunction, loss of regeneration and the majority, if not most, phenotypes of aging.
COMMD4 functions with the histone H2A-H2B dimer for the timely repair of DNA double-strand breaks
