The tumor suppression theory of aging

• Published in: Mechanisms of ageing and development Vol. 200; p. 111583
• Main Author: Wolf, Alexander M.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.12.2021
• Subjects: Aging; Aging - physiology; Caloric Restriction; Cancer; Carcinogenesis - genetics; Carcinogenesis - metabolism; Cell Self Renewal - physiology; Cell senescence; Cell Transformation, Neoplastic; Clonal Evolution - physiology; Humans; Longevity - physiology; Mutation Accumulation; Somatic mutation; Tumor suppression; Somatic mutation; Aging; Cell senescence; Tumor suppression; Cancer
• ISSN: 0047-6374; 1872-6216
• DOI: 10.1016/j.mad.2021.111583

•Somatic mutations accumulating during cell division are the cause of aging and cancer.•Nutrient signaling paces aging through its effect on cell proliferation rate.•Only mutations causing proliferation and clonal expansion are important, functional impairment is mostly irrelevant.•Most phenotypes of aging are the product of tumor suppression via stem cell senescence, apoptosis and differentiation.•Cancer and aging are the consequence of too much and too little self-renewal, the latter evolving to suppress the further. Despite continued increases in human life expectancy, the factors determining the rate of human biological aging remain unknown. Without understanding the molecular mechanisms underlying aging, efforts to prevent aging are unlikely to succeed. The tumor suppression theory of aging introduced here proposes somatic mutation as the proximal cause of aging, but postulates that oncogenic transformation and clonal expansion, not functional impairment, are the relevant consequences of somatic mutation. 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.