Senescence is a fundamental cellular state
Senescence is a fundamental biological mechanism that is both protective in embryonic development, wound healing and tumor suppression, and detrimental as a primary mechanism of aging. Senescent cells are:
Permanently growth arrested. They cannot contribute to tissue repair and regeneration
Resistant to apoptosis. They accumulate
Metabolically active. They secrete factors that promote inflammation and fibrosis
Senescence can be induced by direct DNA damage, nutrient deprivation, hypoxia, epigenetic modification, mitochondrial dysfunction, telomere shortening, and other factors.
Senescent T cells regulate systemic aging
Senescent T cells provoke senescence in healthy cells throughout the body, secrete pro-inflammatory factors, and cause organismal decline.
Data from experimental models using transplant and genetic manipulation of senescent cells demonstrate a causal relationship between senescence, physical capacity, disease onset and progression, and lifespan.
Senescence has now been associated with nearly all age-related diseases, including heart disease, cancer, cognitive dysfunction, and diabetes, as well as global changes such as muscle loss (sarcopenia) and slowed walking speed.
p16 determines senescence
p16 is required for the maintenance of senescence and permanent cell cycle arrest. T cells expressing p16 cannot divide and cannot participate in repair and regeneration, compromising healing after medical interventions and predisposing to age-related disease and dysfunction.
Aging trajectories are determined by senescent cell load
The number of p16-expressing senescent cells depends on both rate of accumulation due to both biological insults and propagation of senescence within the organism, and clearance of senescent cells by healthy immune cells.
The burden of senescence in an organism has a direct impact on health and clinical outcomes.
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Desdin-Mico et al 2021"T cells with dysfunctional mitochondria induce multi morbidity and premature senescence" Science 368:1371-76
Kale et al 2020 "Role of immune cells in the removal of deleterious senescent cells" Immunity and Aging 17:16
Xu et al 2018 "Senolytics improve physical function and increase lifespan in old age" Nature Medicine 24:1246-56
Tchkonia and Kirkland 2018 "Aging, Cell Senescence and Chronic Disease" JAMA 320(13):1319-1320
He and Sharpless 2017 "Senescence in Health and Disease" Cell 169(6):1000-1011
Baker et al 2016 "Naturally occurring p16INK4a-positive cells shorten healthy lifespan" Nature 530:184-89
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