Cells enter a senescent state constantly throughout life, largely because they have reached the Hayflick limit on replication, but also due to molecular damage, cancerous mutations, injury to tissue, radiation, or other causes. A senescent cell stops replicating, swells in size, and begins to secrete a mix of inflammatory signals, growth factors, and other molecules.
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Near all senescent cells are destroyed rapidly, either by programmed cell death or by the immune system, but this stops being the case in later life. Lingering senescent cells accumulate, and signaling that is helpful in the short term, to suppress cancer or aid in healing from injury, becomes disruptive and harmful when sustained over the long term. Senescent cells contribute meaningfully to age-related chronic inflammation, tissue dysfunction, and disease.
The biochemistry of senescence is not as well understood and catalogued as one might expect for a phenomenon that has been studied in one context for another for decades. Only in the past decade has the connection to aging been accepted by the broader research community, but now a great many research groups are mining the biology of senescence in search of ways to suppress the bad behavior of these cells, or selectively destroy them. That last option seems very feasible as a basis for therapy, given that there are never a great many of these cells in the body, even in late old age, and selective destruction via senolytic treatments extends life and reverses numerous manifestations of age-related disease in mice.
Today's research materials are an interesting example of ongoing work that may lead to a taxonomy of the state of senescence. It is likely that different tissues and cell types exhibit meaningful differences in senescent cell biochemistry. Further, it appears that senescence isn't a blanket single phenomenon, but rather distinctions can be made between different stages or phenotypes of senescence. It remains to be determined with any great rigor as to how cells determine which type of senescence they adopt, or how they shift between states within senescence, or how this knowledge might be applied to better produce rejuvenation by targeting senescent cells.
Aged cell variations may control health and onset of age-related diseases
Researchers have proposed that cellular senescence variations during the aging process could lead to control of health and onset of age-related diseases. Based on the characteristics of the secretion of inflammatory cytokines released by aged cells, they hypothesize that there are at least four distinct states of cellular senescence, and that these four states arise from coordinated metabolic and epigenomic changes. The states: 1. initiation (proliferation arrest), 2. early (anti-inflammation), 3. full (increased inflammation and metabolism), and 4. late (decreased inflammation and metabolism). Characterizing and categorizing qualitatively different states of cellular senescence could provide a new understanding of the aging and senescence process.
Many of the cells that make up the body eventually decline in function and stop growing after repeated divisions in a process called “cellular senescence,” an important factor in health and longevity. Premature senescence occurs when genomic DNA is damaged by stressors such as radiation, ultraviolet light, or drugs, but its mechanisms are not yet fully understood. It can be good, like when cells become cancerous, cellular senescence works to prevent the development of malignancy, but it also increases the likelihood of many age-related diseases. It is therefore important for medical science to try to understand and control it.
Although senescent cells lose their ability to proliferate, recent research has shown that they secrete various proteins that act on surrounding cells and promote chronic inflammation and cancer cell growth. This is called the senescence-associated secretory phenotype (SASP). Cellular senescence is thought to be the cause of aging in the entire body. Senescent cells have been shown to accumulate in the bodies of aged mice, and removal of these cells may suppress whole-body aging. In other words, if cellular senescence is controlled, it may become possible to regulate the aging process of the whole body.
Cellular Senescence Variation by Metabolic and Epigenomic Remodeling
Cellular senescence involves at least four distinguishable states in chronological order (initiation, and early, full, and late senescence), which are especially classified by metabolism and SASP features. Under the action of senescenceinducing stresses, the p53–p21 CIP1 and p16 INK4a –retinoblastoma (RB) pathways cause cell cycle arrest at senescence initiation. In early senescence, transforming growth factor (TGF)β is produced possibly for anti-inflammatory defense at least in part via the Notch1-mediated pathway (TGFβ SASP) with increasing morphological changes such as an enlarged cell size.
Then, in full senescence, metabolic activation yields many metabolites, cellular energy, and reactive oxygen species that accelerate senescence progression with secretion of proinflammatory cytokines such as IL-6 and IL-8 (proinflammatory SASP). The levels of proinflammatory SASP tend to be high in oncogene-induced senescence, and low in replicative senescence. Microscopically, fully senescent cells often exhibit cytoplasmic SA β-Gal positivity and nuclear SAHF.
Finally, interferon secretion and metabolic decline occur in late senescence (interferon SASP). In full to late senescence, accumulation of cytoplasmic DNAs activates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway for cytosolic DNA sensing and the interferon response. Thus, there are at least four different states of cellular senescence, suggesting that senescent cells diversely have metabolic and secretory phenotypes.
Source: Fight Aging!