Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor
Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008 Dec 2;6(12):2853-68. doi: 10.1371/journal.pbio.0060301. PMID: 19053174; PMCID: PMC2592359.
This paper identifies SASP, a hallmark of cellular senescence. This phenotype is particularly enhanced by the gain of “oncogenic RAS or loss of p53 function”.
While there were differences between the way the phenotype was expressed between different cells, there were also similarities between them indicating that there is a “conserved core secretory program that any cell undergoing senescence would trigger”. They all had “high levels of secreted inflammatory cytokines, immune modulators, and gwowth factors, suggenting that SASPs might have myriad biological activities”. They found that tumor cells were very likely to become senescent in response to DNA damage. Senescent cells create a “proinflammatory environment”.
Although senescent cells tend to be removed by the immune system, they increase in number with age. This may be because aging or age-related related pathologies dampen immune response and/or increase the rate at which senescent cells are produced.
The authors suggest that senescence has both beneficial and detrimental effects because of antagonistic pleiotropy which may be explained as a “consequence of the declining force of natural selection with age.” Older individuals are fewer in number because of extrinsic hazards and natural selection tends to favor traits that promote “early life fitness” at the cost of longevity.