ASK1 as an Important Regulator of the Senescence-Associated Secretory Phenotype

When senescent cells linger in significant numbers in aged tissues, they cause harm via the senescence-associated secretory phenotype (SASP), a potent mix of pro-growth, pro-inflammatory signals. In the short term, this is necessary to draw the attention of the immune system to potentially cancerous cells, and helps to coordinate wound healing, among other activities. When sustained for the long term, it is increasingly disruptive to normal tissue structure and function, however.

If the desire is to remove the contribution of senescent cells to degenerative aging, suppressing the SASP seems a poor choice when compared to periodic destruction of senescent cells via senolytic drugs. As researchers here note, disabling the SASP over the long term has the effect of increasing cancer risk, even as it reduces other aspects of aging. Periodic destruction of senescent cells, however, allows one to both have the cake and eat it, still gaining the benefits of cellular senescence while reducing the burden of senescent cells.

Cellular senescence is a stress-induced, permanent cell cycle arrest involved in tumor suppression and aging. Senescent cells secrete bioactive molecules such as pro-inflammatory cytokines and chemokines. This senescence-associated secretory phenotype (SASP) has been implicated in immune-mediated elimination of senescent cells and age-associated chronic inflammation. However, the mechanisms regulating the SASP are incompletely understood.

Here, we show that the stress-responsive kinase ASK1 promotes inflammation in senescence and aging. ASK1 is activated during senescence and increases the expression of pro-inflammatory cytokines and chemokines by activating p38, a kinase critical for the SASP. ASK1-deficient mice show impaired elimination of oncogene-induced senescent cells and an increased rate of tumorigenesis. Furthermore, ASK1 deficiency prevents age-associated p38 activation and inflammation and attenuates glomerulosclerosis. Our results suggest that ASK1 is a driver of the SASP and age-associated chronic inflammation and represents a potential therapeutic target for age-related diseases.


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