The accumulation of senescent cells is an important contributing cause of degenerative aging. This is not a recent discovery, enough was known 20 years ago for the first SENS rejuvenation research proposals to prominently feature removal of senescent cells as an approach to treating aging as a medical condition, but it has only become broadly accepted by the research community over the past decade. There has been a considerable growth of interest in cellular senescence, particularly over the last few years as the first (mixed) human data emerged.
There is a something of a land rush underway in the exploration of the biochemistry of senescent cells at the moment, given that every new discovery might lead to potential means of destroying these cells - or perhaps suppressing their harmful signaling in some way - and thus investment, new startup companies to join the growing longevity industry, and potential profit. It remains to be seen which of the many first generation approaches to the selective destruction of senescent cells will win out in the marketplace of medical development, and meanwhile new discoveries are being made by researchers on a fairly regular basis.
Cellular senescence is linked to chronic age-related diseases including atherosclerosis, diabetes, and neurodegeneration. Compared to proliferating cells, senescent cells express distinct subsets of proteins. In this study, we used cultured human diploid fibroblasts rendered senescent through replicative exhaustion or ionizing radiation to identify proteins differentially expressed during senescence. We identified acid ceramidase (ASAH1), a lysosomal enzyme that cleaves ceramide into sphingosine and fatty acid, as being highly elevated in senescent cells. This increase in ASAH1 levels in senescent cells was associated with a rise in the levels of ASAH1 mRNA and a robust increase in ASAH1 protein stability.
Furthermore, silencing ASAH1 in pre-senescent fibroblasts decreased the levels of senescence proteins p16, p21, and p53, and reduced the activity of the senescence-associated β-galactosidase. Interestingly, depletion of ASAH1 in pre-senescent cells sensitized these cells to the senolytics dasatinib and quercetin (D+Q).
Together, our study indicates that ASAH1 promotes senescence, protects senescent cells, and confers resistance against senolytic drugs. Given that inhibiting ASAH1 sensitizes cells towards senolysis, this enzyme represents an attractive therapeutic target in interventions aimed at eliminating senescent cells.