Continued Progress Towards Understanding the Regulators of the Senescence-Associated Secretory Phenotype
Nearly 15 years have passed since the first compelling demonstration of rejuvenation produced by clearance of senescent cells in the tissues of aged mice. At that time the study of senescent cells was fairly slow and sedate, not a major area of research. How things change! At present a very energetic community of academic groups and biotech companies is mining the biochemistry of cellular senescence in search of better ways to selectively destroy these cells, ways to change their behavior to reduce their contribution to systemic inflammation and tissue dysfunction, and even ways to turn back the normally irreversible transition into the senescent state. There are incentives: any new discovery could be the starting point for development of a therapy that significantly slows or reverses aspects of aging.
The damage done by the growing burden of senescent cells found in aged tissues is thought to be near entirely caused by the senescence-associated secretory phenotype (SASP), the mix of pro-growth, pro-inflammatory signaling that is energetically produced by these cells. As the thinking goes, a way to eliminate the SASP could be as beneficial as clearing senescent cells from tissues. There are drawbacks to this approach, which is that the SASP is actually beneficial in the short term, helpful in wound healing and suppression of potentially cancerous cells. Periodic destruction of senescent cells would not interfere in their beneficial short-term behaviors, while chronic dosing to suppress the SASP would do so. Nonetheless, as today's open access paper illustrates, there is a growing interest in finding ways to reduce or even eliminate SASP signaling.
The senescence-associated secretory phenotype (SASP) mediates the biological effects of senescent cells on the tissue microenvironment and contributes to ageing-associated disease progression. Acetate-dependent acetyl-CoA synthetase 2 (ACSS2) produces acetyl-CoA from acetate and epigenetically controls gene expression through histone acetylation under various circumstances. However, whether and how ACSS2 regulates cellular senescence remains unclear.
Here, we show that pharmacological inhibition and deletion of Acss2 in mice blunts SASP and abrogates the pro-tumorigenic and immune surveillance functions of senescent cells. Mechanistically, ACSS2 directly interacts with and promotes the acetylation of PAICS, a key enzyme for purine biosynthesis. The acetylation of PAICS promotes autophagy-mediated degradation of PAICS to limit purine metabolism and reduces deoxyribonucleotide triphosphate (dNTP) pools for DNA repair, exacerbating cytoplasmic chromatin fragment accumulation and SASP.
Altogether, our work links ACSS2-mediated local acetyl-CoA generation to purine metabolism through PAICS acetylation that dictates the functionality of SASP, and identifies ACSS2 as a potential senomorphic target to prevent senescence-associated diseases.