Researchers identified the deubiquitinase USP25 as a direct suppressor of SIRT1 activity, removing K63-linked ubiquitin at lysines K506 and K513 and thereby blunting SIRT1's deacetylase function and accelerating cellular senescence. Mice lacking USP25 displayed reduced age-related decline and improved physiological function, and a cell-penetrating peptide that disrupts the USP25–SIRT1 interaction restored SIRT1 activity and attenuated senescence in cells.
Key Points
- USP25 deubiquitinates SIRT1 at K506 and K513, suppressing deacetylase activity
- USP25-deficient mice showed reduced age-related decline, better physiological function
- Cell-penetrating peptide pSirt1-4 restored SIRT1 activity, attenuated cellular senescence
Longevity Analysis
SIRT1 has long been a target of nutritional and pharmacological longevity strategies, yet most approaches attempt to raise its activity indirectly rather than remove what constrains it. Identifying USP25 as the brake on SIRT1 reframes the problem: clearing an upstream inhibitory modification may matter more than supplying additional substrate or activators. Downstream effects on P53 and PGC1α acetylation link this axis to both the accumulation of senescent cells and the capacity of mitochondria to sustain energy output — two of the clearest determinants of how tissue repair holds up with age.
Original published by Wiley Aging Cell, by YuJuan Zhou, Xinshu Wang, Jiyuan Zhang, Hanqiong Qiang, Xinru Zhao, Jingyi Luo, Yanjun Ji, Jiakai Yao, Linhui Zhai, Tingting Zhang, Ke Li, Yuping Chen, Jian Yuan, Lei Li, Yunhui Li .