In mesenchymal stem cells, the topoisomerase TOP2A declines with age and directly sustains Lamin B1 expression; its loss triggers nuclear membrane rupture, heterochromatin erosion, and senescence, while restoring TOP2A reverses these changes. Pharmacological TOP2A inhibition in mice produced accelerated brain aging and neurodegenerative-like behavior, linking nuclear architectural collapse to organ-level functional decline.
Key Points
- TOP2A declines in senescent stem cells, destabilizing nuclear architecture
- TOP2A sustains Lamin B1, preserving heterochromatin and genomic order
- TOP2A inhibition in mice accelerated brain aging and behavioral decline
Longevity Analysis
Nuclear envelope integrity functions as an upstream gatekeeper of regenerative capacity: once Lamin B1 is lost and heterochromatin unravels, the resulting genomic disorder propagates into inflammatory signaling and tissue-level decline. The murine brain aging data also identify an interference variable — chemical exposure to topoisomerase-inhibiting agents — that can drive senescence independent of chronological age, a consideration for anyone assessing cumulative pharmacological burden. Chromatin architecture joins the short list of targets where restoring a single regulator measurably reverses a senescent phenotype rather than merely slowing it.
Original published by Wiley Aging Cell, by Ke Cheng, Yaru Wang, Yueyuan Pan, Wenjun Zhang, Denghong Yu, Qi Zhou, Zhiqian Zhong, Ruyi Mei, Chaoliang Xu, Ayidana Hayierhan, Yumei Ma, Yien Xu, Qingdong Xie, Pingnan Sun, Junzhi Zhou, Xiaoling Zhou .