悪玉老化細胞を見分けて健康老化へ～悪玉老化細胞抑止のメカニズム～

2026-01-08

2026-01-08 京都大学

老化細胞には、組織の恒常性維持に寄与する「善玉老化細胞」と、炎症や疾患を促進する「悪玉老化細胞」が存在し、後者の抑制が健康寿命延伸の鍵とされている。本研究で、井倉毅准教授らの研究グループは、ヒストンH2AXがアセチル化によってクロマチンから放出される「動的H2AX」となり、老化細胞の悪玉化を抑制する新たな分子機構を解明した。γH2AX foci形状のばらつきを指標とした機械学習解析により、過剰に蓄積した老化細胞が悪玉化していることを特定。さらに、動的H2AXが分子シャペロンVCP/p97を介してMDC1量を制御し、老化細胞の質を健全に保つことが示された。本成果は、老化制御と健康老化の分子基盤を明らかにする重要な知見である。

提供:井倉研究室

<関連情報>

アセチル化依存的なヒストン H2AX の交換反応は、MDC1 の分解を介して病的⽼化を抑制する Acetylation-Dependent Histone H2AX Exchange Suppresses Pathological Senescence via MDC1 Degradation

Masae Ikura,Kanji Furuya,Yasunori Horikoshi,Satoshi Tashiro,Takuma Shiraki&Tsuyoshi Ikura
Molecular and Cellular Biology Published:06 Jan 2026
DOI:https://doi.org/10.1080/10985549.2025.2596729

Abstract

Cellular senescence has a dual role in both tumor suppression and the promotion of age-related diseases. This paradox suggests the existence of functionally distinct “beneficial” and “detrimental” senescent states, yet the molecular basis that governs their fate has remained elusive. Here, we reveal that the dynamic exchange of histone H2AX on chromatin functions as an essential quality control mechanism that dictates the quality of senescence. We demonstrate that the histone acetyltransferase TIP60, in complex with the chaperone FACT, acetylates H2AX at lysine 5 (K5), which in turn drives its dynamic exchange. This histone exchange is indispensable for promoting the degradation of the DNA damage response mediator MDC1, a process we uncover is mediated by a novel DNA-PKcs-p97 signaling axis. Disruption of this TIP60-FACT-H2AX exchange pathway leads to the hyperaccumulation of MDC1 and a shift toward error-prone nonhomologous end joining (NHEJ), inducing a pathological senescent state with oncogenic potential. Our study redefines histone exchange from a passive chromatin event to an active regulatory hub that determines the fate of aging cells. These findings provide a molecular basis for the heterogeneity of senescence and establish a rationale for developing “senomorphic” therapies aimed at improving the quality of aging.