哈佛医学院Vadim N. Gladyshev小组的一项最新研究开发出了哺乳动物衰老和死亡的普遍转录组特征。这一研究成果于2026年5月27日发表在国际顶尖学术期刊《自然》上。
在这里，课题组人员整合了来自4种哺乳动物（狨、大鼠、猕猴和人类）超过25个组织的11,000多个转录组，以开发准确、可解释的啮齿动物和多物种的实际年龄和预期死亡率生物标志物，预测寿命调节干预、死亡时间、慢性疾病和返老还衰。
衰老相关的变化在物种和细胞类型中都是保守的，揭示了哺乳动物衰老和死亡率的普遍转录组特征，包括CDKN1A和LGALS3，其蛋白水平也与英国生物银行的死亡率和多发病有关。在体内和体外损伤积累模型中重现了死亡相关特征，包括炎症、复制性衰老、代谢抑制和γ辐照，这些特征通过细胞永生化、重编程、异慢性异种共生和早期胚胎发生而减弱或逆转。网络分析揭示了衰老和死亡相关特征的模块化结构，包括炎症、干扰素信号、线粒体功能、染色质修饰和细胞外基质组织。
为了量化单个细胞成分的衰老，课题组人员开发了模块特异性时钟，揭示了干预措施的途径特异性效应：慢性疾病主要加速炎症模块衰老，而热量限制和Klotho（也称为Kl）缺乏针对线粒体和代谢模块。转录组和DNA甲基化时钟在人类血液中显示出相关的年龄加速，其中染色质相关模块时钟最强，突出了分子衰老模式之间的机制联系。该研究揭示了死亡调控的保守特征和模块化结构，为量化和靶向跨物种和组织的细胞子系统衰老提供了框架。
研究人员表示，衰老和干预调节健康和死亡率，但这种调节的潜在分子机制尚不清楚。
附：英文原文
Title: Universal transcriptomic hallmarks of mammalian ageing and mortality
Author: Tyshkovskiy, Alexander, Kholdina, Daria, Davitadze, Maria, Molire, Adrian, Moldakozhayev, Alibek, Tongu, Yoshiyasu, Kasahara, Tomoko, Glubokov, Dmitrii, Eames, Alec, Kats, Leonid M., Vladimirova, Anastasiya, Ying, Kejun, Liu, Hanna, Zhang, Bohan, Khasanova, Uma, Moqri, Mahdi, Van Raamsdonk, Jeremy M., Harrison, David E., Strong, Randy, Abe, Takaaki, Dmitriev, Sergey E., Gladyshev, Vadim N.
Issue&Volume: 2026-05-27
Abstract: Ageing and interventions modulate health and mortality1, yet the underlying molecular mechanisms of this modulation remain unclear. Here we integrate more than 11,000 transcriptomes from more than 25 tissues across 4 mammals (mouse, rat, macaque and human) to develop accurate, interpretable rodent and multi-species biomarkers of chronological age and expected mortality, predicting lifespan-modulating interventions, time to death, chronic diseases and rejuvenation. Ageing-related changes were conserved across species and cell types, revealing universal transcriptomic signatures of mammalian ageing and mortality, including CDKN1A and LGALS3, whose protein levels were also associated with mortality and multimorbidity in UK Biobank. Mortality-associated features were recapitulated across in vivo and in vitro damage-accumulation models, including inflammation, replicative senescence, metabolic inhibition and γ-irradiation, and were attenuated or reversed by cell immortalization, reprogramming, heterochronic parabiosis and early embryogenesis. Network analysis uncovered a modular architecture of ageing- and mortality-associated hallmarks, encompassing inflammation, interferon signalling, mitochondrial function, chromatin modification and extracellular matrix organization. To quantify ageing of individual cellular components, we developed module-specific clocks, which revealed pathway-specific effects of interventions: chronic diseases primarily accelerated inflammatory-module ageing, whereas caloric restriction and Klotho (also known as Kl) deficiency targeted mitochondrial and metabolic modules. Transcriptomic and DNA methylation clocks showed correlated age acceleration in human blood, which was strongest for the chromatin-associated module clock, highlighting mechanistic links between molecular ageing modalities. This study reveals conserved signatures and a modular architecture of mortality regulation, providing a framework for quantifying and targeting ageing of cellular subsystems across species and tissues.
DOI: 10.1038/s41586-026-10542-3