Gene Expression ‘Clocks’ Reveal Shared Molecular Signatures of Aging and Mortality Across Mammals

Mass General Brigham researchers identify conserved gene expression signatures linked to biological aging and risk of disease and mortality, offering a new framework for quantifying aging and evaluating interventions that modulate healthspan and lifespan

A team led by investigators at Mass General Brigham has discovered that different tissues in humans and other mammals share common gene expression changes as they age. The research, which is published in Nature, reveals conserved signatures of aging and health decline and introduces new “transcriptomic clocks” that could be used to measure and identify processes that contribute to mortality risk.

“We found that most cell types share these conserved molecular changes with age, despite having very different origins and functions—from immune cells and stem cells to liver cells and muscle cells,” said lead author Alexander Tyshkovskiy, PhD, an investigator in the Division of Genetics in Mass General Brigham’s Department of Medicine. “The same biomarkers were also predictive of time to death in humans and responsive to chronic diseases and lifespan-modulating interventions, such as calorie restriction, in mice. Even cellular stress in laboratory-grown cells, induced by prolonged culturing or radiation, produced similar mortality-associated changes, linking cellular damage to tissue and organismal aging.”

Drawing on more than 11,000 gene expression profiles, the investigators, including collaborators at Tohoku University, analyzed which genes were turned on in more than 25 tissues across four mammals (mouse, rat, macaque, and human) during aging and in response to interventions known to shorten or extend lifespan. Using this resource, the team developed accurate multi-species, multi-tissue clocks that estimate chronological age and expected mortality based on gene activity.

The study also separated gene expression changes associated with aging and mortality into modules that represent different biological processes, such as inflammation, energy production, and extracellular matrix organization. The authors developed individual transcriptomic clocks for each module and showed that different diseases and medical or lifestyle interventions may affect biological age through distinct primary processes.

“These aging clocks represent a potential new way to measure aging in greater detail and could help predict disease and mortality risk, characterize treatment effects, and personalize care based on biological age,” said senior author Vadim N. Gladyshev, PhD, a geneticist in the Division of Genetics in Mass General Brigham’s Department of Medicine. “Future therapies could target both specific aging-related processes—like inflammation or metabolism—and aging as a whole.”

The investigators have made their tools for tracking molecular markers of aging and mortality available to the scientific community for non-commercial use through the interactive web platform and the R package. The authors emphasize that the clocks are currently research tools rather than clinical tests, and additional validation in human studies will be needed before they can be used in patient care.

Authorship: In addition to Tyshkovskiy and Gladyshev, Mass General Brigham authors include Daria Kholdina, Maria Davitadze, Adrian Molière, Alibek Moldakozhayev, Dmitrii Glubokov, Alec Eames, Anastasiya Vladimirova, Kejun Ying, Hanna Liu, Bohan Zhang, and Mahdi Moqri. Additional authors include Yoshiyasu Tongu, Tomoko Kasahara, Leonid M. Kats, Uma Khasanova, Jeremy M. Van Raamsdonk, David E. Harrison, Randy Strong, Takaaki Abe, and Sergey E. Dmitriev.

Disclosures: Tyshkovskiy and Gladyshev are the inventors on a US patent application related to this work.

Funding: The study was supported by funding from the National Institute on Aging, Hevolution, the James Fickel and Michael Antonov Foundations, a Senior Research Career Scientist Award from the Department of Veterans Affairs Office of Research and Development, the Japan Agency for Medical Research and Development (AMED) (JP21zf0127001), JST, ACT-X (JPMJAX24L4), JSPS KAKENHI Grant-in-Aid for Early-Career Scientists (JP22K15354), Takeda Science Foundation, The Uehara Memorial Foundation, The Naito Foundation, Astellas Foundation for Research on Metabolic Disorders, Okinaka Memorial Institute for Medical Research.

Paper cited: Tyshkovskiy, A et al. “Universal transcriptomic hallmarks of mammalian ageing and mortality” Nature DOI: 10.1038/s41586-026-10542-3