“ Cellular senescence is widely recognized as a driver of age-related phenotypes, intrinsically linked to other aging hallmarks such as telomere dysfunction, chronic inflammation, and stem cell exhaustion .”
BUFFALO, NY — September 14, 2026 — A new review was published in Volume 18 of Aging on August 26, 2026, titled “ Assessing mechanisms and evidence of a causal role for cellular senescence and somatic mutations in aging .”
The review examines two biological processes strongly associated with aging—cellular senescence and somatic DNA mutations—and evaluates whether the evidence supports their causal contribution to age-related functional decline.
The review was authored by Lucrezia A. Trastus and Fabrizio d’Adda di Fagagna from IFOM ETS – The AIRC Institute of Molecular Oncology in Milan, Italy . d’Adda di Fagagna is also affiliated with the Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche (IGM-CNR) in Pavia, Italy . Both authors are corresponding authors.
Aging involves many interconnected molecular and cellular changes, making it difficult to distinguish processes that actively drive deterioration from those that simply accompany it. Trastus and d’Adda di Fagagna assess cellular senescence and somatic mutations using necessity and sufficiency as key criteria for causal inference.
For cellular senescence, the evidence for causality is comparatively strong. Senescent cells undergo stable proliferative arrest, which can impair tissue regeneration, particularly when stem cells are affected. Their influence can extend far beyond individual cells through the senescence-associated secretory phenotype (SASP), a complex secretory program that allows senescent cells to alter surrounding tissues and promote senescence in neighboring cells.
Experimental evidence further supports this role. Removing senescent cells in genetically engineered mice has delayed or reduced several age-related pathologies and improved healthspan, with one study also reporting increased median and maximal lifespan. Pharmacological elimination of senescent cells using senolytic approaches has extended these findings. Conversely, transplantation experiments have shown that relatively small numbers of senescent cells can impair physical function or induce frailty and cognitive decline in young mice.
The SASP provides an important explanation for how relatively few senescent cells could have broader effects. Its inflammatory cytokines, chemokines and tissue-remodeling factors can contribute to chronic low-grade inflammation, influence neighboring cell behavior, disrupt extracellular matrix and intercellular barriers, and promote fibrosis. Together, these mechanisms connect cellular senescence with systemic changes characteristic of aging.
The evidence for somatic DNA mutations is less definitive. Mutations accumulate in normal tissues throughout life, and some mutational signatures increase in a clock-like manner with age. Across mammalian species, maximum lifespan is inversely correlated with the rate of somatic mutation accumulation, while DNA repair capacity has also been associated with longevity.
However, mutation accumulation does not necessarily prove that mutations themselves cause aging. Some people with inherited defects that substantially increase somatic mutation burden do not display premature-aging phenotypes. Direct evidence demonstrating that somatic mutations are both necessary and sufficient to produce organismal functional decline also remains limited.
Mutations could nevertheless affect aging through several mechanisms. They may disrupt gene regulation and increase transcriptional noise, impair stem and immune cell function, or allow mutant cells to clonally expand. Such expansion creates genetic mosaics within tissues, and age-associated mutant clones have been observed in apparently normal skin, esophagus and blood.
“ The observed correlation between mutation burden and age is thus hard to separate from senescence-inducing DNA damage signaling events. ”
This distinction is central to the review. DNA damage, DNA-damage signaling and DNA mutations are related but distinct biological events. DNA damage can activate signaling pathways that promote cellular senescence, while inaccurate repair can convert that damage into permanent mutations. As a result, it remains difficult to determine whether age-related dysfunction is caused by the mutations themselves, by the signaling generated by the original DNA damage, or by both.
Evidence from some experimental models favors an important role for DNA-damage signaling. Inhibiting components of this response has attenuated certain accelerated-aging phenotypes or improved age-related tissue dysfunction without necessarily removing the underlying source of DNA damage. DNA lesions can also interfere directly with replication and transcription, potentially contributing to senescence, stem-cell exhaustion and widespread age-related changes in gene expression.
The authors emphasize that important uncertainties remain on both sides. Evidence supporting senescence as a causal contributor to aging comes predominantly from animal models, and sustained clinical benefits of senolytic therapies have not yet been established in large, well-controlled human trials. For somatic mutations, experiments capable of altering DNA sequence while minimizing accompanying DNA-damage signaling will be needed to more directly test causality.
Overall, the review illustrates a central challenge in aging biology: distinguishing drivers from passengers. Current evidence provides comparatively strong support for cellular senescence as a causal contributor to age-related decline, particularly through systemic effects of the SASP. Somatic mutations clearly accumulate with age and may affect tissue function, but whether altered DNA sequences themselves are primary drivers of organismal aging remains unresolved. Understanding how DNA damage, senescence and mutation accumulation interact may ultimately provide a clearer picture of the biological processes that drive aging.
Paper DOI : https://doi.org/10.18632/aging.206414
Corresponding authors: Lucrezia A. Trastus – lucrezia.trastus@ifom.eu , Fabrizio d’Adda di Fagagna – fabrizio.dadda@ifom.eu
Abstract video: https://www.youtube.com/watch?v=XHTBAJHjRZU
Keywords: cellular senescence, somatic mutations, aging, DNA damage, SASP
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Aging-US
Literature review
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Assessing mechanisms and evidence of a causal role for cellular senescence and somatic mutations in aging
26-Aug-2026
F. d’A. d.F. is a founder and investor in TAG Therapeutics, a company dedicated to treating telomere pathologies and age-related disorders. L. A. T. declares no competing interests.