Fundamental Cell-Intrinsic Mechanism Underlying Age-Dependent Accumulation of Senescent Cells

Mar 30, 2026Aging and disease

Basic Cell Process Behind Age-Related Build-Up of Old, Non-Dividing Cells

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Abstract

Accumulation of senescent cells during aging may be influenced by immune-independent mechanisms.

Senescent cells contribute to various age-related diseases.
Ineffective immune clearance and increased half-life of these cells drive their accumulation with age.
Cells from different origins become more susceptible to senescence as they age.
Epigenetic and molecular changes during aging may create conditions that activate the senescence program.
Senotherapeutic interventions alone may not effectively alter the aging process.
Targeting age-associated epigenetic changes could enhance cellular stress resilience and reduce senescent cell accumulation.

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The accumulation of senescent cells during aging contributes to the progression of various age-related pathologies. Ineffective immune clearance, increased half-life of senescent cells, and bystander senescence are considered the primary drivers of this age-associated accumulation. Most of these causes stem from the aging of the immune system, which results in a prolonged persistence of damaged/nonfunctional cells within tissues and allows the internal senescence program to progress to a more severe phenotype. Here, we propose the existence of an additional immune-independent mechanism underlying the accumulation of senescent cells during aging. By reanalyzing existing experimental evidence, we show that cells of diverse identities and tissue origins become increasingly susceptible to senescence with age. The latter implies that epigenetic and molecular changes that cells acquire during aging create a permissive background for the activation of the senescence program. In light of our findings, senotherapeutic interventions alone may be insufficient to substantially alter the trajectory of organismal aging. Effective strategies may need to target upstream drivers of cellular dysfunction, including age-associated epigenetic alterations. Epigenetic rejuvenation could, in principle, enhance cellular stress resilience and thereby reduce the rate at which senescent cells emerge and accumulate.

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Fundamental Cell-Intrinsic Mechanism Underlying Age-Dependent Accumulation of Senescent Cells

Abstract

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