RISING STARS: Targeting premature cellular senescence using senomorphic or senolytic agents to impact diabetes

📖 Top 20% JournalOct 31, 2025Journal of molecular endocrinology

Using drugs that change or remove aged cells to affect diabetes

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Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗

Abstract

Type 2 diabetes mellitus is closely associated with cellular senescence, a state of irreversible cell cycle arrest.

Cellular senescence may play a significant role in the progression and complications of type 2 diabetes.
Oxidative stress, DNA damage, and telomere shortening are linked to the mechanisms underlying cellular senescence in diabetes.
The accumulation of senescent cells in adipose tissue may contribute to both inflammation and metabolic dysfunction in diabetes.
Senotherapeutics could offer potential adjunct therapies by either protecting cells from damage or eliminating senescent cells.
There is a need for clinical trials to evaluate the safety and efficacy of senotherapeutic agents in diabetes management.

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Type 2 diabetes mellitus (DM) is closely associated with cellular senescence (SnC), a state of irreversible cell cycle arrest marked by functional decline. Preventing cellular senescence in already diagnosed DM patients is crucial for limiting disease progression and the onset of co-morbidities. The relationship between oxidative stress, DNA damage, and telomere shortening provides a mechanistic framework for elucidating the role of cellular senescence in the pathogenesis and progression of type 2 DM. This senescence-driven model of metabolic dysfunction not only accounts for impaired β-cell function and insulin resistance but also for the systemic complications observed in DM patients. The accumulation of senescent cells, particularly in metabolically active tissues such as adipose tissue, is increasingly recognised as both a cause and a consequence of the chronic inflammatory environment that characterises diabetes. Evidence from in vitro and preclinical studies highlights the detrimental effects of the senescence-associated secretory phenotype, reinforcing tissue damage through paracrine and autocrine signalling mechanisms. Despite its complexity, approaches targeting the senescent phenotype offer a promising avenue for adjunct therapies. Senotherapeutics, such as senomorphic agents that protect cells from cytotoxic damage and mitigate oxidative stress, can potentially protect against disease onset, whereas senolytic agents have the potential to eliminate senescent cells to limit metabolic disease progression, mitigate complications, and ultimately improve patient outcomes. There is, however, an urgent need to translate the preclinical findings into clinical trials to assess the safety, efficacy, and long-term effects of senotherapeutic agents.

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