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A multidisciplinary team from ÌìÃÀ´«Ã½, together with French CNRS and Inserm, reports that pancreatic aging is not a stochastic degenerative process but instead follows a tightly coordinated epigenetic programme, that radically differs from the impact of chronic hyperglycemia.

What excites us most is that we can predict risk earlier and potentially intervene before disease becomes established, an approach that may be far more effective than treating diabetes after irreversible damage in insulin secreting cells has occurred." Dr Amna Khamis Visiting Researcher Department of Metabolism, Digestion and Reproduction

These findings, and led by and Professor Philippe Froguel from the Department of Metabolism, Digestion and Reproduction, redefine the biological framework linking aging to type 2 diabetes (T2D).

Globally, nearly 600 million individuals live with diabetes, a number projected to exceed 1.4 billion by 2050. T2D accounts for approximately 90% of cases and arises from the interplay between genetic susceptibility, obesity and, critically, aging, the strongest risk factor. Disease progression is marked by declining glycaemic control in part due to insulin secretion progressive failure, and by the emergence of multi-organ complications, with a majority of patients failing to achieve sustained metabolic balance.

By profiling human pancreatic islets from organ donors, the authors uncover a structured epigenetic remodeling process accompanying aging. Age-dependent DNA methylation changes are not randomly distributed but selectively target regulatory regions controlling genes essential for pancreatic β-cell function and for insulin secretion. This coordinated remodeling supports the maintenance of metabolic homeostasis, indicating that physiological aging encompasses adaptive, rather than purely degenerative, mechanisms.

In sharp contrast, the presence of T2D is characterized by a profound disruption of this epigenetic architecture. The study reveals widespread, uncoordinated alterations affecting key insulin-secretion pathways, coupled with signatures of cellular stress, inflammation and loss of β-cell identity. These findings provide a mechanistic basis for the progressive decline in pancreatic function and the frequent transition toward insulin dependence.

Importantly, the authors develop an epigenetic score reflecting the biological age of the pancreas, but derived from circulating markers. This score correlates with insulin secretory capacity and enhances diabetes risk prediction when integrated with genetic information.

Together, these results support a paradigm shift in T2D: from a disease-centric model to one rooted in the biology of aging. Targeting early epigenetic alterations and preserving pancreatic functional integrity may offer new avenues for prevention and disease interception before irreversible dysfunction occurs.

Dr Amna Khamis, final author, said: "What excites us most is that  we can predict risk earlier and potentially intervene before disease becomes established, an approach that may be far more effective than treating diabetes after irreversible damage in insulin secreting cells has occurred."

Professor Philippe Froguel, corresponding author, said: "Aging should not be seen as the Titanic ending: rather there is a coordinated epigenetic process of adaptation to new conditions of life. The real chaos is caused by diabetes itself and that can explain why, with time, usual treatments don't work and insulin therapy is needed."

Maurin, L., Marselli, L., Boissel, M. et al. . Nat Commun 17, 4811 (2026). https://doi.org/10.1038/s41467-026-73222-w