The role of the SIRT1 and mTOR pathways in exercise-induced β-cell senescence reduction in type 2 diabetes mellitus

Oct 30, 2025Cellular and molecular life sciences : CMLS

How SIRT1 and mTOR pathways may help exercise reduce aging of insulin-producing cells in type 2 diabetes

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Abstract

Exercise may improve glucose homeostasis and reduce the risk of Type 2 diabetes mellitus by activating and inhibiting signaling.

Type 2 diabetes mellitus is linked to insulin resistance, high blood sugar levels, and pancreatic β-cell dysfunction.
SIRT1 enhances insulin secretion and reduces oxidative stress while suppressing inflammation.
Hyperactivation of mTOR signaling is associated with increased cellular senescence and metabolic dysfunction.
Exercise upregulates SIRT1 activity and downregulates mTOR signaling, improving cellular function.
Preclinical and clinical studies suggest that exercise can mitigate β-cell senescence and improve metabolic health.
Pharmacological strategies targeting SIRT1 and mTOR show promise but need further clinical validation.

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Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance, chronic hyperglycemia, and pancreatic β-cell dysfunction, driven in part by cellular senescence and chronic inflammation. The sirtuin 1 () and mechanistic target of rapamycin () pathways play critical roles in regulating cellular metabolism, stress responses, and aging, making them key targets for mitigating β-cell senescence and T2DM progression. SIRT1, a NAD + -dependent deacetylase, enhances insulin secretion, reduces oxidative stress, and suppresses inflammation by modulating transcription factors such as NF-κB and PGC-1α. Conversely, mTOR signaling, when hyperactivated, promotes cellular senescence and metabolic dysfunction. Exercise has emerged as a potent non-pharmacological intervention. It upregulates SIRT1 activity through increased NAD⁺ levels and AMP-activated protein kinase (AMPK) activation, while also downregulating excessive mTOR signaling. These effects enhance autophagy, reduce oxidative stress, and improve mitochondrial function, thereby preserving β-cell mass and function. Preclinical and clinical studies demonstrated that exercise-induced SIRT1 activation and mTOR inhibition mitigate β-cell senescence, improve glucose homeostasis, and reduce the risk of T2DM. Pharmacological strategies targeting SIRT1 activation and mTOR inhibition, such as NAD + boosters and rapamycin analogs, show promise in preclinical models but require further clinical validation. Understanding the interplay between the SIRT1 and mTOR pathways offers novel therapeutic avenues for preserving β-cell function, preventing T2DM, and promoting healthy aging. Future research should focus on optimizing exercise regimens and developing targeted interventions to harness the synergistic benefits of SIRT1 activation and mTOR inhibition in metabolic health.

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The role of the SIRT1 and mTOR pathways in exercise-induced β-cell senescence reduction in type 2 diabetes mellitus

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