Metformin Therapy Increases Leukocyte Telomere Length, Telomerase Activity, and Longevity Gene Expression in Asian Indians with Prediabetes: A 24-Week Participant-Blind, Outcome-Assessor-Blinded Randomized Controlled Trial.

BACKGROUND: Asian Indians exhibit disproportionately high rates of prediabetes progression to type 2 diabetes, associated with accelerated biological aging. Metformin has been proposed to exert anti-aging effects independent of glycemic control; however, adequately powered randomized controlled trials evaluating telomere biology in prediabetes are lacking. METHODS: We conducted a participant-blind, outcome-assessor-blinded randomized placebo-controlled trial in North Indian individuals aged 30-60 years with prediabetes. A total of 322 individuals were screened, of whom 195 were excluded for various reasons. Consequently, 127 participants met the eligibility criteria and were enrolled in the study. Participants received metformin 500mg twice daily (n=63) or placebo (n=64) for 24 weeks, alongside lifestyle counseling. Primary outcomes were leukocyte telomere length (LTL), telomerase activity (TA), and longevity gene expression (SIRT1, p66Shc, p53, mTOR) measured in peripheral blood mononuclear cells using quantitative PCR. Secondary outcomes included anthropometric and metabolic parameters. RESULTS: Among 127 randomized participants, 112 (88.2%) completed the study. Metformin significantly increased LTL compared to placebo (mean change +0.247±0.298 vs +0.036±0.068; 29.6% vs 4.4% elongation; between-group p<0.0001), TA increased substantially in the intervention group (+0.528±0.412, 39.3% increase, p<0.0001), vs minimal change in placebo (-0.019±0.279, p=0.6035; between-group p<0.0001). SIRT1 expression increased significantly (Δ +0.249±0.535 vs +0.029±0.097; p=0.0037), while mTOR expression showed a context-dependent increase requiring mechanistic interpretation (p=0.0004). These effects occurred independent of sustained glycemic improvement. CONCLUSIONS: Metformin over 24 weeks significantly elongated LTL, raised telomerase activity, and upregulated SIRT1, independent of glycemic control. While demonstrating metformin's geroprotective potential in healthy Asian Indians, the marked LTL response requires cautious interpretation, and validation in larger, long-term studies is needed.