Metformin Effect on Biological Aging in Prediabetes: Latest 2026 Published Indian Research

Metformin therapy significantly increased leukocyte telomere length, telomerase activity and SIRT1 gene expression in Indian adults with prediabetes over 24 weeks, suggesting that it exerts potent, pleiotropic gero-protective effects independent of glycemic control, a recent study has concluded.

This study is published in the September 2026 issue of Mechanisms of Ageing and Development.

Asian Indians have a high risk of progression from prediabetes to type 2 diabetes, a condition often associated with accelerated biological ageing. While metformin is widely used for hyperglycemia management, its potential effects beyond glucose control, particularly on ageing-related pathways, remain unclear. Previous studies exploring metformin’s influence on ageing biomarkers have been limited by small sample sizes, shorter durations, or evaluation of individual markers.

Study Overview

This study assessed the impact of metformin on cellular ageing markers, including leukocyte telomere length (LTL), telomerase activity (TA) and longevity-associated gene expression. It is among the first, the largest and longest studies to simultaneously evaluate LTL, TA and multiple ageing-related genes, including SIRT1, p66Shc, p53 and mTOR, in individuals with prediabetes.

The participant-blind, outcome-assessr–blinded randomised placebo-controlled trial included North Indian adults aged 30–60 years with prediabetes. Of the 322 individuals screened, 127 participants met the eligibility criteria and were randomised to receive either metformin 500 mg twice daily (n=63) or placebo (n=64) for 24 weeks. Both groups received lifestyle counselling. A total of 112 participants (88.2%) completed the study, with 56 participants in each group.

The primary outcomes included leukocyte telomere length (LTL), telomerase activity (TA), and expression of longevity-associated genes SIRT1, p66Shc, p53, and mTOR. These parameters were assessed in peripheral blood mononuclear cells using quantitative real-time polymerase chain reaction (qPCR). Secondary outcomes included anthropometric and metabolic parameters.

Some of the key results from the study include:

Metformin Increased Leukocyte Telomere Length (LTL)

• The metformin group showed an increase from 0.834 ± 0.138 at baseline to 1.081 ± 0.237 at six months, representing a mean change of +0.247 ± 0.298 (29.6% elongation; p<0.0001). In contrast, the placebo group demonstrated an increase from 0.821 ± 0.164 to 0.857 ± 0.139 (mean change +0.036 ± 0.068; 4.4% elongation; p=0.0002). The difference in change scores between the groups was highly significant (p<0.0001).

Increased Telomerase Activity (TA) with Metformin

• Telomerase activity (TA) increased significantly in the metformin group, rising from 1.345 ± 0.204 at baseline to 1.873 ± 0.329 at six months (mean change +0.528 ± 0.412; 39.25% increase; p<0.0001). In comparison, the placebo group showed a decline from 1.350 ± 0.208 to 1.331 ± 0.222 (mean change −0.019 ± 0.279; 1.41% decrease; p=0.6035). The between-group difference was statistically significant (p<0.0001).

Upregulation of Sirtuin 1 (SIRT1) Expression

• Metformin therapy increased SIRT1 expression, a longevity-associated gene involved in cellular stress response pathways. The metformin group showed an increase from 0.818 ± 0.148 at baseline to 1.067 ± 0.494 at six months (mean change +0.249 ± 0.535; 30.41% elevation; p=0.001). The placebo group showed a smaller increase from 0.819 ± 0.175 to 0.848 ± 0.144 (mean change +0.029 ± 0.097; 3.54% elevation; p=0.0315). The between-group difference was statistically significant (p=0.0037).

Figure: Effect of Metformin on Cellular Aging Markers in Prediabetes

Changes in Mechanistic Target of Rapamycin (mTOR) Expression Observed

• The study observed a significant increase in mTOR expression following metformin therapy, from 1.100 ± 0.187 at baseline to 1.670 ± 1.373 at six months (mean change +0.570 ± 1.418; 51.82% elevation; p=0.0043). In contrast, the placebo group exhibited a decline from 1.142 ± 0.207 to 0.980 ± 0.344 (mean change −0.162 ± 0.292; 14.21% reduction; p=0.0001). The between-group difference was statistically significant (p=0.0004).

No Significant Change in p66Shc and p53 Expression

• For p66Shc, the metformin group showed a mean change of +0.013 ± 0.262, compared with −0.013 ± 0.302 in the placebo group. The between-group difference was not statistically significant (p=0.6194). For p53, expression increased in both groups, with a mean change of +0.035 ± 0.024 in the metformin group and +0.036 ± 0.022 in the placebo group. No significant between-group difference was observed (p=0.8376). These findings were likely attributed to short treatment duration.

The molecular changes in this research were observed independently of sustained glycemic improvement.

Commenting on the potential of viewing prediabetes as accelerated biological ageing and metformin’s possible geroprotective role, Dr Surya Prakash Bhatt, Senior Research Scientist at AIIMS, New Delhi, and lead author of the study said, "Prediabetes may represent accelerated cellular ageing, particularly in Asian Indians, who often develop metabolic abnormalities at younger ages and lower BMI, with greater abdominal fat, insulin resistance and pervasive inflammation.

Our 24-week randomized controlled trial involving 127 Asian Indian adults with prediabetes, metformin 500 mg twice daily increased leukocyte telomere length by 29.6%, telomerase activity by approximately 39.3%, and SIRT1 expression by 30.4%. These changes occurred without sustained, significant between-group improvement in glycaemic control. These indicate that metformin has a marked effect on markers of longevity in Indians.

Metformin is a unique candidate because it is an established, widely used glucose-lowering drug that may also influence several biological pathways associated with ageing. The study suggests potential effects on telomere maintenance, telomerase activity and SIRT1, beyond its conventional metabolic action. Its established clinical use makes it a practical candidate for investigating geroprotection, although these findings do not yet prove that it slows clinical ageing or extends lifespan".

Commenting on the findings of the study, Dr Anoop Misra, Executive Chairman of Fortis C-DOC Hospital for Diabetes and Allied Sciences, Greater Kailash, Delhi, said "Geroprotection and longevity are increasingly important areas of scientific interest. These findings raise the intriguing possibility that metformin, traditionally used for diabetes prevention and glycaemic control, may also influence biological ageing. Starting treatment during prediabetes could potentially target cellular ageing pathways before overt diabetes develops.

The increases in telomere length, telomerase activity and SIRT1 expression provide a promising molecular basis for further investigation. However, these findings do not establish that metformin delays clinical ageing or extends healthspan or lifespan on long term use. The next step is to determine whether these molecular changes translate into meaningful long-term health benefits."

Safety Findings

Metformin was generally well tolerated during the study. Mild gastrointestinal symptoms, including nausea, bloating and diarrhoea, were reported in eight participants (14.3%) in the metformin group compared with two participants (3.6%) in the placebo group during the first two weeks. No serious adverse events were reported.

Potential Clinical Importance

• Hyperglycemia is associated with accelerated biological aging at a cellular level.
• The current research findings represent molecular proof-of-concept for metformin-induced attenuation of biological aging in prediabetes.
• Metformin may slow biological aging in a high-risk Asian Indian prediabetic population.

The study findings concluded that 24 weeks of metformin treatment significantly increased leukocyte telomere length by 29.6%, telomerase activity by 39.3%, and SIRT1 and mTOR gene expression. These molecular changes occurred largely without sustained glycemic improvement, suggesting potential effects on ageing-related pathways beyond glucose control.

Abbreviations: LTL: Leukocyte Telomere Length, TA: Telomerase Activity, SIRT1: Sirtuin 1, p66Shc: 66-kDa Src Homology 2 Domain-Containing Protein, p53: Tumour Protein p53, mTOR: Mechanistic Target of Rapamycin, qPCR: Quantitative Polymerase Chain Reaction, PBMCs: Peripheral Blood Mononuclear Cells, HbA1c: Glycated Haemoglobin, FBG: Fasting Blood Glucose, BMI: Body Mass Index, HDL: High-Density Lipoprotein, LDL: Low-Density Lipoprotein, SD: Standard Deviation, T/S: Telomere-to-Single-Copy Gene Ratio, T2D: Type 2 Diabetes.