Metformin Shows Promise in Slowing Aging in Monkeys

Now in Monkeys

Metformin, a well-established anti-diabetes drug, has been investigated as a potential geroprotective agent since a study suggested that diabetes patients on metformin outlived age-matched healthy controls². While subsequent research raised questions about these claims³, metformin remains a strong candidate for further study.

A study by the Interventions Testing Program (ITP) did not find a life-extension benefit in mice treated with metformin⁴, although smaller studies have produced more favorable results. In various animal models, metformin has alleviated several hallmarks of aging and is associated with reduced health risks in humans. The Targeting Aging with Metformin (TAME) study is expected to clarify the drug's effects, pending further progress.

A new study conducted by a team of Chinese scientists has broken new ground by examining metformin's effects in cynomolgus monkeys—a closer biological match to humans than mice.

Improved Cognitive Function

The study lasted 40 months and included a comprehensive evaluation of physiological, imaging, histological, and molecular aspects. For the study group, the researchers used male cynomolgus monkeys aged 13 to 16 years (equivalent to 40 to 50 human years). Three control groups were also included: old, young, and middle-aged monkeys. The dose administered was 20 mg/kg, which is the standard long-term anti-diabetes dose for humans.

Metformin was well tolerated, and the treatment yielded notable health benefits. Notably, the monkeys receiving metformin showed enhanced cognitive performance in both memory and learning tasks.

Cortical Thickness Changes

The study also demonstrated changes in cortical thickness in certain brain regions. While controls exhibited a decrease in cortical thickness with age, metformin-treated monkeys showed preserved cortical thickness in the frontal lobe and a trend toward increased thickness in the parietal lobe.

Less Transcriptomic Aging and Inflammation

The research team conducted organism-wide, genome-wide RNA sequencing across 79 tissues and organs. They categorized the genes into four clusters based on age-related expression changes:

• D: Decreases with age
• U: Increases with age
• UD: Increases then decreases
• DU: Decreases then increases

Metformin treatment significantly mitigated age-dependent changes in all four clusters.

Table: Effect of Metformin on Gene Clusters

Senescence and Fibrosis

Metformin also reduced the accumulation of senescent (p21-positive) cells in various tissues and mitigated fibrosis in the lung, kidney, and heart. Muscle aging slowed, and epigenetic stability was improved, with lower endogenous retroviral activity.

A "striking" finding was metformin's potent anti-inflammatory effects. Chronic inflammation, a hallmark of aging that underlies many age-related diseases, was notably reduced in organs such as the liver and stomach. There was also decreased immune cell infiltration in the lung, liver, and kidney.

Biological Aging Clock Reversal

The researchers developed a series of biological age clocks using multi-omics data and found that metformin treatment led to a 6.41-year reduction in biological age. The greatest effects were observed in the brain, lung, kidney, and liver, with all 13 analyzed tissues showing some degree of clock reversal.

Single-nucleus transcriptomics revealed that hepatocytes (liver cells) and various brain cells demonstrated the most significant slowing of biological aging after treatment.

The drug also reduced aging-associated periodontal bone loss, which not only results from aging but also may exacerbate it by increasing inflammation⁵.

Study Limitations

This study’s limitations include its small sample size and the use of only male monkeys, which restricts the generalizability of the findings, especially considering the differences in aging between males and females.

Conclusion

"Over 3 years, we evaluated metformin’s systemic geroprotective effects in healthy monkeys, taking advantage of their physiology and organ structure akin to humans, as well as their disease and medication responses. Our results indicate metformin’s capacity to ameliorate aging across the primate body, with multidimensional aging clocks showing a rejuvenation trend post-treatment… Our study reveals metformin’s tissue- and cell-specific geroprotective actions, notably enhancing cognitive performance in primates."

Footnotes

1. Yang, Y., Lu, X., Liu, N., Ma, S., Zhang, H., Zhang, Z., … & Liu, G. H. (2024). Metformin decelerates aging clock in male monkeys. Cell. ↩
2. Bannister, C. A., Holden, S. E., Jenkins‐Jones, S., Morgan, C. L., Halcox, J. P., Schernthaner, G., … & Currie, C. J. (2014). Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non‐diabetic controls. Diabetes, Obesity and Metabolism, 16(11), 1165-1173. ↩
3. Stevenson-Hoare, J., Leonenko, G., & Escott-Price, V. (2023). Comparison of long-term effects of metformin on longevity between people with type 2 diabetes and matched non-diabetic controls. BMC Public Health, 23(1), 804. ↩
4. Strong, R., Miller, R. A., Antebi, A., Astle, C. M., Bogue, M., Denzel, M. S., … & Harrison, D. E. (2016). Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer. Aging Cell, 15(5), 872-884. ↩
5. Hajishengallis, G., & Chavakis, T. (2021). Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities. Nature Reviews Immunology, 21(7), 426-440. ↩