Is aging reversible? This timeless question has now been answered by scientists from the Chinese Academy of Sciences (CAS).

Specifically, a pivotal discovery by CAS scientists in the field of aging has shown that metformin, commonly used for type 2 diabetes, can alleviate human cellular senescence, markedly slowing down aging in primates. This breakthrough offers fresh insights into the biology of aging and holds promise for developing interventions for humans as they grow older.

The research was conducted by LIU Guanghui’s team from the Institute of Zoology (IOZ) of CAS, ZHANG Weiqi’s team from the Beijing Institute of Genomics (National Center for Bioinformation), and QU Jing’s team, also from IOZ. The results were published in Cell.

Cynomolgus monkeys (Macaca fascicularis) were used in the study due to their physiological and functional similarities to humans, which make them an excellent model for aging studies.

Researchers employed a multidisciplinary approach, including physiological assessments, medical imaging, multiparameter blood tests, multi-tissue pathological analysis, and multi-omics, to monitor the metformin-treated male monkeys for 40 months.

Their findings reveal that extended metformin therapy yielded geroprotective benefits, notably mitigating atrophy of the cerebral cortex, boosting cognitive abilities, slowing periodontal bone loss, and augmenting the rejuvenation of various tissues and organs, including the liver, heart, lungs, intestines, and muscle tissue.

Metformin’s protective effect against aging may be independent of its traditional role in blood sugar and metabolic regulation, the research found. It acts directly on neurons, activating the Nrf2-mediated antioxidant gene expression network, thereby delaying cellular aging.

This finding provides a scientific basis for the geroprotective mechanism of metformin and will inform the advancement of therapeutics for aging intervention.

The research team also utilized machine learning models to build a multi-dimensional model for assessing primate tissue and organ aging, in order to accurately evaluate the systemic effects of metformin in delaying aging.

The study found that metformin can reduce biological age indicators in primates, including multi-tissue DNA methylation age and transcriptome age, as well as plasma protein and metabolite age, with the most pronounced reduction being 6 years—equivalent to 18 human years.

This geroprotective effect was particularly significant in the frontal lobe area of the brain and the liver. High-precision single-cell aging clock assessments showed that metformin significantly delayed the aging process of various neural cells in the brain and hepatocytes in the liver, effectively reducing the biological age of these cells by 5 to 6 years, or about 15 to 18 years in humans.

This study not only injects new vitality into the field of aging intervention but also establishes new paradigms and standards for evaluating the efficacy and safety of human aging interventions.

It represents an important advance in the quest to delay human aging, with geriatric medicine research gradually shifting its focus from treating individual chronic diseases to systemic intervention against aging.

Figure 1. Metformin slows brain aging in primates (Image from LIU Guanghui's lab)

Metformin enhances frontal lobe dendrites in elderly monkeys. (Image from LIU Guanghui's lab)