Those of us feeling the all too familiar effects of time may look to cut back on certain “excesses” and keep fit (in both body and mind) to maintain a healthy aging process. Now, a team of fitness enthusiasts has revealed that long-term treatment with the diabetes drug metformin maintains an aging population of monkeys “in form,” including at the epigenetic level!
An athletic team of researchers instructed by Jing Qu, Weiqi Zhang, and Guang-Hui Liu (University of Chinese Academy of Sciences) knew of metformin’s potential to slow aging in various models, alleviate senescence in human cells, and reduce mortality rates in diabetic patients. With this in mind, the team evaluated the effects of a 40-month metformin treatment in adult male cynomolgus monkeys (≈10 human years) via pan-tissue transcriptome, DNA methylome, plasma proteome, and metabolome profiling to define whether this common drug could delay aging and ameliorate tissue degeneration.
Let’s hear from Yang, Lu, Liu, Ma, Zhang, Zhang, and Colleagues on how metformin maintains aged monkeys in form:
- Initial results imply the overall safety of long-term metformin treatment, which enhances memory and cognitive function and postpones aging-associated structural deterioration of the brain
- Genome-wide RNA-seq analyses of tissues/organs revealed that metformin treatment inhibits aging-related inflammatory response, apoptosis, fibrosis, and reactive oxygen species pathways and reactivates aging-repressed pathways involved in development/morphogenesis
- Metformin administration ameliorates classic hallmarks of aging in multiple tissues, reduces signs of systemic inflammation, and rectifies indicators of aging-associated epigenetic instability (such as H3K9me3 loss)
- Long-term metformin exposure minimally affects blood sugar/body weight in healthy elderly monkeys
- The quantification of metformin-induced biological age deceleration via computational models of monkey aging clocks based on multi-omics data (including DNA methylation) reveals that metformin delays aging across various tissues
- The development of a comprehensive multi-dimensional primate aging clock demonstrates that metformin slows liver aging/enhances hepatoprotection
- Metformin also slows brain aging and provides neuroprotection in elderly monkeys, offers neuroprotection in a human stem cell-derived neuronal senescence model, and induces a 6-year delay in brain aging, suggesting potential applications in treating neurodegenerative and other chronic conditions
- Metformin functions primarily via cell autonomous pathways, with the transcription factor Nrf2’s intrinsic antioxidant mechanisms playing a critical role
- Nrf2 activation partially mediates the protective effects of metformin on aged monkey neurons
These fitness-forward findings suggest that extended metformin treatment (at doses/schedules suitable for humans) induces a “systemic reduction of multi-dimensional biological age” and, as such, maintains the minds and bodies of monkeys in form. Future studies into metformin treatment may seek evidence of functional rejuvenation, define side effects, assess mortality/long-term effects following cessation, and further explore research into pathways beyond Nrf2.
For more on how metformin can maintain aged monkeys (and perhaps humans) in form, see Cell, September 2024.