Researchers here note that delivering metformin via injection rather than the usual oral administration removes unwanted side-effects and better improves cognitive function in old mice. Near all testing of metformin has used oral administration, and the effects on pace of aging and life span are, frankly, too unreliable and too small to justify the present level of interest in the drug on the part of the longevity community. Administration by injection might be a different story, but waiting on further research and confirming data would be a wiser course of action than immediate excitement. Even then, this is tinkering with the damaged state of metabolism, not a form of repair. The upside is always going to be more limited than that of approaches that address underlying causes of aging.

Many studies have shown that in patients with type 2 diabetes, chronic administration of metformin causes side effects such as abdominal or stomach pain, diarrhea, early satiety, decreased appetite, risk of vitamin B-12 deficiency, and lactic acidosis. In the current study, we treated non-diabetic mice with metformin for 10 months. Unequivocally, our results show that chronic metformin treatment may lead to severe disabilities, including cancer, cataracts, and dermatitis. Studies in nematodes and other smaller organisms suggest that the side effects of chronic metformin treatment may be caused by changes in the gut microbiome.

To avoid the side effects of metformin, we treated mice with metformin by tail vein injection, which is believed to have little effect on the composition of gut microbes. Interestingly, it appears that metformin treatment by tail vein injection results in better cognitive function performance than oral administration. Consequently, we speculate that gut microbes may play an important role in mediating the side effects of metformin, and this potential role needs to be further explored. The beneficial effects of metformin on cognitive function are associated with the restoration of vascular integrity, producing a richer cerebral blood flow, as well as activation of neurogenesis in the subventricular zone. The mechanism of metformin administration enhanced glycolysis through increased mRNA expression of GAPDH, which ultimately increased angiogenesis and neurogenic potential of neural stem cells.

To avoid the side effects of metformin, our study proposes careful reconsideration of lower doses of metformin treatment by tail vein injection for translational research. Altogether, our study shows an improved method for metformin treatment, which might contribute to a reduction in the side effects of metformin and lead to better therapeutic value for anti-aging in humans.