Journal Article

Metformin treatment of diverse Caenorhabditis species reveals the importance of genetic background in longevity and healthspan extension outcomes

Foulger, Anna C., Bhaumik, Dipa, Sedore, Christine A., Harinath, Girish, Chao, Elizabeth A., Xue, Jian, Chen, Esteban, Inman, Delaney, Johnson, Erik, Phillips, Patrick C., Onken, Brian, Lithgow, Gordon J., Jones, Eleanor Grace, Coleman‐Hulbert, Anna L., Hall, David, Hope, June, Plummer, Todd, Morshead, Mackenzie, Banse, Stephen A., Huynh, Phu, Guo, Max, Driscoll, Monica, Guo, Suzhen

2022

Overview

Metformin, the most commonly prescribed anti‐diabetes medication, has multiple reported health benefits, including lowering the risks of cardiovascular disease and cancer, improving cognitive function with age, extending survival in diabetic patients, and, in several animal models, promoting youthful physiology and lifespan. Due to its longevity and health effects, metformin is now the focus of the first proposed clinical trial of an anti‐aging drug—the Targeting Aging with Metformin (TAME) program. Genetic variation will likely influence outcomes when studying metformin health effects in human populations. To test for metformin impact in diverse genetic backgrounds, we measured lifespan and healthspan effects of metformin treatment in three Caenorhabditis species representing genetic variability greater than that between mice and humans. We show that metformin increases median survival in three C. elegans strains, but not in C. briggsae and C. tropicalis strains. In C. briggsae, metformin either has no impact on survival or decreases lifespan. In C. tropicalis, metformin decreases median survival in a dose‐dependent manner. We show that metformin prolongs the period of youthful vigor in all C. elegans strains and in two C. briggsae strains, but that metformin has a negative impact on the locomotion of C. tropicalis strains. Our data demonstrate that metformin can be a robust promoter of healthy aging across different genetic backgrounds, but that genetic variation can determine whether metformin has positive, neutral, or negative lifespan/healthspan impact. These results underscore the importance of tailoring treatment to individuals when testing for metformin health benefits in diverse human populations. We monitored metformin impact in nine strains spanning three Caenorhabditis species that feature a nucleotide diversity greater than that between mouse and humans. We find that metformin promotes healthy aging across diverse genetic backgrounds, but that genetic background can determine whether metformin has a positive, neutral, or negative effect. Data demonstrate the potential broad reach of metformin but also underscore that individual genetics will underlie efficacy over a diverse test set.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Aging / Aging - genetics / Animal models / Animals / anti‐diabetes drug / biguanide / Caenorhabditis / Caenorhabditis briggsae / Caenorhabditis elegans - drug effects / Cardiovascular diseases / Cognitive ability / Diabetes mellitus / genetic diversity / Genetic variability / healthspan / Humans / Hypoglycemic Agents - pharmacology / Hypoglycemic Agents - therapeutic use / Life span / Locomotion / Longevity / Longevity - genetics / Metformin / Metformin - pharmacology / Metformin - therapeutic use / Original Paper / Original Papers / Survival / Treatment Outcome