Gemfibrozil promotes longevity and health by restricting amino acid uptake through the Dipeptide transporter, PEPT1

The FDA-approved fibrate, gemfibrozil, has been used clinically to treat hyperlipidaemia, showing efficacy both in lowering triglycerides and increasing high-density lipoproteins. However, in recent years, the drug has been increasingly investigated for potential clinical use in other diseases. Here, we show for the first time that gemfibrozil promotes healthy lifespan across multiple evolutionarily diverse species. Interestingly, we find this novel pro-longevity role to be independent of PPAR- \(α\) , the canonical target of all fibrates, and instead through an inhibitory interaction with a cell-surface dipeptide transporter, Slc15a1 (PEPT1). In both PEPT1-expressing cells and in isolated murine intestinal segments, treatment with gemfibrozil displayed a significant decrease in global amino acid levels, reminiscent of protein restriction. In vitro, gemfibrozil treatment also lowered signalling through mTOR; a master regulator of metabolism that is responsive to cellular amino acid levels and a viable therapeutic target under investigation to recapitulate the beneficial effects of dietary restriction in a nutrient-replete environment. In aged 20-month old female mice, a 6-month gemfibrozil regimen resulted in an improvement in frailty, positively impacting parameters such as hearing loss, piloerection and grip strength. Finally, in a DSS-induced colitis mouse model, gemfibrozil appeared to alleviate symptoms; an effect often observed with PEPT1 inhibition. Overall, our study reveals a potential role of gemfibrozil, a largely safe clinically approved drug in circumventing the negative consequences of overnutrition often seen in a modern-day diet, and as an effective means to promote lifespan and healthspan.