SGLT2 Inhibitors as Calorie Restriction Mimetics: Insights on Longevity Pathways and Age-Related Diseases

Abstract Sodium-glucose cotransporter-2 (SGLT2) inhibitors induce glycosuria, reduce insulin levels, and promote fatty acid oxidation and ketogenesis. By promoting a nutrient deprivation state, SGLT2 inhibitors upregulate the energy deprivation sensors AMPK and SIRT1, inhibit the nutrient sensors mTOR and insulin/IGF1, and modulate the closely linked hypoxia-inducible factor (HIF)-2α/HIF-1α pathways. Phosphorylation of AMPK and upregulation of adiponectin and PPAR-α favor a reversal of the metabolic syndrome which have been linked to suppression of chronic inflammation. Downregulation of insulin/IGF1 pathways and mTOR signaling from a reduction in glucose and circulating amino acids promote cellular repair mechanisms, including autophagy and proteostasis which confer cellular stress resistance and attenuate cellular senescence. SIRT1, another energy sensor activated by NAD+ in nutrient-deficient states, is reciprocally activated by AMPK, and can deacetylate and activate transcription factors, such as PCG-1α, mitochondrial transcription factor A (TFAM), and nuclear factor E2-related factor (NRF)-2, that regulate mitochondrial biogenesis. FOXO3 transcription factor which target genes in stress resistance, is also activated by AMPK and SIRT1. Modulation of these pathways by SGLT2 inhibitors have been shown to alleviate metabolic diseases, attenuate vascular inflammation and arterial stiffness, improve mitochondrial function and reduce oxidative stress-induced tissue damage. Compared with other calorie restriction mimetics such as metformin, rapamycin, resveratrol, and NAD+ precursors, SGLT2 inhibitors appear to be the most promising in the treatment of aging-related diseases, due to their regulation of multiple longevity pathways that closely resembles that achieved by calorie restriction and their established efficacy in reducing cardiovascular events and all-cause mortality. Evidence is compelling for the role of SGLT2 inhibitors as a calorie restriction mimetic in anti-aging therapeutics.