SGLT inhibitors for improving healthspan and lifespan

• Published in: Progress in cardiovascular diseases Vol. 81; pp. 2 - 9
• Main Authors: O'Keefe, James H., Weidling, Robert, O'Keefe, Evan L., Franco, William G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2023
• Subjects: Aging; Autophagy; Cancer; Cardiovascular; Central nervous system; Diabetes Mellitus, Type 2; Emphysema; Geroprotection; Glucose; Humans; Hypoglycemic Agents; Longevity; Neoplasms; Neurodegenerative Diseases; SLGTi; Sodium-Glucose Transporter 2 Inhibitors; RCT; Cardiovascular; TNF-; Central nervous system; CNS; Autophagy; BP; SLGTi; Aging; Geroprotection; mTOR; DPP4i; CKD; HbA1c; PGC1-α; AF; BDNF; T2D; Longevity; CVD; CV; AMPK; HF; SIRT; Cancer; cancer; SGLTi
• ISSN: 0033-0620; 1532-8643; 1873-1740
• DOI: 10.1016/j.pcad.2023.10.003

Sodium-glucose cotransporter inhibitor (SLGTi), initially approved as a glucose-lowering therapy for type 2 diabetes is associated with decreased risks for many of the most common conditions of aging, including heart failure, chronic kidney disease, all-cause hospitalization, atrial fibrillation, cancer, gout, emphysema, neurodegenerative disease/dementia, emphysema, non-alcoholic fatty liver disease, atherosclerotic disease, and infections. Studies also suggest SLGTi improves overall life expectancy and reduces risks of cardiovascular disease death and cancer death. These wide-ranging health benefits are largely unexplained by the modest SLGTi -induced improvements in standard risk factors. SLGTi produces upregulation of nutrient deprivation signaling, while simultaneously triggering downregulation of nutrient surplus signaling. This in turn promotes autophagy—cellular housekeeping whereby senescent and damaged organelles are broken down and recycled, which helps to maintain cellular integrity and prevent apoptotic cell death. SLGTi decreases oxidative stress and endoplasmic reticulum stress, restores of mitochondrial health, stimulates mitochondrial biogenesis, and diminishes proinflammatory and profibrotic pathways. These actions help to revitalize senescent cells, tissues, and organs. Their cumulative effects in preventing premature disease and death suggest that SLGTi may slow aging and improve life expectancy, and its mechanisms of action lend strong biological plausibility to this hypothesis. Further randomized trials are warranted to test whether SLGTi —a safe and well-tolerated, once-daily pill, might improve lifespan and healthspan.