SGLT inhibitors for improving Healthspan and lifespan

Corresponding author at: 4321 Washington, Suite 2400, Kansas City, MO 64111, United States of America., jokeefe@saintlukeskc.org (J.H. O’Keefe).

Sodium-glucose cotransporter inhibitor/inhibition (SGLTi), 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 show that SGLTi improves overall life expectancy and reduces risks of cardiovascular death and cancer death. These wide-ranging health benefits are largely unexplained by the SGLTi’s modest improvements in standard risk factors. SGLTi produces upregulation of nutrient deprivation signaling and downregulation of nutrient surplus signaling. This in turn promotes autophagy, which helps to optimize cellular integrity and prevent apoptotic cell death. SGLTi 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. In summary, SGLTi appears to slow aging, prevent disease, and improve life expectancy, and its mechanisms of action lend strong biological plausibility to this hypothesis. Further randomized trials are warranted to test whether SGLTi, a safe and well-tolerated, once-daily pill, might improve healthspan and lifespan.

The innate aging process is the most important risk factor for the majority of serious chronic disease and death. Aging is characterized by the progressive erosion of optimal physiological function beginning at the cellular level and culminating in musculoskeletal frailty with an increased risk for developing chronic cardiovascular (CV) disease (CVD), metabolic, neurodegenerative, infectious and neoplastic diseases. Due to the increasingly well-understood biological mechanisms of aging, this process may be theoretically modifiable using targeted therapeutic interventions. In recent decades, scientists have explored a range of nutritional and pharmacological interventions aimed at extending lifespan in lower organisms. Optimal diet and exercise appear to be effective at extending lifespan as well as healthspan—the number of years a person lives in a state of good health with full mental and physical capabilities.1,2 Aerobic exercise/cardiorespiratory fitness and calorie restriction/fasting have been shown to improve insulin sensitivity, which provides potent protection against age-related disease and premature death.2,3

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