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

Abstract

SGLT2 inhibitors induce glycosuria, reduce insulin levels, 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/IGF-1, and modulate the closely-linked HIF-2α/HIF-1α pathways. Phosphorylation of AMPK and upregulation of adiponectin and PPAR-α favour a reversal of the metabolic syndrome which have been linked to suppression of chronic inflammation. Downregulation of insulin/IGF1 pathways and mTOR signalling 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, TFAM and NRF2 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 to other calorie restriction mimetics such as metformin, rapamycin, resveratrol and NAD+ precursors, SGLT2 inhibitors appear to be the most promising in the treatment of ageing-related diseases, due to its regulation of multiple longevity pathways that closely resemble that achieved by calorie restriction, and their established efficacy in reduction in cardiovascular events and all-cause mortality. Evidence is compelling for the role of SGLT2 inhibitors as a calorie restriction mimetic in anti-ageing therapeutics.

Insulin Growth Factor Phenotypes in Heart Failure With Preserved Ejection Fraction, an INSPIRE Registry and CATHGEN Study

“…21 On the other hand, a decrease in IGF signaling and subsequent phosphoinositide-3-kinase/Protein kinase (PI3K/Akt) activation may shift the metabolic focus from growth toward maintenance and cellular repair. 21,28,29 This can in turn attenuate senescence-related cardiac hypertrophy and interstitial fibrosis, inflammation and oxidative stress which are likely protective in HFpEF. 21 Decreased IGF activation could also decrease tumorogenesis or cancer progression and may explain in part the association between lower circulating IGF and survival in older cohorts.…”

Mini Review: Effect of GLP-1 Receptor Agonists and SGLT-2 Inhibitors on the Growth Hormone/IGF Axis

“…), as well as by inhibiting insulin/IGF-1 signaling, ultimately leading to decreased circulating glucose and amino acids. Therefore, SGLT-2is appear to mimic nutrient deprivation states, thus attenuating cellular ageing and stress, and to alter cellular metabolic programming through a dormancy state with increased production of ketone bodies ( 90 ).…”

Diabetes Mellitus and Heart Failure

“…SGLT are active glucose co-transporters in the renal tubules preventing glycosuria by means of filtered glucose reabsorption along with sodium into the circulation. SGLT2, which is located almost exclusively in the S1 segment of the proximal renal tubules, carries out 90% of glucose resorption, whereas SGLT1, which is located distally in the S3 segment of the proximal tubule, reabsorbs the remaining 10% of filtered glucose [97]. SGLT1 is also located in the small intestines, heart, skeletal muscles, pancreas, and salivary glands.…”

“…Despite SGLT2 localization predominantly in the renal tubules, SGLT-2i have important systemic effects [97]. In this regard, clinical studies have shown that SGLT-2i not only improve glycemic control but additionally reduce major adverse CV events and hospitalization for heart failure (HF) and improve outcome in CKD, both in patients with DM and those without DM [98,99].…”