Table 1.

Summary of the main findings relative to the effects of SGLT-2i on: 1- lifespan and healthspan in mice; 2- aging pathways in animal models; 3- markers of inflammaging in humans; and 4- the incidence of age-related diseases in patients with or without diabetes.

Effect	Findings	References
Effect on healthspan and lifespan in mice	Sglt2 inhibitor TA-1887 increased the mean lifespan of cachectic db/db mice under a long-term high-fat diet	Sugizaki T et al., 2017 [25]
	Canagliflozin extended median survival by 14% and increased by 9% the age for 90th percentile survival of male mice, improving also the mice’s healthspans	Miller RA et al., 2020 [28] Snyder JM et al., 2022 [29]
	Canagliflozin improved exploratory and locomotor activity in 30-month-old male but not female mice	Jayarathne HSM et al., 2022 [31]
Effect against aging pathways in animal models	Ketone bodies-mediated inhibition of mTOR and modulation of other nutrient-sensing pathways (AMPK-SIRT1)	Zhou H et al., 2018 [43] Tomita I et al., 2020 [39]
	Rescue of normal mitochondrial fusion/fission dynamics and normalization of mitochondrial membrane potential with attenuated oxidative stress	Durak A et al., 2018 [52] Lee YH et al., 2019 [40]
	Inhibition of cellular senescence in multiple tissues and models	Madonna R et al., 2020 [62] Kim MN et al., 2021 [61]
	Inhibition of the NLPR3 inflammasome	Leng W et al., 2016 [75]
Effect against inflammaging in humans	Macrophages from SGLT2-i treated patients have a reduced secretion of IL-1β compared with patients on other therapies with similar glycemic control	Kim SR et al., 2020 [78]
	Patients treated with SGLT-2i have lower circulating levels of IL-6, compared with patients on other therapies and comparable glycemic control	Garvey et al., 2018 [88] Heerspink et al., 2019 [87] La Grotta et al., 2022 [79]
	Treatment with SGLT-2i reduce the circulating levels of a plethora of pro-inflammatory and pro-fibrotic markers, which mediate part of the renoprotective effects of the drugs	Sen T et al., 2021 [89] Tye SC et al., 2021 [90]
Effect against age- related diseases in humans	SGLT-2i reduce the incidence of major adverse cardiovascular events, hospitalizations for heart failure, CV-related death, all-cause mortality, and renal outcomes in patients with type 2 diabetes	Wang C et al., 2019 [91] McGuire DK et al., 2020 [83] Li CX et al., 2021 [17]
	SGLT-2i reduce the incidence hospitalizations for heart failure, CV-related death, all-cause mortality, and renal outcomes also in patients without diabetes but with heart failure or kidney disease	McMurray JJV et al., 2019 [19] Heerspink HJL et al., 2020 [18] Silverii GA et al., 2021 [20]
	Treatment with dapagliflozin decrease the incidence of new-onset type 2 diabetes in patients with chronic kidney disease or heart failure	Rossing P et al., 2022 [109]
	SGLT-2i improve hepatic steatosis in patients with diabetes	Reviewed in Scheen AJ et al., 2019 [30]