SIRT7 Deficiency Protects against Aging-Associated Glucose Intolerance and Extends Lifespan in Male Mice

Abstract

Sirtuins (SIRT1–7 in mammals) are evolutionarily conserved nicotinamide adenine dinucleotide-dependent lysine deacetylases/deacylases that regulate fundamental biological processes including aging. In this study, we reveal that male Sirt7 knockout (KO) mice exhibited an extension of mean and maximum lifespan and a delay in the age-associated mortality rate. In addition, aged male Sirt7 KO mice displayed better glucose tolerance with improved insulin sensitivity compared with wild-type (WT) mice. Fibroblast growth factor 21 (FGF21) enhances insulin sensitivity and extends lifespan when it is overexpressed. Serum levels of FGF21 were markedly decreased with aging in WT mice. In contrast, this decrease was suppressed in Sirt7 KO mice, and the serum FGF21 levels of aged male Sirt7 KO mice were higher than those of WT mice. Activating transcription factor 4 (ATF4) stimulates Fgf21 transcription, and the hepatic levels of Atf4 mRNA were increased in aged male Sirt7 KO mice compared with WT mice. Our findings indicate that the loss of SIRT7 extends lifespan and improves glucose metabolism in male mice. High serum FGF21 levels might be involved in the beneficial effect of SIRT7 deficiency.

Role of sirtuins in epigenetic regulation and aging control

“…Conflicting data have been obtained for SIRT7. In particular, it has recently been demonstrated that male mice with SIRT7 knockout have an increased median lifespan and exhibit a slower decrease in physiological parameters (Mizumoto et al, 2022). This result contrasts with observations from earlier studies, in which the SIRT7 knockout significantly shortened the lifespan.…”

The Emerging Role of SIRT7 in Glucose and Lipid Metabolism

“…Intriguingly, the expression levels of Fgf21 and Nrg4 are increased in the BAT of Sirt7 KO mice ( Figure 2 E) [ 21 ]. Furthermore, hepatic Fgf21 mRNA expression and the serum FGF21 levels of aged Sirt7 KO mice are higher than those of control mice [ 124 ]. These findings suggest that SIRT7 deficiency improves insulin sensitivity, at least in part, through the enhancement of BAT thermogenesis and overexpression of insulin-sensitizing batokines.…”