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SGLT2 inhibition eliminates senescent cells and alleviates pathological aging
Goro Katsuumi1,2, Ippei Shimizu3,4, Masayoshi Suda1,5
1Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Abstract:
It has been reported that accumulation of senescent cells in various tissues contributes to pathological aging and that elimination of senescent cells (senolysis) improves age-associated pathologies. Here, we demonstrate that inhibition of sodium-glucose co-transporter 2 (SGLT2) enhances clearance of senescent cells, thereby ameliorating age-associated phenotypic changes. In a mouse model of dietary obesity, short-term treatment with the SGLT2 inhibitor canagliflozin reduced the senescence load in visceral adipose tissue and improved adipose tissue inflammation and metabolic dysfunction, but normalization of plasma glucose by insulin treatment had no effect on senescent cells. Canagliflozin extended the lifespan of mice with premature aging even when treatment was started in middle age. Metabolomic analyses revealed that short-term treatment with canagliflozin upregulated 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, enhancing immune-mediated clearance of senescent cells by downregulating expression of programmed cell death-ligand 1. These findings suggest that inhibition of SGLT2 has an indirect senolytic effect by enhancing endogenous immunosurveillance of senescent cells.
Insights
Inhibition of sodium-glucose co-transporter 2 (SGLT2) enhances the body's natural clearance of senescent cells, improving age-related conditions. This SGLT2 inhibition offers an indirect senolytic effect, boosting immune surveillance against aging cells.
Area of Science:
- Gerontology
- Metabolic Diseases
- Immunology
Background:
- Cellular senescence contributes to aging pathologies.
- Senolysis, the elimination of senescent cells, can improve age-associated diseases.
- Sodium-glucose co-transporter 2 (SGLT2) inhibitors are used to manage metabolic conditions.
Purpose of the Study:
- To investigate the effect of SGLT2 inhibition on senescent cell clearance.
- To determine if SGLT2 inhibition ameliorates age-associated pathologies.
- To elucidate the mechanism by which SGLT2 inhibition impacts senescent cells.
Main Methods:
- Treatment of mice with the SGLT2 inhibitor canagliflozin.
- Assessment of senescence load in visceral adipose tissue.
- Metabolomic analysis to identify molecular pathways involved.
- Evaluation of lifespan in premature aging mouse models.
Main Results:
- Canagliflozin reduced senescent cell burden and improved metabolic dysfunction in obese mice.
- SGLT2 inhibition, but not insulin-induced glucose normalization, affected senescent cells.
- Canagliflozin extended lifespan in mice with premature aging.
- Upregulation of 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside was observed, enhancing immune-mediated clearance via PD-L1 downregulation.
Conclusions:
- SGLT2 inhibition exhibits an indirect senolytic effect.
- Enhanced immune-mediated clearance of senescent cells is a key mechanism.
- SGLT2 inhibition holds potential for treating age-related diseases by improving immunosurveillance.
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