SGLT2 Inhibition Eliminates Senescent Cells and Alleviates Pathological Aging

Overview

Journal Nat Aging

Specialty Geriatrics

Date 2024 May 30

PMID 38816549

Authors

Goro Katsuumi

Ippei Shimizu

Masayoshi Suda

Yohko Yoshida

Takaaki Furihata

Yusuke Joki

Chieh-Lun Hsiao

Liang Jiaqi

Shinya Fujiki

Manabu Abe

Masataka Sugimoto

Tomoyoshi Soga

Tohru Minamino

Affiliations

Soon will be listed here.

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.

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References

Hashimoto M, Asai A, Kawagishi H, Mikawa R, Iwashita Y, Kanayama K . Elimination of p19-expressing cells enhances pulmonary function in mice. JCI Insight. 2016; 1(12):e87732. PMC: 5033852. DOI: 10.1172/jci.insight.87732. View

Han S, Georgiev P, Ringel A, Sharpe A, Haigis M . Age-associated remodeling of T cell immunity and metabolism. Cell Metab. 2022; 35(1):36-55. PMC: 10799654. DOI: 10.1016/j.cmet.2022.11.005. View

Sturmlechner I, Zhang C, Sine C, van Deursen E, Jeganathan K, Hamada N . p21 produces a bioactive secretome that places stressed cells under immunosurveillance. Science. 2021; 374(6567):eabb3420. PMC: 8985214. DOI: 10.1126/science.abb3420. View

Leung G, Schmidt W, Bergo M, Gavino B, Wong D, Tam A . Biochemical studies of Zmpste24-deficient mice. J Biol Chem. 2001; 276(31):29051-8. DOI: 10.1074/jbc.M102908200. View

Kunieda T, Minamino T, Nishi J, Tateno K, Oyama T, Katsuno T . Angiotensin II induces premature senescence of vascular smooth muscle cells and accelerates the development of atherosclerosis via a p21-dependent pathway. Circulation. 2006; 114(9):953-60. DOI: 10.1161/CIRCULATIONAHA.106.626606. View

Dai X, Bu X, Gao Y, Guo J, Hu J, Jiang C . Energy status dictates PD-L1 protein abundance and anti-tumor immunity to enable checkpoint blockade. Mol Cell. 2021; 81(11):2317-2331.e6. PMC: 8178223. DOI: 10.1016/j.molcel.2021.03.037. View

Chaib S, Tchkonia T, Kirkland J . Cellular senescence and senolytics: the path to the clinic. Nat Med. 2022; 28(8):1556-1568. PMC: 9599677. DOI: 10.1038/s41591-022-01923-y. View

Nakayama H, Abe M, Morimoto C, Iida T, Okabe S, Sakimura K . Microglia permit climbing fiber elimination by promoting GABAergic inhibition in the developing cerebellum. Nat Commun. 2018; 9(1):2830. PMC: 6053401. DOI: 10.1038/s41467-018-05100-z. View

Yokoyama M, Shimizu I, Nagasawa A, Yoshida Y, Katsuumi G, Wakasugi T . p53 plays a crucial role in endothelial dysfunction associated with hyperglycemia and ischemia. J Mol Cell Cardiol. 2019; 129:105-117. DOI: 10.1016/j.yjmcc.2019.02.010. View

10.

Krishnamurthy J, Torrice C, Ramsey M, Kovalev G, Al-Regaiey K, Su L . Ink4a/Arf expression is a biomarker of aging. J Clin Invest. 2004; 114(9):1299-307. PMC: 524230. DOI: 10.1172/JCI22475. View

11.

Xu M, Palmer A, Ding H, Weivoda M, Pirtskhalava T, White T . Targeting senescent cells enhances adipogenesis and metabolic function in old age. Elife. 2015; 4:e12997. PMC: 4758946. DOI: 10.7554/eLife.12997. View

12.

Jenkins B, Blagih J, Ponce-Garcia F, Canavan M, Gudgeon N, Eastham S . Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity. Cell Metab. 2023; 35(7):1132-1146.e9. DOI: 10.1016/j.cmet.2023.05.001. View

13.

Ma E, Poffenberger M, Wong A, Jones R . The role of AMPK in T cell metabolism and function. Curr Opin Immunol. 2017; 46:45-52. DOI: 10.1016/j.coi.2017.04.004. View

14.

Childs B, Baker D, Wijshake T, Conover C, Campisi J, van Deursen J . Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science. 2016; 354(6311):472-477. PMC: 5112585. DOI: 10.1126/science.aaf6659. View

15.

Suda M, Shimizu I, Katsuumi G, Yoshida Y, Hayashi Y, Ikegami R . Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice. Nat Aging. 2023; 1(12):1117-1126. DOI: 10.1038/s43587-021-00151-2. View

16.

Yousefzadeh M, Flores R, Zhu Y, Schmiechen Z, Brooks R, Trussoni C . An aged immune system drives senescence and ageing of solid organs. Nature. 2021; 594(7861):100-105. PMC: 8684299. DOI: 10.1038/s41586-021-03547-7. View

17.

Shimizu I, Yoshida Y, Katsuno T, Tateno K, Okada S, Moriya J . p53-induced adipose tissue inflammation is critically involved in the development of insulin resistance in heart failure. Cell Metab. 2012; 15(1):51-64. DOI: 10.1016/j.cmet.2011.12.006. View

18.

Lopez-Otin C, Blasco M, Partridge L, Serrano M, Kroemer G . Hallmarks of aging: An expanding universe. Cell. 2023; 186(2):243-278. DOI: 10.1016/j.cell.2022.11.001. View

19.

Palmer A, Xu M, Zhu Y, Pirtskhalava T, Weivoda M, Hachfeld C . Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell. 2019; 18(3):e12950. PMC: 6516193. DOI: 10.1111/acel.12950. View

20.

Hennekam R . Hutchinson-Gilford progeria syndrome: review of the phenotype. Am J Med Genet A. 2006; 140(23):2603-24. DOI: 10.1002/ajmg.a.31346. View