Sodium-glucose co-transporter 2 (SGLT2) inhibitors are glucose-lowering drugs widely used for the treatment of diabetes and cardiovascular disease. By showing that the SGLT2 inhibitor canagliflozin eliminates senescent cells in mice, a study in Nature Aging reveals an unexpected mode of action for SGLT2 inhibitors and opens possibilities for the treatment of aging-related diseases.

As cells divide over time, they accumulate damage to their DNA and other cellular components. Such damaged cells can enter a state of irreversible growth arrest, termed cellular senescence. In physiological conditions, senescent cells can be removed by the immune system, facilitating tumor suppression, wound healing and protection against fibrosis. However, as we age, our body accumulates senescent cells, contributing to pathological aging. Senolytic drugs – compounds that kill senescent cells – have shown therapeutic activity in several mouse models of human disease, including atherosclerosis and metabolic disease. Here, Katsuumi et al. investigated whether SGLT2 inhibitors, known to improve various metabolic and cardiovascular abnormalities, have a senolytic effect.

Using a mouse model of high fat diet (HFD)-induced obesity, the researchers showed that treatment with canagliflozin reduced senescence in visceral adipose tissue and improved metabolic dysfunction. Metabolomic analysis showed that SGLT2 inhibition increased the plasma level of 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, a metabolite known to activate AMP-activated protein kinase (AMPK). Given that AMPK activity negatively regulates the expression of programmed cell death-ligand 1 (PD-L1), a major immune checkpoint protein that is expressed in senescent cells, the team decided to investigate the effect of SGLT2 inhibition on PD-L1. They found that the number of PD-L1-positive senescent cells was increased in the visceral adipose tissue of HFD-fed mice compared with the normal chow group, and that this increase was reduced by SGLT2 inhibition. Administration of CD3-neutralizing antibody attenuated the effects of canagliflozin on senescent cells, suggesting that the senolytic effects of canagliflozin are partly due to T cell activation.

In conclusion, the results suggest that SGLT2 inhibition induces senolysis by enhancing the immunosurveillance of senescent cells via PD-L1 downregulation. In the study, SGLT2 inhibition also efficiently eliminated senescent cells from atherosclerotic plaques in ApoE-knockout mice and delayed premature aging in a mouse model of progeria, opening new paths for the treatment of aging-related diseases.

Original reference: Katsuumi, G. et al. Nat. Aging https://doi.org/10.1038/s43587-024-00642-y (2024)