# Comparative analysis of senolytic drugs reveals mitochondrial determinants of efficacy and resistance

## TL;DR

This study compares 21 drugs that target aging cells and finds that mitochondrial health affects how well these drugs work, suggesting ways to improve their effectiveness.

## Contribution

The study identifies mitochondrial integrity as a key factor in resistance to senolytic drugs and proposes metabolic interventions to enhance their efficacy.

## Key findings

- ABT263 and ARV825 were the most effective senolytic drugs across multiple cell models.
- Senolytic resistance is driven by mitochondrial integrity maintained via V-ATPase activity.
- Metabolic interventions like ketogenic diet or SGLT2 inhibition improved senolytic efficacy in mice.

## Abstract

Cellular senescence contributes to aging and disease, and senolytic drugs that selectively eliminate senescent cells hold therapeutic promise. Although over 20 candidates have been reported, their relative efficacies remain unclear. Here we systematically compared 21 senolytic agents using a senolytic specificity index, identifying the Bcl-2 inhibitor ABT263 and the BET inhibitor ARV825 as most effective senolytics across fibroblast and epithelial senescence models. However, even upon extended treatment with these most potent senolytics, a proportion of senescent cells remained viable. We found that senolytic resistance was driven by maintenance of mitochondrial integrity through V-ATPase-mediated clearance of damaged mitochondria. Imposing mitochondrial stress via metabolic workload enhanced the senolytic efficacies of ABT263 and ARV825 in vitro, and in mouse models, ketogenic diet adoption or SGLT2 inhibition similarly potentiated ABT263-induced and ARV825-induced senolysis, reducing metastasis and tumor growth. These findings suggest that mitochondrial quality control is a key determinant of resistance to ABT263-induced and ARV825-induced senolysis, providing a possible framework for rational combination senotherapies.

Wakita et al. systematically compare the efficacy of 21 senolytics and identify a subpopulation of senolytic-resistant cells. They demonstrate a mitochondrial basis of senolytic resistance and show that metabolic interventions enhance senescent cell clearance in vivo.