Photoactivatable senolysis with single-cell resolution delays aging.
Donglei ShiWenwen LiuYing GaoXinming LiYunyuan HuangXiaokang LiTony David JamesYuan GuoJian LiPublished in: Nature aging (2023)
Strategies that can selectively eliminate senescent cells (SnCs), namely senolytics, have been shown to promote healthy lifespan. However, it is challenging to achieve precise, broad-spectrum and tractable senolysis. Here, we integrate multiple technologies that combine the enzyme substrate of senescence-associated β-galactosidase (SA-β-gal) with fluorescence tag for the precise tracking of SnCs, construction of a bioorthogonal receptor triggered by SA-β-gal to target and anchor SnCs with single-cell resolution and incorporation of a selenium atom to generate singlet oxygen and achieve precise senolysis through controllable photodynamic therapy (PDT). We generate KSL0608-Se, a photosensitive senolytic prodrug, which is selectively activated by SA-β-gal. In naturally-aged mice, KSL0608-Se-mediated PDT prevented upregulation of age-related SnCs markers and senescence-associated secretory phenotype factors. This treatment also countered age-induced losses in liver and renal function and inhibited the age-associated physical dysfunction in mice. We therefore provide a strategy to monitor and selectively eliminate SnCs to regulate aging.
Keyphrases
- photodynamic therapy
- single cell
- rna seq
- single molecule
- high fat diet induced
- endothelial cells
- dna damage
- fluorescence imaging
- induced apoptosis
- high glucose
- high throughput
- cell cycle arrest
- stress induced
- oxidative stress
- mental health
- physical activity
- cancer therapy
- signaling pathway
- insulin resistance
- wild type
- cell death
- diabetic rats
- skeletal muscle
- adipose tissue
- drug induced