Photoactivatable senolysis with single-cell resolution delays aging.

Area of Science:

• Biogerontology
• Molecular Biology
• Photodynamic Therapy

Background:

• Senescent cells (SnCs) accumulate with age and contribute to aging and age-related diseases.
• Current senolytic strategies face challenges in precision, broad-spectrum efficacy, and tractability.
• Developing targeted methods to eliminate SnCs is crucial for promoting healthy lifespan.

Purpose of the Study:

• To develop a novel senolytic strategy for precise monitoring and elimination of senescent cells.
• To create a photosensitive senolytic prodrug activated by senescence-associated β-galactosidase (SA-β-gal).
• To evaluate the efficacy of this strategy in counteracting aging phenotypes in vivo.

Main Methods:

• Integration of SA-β-gal enzyme substrate with fluorescence tagging for SnC tracking.
• Construction of a bioorthogonal receptor triggered by SA-β-gal for single-cell targeting.
• Incorporation of a selenium atom for photodynamic therapy (PDT)-induced singlet oxygen generation.
• Generation and testing of the photosensitive senolytic prodrug KSL0608-Se in naturally-aged mice.

Main Results:

• KSL0608-Se-mediated PDT selectively targeted and eliminated SA-β-gal-positive senescent cells.
• The treatment prevented the upregulation of age-related SnC markers and senescence-associated secretory phenotype factors.
• KSL0608-Se treatment countered age-induced liver and renal function decline and improved physical function in aged mice.

Conclusions:

• A novel strategy combining SA-β-gal-triggered targeting and selenium-based PDT enables precise senolysis.
• KSL0608-Se is an effective photosensitive senolytic prodrug for monitoring and eliminating senescent cells.
• This approach offers a promising therapeutic avenue for regulating aging and age-related dysfunction.