Nature agingOct 8, 2025

The secreted molecule sensor CtBP2 connects metabolism to a healthy lifespan

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

CtBP2 may act as a secreted metabolite-sensing signal linking reductive metabolism with healthier aging.

Evidence

This mixed preclinical and observational study used aged mice, mechanistic assays, and human serum data to link exosomal CtBP2 with longer lifespan, reduced frailty, CYB5R3/AMPK activation, lower levels with age, lower cardiovascular disease incidence, and longevity-family enrichment.

Caveat

The human findings are associative, and the interventional lifespan and healthspan evidence comes from aged mice rather than clinical testing.

Simplified

Within each cell, metabolite-sensing factors respond to coordinate metabolic homeostasis. How metabolic homeostasis is regulated intercellularly and how this may become dysregulated with age, however, remains underexplored. Here we describe a system regulated by a metabolite sensor, CtBP2. CtBP2 is secreted via exosomes in response to reductive metabolism, which is suppressed by oxidative stress. Exosomal CtBP2 administration extends lifespan in aged mice and improves healthspan in particular by reducing frailty. Mechanistically, we identify activation of CYB5R3 and AMPK downstream of exosomal CtBP2. Consistently, serum CtBP2 levels decrease with age and are negatively associated with cardiovascular disease incidence in humans yet are elevated in individuals from families with a history of longevity. Together our findings define a CtBP2-mediated metabolic system with potential for future clinical applications.