AutophagyJul 30, 2026

Using diet to improve cell cleanup reduces age-related heart scarring and stiffness

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Aug 3, 2026

Abstract

BHB supplementation via a cyclic ketogenic diet restored chaperone-mediated autophagy (CMA) and improved cardiac function in aged mice.

Cardiac fibrosis is associated with excessive collagen production, which is linked to aging and heart failure.
CMA activity is suppressed in the aging heart, leading to increased collagen synthesis in fibroblasts.
SHMT2 accumulates with aging and promotes collagen production by enhancing glycine availability.
Aged mice show systemic downregulation of the ketone body beta-hydroxybutyrate (BHB).
BHB supplementation improves cardiac function and reduces fibrosis by activating the HCAR2 receptor and reactivating CMA.
The polysaccharide from Lycium barbarum mimics BHB's effects by rejuvenating ketogenesis.

Simplified

Cardiac fibrosis, a major pathological hallmark of aging that leads to heart failure, is characterized by excessive collagen deposition. Our knowledge of what sustains collagen synthesis in the aging heart is still very preliminary. Here, we uncover a central role for chaperone-mediated autophagy (CMA), a selective lysosomal degradation pathway, in this process. We demonstrate that CMA is suppressed in the aging heart, which promotes collagen overproduction in fibroblasts, whereas enhancing CMA activity ameliorates fibrosis and diastolic dysfunction. Mechanistically, we identify SHMT2 (serine hydroxymethyltransferase 2) as a CMA substrate whose accumulation with aging drives collagen synthesis by increasing glycine availability. Integrative omics revealed a systemic downregulation of the ketone body β-hydroxybutyrate (BHB) in aged mice. BHB supplementation - via a cyclic ketogenic diet - restored CMA, attenuated fibrosis, and improved cardiac function. This recovery was mediated through BHB-induced activation of the HCAR2 receptor and subsequent phosphorylation of HSPA8/HSC70, which systemically reactivates the CMA machinery. Furthermore, we show that Lycium barbarum polysaccharide (LBP) rejuvenates hepatic ketogenesis and mimics the benefits of BHB. Our findings establish a BHB-HCAR2-CMA-SHMT2 regulatory axis as a critical mechanism driving aging-related cardiac fibrosis and highlight nutritional strategies that target CMA as promising therapies against cardiac aging.

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Using diet to improve cell cleanup reduces age-related heart scarring and stiffness

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