Targeting chaperone-mediated autophagy by nutritional interventions mitigates age-related cardiac fibrosis and diastolic dysfunction.

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.Abbreviations AcAc: acetoacetic acid; BHB: β-hydroxybutyrate; CMA: chaperone-mediated autophagy; COL1: collagen type I; COL3: collagen type III; ECM: extracellular matrix; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HCAR2: hydroxycarboxylic acid receptor 2; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; HF: heart failure; HK2: hexokinase 2; IVRT: isovolumic relaxation time; KD: ketogenic diet; LAMP2A: lysosome associated membrane protein 2A; LBP:Lycium barbarumpolysaccharide; PKM/PKM2: pyruvate kinase M1/2; SHMT2: serine hydroxymethyltransferase 2; VIM: vimentin.