Sugar Stress Ages Heart Cells by Clogging Their Recycling System

Heart failure with preserved ejection fraction (HFpEF) is a predominantly age-driven inflammatory disease with no effective disease-modifying treatments. Understanding what connects normal cardiac aging to this failing phenotype is a critical unmet need. This study investigates whether endogenous glycative stress—the spontaneous chemical damage caused by glucose-derived reactive compounds—can trigger a chain of events leading to cardiomyocyte senescence, a known driver of tissue inflammation.

Using physiologically aged C57BL/6J mice (≥20 months) compared to young controls (4–6 months), the researchers applied comprehensive glycomics via nano-liquid chromatography tandem mass spectrometry (nanoLC-MS/MS) to map AGE accumulation across cardiac compartments. They found that mitochondria are the dominant intracellular reservoir of AGEs in the aging heart, with modification driven chiefly by methylglyoxal (MGO) and glyoxal (GO)—α-oxoaldehydes produced during normal glucose metabolism. This was associated with declining glyoxalase-1 (Glo-1) detoxification capacity, mild mitochondrial dysfunction, and structural remodeling of the mitochondrial network.

Lysosomes in aged hearts were enlarged, more numerous, less acidic, and frequently loaded with lipofuscin—indigestible oxidized material. Critically, about 7% of aged cardiomyocytes displayed hallmarks of proinflammatory senescence, including elevated p16INK4a, senescence-associated β-galactosidase (SA-β-Gal) activity at pH 6, and upregulation of multiple SASP components (IL-1α, IL-1β, IL-6, CCL-2, MMP9, and others) measured by quantitative RT-PCR.

To establish causality, the team exposed H9c2 myoblasts to exogenous methylglyoxal (glycative stress model). This in vitro model reproduced mitochondrial AGE accumulation, functional impairment, and activation of the mitochondria–lysosome quality-control axis. Crucially, AGE-modified mitochondria impaired lysosomal acidification and proteolytic capacity, preventing mitophagic clearance and promoting lipofuscin accumulation—ultimately driving a subset of cells into proinflammatory senescence. This sequence of events mirrors what was observed in vivo, providing mechanistic evidence that mitochondrial AGE buildup is a causal upstream trigger, not merely a bystander.

These findings reframe mitochondrial glycative damage as a novel senescence-inducing stress pathway in post-mitotic cardiomyocytes. Unlike cells that can dilute damage through division, cardiomyocytes must rely entirely on lysosomal recycling; when AGE-laden mitochondria impair that system, damaged organelles accumulate unchecked. The resulting chronic unresolved stress drives geroconversion—the irreversible transition from quiescence to senescence—which propagates inflammation through the SASP. This mechanism likely contributes to the low-grade myocardial inflammation characteristic of HFpEF and represents a potential therapeutic target.