Asprosin Reverses Stem Cell Aging to Repair Damaged Hearts
A declining hormone called asprosin may rejuvenate aging stem cells via a glycolysis-epigenetics axis, boosting heart repair after heart attack.
Summary
Asprosin, a protein derived from fibrillin-1, declines with age in both mice and humans. Researchers found that restoring asprosin in aged mesenchymal stem cells (MSCs) reversed key senescence markers and improved their ability to proliferate, migrate, and support new blood vessel growth. Mechanistically, asprosin activates the PI3K/Akt-HIF-1 pathway, boosting glycolysis and lactate production, which drives a histone lactylation mark (H3K18la) that epigenetically unlocks genes for DNA repair and cell renewal. In a mouse heart attack model, aged MSCs engineered to overexpress asprosin showed better survival in the heart and meaningfully improved cardiac function. The findings position asprosin as a novel rejuvenation factor and suggest a 'Glycolysis-Lactylation-Epigenetics' axis as a druggable target for stem cell-based cardiac therapies.
Detailed Summary
Stem cell therapies for heart disease face a fundamental problem: the stem cells most readily available from older patients are themselves aged and dysfunctional. This study tackles that bottleneck by identifying asprosin — a fasting-induced hormone cleaved from the fibrillin-1 (Fbn1) protein — as a master regulator of mesenchymal stem cell (MSC) youth and repair capacity.
The research team, based at the Chinese PLA General Hospital, used multi-omics public datasets to confirm that Fbn1 and its derivative asprosin decline across tissues with aging, with a particularly pronounced drop in MSCs. They validated this in human cohorts showing an inverse correlation between age and circulating asprosin levels, independent of body weight. In young obese mice, asprosin tracked with adipose mass, but this relationship broke down in aged obese animals, pointing to age-specific dysregulation.
Using CRISPR-Cas9 knockout and lentiviral overexpression, the team showed that asprosin loss worsens oxidative stress-induced premature senescence, while restoration of asprosin rescues MSC self-renewal. Recombinant asprosin protein enhanced proliferation, directed migration, and boosted pro-angiogenic secretion (VEGF, TIMP1) in senescent MSCs. The mechanism runs through PI3K/Akt-HIF-1 signaling, which ramps up glycolysis, elevates lactate, and drives H3K18 lactylation — an epigenetic mark that opens chromatin at genes governing DNA repair and cell cycle progression, as confirmed by integrated CUT&Tag and RNA-seq.
In a myocardial infarction mouse model, intramyocardial injection of asprosin-overexpressing aged MSCs improved cell retention, left ventricular ejection fraction, reduced adverse cardiac remodeling, and promoted peri-infarct angiogenesis compared to controls.
Caveats include the study's reliance on a mouse MI model and in vitro senescence systems, with no human clinical data. The requirement for post-translational modifications for recombinant asprosin bioactivity complicates straightforward therapeutic translation.
Key Findings
- Circulating asprosin declines with age in humans and mice, inversely correlating with biological aging.
- Asprosin overexpression in aged MSCs restores proliferation, migration, and pro-angiogenic secretion.
- Mechanism involves PI3K/Akt-HIF-1 activation driving glycolysis, lactate production, and H3K18 lactylation.
- H3K18la epigenetically upregulates DNA repair and cell renewal gene programs in MSCs.
- Asprosin-overexpressing aged MSCs improved heart function and reduced remodeling in MI mice.
Methodology
The study combined gain- and loss-of-function models (CRISPR-Cas9 knockout and lentiviral overexpression), Seahorse metabolic flux analysis, and integrated H3K18la CUT&Tag with RNA-seq to map the epigenetic landscape. Therapeutic validation used intramyocardial injection of engineered aged MSCs in a mouse MI model with echocardiographic endpoints.
Study Limitations
All in vivo efficacy data come from mouse MI models, and direct human cardiac repair outcomes remain untested. Recombinant asprosin requires specific post-translational modifications for bioactivity, complicating pharmaceutical development. The study does not address potential systemic effects or safety of sustained asprosin elevation in aged organisms.
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