Hormone asprosin rejuvenates aging stem cells and repairs infarcted hearts in mice

A single hormone may hold the key to making old stem cells young again. In a study published in the Journal of Advanced Research, a team led by researchers at the Chinese PLA General Hospital reports that asprosin, a protein hormone first discovered for its role in blood glucose control, can reverse senescence in mesenchymal stem cells through a striking metabolic-epigenetic mechanism. When the team engineered aging stem cells to overproduce asprosin and transplanted them into mice suffering heart attacks, the treated cells survived longer in the damaged tissue, stimulated new blood vessel growth, reduced scarring, and measurably improved the heart’s pumping function. The finding offers a potential solution to one of regenerative medicine’s most stubborn problems: the stem cells used in therapy often arrive exhausted before they ever reach the patient.

Mesenchymal stem cells, or MSCs, are the workhorses of cell-based repair. Harvested from bone marrow or fat, they secrete factors that calm inflammation, encourage angiogenesis, and limit the destructive remodeling that follows a myocardial infarction. Yet clinical trials in ischemic heart disease have produced frustratingly inconsistent results, and the new study points to a likely culprit: senescence. Donor age and the replicative stress of the large-scale expansion needed to produce clinically useful cell numbers both push MSCs into a senescent state, robbing them of the proliferative capacity, migratory behavior, and paracrine output that make them therapeutic in the first place. The harsh, oxygen-starved environment of an infarcted heart can then induce premature senescence in the transplanted cells themselves, further eroding any benefit.

The researchers began with an epidemiological puzzle. Asprosin, encoded by the FBN1 gene that also produces the structural protein fibrillin-1, is known to rise with obesity, driving hepatic glucose release in younger organisms. But when the team measured circulating asprosin in aged mice, they found that despite significant age-related weight gain, levels failed to rise, and aged animals even developed the impaired glucose tolerance that young obese mice display alongside high asprosin. Public transcriptomic datasets revealed why: Fbn1 expression declines with age across a remarkable range of tissues, including white adipose tissue, heart, lung, skeletal muscle, and skin, with the attrition more pronounced in males. Western blotting confirmed matching reductions in asprosin protein in fat, heart, and muscle across young, middle-aged, and old mice.

The human evidence proved equally compelling. In a cohort of 95 normal-weight men, recruited with an a priori power calculation to control for the confounding effect of adiposity, fasting plasma asprosin showed a significant negative correlation with age, with a Spearman coefficient of -0.374. Aging, in other words, appears to override the adiposity-driven regulation that dominates asprosin levels in youth. Single-cell RNA sequencing data from mice, rats, and humans then revealed something unexpected: MSCs, not mature adipocytes, are the dominant FBN1-expressing cell type across fat, muscle, and bone marrow. Pseudotime trajectory analysis showed FBN1 expression falling steadily as multipotent progenitors commit to differentiated lineages, tying the hormone directly to stemness itself. Both chronically aged and acutely senescent MSCs, the latter produced by hydrogen peroxide treatment, showed coordinated declines in Fbn1 transcription, intracellular asprosin, and secreted asprosin.

To test whether asprosin actively governs senescence rather than merely tracking it, the team built CRISPR-Cas9 lentiviral vectors targeting the furin cleavage site within the Fbn1 gene, selectively ablating the hormone while preserving fibrillin-1’s structural role. Asprosin-deficient young MSCs proliferated poorly and, when challenged with hydrogen peroxide, accumulated in the G1 phase of the cell cycle, stained heavily for senescence-associated beta-galactosidase, lost clonogenic potential, and under high oxidative stress underwent increased apoptosis. The mirror-image experiment was more dramatic: overexpressing human asprosin in aged MSCs restored proliferation, pushed cells back into S phase, reduced senescence markers, and enhanced colony formation. Recombinant asprosin produced in human cells, at concentrations from 10 nanograms per milliliter up to 10 micrograms per milliliter without cytotoxicity, reproduced these effects across mouse bone marrow cells, mouse fat-derived cells, and human adipose-derived stem cells.

The mechanism traces through metabolism. Gene set enrichment analysis of asprosin-treated senescent MSCs showed activation of the PI3K-AKT and HIF-1 signaling pathways and a strong enrichment of glycolysis-related gene sets, with no change in oxidative phosphorylation. Seahorse metabolic flux assays confirmed that asprosin raised the extracellular acidification rate, basal glycolysis, and compensatory glycolytic capacity, while lactate production rose and was abolished by the glycolysis inhibitor 2-deoxyglucose. Asprosin upregulated the glucose transporter GLUT1 and rate-limiting enzymes including hexokinase 2 and the phosphofructokinases PFKL and PFKP. Pharmacological inhibition of AKT with MK2206 or of HIF-1alpha with KC7F2 blocked every one of these metabolic shifts, and either inhibitor, or 2-deoxyglucose, erased asprosin’s boosts to proliferation and migration. Notably, mTOR stayed inactive, indicating that asprosin works through a signaling route distinct from classical growth factor pathways. Intriguingly, the proangiogenic paracrine effect, driven by elevated VEGF-A and TIMP-1, depended on AKT-HIF-1 signaling but not on glycolysis itself.

That distinction between bioenergetics and gene regulation is where the study’s most novel layer emerges. Lactate, the end product of glycolysis, is now known to serve as a substrate for histone lactylation, a recently discovered post-translational modification in which lactate is covalently attached to lysine residues on histone proteins. The team showed that asprosin treatment increased global lysine lactylation and, specifically, lactylation of histone H3 at lysine 18, or H3K18la, in senescent MSCs, mirroring the effect of exogenous lactate. Blocking lactate production with sodium oxamate or inhibiting the p300 writer enzyme with A485 abolished both the H3K18la increase and the functional rejuvenation. CUT&Tag sequencing then mapped the epigenetic landscape: asprosin broadened H3K18la deposition genome-wide, and 70 percent of the genes it upregulated carried promoter-associated H3K18la marks. Among the targets were genes governing cell cycle progression and migration, and, critically, a network of DNA repair and replication fidelity genes, including Mcm8, Nucks1, Recql, Grwd1, and Foxp1, whose promoters gained H3K18la enrichment. When asprosin was knocked out, hydrogen peroxide-induced DNA double-strand breaks, marked by gamma-H2AX foci, worsened and repair faltered.

The therapeutic payoff came in a mouse model of acute myocardial infarction. Senescent MSCs transduced with an asprosin-overexpressing lentivirus, or with an empty vector, were injected into the infarct border zone. Immunofluorescent quantification on days 3 and 7 showed significantly higher retention of the asprosin-engineered cells. Over 28 days, mice receiving asprosin-overexpressing MSCs survived at higher rates than untreated infarct controls, while the empty-vector cells conferred no survival benefit. Echocardiography revealed improved left ventricular ejection fraction only in the asprosin group, which also showed reduced heart-to-lung and heart-to-body weight ratios, smaller fibrotic areas on Masson’s trichrome staining, and increased numbers of CD31-positive endothelial and alpha-SMA-positive smooth muscle cells in the peri-infarct zone, indicating robust new vessel formation.

The authors frame their intervention as a third way beyond existing anti-senescence strategies. Senolytics clear damaged cells, and NAD-boosting compounds offer generic metabolic support, but asprosin instead performs what they call functional reprogramming: it directly reverses the senescent state by activating a specific glycolysis-H3K18la axis, restoring a regenerative phenotype without deleting the cells or merely nourishing them. The team also showed that asprosin’s bioactivity depends on post-translational modifications present only in eukaryotic production systems, as bacterially derived protein failed to elicit the same transcriptional response, a caution for any future pharmaceutical development. Significant hurdles remain before clinical translation: the murine infarct model does not capture the comorbidities of human patients, lentiviral overexpression carries a theoretical insertional mutagenesis risk that local, cell-based delivery is designed to minimize, and the MSC-specific asprosin receptor has yet to be identified. Still, with efficacy demonstrated across species, tissue sources, and a broad safe concentration range, asprosin-engineered stem cells now stand as one of the most mechanistically complete rejuvenation strategies yet described, and a promising enhancement partner for the next generation of cardiac cell therapy.

Subject of Research: Asprosin-driven metabolic and epigenetic rejuvenation of senescent mesenchymal stem cells for cardiac repair after myocardial infarction

Article Title: Asprosin-driven metabolic-epigenetic rewiring attenuates mesenchymal stem cell senescence with therapeutic benefits for infarcted hearts

Article References: Zhang, Z., Wang, Z., Zhu, L., Chen, T., Chen, R., Wu, Z., Chen, J., Zhang, H., Wang, M., Liu, J., Hua, N., Hu, S., & Chen, Y. (2026). Asprosin-driven metabolic-epigenetic rewiring attenuates mesenchymal stem cell senescence with therapeutic benefits for infarcted hearts. Journal of Advanced Research, 88, 1055-1075. https://doi.org/10.1016/j.jare.2026.01.073

Image Credits: AI Generated

DOI: 10.1016/j.jare.2026.01.073

Keywords: asprosin, mesenchymal stem cells, senescence, histone lactylation, H3K18la, glycolysis, myocardial infarction, FBN1, epigenetics, cardiac repair, regenerative medicine, HIF-1alpha