Single-cell profiling unveils a geroprotective role of Procyanidin C1 in hematopoietic immune system via senolytic and senomorphic effects.

Abstract

Aging of hematopoietic and immune system (HIS) leads to cellular senescence and immune dysregulation, contributing to age-related diseases. Here, we show that Procyanidin C1 (PCC1), a compound with both senolytic and senomorphic properties, can counteract aging-related changes in HIS. Using single-cell RNA sequencing and validation experiments, we found that aging induced cellular senescence, inflammation, and immune dysregulation in the bone marrow and spleen tissues of mice. Long-term PCC1 treatment improved key physiological parameters especially the grip strength of aged mice. Further single-cell analysis revealed PCC1's broad geroprotective effects on HIS, including an increase in the proportion of B cells (BCs) and hematopoietic stem cells (HSCs), suppression of senescence-associated markers, and restoration of normal immune processes. Specifically, PCC1 mitigated inflammation and restored immune homeostasis in BCs by suppressing Cebpb expression and age-associated BCs. Moreover, PCC1 reversed aging-induced alterations in HSCs through upregulating Nedd4 and CD62L-Ca2+ axis expression. Finally, we identified senescent cells (SnCs) using machine learning and gene set enrichment analysis, revealing that PCC1 induced apoptosis of SnCs and regulated their metabolic processes, particularly in granulocytes and myeloid cells. The experimental validation further confirmed the senolytic and senomorphic effects of PCC1 both in vivo and in vitro. Overall, PCC1 holds potential as a therapeutic agent for alleviating immune dysfunction and promoting healthy aging via senolytic and senomorphic effects.