Pyrroloquinoline Quinone Reprograms the Single‐Cell Landscape of Immune Aging in Hematopoietic Immune System

Aging is an inevitable biological process, driven in part by increased oxidative stress, which accelerates cellular damage and contributes to immune system dysfunction. Therefore, targeting oxidative stress has emerged as a potential strategy. Pyrroloquinoline quinone (PQQ), a potent antioxidant, has demonstrated significant efficacy in reducing oxidative stress and modulating immune responses, making it a promising therapeutic candidate. In this study, we investigated the effects of aging on the hematopoietic immune system (HIS) through single-cell RNA sequencing (scRNA-seq) of spleen and bone marrow cells in murine models. Our results revealed widespread age-related inflammation and oxidative stress within immune cell populations. Notably, long-term PQQ supplementation improved physiological parameters and reduced blood inflammatory factors levels in aged mice. Subsequent scRNA-seq analysis demonstrated that PQQ supplementation effectively reduced oxidative stress levels across various HIS cell types and reversed aging-related phenotypes, such as inflammatory responses and immunosenescence. Additionally, PQQ reversed aging-induced disrupted signaling and restored immune homeostasis, particularly in B cells and hematopoietic stem cells (HSCs). Importantly, we identified critical molecular targets, including ASPP1, which mediates PQQ's anti-apoptotic effects in B cells, and Yy1 and CD62L, which were upregulated by PQQ to restore HSCs self-renewal and differentiation potential. Furthermore, the machine learning program and experimental validation demonstrated the senolytic and senomorphic effects of PQQ in vivo and vitro. These findings underscore PQQ's potential not only in mitigating oxidative stress but also in restoring immune homeostasis and promoting cellular regeneration, highlighting its therapeutic potential in addressing immune aging and improving physiological function.