Senescent cells accumulate in the aged body, generating a potent mix of pro-inflammatory signaling known as the senescence-associated secretory phenotype (SASP) that is disruptive to tissue structure and function. Over the last decade or so, researchers have devoted an increasing amount of time and effort into firstly understanding these cells, and secondly finding potential ways to reduce their contribution to age-related disease and mortality. While most efforts are directed towards the selective destruction of senescent cells via senolytic therapies, a growing number of projects are identifying senomorphic therapies that might reduce the SASP, and thereby reduce the harmful impact of lingering senescent cells. Such therapies would have to be taken continuously versus the intermittent use of senolytics, but nonetheless papers such as the one noted here are emerging on a regular basis.
Cellular senescence is an aging-related mechanism characterized by cell cycle arrest, macromolecular alterations, and a senescence-associated secretory phenotype (SASP). Recent preclinical trials established that senolytic drugs, which target survival mechanisms of senescent cells, can effectively intervene in age-related pathologies. In contrast, senomorphic agents inhibiting SASP expression while preserving the survival of senescent cells have received relatively less attention, with potential benefits hitherto underexplored.
By revisiting a previously screened natural product library, which enabled the discovery of procyanidin C1 (PCC1), we noticed pyrroloquinoline quinone (PQQ), a redox cofactor that displayed remarkable potential in serving as a senomorphic agent. In vitro data suggested that PQQ downregulated the full spectrum expression of the SASP, a capacity observed in several stromal cell lines. Proteomics data supported that PQQ directly targets the intracellular protein HSPA8, interference with which disturbs downstream signaling and expression of the SASP. PQQ restrains cancer cell malignancy conferred by senescent stromal cells in culture while reducing drug resistance when combined with chemotherapy in anticancer regimens. In preclinical trials, PQQ alleviates pathological symptoms by preventing organ degeneration in naturally aged mice while reserving senescent cells in the tissue microenvironment.
Together, our study supports the feasibility of exploiting a redox-active quinone molecule with senomorphic capacity to achieve geroprotective effects by modulating the SASP, thus providing proof-of-concept evidence for future exploration of natural antioxidant agents to delay aging and ameliorate age-related conditions. Prospective efforts are warranted to determine long-term outcomes and the potential of PQQ for the intervention of geriatric syndromes in clinical settings.
Link: https://doi.org/10.1111/acel.70138
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