Cepharanthine Identified as a Novel Senolytic
Senescent cells accumulate with age and generate inflammatory secretions that are disruptive to tissue structure and function. Targeted clearance of some fraction of these lingering senescent cells in aged tissues via senolytic therapies has been shown to reverse aspects of aging and extend life in mice. The small human clinical trials conducted to date have shown, on balance, promising results. Spurred by the very impressive animal data, the research community has been searching for novel mechanisms for selective destruction of senescent cells and novel senolytics. Interesting new approaches emerge a few times every year, some of which are low cost supplements and plant extracts, such as the candidate noted here. Unfortunately low cost therapies do not tend to lead to compelling human data, as clinical trials are expensive to run; if there is no profit to be made, finding funding is challenging. Academic institutions can and do run trials, but relatively few of them, and rarely large ones. Indeed, most of the trials of low cost senolytic treatments conducted to date were both small and run by academic institutions.
Current intervention strategies targeting senescent cells are primarily categorized into two types: senomorphics (modulation of the senescent phenotype) and senolytics (elimination of senescent cells). Senomorphics aim to mitigate the inflammatory microenvironment by using drugs (e.g., the mTOR inhibitor rapamycin, metformin) to inhibit senescence-associated secretory phenotype (SASP)-related signaling pathways without affecting cell survival. In contrast, senolytics aim to solve the problem at its source by selectively inducing apoptosis in senescent cells to completely eradicate SASP production. Representative senolytics include the BCL-2 family inhibitor navitoclax and the classic combination of dasatinib and quercetin. The latter has been shown to effectively clear senescent cells and improve various age-related functional declines in animal models and has shown promising results in clinical trials for Alzheimer's disease (Phase I), idiopathic pulmonary fibrosis and diabetic kidney disease.
However, existing senolytic compounds still have room for optimization in terms of selectivity, potency or long-term safety. This has prompted researchers to turn to natural products with diverse structures and unique mechanisms to find a new generation of lead molecules, such as PCC1, fisetin, and halophyte extracts.
Based on this, our study first established a system for the quantitative screening of senolytic small molecules and identified a potential candidate - cepharanthine (CEP) - through high-throughput screening. CEP is a bisbenzylisoquinoline alkaloid extracted from plants of the Stephania genus, possessing a wide range of anti-inflammatory, antioxidant, and anti-tumor activities. Previous research suggested its potential to intervene in inflammation, hinting at its anti-aging value. However, whether CEP possesses clear senolytic activity and the unique molecular mechanisms underlying its selective clearance effect have not yet been systematically elucidated.
CEP selectively eliminates senescent cells by cooperatively and in parallel regulating the PI3K/AKT and PERK-ATF4-CHOP pathways, differentially inducing PUMA/NOXA and triggering mitochondrial intrinsic apoptosis. In zebrafish, C. elegans, naturally aged mice, and progeroid mice, CEP clears senescent cells, reduces SASP levels, improves organ function and prolongs lifespan.