The SenNet Consortium Intends to Map Senescent Cells Throughout the Human Lifespan
As noted last year, the NIH is setting up the SenNet program to fill in some of the larger gaps in the present detail-level knowledge of the role of senescent cells in aging. The goal is to better steer the numerous efforts presently underway to develop improved senolytic therapies that clear senescent cells from old tissues, thereby producing rapid rejuvenation. Senolytic therapies have produced promising results in animal studies, and the potential for this class of treatment to significantly improve late life health in humans is an attractive prospect.
Multiple lines of evidence suggest that senescent cells (SnCs) drive aging and diverse age-related diseases in preclinical models. Interventions targeting SnCs impact multiple morbidities of old age. In 2011, it was established that genetic clearance of SnCs delays the onset of multiple age-related pathologies in transgenic mice. In 2016, it was established that genetic clearance of SnCs in mice delays all-cause mortality, extending median not maximum lifespan, implicating SnCs in many diseases that kill mice, including cancer, chronic kidney disease, and cardiomyopathy. These genetic studies incentivized the development of senotherapeutics - drugs that selectively target SnCs, either killing them (senolytics) or suppressing the SASP (senomorphics). The first senolytics were described in 2015. Since then, dozens of senotherapeutics have been described, including natural products, repurposed drugs, proteolysis-targeted chimeras, and chimeric antigen receptor T cells.
Despite this promise of SnCs as a therapeutic target, there is sparse information about the identity and features of SnCs in human tissues. Little is known about where and when SnCs arise in humans or the extent of SnC and SASP heterogeneity in vivo. Such knowledge could guide therapeutic and organ-specific targeting of SnCs. Clearly, there is a compelling need to develop tools to map and identify human SnCs with spatial and temporal resolution. To address this need, the SenNet Consortium was created in 2021. The goal of SenNet is to functionally characterize the heterogeneity of SnCs in 18 tissues from healthy humans across lifespan at the single-cell resolution, using mice and other models and perturbations for validation.