Considering the Near Future of Senotherapeutics
Senescent cells accumulate with age, and this accumulation drives a sizable fraction of the dysfunction of degenerative aging. While never present in very large numbers, these cells energetically secrete signal molecules that provoke inflammation and tissue remodeling. As noted here, a major theme in the development of senotherapeutic drugs to either selectively destroy senescent cells or broadly suppress the disruptive signaling of senescent cells is the need for greater understanding of the diversity of cellular senescence. Different tissues, different cell types, different origins of the senescent state may all be meaningfully different in their responses to drugs targeting one or another of the mechanisms identified to be important in cellular senescence. While early senolytic drugs are quite impressive in the benefits they produce in aged mice, later therapies produced in an environment of greater understanding will be better.
During the first senotherapeutics conference organized by the Phaedon Institute at the Buck Institute for Research on Aging, experts on the molecular and cellular mechanisms of aging, pathogenesis of age-related diseases, and drug discovery and development convened to delve into ideas on the past, present, and future of targeting senescent cells. A focal point of discussion revolved around the heterogeneity of cellular senescence, and its profound implications for the development of treatments. Presenters highlighted the diverse profiles of senescent cells, emphasizing differences in gene expression, secretory patterns, and functional roles, in addition to the importance of the tissue microenvironment.
Senescent cells represent a potential target for geroprotection and reduction of multimorbidity, but owing to current regulations, clinicians and pharmaceutical companies are focusing on the use of senotherapeutics for specific and selective age-related diseases. A Phase 2B trial sponsored by Unity Biotechnology is currently ongoing for the treatment of Diabetic Macular Edema (DME) using the senolytic agent UBX1325, which inhibits Bcl-XL. The Translational Geroscience Network runs a number of Phase 1 and Phase 2 trials using senolytic compounds, such as Dasatinib, Quercetin, and Fisetin, for the treatment of sepsis, chronic kidney disease, lung fibrosis, and Alzheimer's disease. Additionally, many other pathological conditions have been discussed as potential indications for the use of therapeutic compounds. For example, efforts are currently being made to selectively target senescent cell subtypes in pre-clinical models of skin and muscle dysfunctions with novel senolytic small molecules in development at Rubedo Life Sciences and Boehringer-Ingelheim, respectively.
While these represent pioneering studies and the opportunity to demonstrate the unequivocal pathological role of certain senescence subsets, challenges remain in the path to harnessing the therapeutic potential of targeting cellular senescence. Participants emphasized the need for a more comprehensive understanding of the dynamic nature of senescent cells, their role and localization in various tissues and tissue areas, and the need for more accurate and sensitive biomarkers. This discussion highlighted the importance of multi-laboratory and multi-center efforts in adapting the newest technologies with single-cell resolution for the identification and specification of senescent cells in vivo. These studies can offer novel targets for interventions and novel markers for a standardized evaluation of the efficacy of anti-senescence approaches in humans. Overall, the pleiotropic diversity and heterogeneity of cellular senescence invites the development of diverse strategies and modalities to target subsets of senescent cells according to their physiopathological roles. The ongoing effort in academic and industrial laboratories to develop different senotherapeutics is strategic to enable advancement in the clinic of multiple novel therapeutic opportunities, possibly in parallel.