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While early senolytic therapies to clear senescent cells do well in mice, clearing a third to a half of the lingering senescent cells in some tissues and rapidly reversing many aspects of aging, to go much further than this will require a greater understanding of cellular senescence. Unfortunately, it is becoming clear that what we call senescence varies considerably from cell type to cell type, and there is much yet to be discovered regarding targets for therapy, ways to assess the burden of senescence, and more.
Despite significant advances in the characterization of senescent cells (SnCs), many questions about the biology of these cells remain open. Firstly, it is necessary to understand which markers are necessary and sufficient to define that a cell is in a “full” or “deep” senescent state. Similarly, the dynamics and adaptability of SnCs still need to be better understood, including how plastic those cells are for the expression of senescent cell anti-apoptotic pathways (SCAPs), the structure of intracellular compartments, or senescence-associated secretory phenotype (SASP) composition, the pathways governing these transitions, and how intense these phenotypic variations must be to influence the non-autonomous role played by SnCs. Understanding these aspects may also allow us to infer whether differences within SnCs of cell populations occur due to different states in different SnCs or the plasticity of individual SnCs. Finally, it is also imperative to comprehend the heterogeneity and the cause-and-effect between subcellular features and the outcome of SnCs. New evidence regarding the above questions can also contribute to understanding questions such as how long an SnC lives and whether death is the only possible outcome.
A better understanding of essential features of SnCs can also contribute to translational issues in which cellular senescence appears to be relevant. Questions like the role of SASP in acute responses and chronic conditions and the most relevant SASP molecules for pathophysiological responses may allow the mitigation of detrimental impacts or the increase of beneficial effects played by SnCs. It is also mandatory to uncover novel avenues for senotherapies, such as senolytics (for instance, by targeting the heterogeneity of this phenotype), senopreventives (by elucidating mechanisms allowing senescence entry), and senomorphics (by affecting the detrimental effects of SASP selectively). Nevertheless, several barriers need to be overcome to allow the clinical application of basic concepts in cellular senescence, such as the lack of specific therapies to reduce detrimental but not beneficial effects played by SnCs, the best time to affect senescence in pathophysiological responses, and how to assess the effectiveness of senotherapies.
In conclusion, although several clinical trials targeting SnCs are ongoing, various questions about the biology of SnCs remain open, resulting in a gap between molecular and cellular data. Concerning the need, initiatives such as SenNet aiming to create openly accessible atlases of SnCs should contribute enormously to the area. Advances in understanding the subcellular structure, the heterogeneity, and the dynamics of SnCs require the integration of molecular and cellular techniques with data analysis packages to evaluate high throughput evidence from microscopy and flow cytometry. It is also necessary to develop new equipment or protocols for long-term live cell tracking or high-resolution microscopy beyond new molecular reporters, allowing the chronic study of live cells. Combining evidence from these diverse sources can transform the field, enhancing our comprehension of how SnCs acts on human health and extending beyond the advancement of more effective and specific senotherapies.