Targeting cellular senescence in physiological, pathological and iatrogenic conditions

Cellular senescence, a cell state characterized by a stable cell-cycle arrest and the production of a plethora of factors termed senescent associated secretory phenotype (SASP), is a driver of different physiological and pathological processes, such as tissue remodeling, aging, injury and cancer. Experimental and clinical evidence suggests that cellular senescence can have both beneficial and detrimental effects depending on the biological context. Most importantly, over the last decades, a paradigm has emerged suggesting that the accumulation and persistence of senescent cells determine an environment of chronic inflammation and altered immunosurveillance, which accelerates aging and different age-related diseases such as cancer, chronic kidney disease and cardiovascular disease. Consistently, recent evidence demonstrates that the clearance of senescent cells by senolytics delays aging, improves heart and kidney function in aging mice, decreases the incidence of tumor recurrence, metastasis and even cancer-related fatigue in mice treated with chemotherapy. Similarly compounds that delay the accumulation of senescent cells (gerosuppressive) or block the deleterious effect of the SASP without inducing senescent cell death (senostatic) have been proven to prolong the life span of multiple organisms and decrease the severity of aging-related conditions. These evidence, have opened at the exciting possibility that compounds that target senescence may be used at the same time for the cure of different diseases. Mitochondria, derived from endosymbiotic proteobaceteria, are essential organelles for many aspects of cellular homeostasis, including energy harvesting. Changes in mitochondrial number, morphology, and function not only impact cellular metabolism, but also critically influence whole body metabolism, health, and lifespan. Emerging evidence has pinpointed mitochondria as one of the key modulators in the development of senescence and in particular of the SASP.5 Interestingly, senescence cells exhibit a variety of changes in terms of the structure, dynamics and function of mitochondria. For instance, mitochondria regulate the survival of senescent cells and several senolytic compounds, such as Navitoclax target the anti-apoptotic B-cell lymphoma2 (BCL-2) protein located in mitochondria. Moreover, compounds that target the mitochondrial function such as rapamycin and metformin can act as senostatic. Finally, alterations of mitochondrial membrane proteins and changes in the mitochondrial function can also trigger cellular senescence a phenomenon termed mitochondrial dysfunction-associated senescence (MiDAS). The observation that senescence cells and mitochondrial dysfunction either alone or in combination are causative processes of aging offers tremendous therapeutic potential.By using different drug screening platforms, members of this Sinergia grant have identified a set of novel and clinically available compounds with activity on mitochondrial regulatory circuits and senescence that could impact on different age-related diseases. These compounds will be cross-validated using different approaches prior to assess their efficacy in different models. Finally, data derived from these experimental models will be integrated by using different “omics” to identify common and specific pathways of cellular senescence that may be targeted in future studies. Here, we propose an interdisciplinary and collaborative strategy aimed at elucidating the role of cellular senescence and mitochondrial dysfunction in different biological contexts of critical clinical relevance, including aging, cancer, acute and chronic tissue injury following pathological or iatrogenic insults. The study will lead to the identification of novel common or tissue-specific elements of cellular senescence and mitochondrial dysfunction potentially identify novel pharmacological therapies to modulate age-related diseases.