Cellular senescence is a dynamic multistep process induced by various stimuli. These include oncogenic activation, oxidative/genotoxic stress, mitochondrial dysfunction, and chemo/radiotherapy. Senescence is characterized generally by an irreversible cell growth arrest, changes in cellular metabolism, chromatin re-organization (senescence associated heterochromatin foci; SAHF) and induction of a proinflammatory secretome (Senescence Associated Secretory Phenotype; SASP). Transient presence of senescent cells and the SASP limit tissue damage, restore homeostasis and mitigate preneoplastic cell growth. While aspects of cellular senescence and the SASP are physiologically beneficial to preserve organ and tissue homeostasis. Paradoxically, the accumulation and chronic presence of senescent cells can be detrimental.
The persistence of senescent cells and SASPs can drive neoplastic conversion. Further, the accumulation of senescence cells within a tumor can enhance both immune evasion and suppression. Promising therapeutic approaches focusing on either clearance of senescent cells (senolytics) or prevention of their proinflammatory impact (SASP blockade) are in development. In cancer, a “one-two punch” approach in which an initial drug that selectively induces senescence in the tumor cells is combined or quickly followed by a senolytic agent that eradicates the senescent cells, has recently been proposed to potentiate conventional therapies.
Evidence is emerging that the accumulation of senescent cells in organs can be a significant contributing factor in autoimmunity, fibrosis, and subsequent organ dysfunction. Clearance of senescent cells can alleviate fibrotic progression but there are no current interventions available that can efficiently and durably reverse fibrosis. Thus, potential therapeutic approaches that inhibit or reverse fibrosis could come in the form of senomorphics that alter the fibrosis-associated SASP profile or senolytics capable of selectively eliminating senescent myofibroblasts/fibroblasts or mesenchymal cells in the respective tissue.
Immunosenescence is an emerging aspect of senescence, in which both the innate and adaptive arms of the immune system are dysregulated. It manifests by chronic inflammation (inflammaging), autoimmunity, defective responses to vaccines and pathogens, and reduced tissue/organ immune surveillance. Therapies in this area aim toward enhancing or normalizing immune cell functions that could have significant impact in resolution of autoimmunity and potentiation of cancer immunotherapies.
Specific Areas of Interest Include:
- Reduce the survival and/or prevent the induction of therapy induced senescent tumor cells
- Modulate cellular immuno-senescence to attenuate autoimmunity and enhance anti-tumor/vaccine responses
- Therapeutically target senescent cells in fibrosis to enhance immune clearance, induce cell death or drive tissue repair
- Therapeutic approaches include senolytics and senomorphics