Senescence

242005089_cells_Illustration HiRes.png

Cellular senescence is a dynamic multistep process activated in response to various forms of external stimuli, damage and stress. Senescence is characterized by cell cycle arrest, changes in cellular metabolism, chromatin re-organization (senescence associated heterochromatin foci; SAHF) and induction of a proinflammatory secretome (senescence associated secretory phenotype; SASP). These actions are meant to limit tissue damage, restore homeostasis and mitigate preneoplastic cell growth. While aspects of cellular senescence are beneficial in life as a mean to preserve organ and tissue homeostasis, accumulation of senescent cells can also be detrimental.

In cancer, cellular stresses such as oncogenic activation, oxidative/genotoxic stress, mitochondrial dysfunction and chemo/radiotherapy can induce cellular senescence and the persistence of senescent cells can eventually cause neoplastic conversion as well as SASP-related chronic inflammation. Further the accretion of senescence cells within the tumor can lead to immune evasion and immune 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 as a means to potentiate conventional therapies.

Similarly, evidence is emerging that the accumulation of senescent cells in organs, such as the heart, lungs, and kidneys, can be a significant contributing factor in autoimmunity, fibrosis and subsequent organ dysfunction. While this correlation is best exemplified in age-related fibrotic diseases, such as IPF and cardiomyopathy, our increasing understanding of cellular senescence points to an inflammatory signaling component that occurs irrespective of aging, and for which the molecular mechanisms remain unclear. 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 senescence program or alter the fibrosis-associated SASP profile or senolytics capable of selectively destroying senescent myofibroblasts/fibroblasts or mesenchymal cells in the respective tissue.

Another emerging aspect of senescence is the concept of immunosenescence, in which both the innate and adaptive arms of the immune system are deficient or deregulated. Immunosenescence manifests by chronic inflammation (inflammaging), 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 enhance anti-tumor and vaccine responses
  • Therapeutically target senescent cells in fibrosis to enhance immune clearance, induce cell death or drive reparative reprogramming
  • Therapeutic approaches include senolytics and senomorphics