Humans have always dreamed of reversing or even preventing aging. To this end, humankind has been searching for the elusive “fountain of youth”. While this quest predictably has not succeeded, there are indications that we may have found a way to counter tissue aging by targeting and eliminating “old” cells in the body. Cellular senescence or aging at the cellular level was first described by Leonard Hayflick in the early sixties. Further research in this area has shown cellular senescence to be a stress-induced, durable arrest of cellular multiplication and growth.
Cellular Senescence in Disease and Health
Originally, cellular senescence was demonstrated to be a molecular mechanism in response to stress, to prevent cancer in mammals by halting the growth of premalignant cells. Further research has elucidated its role in wound healing and tissue repair following injury. In addition, cellular senescence is also associated with a variety of chronic diseases such as liver and lung fibrosis, diabetes, and atherosclerosis.
Sufficient scientific evidence over the past few decades indicates that cellular aging is directly linked to aging of the individual. Likewise, senescent cells have been shown to contribute to many aging-related degenerative and hyperplastic changes in the body. A few examples include the initimal thickening and medial hypertrophy of pulmonary arteries leading to pulmonary hypertension, and aging-related skin changes due to age-related dermal and epidermal thinning and loss of collagen. Furthermore, age-related neurodegenerative changes may contribute to or lead to cognitive impairment, Alzheimer’s disease, or Parkinson’s disease. Similarly, age-related macular degeneration, insulin insensitivity, obstructive pulmonary diseases, and other similar diseases may be related to molecular changes following cellular senescence.
Importantly, senescent cells play a crucial role in cancer pathophysiology. They can induce inflammatory response, stimulate secretion of cytokines and chemokines, and induce proliferative changes. Additionally, scientific evidence suggests that senescent cells can drive malignant phenotypes including epithelial-to-mesenchymal transition (EMT).
To complicate matters, original studies on senescent cells had identified their primary role as a growth suppressor by causing cell-cycle arrest in the event of genetic damage. This role was hypothesized to prevent malignant proliferation, and the hypothesis still holds true today. In addition, the inflammatory and immune responses which are induced can help clear DNA-damaged cells. This immune-mediated clearance is also important for wound healing and tissue repair following injury.
In spite of these seemingly contrasting effects of senescence, there is a degree of consensus in the scientific community that transient presence of senescent cells has beneficial effects, while their chronic presence is counterproductive.
CAR T cells as senolytic agents
Though it has not definitively been demonstrated, there is speculation based on scientific evidence that in all mammals including humans, senescent cells likely express unique markers that accumulate with age and at sites of senescence-related pathophysiologies. A recent study made a breakthrough wherein Scott Lowe and colleagues at Memorial Sloan Kettering Cancer Center identified urokinase-type plasminogen activator receptor (uPAR), a cell-surface protein as a unique marker for senescent cells. This is a significant advance because researchers would be able to use this protein to specifically target aging cells (“senolytic”).
Chimeric antigen receptor (CAR)-modified T cells (CAR T cells) are a new modality of immunotherapy, specifically adoptive T cell therapy. This novel modality is currently in the spotlight owing to promising results observed utilizing this form of therapy, particularly in oncology. CARs are synthetic receptors that can be engineered to bind antigens of interest. These genetically engineered T cells have seen success in the treatment oncological diseases. There are currently two approved drugs on the market utilizing CAR T cells. Armed with this knowledge, Lowe and his colleagues engineered CAR T cells to target the cell-surface protein uPAR on senescent cells. They tested these CAR T cells in mouse models of liver fibrosis and found that this successfully eliminated senescent cells. Additionally, in mouse models of lung cancer, CAR-T cells significantly improved survival, primarily by clearing premalignant/malignant senescent cells. Following up on these highly promising data, this team aims to test senolytic CAR T cells against other diseases that are associated with cellular senescence, including atherosclerosis, diabetes, and osteoarthritis. Michel Sadelain, a co-author on this study is encouraged by these findings, stating "this study demonstrates that T cell engineering and CAR therapy can be effective beyond cancer immunotherapy."
Conclusion
Not only do CAR T cells hold promise in targeting senescent cells therapeutically, but they also will help the medical community understand the physiology of cellular senescence and the effects of stress. Improved insights into the field of senescence will have far-reaching consequences, especially with a notable demographic shift towards a more aging population.
Written by Sandeep Pingle, MD, PhD, Scientist
Keywords: CureScience, CAR T cells, Cellular Senescence
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