Adoptive Natural Killer Cell Therapy as a Senolytic Strategy
Adoptive cell therapies involve introducing immune cells to attack a specific issue in the body, most often cancer. The earliest forms of adoptive cell therapy used immune cells from another individual, but more modern approaches use a patient's own cells, expanded in culture and potentially engineered in various ways. Think of chimeric antigen receptor T cell (CAR-T) therapies, for example. Both T cells and natural killer (NK) cells have been employed as a basis for adoptive cell therapies targeted at cancer.
In today's open access paper, researchers consider another potential use for adoptive NK cell therapy, as a way to produce lasting clearance of senescent cells in aged tissues. It is clear that NK cells, along with several other immune cell types, are involved in the normal processes of destruction of senescent cells as they show up in the body. Unfortunately, this immune mediated clearance of senescent cells slows down with advancing age, allowing the build up of lingering senescent cells throughout the body. Senescent cells produce signaling that is useful under various circumstances, such as suppression of potentially cancerous damage and coordination in wound healing, but when sustained for the long term becomes highly disruptive to tissue structure and function.
Researchers have already demonstrated that CAR-T therapies can be adapted to target senescent cells. It is plausible that NK cell therapies can also serve this purpose. The question is whether the cost is worth it, when other forms of senolytic therapy that are capable of training the immune system to more aggressively attack senescent cells, including the Deciduous Therapeutics approach, are far cheaper. The primary issue with adoptive cell therapies at the present time is their high cost, an unavoidable outcome of any therapy that requires weeks or months of effort to grow, engineer, and quality control large numbers of cells from a patient sample. That doesn't compete well with the need to treat every older individual on some intermittent, recurring basis.
Adoptive NK cell therapy: a potential revolutionary approach in longevity therapeutics
As the global population ages, the prevalence of associated diseases becomes increasingly apparent. The pursuit of healthy aging, characterized by heightened resistance to lethal diseases, is the cornerstone of preventive medicine. The aging process is a complex process involving cellular senescence and inflammation, with the immune system playing a pivotal role in managing these aspects. Timely clearance of senescent cells (SNCs) is central to maintaining tissue and organismal homeostasis. Unfortunately, immunosenescence, a progressively dysregulated immune state with age, fails to eliminate SNCs, leading to their accumulation. This often coincides with the release of senescence-associated secretory phenotypes (SASPs), inhibiting immunity and increasing vulnerability to aging-associated diseases (AADs).
Consequently, targeting immunosenescence and SNCs emerges as a crucial therapeutic strategy to preserve and extend healthy aging. While adaptive immunity has traditionally taken center stage in immunogerontological studies, growing evidence underscores the substantial impact of innate immunity in AADs. Natural killer (NK) cells, integral to the innate immune system, uniquely identify and eliminate aberrant cells such as tumor cells and virus-infected cells. Moreover, NK cells promptly address SNCs, and coordinate with other immune components through cytokine and chemokine production to surveil and eliminate cancer cells. Although whether the same occurs against SNCs remains to be determined.
Evidence from healthy elderly individuals, especially those exhibiting physical fitness, independence in daily activities, or adequate cognitive function, the number and function of NK cells are highly preserved. Conversely, diminished NK cell activity in elderly individuals is associated with disorders such as atherosclerosis and an elevated risk of mortality. Accordingly, preserving NK cell function during aging is deemed crucial for healthy aging and longevity. Alternatively, NK-cell-based therapies, notably adoptive NK cell therapy, aligning with their established role in cancer and viral infection treatments, show promise in rejuvenating immunosenescence, eliminating SNCs and alleviating SASPs, that lead to AADs.