Abstract
In the context of aging and age-associated diseases, Natural Killer (NK) cells have been revealed as a key cell type responsible for the immune clearance of senescent cells. Subsequently, NK cell-based therapies have emerged as promising alternatives to drug-based therapeutic interventions for the prevention and treatment of age-related disease and debility. Given the promise of NK cell-mediated immunotherapies as a safe and effective treatment strategy, we outline an improved method by which primary NK cells can be efficiently enriched from human peripheral blood across multiple donors (ages 20-42 years old), with a practical protocol that reliably enhances both CD56dim and CD56bright NK cells by 15-fold and 3-fold, respectively. Importantly, we show that our co-culture protocol can be used as an easily adaptable tool to assess highly efficient and selective killing of senescent cells by primary NK cells enriched via our method using longer co-culture durations and a low target to effector ratio, which may be more physiological than has been achieved in previous literature.
Highlights
Advanced age is the greatest risk factor for most chronic diseases, with over 90% of adults aged 65 or older experiencing at least one chronic disease such as cancer, diabetes and cardiovascular disease [1]
We show that our co-culture protocol can be used as an adaptable tool to assess highly efficient and selective killing of senescent cells by primary Natural Killer (NK) cells enriched via our method using longer co-culture durations and a low target to effector ratio, which may be more physiological than has been achieved in previous literature
A statistically significant percentage of cells with increased SA-β-gal activity was observed in cells exposed to x-rays or etoposide (87% and 81%, respectively) nine days after treatment compared to non-senescent control cells (1%) (Supplementary Figure 1B, 1C)
Summary
Advanced age is the greatest risk factor for most chronic diseases, with over 90% of adults aged 65 or older experiencing at least one chronic disease such as cancer, diabetes and cardiovascular disease [1]. Many aging phenotypes and pathologies, including diverse age-associated diseases and disorders, are causally linked to the accumulation of senescent cell burden with increasing age [3, 4]. Senescent cells are thought to be cleared by the immune system, but increasing age or disease severity allows senescent cells to escape the process of immunosurveillance and accumulate in older individuals [6]. The removal of senescent cells via drugs that selectively kill senescent cells (“senolytic” drugs) or genetic manipulation in transgenic mouse models can prevent or delay tissue dysfunction, improve age-related pathologies, and extend health span, suggesting that a reduced senescent cell burden in aging adults merits further study as a therapeutic target for the treatment and prevention of disease of aging [7, 8]
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