Abstract
The aging process intricately involves immune system dynamics, with a crucial role in managing senescent cells (SNCs) and their senescence-associated secretory phenotypes (SASPs). Unfortunately, immunosenescence, a progressively dysregulated immunity with age, hampers effective SNC elimination, leading to accumulation, coupled with the release of SASPs, which, in turn, inhibits immunity and heightened susceptibility to aging-associated diseases (AADs). Natural killer (NK) cells, integral to the innate immune system, play a pivotal role in addressing SNCs swiftly. These cells also coordinate with other components of both innate and adaptive immunity to surveil and eliminate these cells. Accordingly, preserving NK cell function during aging is crucial for evading AADs and promoting healthy aging. Alternatively, NK-cell-based therapies present promising avenues for addressing the challenges associated with aging. Notable, recent studies in adoptive NK cell therapy have shown promise in rejuvenating immunosenescence, eliminating SNCs, and alleviating SASPs. This progress provides the proof-concept of adoptive NK cell therapy for senotherapy and holds promise as an emerging revolution in longevity therapeutics.
Adoptive NK cell therapy sounds very promising for elimination of senescent cells. It might give better targeting in a broader number of tissues that small molecules could.
Our research group has pioneered a feeder-cell-free method for substantial NK cell expansion
I wonder what this means?
Kill those zombie cells!!
Chelyapov et al., described a studying in vitro where activated NK cells attack SNCs on highly cooperated level [27]. They assessed the senescent markers, p16 and β-galactosidase, in PBMCs before and after adoptive NK cell therapy from 5 healthy individuals, supporting the removal of immunosenescent cells in human [27]. Similarly, Tang et al., uncovered that senescence and exhaustion T cells were eliminated, and the secretions of SASP factors were decreased after adoptive NK cell therapy [26].
Urokinase plasminogen activator receptor (uPAR), upregulated on SNCs across different cell types, was paralleled with β-galactosidase-positive cells. Plasma levels of soluble uPAR positively correlate with the pace of aging in humans. uPAR chimeric antigen receptor (CAR) T cells can eliminate SNCs and improve aging-associated metabolic dysfunction [57]. Therefore, uPAR may serve as a suitable candidate biomarker of therapeutic efficacy.
Whether or not these macrophages are truly ‘senescent’ or have an alternative cell state is a topic of debate; regardless, given that we observe a fraction of uPAR-expressing macrophages that also coexpress SA-β-gal and senescence-associated transcriptional signatures accumulating in aged tissues, it seems likely that their elimination contributes to the phenotypes we observe.