Senolytics — drugs that selectively destroy senescent cells (senolytics) — have been shown to powerfully rejuvenate mice and to reverse multiple diseases of aging in animals, from atherosclerosis, to kidney disease, to osteoporosis, to Parkinson’s disease — and beyond. But because these drugs target pathways that are necessary for normal cell function, they can come with side-effects — the most notable being the crash in platelets (and resulting risk of fatal bleeds or strokes) that can accompany the experimental senolytic navitoclax.
But our bodies are actually equipped with an inborn army of immune cells that selectively identify and destroy senescent cells. To date, the most important of these “immunosenolytic” cells soldiers have seemed to be Natural Killer cells (NK cells) — though we will have an announcement to make on this front in the coming months. But if the body already has this defensive force, how do senescent cells still manage to accumulate in our tissues with age and wreak havoc on our health?
As part of SENS Research Foundation’s work to eradicate dysfunctional cells driving aging (ApoptoSENS), Dr. Amit Sharma and his team at SRF are developing ways to either rejuvenate our own NK cells’ ability to detect and destroy senescent cells in aging tissues, or to augment that capacity with NK cells engineered to be more lethal senescent cell hunters. To reach those goals, they realized they needed a more efficient way to enrich NK cells from mixed white blood cells isolated from human blood. In new peer-reviewed scientific paper, they show how they did it.
Their main innovation might seem to be an obvious one: to actually isolate NK cells and activate them to better mimic the situation in vivo. Previous studies have mostly used mixed populations of blood cells, sometimes removing T-cells or other specific cell types but never ensuring that they had isolated NK cells exclusively. Dr. Sharma used an existing kit to make sure that what they were seeing came from the NK cells and not from other cell types.
They also saw that the way that previous researchers had studied NK cells’ ability to destroy senescent cells was quite different from the conditions NK cells actually confront as they patrol for NK cells in the body, potentially leading scientists to chase after interventions that work well in a Petri dish but have no effect or are unsafe when carried out in living, breathing humans. This is probably because most scientists conducting these studies don’t have a specialized background in immunology: instead, they design their experiments based on a general background in the biology of aging or cancer biology, or as specialists in senescence per se, but
The biggest problem the SRF group corrected is that previous studies have cultured low numbers of senescent cells together with very high numbers of NK cells, creating a situation where NK cells are effectively shooting zombie fish in a barrel. Dr. Sharma’s team tested more realistic conditions in which one NK cell encounters one senescent cell, or no more than three, instead of ratios as high as one senescent cell target to 20 or even 80 NK cells.
Conversely, having given NK cells so many senescent cell targets that they can hardly fail to kill some, most previous studies have only set NK cells loose for a few hours, when NK cells have a half-life in the body of ten hours. So the ApoptoSENS team led by Dr. Sharma gave NK cells more time to engage their enemies, which better reflects how long they actually hang out in tissues, with experiments running from 16 hours to four days. This also gives the NK cells the ability to reveal their full range of powers, since some of their cell-killing weapons only engage over extended time periods.
Finally, previous studies on NK cells’ immune surveillance of senescent cells have cultured them in very high levels of interleukin-2 (IL-2), an immune-signaling molecule that triggers NK cells to create more of themselves and makes them more aggressive. At SRF, Dr. Sharma used levels that reflect levels in the body.
The first set of discoveries revealed by this new system: even when the ratio between NK and their potential targets is quite low, introducing more NK cells into the mix tends to kill more senescent cells, but at the expense of killing more and more healthy bystander cells.
All around, the new paper sets up the SRF ApoptoSENS team — and other scientists who can now read the findings for themselves — on a better path to identify ways to rejuvenate or reinforce senescent cell immune surveillance, reinvigorating NK cells to make them battle-ready once again.
Kim K, Admasu TD, Stolzing A, Sharma A. Enhanced co-culture and enrichment of human natural killer cells for the selective clearance of senescent cells. Aging (Albany NY). 2022 Mar 4;14(5):2131-2147. doi: 10.18632/aging.203931. Epub 2022 Mar 4. PMID: 35245208; PMCID: PMC8954966.