By Megan Molteni
A natural killer cellNIAID
Scientists have started to test whether natural killer, or NK, cells can be trained to go after hard-to-cure blood cancers in human patients. But making these sentinels of the innate immune system a potential boon to human health spans might be simpler: Rather than needing to be genetically engineered or primed with synthetic antibodies, they just need to be turned on.
In mice, researchers reported on Monday in the journal Med, activating NK cells can eliminate the senescent cells partly responsible for many diseases of aging. If the results hold up, they could offer a promising alternative to “senolytics” — experimental drugs that destroy these zombified cells that pile up and pollute your tissues as you get older. Although dozens of such drugs have postponed or even reversed diseases of aging in mouse experiments, clinical trials have thus far underwhelmed.
“It’s an interesting approach that works in experimental animals with two different conditions,” said geriatrician James Kirkland of the Mayo Clinic, whose discovery that giving old mice senescent cell-crushing compounds makes the animals live longer, healthier lives, helped take senolytics from backwater to boomtown. “We’re going to need multiple ways of getting at senescent cells,” he said. “Any step forward is important, and this is quite a nice step forward.” But he cautioned that a single senolytic strategy is unlikely to work for all age-related conditions.
For decades, scientists had largely ignored senescent cells — old and arrested in a permanent state of suspended animation — dismissing them as a quirk of evolution, a clever way for the body to keep damaged cells from proliferating into cancer. But more recently, Kirkland and other researchers established that senescence is actually a driver of the decrepitude that comes with old age. As cells stop dividing, they don’t exactly go dormant. In their zombie-like state, they start spewing a cocktail of toxic molecules that cause inflammation, damage surrounding tissues, and contribute to diseases like osteoarthritis, atherosclerosis, diabetes, and Alzheimer’s.
That realization spurred the creation of at least two dozen companies developing ways to systematically purge the body of senescent cells. Senolytics attracted this wave of investment because it promises a scintillating and fundamental shift in medicine — away from the one-drug-one-target-one-disease paradigm of the last century, toward correcting a root cause behind many of them with a single treatment.
One of those researchers is the new study’s senior author, Anil Bhushan of the University of California, San Francisco. In 2019, his lab traced the progression of type 1 diabetes in mice and human pancreatic cells. They discovered that signatures of senescence preceded the onset of disease. When his team removed the senescent pancreatic cells in mice, their metabolism stabilized and their diabetes symptoms went away.
What Bhushan took away from that study was that senescence didn’t just happen when the body’s biological clocks wound down too far. It occurred in acute diseases too. “There’d been talk in the field that an immune surveillance system maintained tissue homeostasis,” said Bhushan. “We postulated that that system was failing in the disease state and gradually failing in aging, so the only time we’d see senescent cells is when this system fails.”
To test that hypothesis, his team first went looking for clues as to the identity of their indolent immune cells. By comparing the transcriptional profile — which genes were turned on and off — in senescent pancreatic cells to healthy ones, they uncovered that the senescent ones boosted production of their antigen-presenting machinery. These are the proteins that, if a cell were infected with a pathogen, would shuttle little bits of the bacteria or virus to its surface, displaying them for immune cells to find. Then they cross-referenced those results with an analysis of senescent stem cells that accumulate in the fat tissues of obese mice who are fed a chronic, high-fat diet. Those cells also upregulated antigen-presenting molecules, and one in particular: CD1d. “That was the lock,” said Bhushan. “And once we’d found it, the key was then obvious.
Only one kind of immune cell binds to CD1d — invariant natural killer T cells, or iNKTs. Comprising less than 1% of all peripheral blood immune cells, iNKTs are rare but critical components of the body’s surveillance system, scanning for infected and defective cells in need of removal. When they find them, iNKTs expel torrents of cytokines, which signal to other immune cells to do the dirty work. Bhushan figured that something was interfering with that process. And though he wasn’t sure what it was, he knew there was a way to fix it.
In the early 1990s, Japanese scientists from Kirin Brewery’s pharmaceutical research lab, looking for anticancer treatments in the porous bodies of marine sponges collected in the Okinawan sea, purified a lipid compound called ɑ-galactosylceramide. And they discovered that when CD1d grabs onto this ɑ-GalCer lipid, it turns on iNKTs like crazy in mice.
So Bhushan’s team shot up some of their diet-induced obese mice with ɑ-GalCer. Within days, the levels of senescent cells in the mouse fat tissues had dropped. So did their fasting glucose. Their insulin sensitivity also improved. Their metabolism started to look normal.
To see how generalizable the effect was, they repeated the experiment with mice whose lung tissues had been damaged by a chemotherapy drug — a common model for idiopathic pulmonary fibrosis, a serious and incurable human lung disease, and one of the nastier complications of Covid-19. In those mice, ɑ-GalCer successfully activated iNKTs, again resulting in the removal of senescent cells. The treated mice had fewer damaged cells, and they also lived longer than the control group.
Finally, Bhushan and his colleagues looked at how well activated iNKT cells could tell senescent human cells from healthy ones when cultured together. After 18 hours, 100% of the senescent cells had been destroyed; the vast majority of healthy cells went unscathed. That could give the iNKT approach a potential advantage over the senolytics drugs already in development.
Most of them are repackaged cancer drugs that work by flipping on senescent cells’ self-destruct buttons. But because zombie cells share a lot of molecular features with their fully animated counterparts, those drugs run the risk of creating lots of collateral damage. Clinical trials of one such drug, 17-DMAG, were abandoned due to toxic side effects in the kidney and brain. Other groups are trying to solve this by engineering a different kind of immune cell, the CAR-T cell, to become a better anti-aging treatment. But CAR-Ts come with their own dangerous side effects and are expensive to make.
Bhushan is optimistic that by returning the cells best trained to suss out senescent cells to the ranks of active immune duty, both these safety and cost concerns can be ameliorated. “We have this built in specificity of the immune cells — part of their job is telling senescent cells apart from healthy ones — we’re just helping them do their job,” he said.
It’s still an open question. But clinical trials to answer it could be underway by the end of next year. Bhushan’s initial discoveries are now being developed by a biotech startup called Deciduous Therapeutics, which he co-founded in 2018. Deciduous is backed by 8VC, CRV, and Laura Deming’s Longevity Fund, and has until now, been operating in stealth. CEO and co-founder Robin Mansukhani told STAT that the company has been focusing on developing compounds that can best stimulate human iNKTs, whose receptors are structurally a bit different from those of a mouse. He expects Deciduous to file its first investigational new drug application to start human testing within the next 18 months, likely for a metabolic disease or fibrotic lung disorder.
Investors pumped the brakes on senolytics after one of the biggest and brightest stars of the nascent sector and another Longevity Fund portfolio company, Unity Biotechnology, announced last August that its lead drug candidate had failed to reduce knee pain in patients with osteoarthritis. The experimental drug was immediately and unceremoniously dumped, along with nearly one-third of Unity’s staff.
But despite the recent slowdown, Mansukhani remains optimistic. “The issue in the field has always been ‘what is the actual immune system process behind senescence clearing?’” he said. “And I feel like we’ve uncovered that.
Mayo’s Kirkland cautions that deciphering one chapter of the immune system user’s manual isn’t likely to be the whole story. Senescence can be caused by lots of things — aging, yes, but also obesity, chemotherapy drugs, and radiation. There are about 40 to 50 different things that can push a cell into a death spiral, said Kirkland. “That makes it really hard to define what a senescent cell is, because its molecular makeup depends on how its senescence was induced.”
But the good news, according to Kirkland, is that all the fundamental aging processes — mitochondria powering down, oxygen radicals disfiguring DNA, rampant inflammation, the spiral toward senescence — appear to be tightly interlinked. “It’s looking increasingly like if you hit one part of this network of things going on, you affect all the rest, and usually in a positive way,” he said.
Kirkland, together with his team at Mayo, have had some success with a cocktail of dasatinib and quercetin. In 2019, they reported positive results from a Phase 1 pilot study of nine diabetic kidney disease patients — senescent cells were reduced. A Phase 2 study is now underway. And his team has several more trials for serious conditions, including osteoporosis and Alzheimer’s disease, in the pipeline. Kirkland serves as a scientific adviser to a new senolytics company called NRTK Biosciences that has yet to receive funding and anti-aging supplement company Elysium Health.
But the real question for the future, said Kirkland, is which interventions can you combine to get an additive, synergistic effect? Something that actually alleviates not just one disease of aging, but many, or even all of them? “Figuring out how immune cells interplay with senescence is going to be the start of looking for those combinations.”
That’s what’s next for Bhushan’s lab — a painstaking process of deleting different antigen-displaying peptides across dozens of types of immune cells, and mapping out the almost infinitely complex network of interactions brewing in the toxic stew surrounding senescent cells.
“We know we only have part of the story,” Bhushan said. “We know we can fix whatever is going wrong with iNKTs, but we still don’t know exactly what that is.”
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