Researchers headed by a team at Cold Spring Harbor Laboratory (CSHL) have developed an anti-aging chimeric antigen receptor (CAR) T cell therapy targeting the senescent cells that accumulate in organisms as they age, and which are thought to be responsible for many of the diseases linked with getting older.
The team, headed by assistant professor Corina Amor Vegas, MD, PhD, tested the senolytic CAR T cell therapy in aging mice, finding that treatment ameliorated metabolic dysfunction —for example, improving glucose tolerance—and improved exercise capacity. Encouragingly, a single treatment with the senescent cell-targeting CAR T cells had long-term therapeutic and preventive effects in the mice.
The scientists reported on their findings in Nature Aging, in a paper titled “Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction,” in which they concluded, “Our study provides proof-of-principle evidence that senolytic cell therapies can ameliorate symptoms associated with physiological aging.”
Senescent cells are those that stop replicating. As we age, they build up in our bodies, resulting in harmful inflammation. “Cellular senescence is a stress response program characterized by stable cell cycle arrest and the production of the senescence-associated secretory phenotype (SASP), which includes pro-inflammatory cytokines and matrix remodeling enzymes,” the team explained. As we age, a combination of increased tissue damage and decreased immune system function leads to the accumulation of senescent cells, and this generates “… a chronic proinflammatory milieu that leads to a range of age-related tissue pathologies.” While several drugs currently exist that can eliminate these cells, many must be taken repeatedly over time.
As an alternative, Amor Vegas and colleagues turned to CAR T cells as an approach to targeting senescent cells. “Unlike small molecules, CAR T cells only require that the target antigen is differentially expressed on target cells compared to normal tissues; moreover, as ‘living drugs’, these therapeutics have the potential to persist and mediate their potent effects for years after single administration,” they further stated.
The team had previously shown that CAR T cells targeting the cell surface protein uPAR, which is upregulated on senescent cells, could deplete senescent cells in young mice and reverse liver fibrosis. For their newly reported study the team explored whether CAR T cells could safely eliminate senescent cells in aged mice, and impact on healthspan.
They discovered that the uPAR CAR T cells could eliminate senescent cells in the older mice, which then lived healthier lives. The CAR T cell-treated animals had lower body weight, improved metabolism and glucose tolerance, and demonstrated increased physical activity. All the observed benefits came without any tissue damage or toxicity. “Collectively, these results show that uPAR CAR T cells can safely and effectively remove senescent uPAR-positive cells in the tissues of naturally aged mice and ameliorate age-dependent metabolic and physical dysfunction,” the team reported.
Many of the features associated with metabolic syndrome in aged mice can be recapitulated in young animals given a high-fat diet (HFD). “… indeed, obesity has been described to accelerate the ‘aging clock’” the team noted. In their reported study the team also tested the senolytic CAR T cell therapy in young mice that had been fed a HFD. “… we modeled metabolic syndrome by feeding mice an HFD, which induces obesity and metabolic stress,” they added. In these animals, CAR T cell therapy was also associated with significantly lower body weight, better fasting blood glucose levels and improvements in both glucose and insulin tolerance, when compared with control animals.” Perhaps the most striking observation of the current work was the ability of uPAR CAR T cells to act prophylactically to blunt age-induced and diet-induced metabolic decline,” they wrote. Vegas added, “If we give it to aged mice, they rejuvenate. If we give it to young mice, they age slower. No other therapy right now can do this.”
Perhaps the greatest power of CAR T cells is their longevity. The team found that just one dose at a young age can have lifelong effects. “Importantly, a single administration of these senolytic CAR T cells is sufficient to achieve long-term therapeutic and preventive effects,” the team noted in their report. That single treatment can protect against conditions that commonly occur later in life, such as obesity and diabetes. “Unlike senolytic approaches based on small molecules, uPAR CAR T cells have long-lasting effects after the administration of a single low dose, causing a marked impairment in age-induced or HFD-induced metabolic syndrome when mice were treated during youth or administration of HFD, respectively,” they added.
“T cells have the ability to develop memory and persist in your body for really long periods, which is very different from a chemical drug,” commented Vegas. “With CAR T cells, you have the potential of getting this one treatment, and then that’s it. For chronic pathologies, that’s a huge advantage. Think about patients who need treatment multiple times per day versus you get an infusion, and then you’re good to go for multiple years.”
CAR T cells have been used to treat a variety of blood cancers, but Vegas is one of the first scientists to show that CAR T cells’ medical potential may extend further than cancer. “The persistence of the uPAR-targeted CAR T cells and the durability of the effects after a single low-dose treatment highlight the clinical potential of the senolytic CAR T cell approach for the treatment of chronic pathologies,” the authors concluded. The lab is now investigating whether CAR T cells let mice live not only healthier but also longer.