Obesity and aging increase the risk of diabetes and fatty liver. Scientists have figured out what might help stop these problems. (CREDIT: Creative Commons)
Chimeric Antigen Receptor (CAR) T cells, renowned for their groundbreaking impact on the treatment of blood cancers, are now emerging as potential allies in the battle against aging-related diseases.
Recent laboratory research led by Memorial Sloan Kettering Cancer Center (MSK) and Cold Spring Harbor Laboratory has illuminated the potential of CAR T cells to combat diseases caused by the accumulation of senescent cells, those cells that cease dividing due to age or damage.
The study has unveiled remarkable results, indicating that an infusion of CAR T cells designed to target senescent cells could improve metabolic function in both older mice and those prematurely aged by a high-fat diet. In a surprising twist, even young, healthy mice benefited from a single dose of these innovative CAR T cells, which helped prevent future metabolic decline. The findings of this study were published in the prestigious journal Nature Aging.
Dr. Scott Lowe, Chair of the Cancer Biology and Genetics Program at MSK's Sloan Kettering Institute and the senior author of the study, commented on the broad potential of this approach: "When you hear 'CAR T cell therapy,' you think 'cancer' — and it makes sense that it was pioneered at a place like MSK. But what we're learning is that this approach of engineering immune cells to target disease has much broader possibilities."
The study entailed subjecting younger mice to a high-fat diet for two months, leading to obesity and metabolic stress. Subsequently, these mice received an infusion of CAR T cells, resulting in lower body weight, improved fasting blood glucose levels, and enhanced glucose and insulin tolerance, all while continuing the high-fat diet.
Notably, these mice also exhibited a reduction in senescent cells in the pancreas, liver, and fatty tissues compared to the control group. Similar improvements were observed in older mice, whose metabolic function had diminished naturally due to aging.
Even more impressively, older mice that received the CAR T cell treatment displayed increased endurance during exercise, and the treatment appeared to have no significant adverse effects. However, the researchers emphasize the need for further investigations to determine whether this approach can not only improve the "healthspan" but also extend the lifespan of these mice.
Scott Lowe, PhD, Chair of the Cancer Biology and Genetics Program in MSK’s Sloan Kettering Institute. (CREDIT: MSKCC)
Dr. Lowe explained, "We're continuing to learn new things about senescence on a biological level. It will take time, but we're interested in working with industry partners to move the laboratory findings into clinical trials."
Numerous diseases associated with aging and chronic inflammation could potentially benefit from this novel approach, according to Dr. Lowe. These conditions include chronic obstructive pulmonary disease (COPD), nonalcoholic steatohepatitis (NASH), osteoarthritis, metabolic syndrome, and even certain neurodegenerative diseases.
Immunologist Michel Sadelain, MD, PhD. (CREDIT: MSKCC)
Collaborating with Dr. Lowe's lab, immunologist Dr. Michel Sadelain and his team played a crucial role in this research. Dr. Sadelain, recognized for his pioneering work in CAR T cell therapy, recently received the 2024 Breakthrough Prize in Life Sciences.
The study was co-led by Inés Fernández-Maestre, a graduate student in the lab of MSK physician-scientist Dr. Ross Levine, and Dr. Corina Amor Vegas, a former graduate student in the Lowe Lab who now heads her own lab at Cold Spring Harbor and is the corresponding author of the paper.
A microscope image of an aged mouse liver showing signs of chronic inflammation (clusters of dark purple cells). (CREDIT: MSKCC)
Senescent cells, a focus of this groundbreaking research, are damaged cells that have entered a protective shutdown mode, ceasing division and actively signaling the immune system for assistance. While this mechanism can benefit wound healing and control runaway cell division, it can also lead to chronic inflammation as senescent cells accumulate with age.
In 2020, MSK researchers identified a molecule on the surface of senescent cells, called urokinase plasminogen activator receptor (uPAR), which was largely absent in other cell types. This discovery paved the way for the design of CAR T cells that could specifically recognize and target uPAR, a strategy successfully tested in various mouse models of senescence-related diseases, as reported in Nature.
Left to Right: Co-first study authors Inés Fernández-Maestre and Dr. Corina Amor Vegas. (CREDIT: MSKCC)
The new research extends the understanding of senolytic (senescence-targeting) cell therapies to improve symptoms associated with aging. Unlike traditional small-molecule drugs, CAR T cells offer a more versatile approach, as they can persist in the body for extended periods, reducing the need for repeated treatments.
Dr. Amor Vegas emphasized this advantage, stating, "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."
Furthermore, CAR T cell therapies can be engineered with safety features to minimize side effects and target multiple cell surface molecules simultaneously, reducing the risk of harming healthy cells.
An immunofluorescence image of an aged mouse liver. Expression of β-galactosidase (white) and uPAR (yellow) in senescent cells serve as target for engineered CAR T cells. Elimination of these cells improved age-related metabolic dysfunction. (CREDIT: MSKCC)
The research team's experiments uncovered several critical insights. They found that uPAR-positive cells increase with age and significantly contribute to aging-related dysfunction in tissues. Additionally, uPAR-targeting CAR T cells effectively eliminated senescent cells in mice without major side effects, and the treatment enhanced metabolic health in both naturally aging mice and those affected by diet-related metabolic disease.
Dr. Lowe highlighted the unique challenges of using CAR T cells to treat age-associated diseases, stating, "If only a few cancer cells survive treatment, they may keep dividing to enable the tumor to relapse. Since senescent cells don't divide, clearing most but not all of them should still produce substantial health benefits."
Despite these challenges, the pursuit of therapies for diseases less lethal than cancer demands a high safety standard. Dr. Sadelain expressed confidence in the ongoing efforts to develop safer and more cost-effective cellular therapies, which are expected to expand the range of diseases treatable with CAR T cell therapies in the coming years.
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