The Fountain of Youth May be Within You

For thousands of years, humans have strived to outrun the inescapable landscape of time, whether by a centuries-long search for an age-regressing fountain or by using overpriced skincare products. However, as technology and medicine have advanced, this goal is starting to come to fruition. In the past 200 years, the average human lifespan has doubled due to improvements in technology, medicine, and nutrition. However, this drastic increase in longevity is accompanied by yet another challenge: age-associated illnesses. As organisms age, their cells and chromosomes replicate to maintain bodily structures. Each chromosome is capped by a telomere, a region of repetitive DNA sequences that protects the primary genetic data from being cut off during replication. However, in response to the shortening of telomeres, the cells enter cellular senescence, a state in which they stop multiplying indefinitely and eventually die. This state is uniquely problematic because cells undergoing a programmed death are cleared out by immune cells called phagocytes. In contrast, senescent cells build up in organisms over time and secret pro-inflammatory cytokines that lead to tissue decline, inflammation, and consequently, disease. 

However, researchers from Cold Spring Harbor Laboratory (CSHL) have found a treatment that may hold the key to alleviating some symptoms of aging—chimeric antigen receptor (CAR) T cells. T cells are white blood cells that help the immune system identify and fight harmful antigens. CAR T cells are produced by engineering each patient's unique T cells with an artificial gene that produces CAR proteins. Upon formation, these proteins are programmed to recognize specific proteins on the surface of target senescent cells. After being genetically engineered, the CAR T cells are replicated and injected back into the patient. 

CAR T cells identify senescent cells by searching for an increased presence of urokinase plasminogen activator receptors (uPAR) that play a role in tissue remodeling. When the CAR T cells find their targets, the CAR T cells bind to the target cell and secrete two substances: perforin and granzyme. Perforin, a pore-forming protein, corrodes a hole in the senolytic cell's membrane and allows the second toxin, granzyme, to enter. Granzymes are digestive enzymes that cleave vital protein bonds in cells, which lead to the senescent cells’ death. CAR T cells can be used to clear out senescent cell buildups, relieving tissue and muscle decline—common symptoms of aging. This leads to a decreased risk of age-related diseases, and a theorized increase in lifespan. 

To test the effectiveness of this process, the CSHL scientists tested doses of CAR T cells on 12 elderly mice and compared the experimental mices’ CAR T cell count  to untreated mices’. They found that at an optimal dose of 500,000 CAR T cells, mice receiving the treatment had a decrease in senescent cells, particularly in their pancreas, liver, and fatty tissues. These regions have an unusually high presence of senescent uPAR-possessing cells, ranging from 67 to 92 percent of total cell makeup in certain areas. The researchers also found a decrease in Senescence-Associated Secretory Phenotype cytokines, which are proteins that lead to increased inflammation and tissue injury. Overall, this experiment provided concrete evidence that the CAR T cells could successfully find and destroy senescent build-ups. 

In addition, the treatment alleviated metabolic dysfunction in the aging mice. The treated mice had comparatively lower insulin levels after fasting, followed by a drastic increase after digesting glucose. This improved response time indicates that the mice's pancreatic beta cells and insulin producers functioned better than those of the untreated mice. Furthermore, each cell had enhanced peripheral insulin sensitivity, meaning they could more readily process the glucose delivered by the insulin. If the cells can't process the insulin normally, blood sugar levels and subsequent risk of diabetes will rise. CAR T cells' role in regulating insulin is another substantial finding, because as organisms age, their insulin resistance increases. Though scientists haven't yet confirmed the exact reason why CAR T cells affect insulin, they offer a promising avenue for mitigating the age-related deterioration of metabolism. 

The study of CAR T cells is particularly innovative due to its long-lasting effects. Senescent cell accumulations can be cleared by external drugs called senolytics, though each dose is only temporarily effective and requires frequent administration of doses. However, when researchers injected each of three-month-old mice with a single dose of CAR T cells and monitored their blood levels, the modified cells were still detectable up to one year after the initial dose, which is half their average lifespan. The cells last so long because, unlike the senolytics, they are alive. The CAR T cells can replicate and continue to relieve age-related symptoms.

Though the CAR T cell treatment appears to have no adverse effects, one evident limitation is the scope of research. So far, CAR T cell treatment serves as protection from age-associated illness, rather than a completely definitive extension of life. They help decrease the chance of death by disease, but require much more experimenting to prove a consistent increase in lifespan. Additionally, the CAR T cells have only been clinically tested on mice, which limits our ability to fully understand the treatment's impacts. The results of this study are promising, but further research is needed to understand how effective CAR T cells are on a larger scale. The CSHL researchers are interested in testing their treatment on humans, but acknowledge that they have a long road ahead of them to optimize their approach. But scientists will continue to experiment with different methods to slow down aging, bringing us one small step closer to reaching immortality, a goal yet to be tarnished by the rust of time.