Recent developments in immunotherapy offer a glimmer of hope in the pursuit of longevity and the alleviation of age-related diseases. Utilizing engineered chimeric antigen receptor T (CAR T) cells, a recent study has shed light on a promising new approach to combating the effects of aging, particularly metabolic dysfunction and decreased physical fitness (Amor C, Fernández-Maestre I, Chowdhury S. et al. Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction. Nat Aging. 2024.

The Senescence Dilemma and Senolytic Therapies

As organisms age, their bodies accumulate senescent cells—cells that have stopped dividing and that contribute to age-related tissue decline. These cells are not just passive bystanders; they actively secrete inflammatory and debilitating molecules, exacerbating the aging process and contributing to various age-related pathologies. Historically, interventions such as genetic ablation have demonstrated that clearing these cells can improve health outcomes in animal models of aging.

While small-molecule drugs, known as senolytics, have been developed to target and eliminate these senescent cells, their application is hindered by the need for continuous administration. Amor et al. propose a more enduring solution: senolytic CAR T cells.

CAR T cell therapy is an innovative treatment utilizing an individual’s T cells (specialized immune cells) genetically modified in the lab. T cells, extracted from the patient’s blood, are modified with a gene that codes for the CAR component; this modification allows the T cells to recognize a specific marker on the surface of targeted cells. After this genetic alteration, the cells are cultured in the lab to increase their numbers and infused back into the donor. These engineered cells can now efficiently target and destroy cells of interest. This therapy has shown significant success in treating some forms of blood cancer.

uPAR-Targeted CAR T Cells: A Novel Approach to Senolytics

The first step in engineering an efficient CAR T cell therapy is the selection of a target protein. Senescent cells accumulate urokinase plasminogen activator receptor (uPAR) during aging; this study therefore utilized CAR T cells engineered to target cells containing uPAR.

The findings demonstrate that treatment with the anti-uPAR CAR T cells improved exercise capacity in aged mice, as well as ameliorated metabolic dysfunction, such as enhancing glucose tolerance. In addition to aging mice, researchers also looked at this therapy’s effects in the context of a high-fat diet. High-fat diets in mice induce metabolic dysfunction and speed senescent changes. This intervention, when applied to mice on a high-fat diet, showed similar improvements, indicating its broad applicability.

Exploring the Mechanisms

With few exceptions, all cells undergo some form of age-related senescence. The question of which specific uPAR-positive cell populations are responsible for the observed improvements in metabolic function remains unclear. While other studies have linked the elimination of senescent cells in specific tissues, such as pancreatic beta cells or adipose tissue, to improved metabolic outcomes, the current study broadens this understanding to include cells of the immune system.

Interestingly, the study notes that targeting macrophages, the senescent cells of the immune system, might play a significant role in the aging process. The authors believe that the elimination of macrophages contributes positively to the observed health improvements; however, the scope of this study is limited.

Advantageous Therapeutic Application

The unique advantage of senolytic CAR T cells lies in their specific targeting mechanism based on the expression of a particular surface antigen. Beyond this study’s selective targeting of uPAR, the versatility of CAR T allows for the targeting of multiple antigens, potentially providing a means to more specifically target distinct tissue types and cell populations. This feature might allow for a fine-tuning of the specified target, reducing the side effects inherent to traditional pharmacological therapies and improving safety.

The persistence and durability of the effects of uPAR-targeted CAR T cells after a single low-dose treatment underscores the clinical potential of this approach in treating chronic age-related diseases. This innovative therapy could revolutionize the way we approach aging and age-related pathologies, offering hope for more effective, long-lasting treatments. Although promising as a persistent single-dose therapy, the 12-month duration of this experiment limits the ability to interpret both the maximal efficacy of a single treatment and its potential to promote longevity. A more extensive long-term study is required to understand if these acute improvements would translate into lasting health benefits and lifespan modulation.

With an ever-increasing aged population, the need for effective treatments for age-related diseases becomes increasingly critical. The development of senolytic CAR T cells targeting uPAR opens new avenues in the fight against aging and its associated diseases. While further research is needed to fully understand and harness this technology, the prospects are promising, offering a potential paradigm shift in how we address the challenges of aging.