CAR T crashers – how combating senescence boosts healthspan

A new paper explores how innovative use of CAR T cells in aged mice revealed significant improvements in metabolic function and longevity.

Cellular senescence is a state of stable cell cycle arrest that normal cells enter in response to various internal and external stimuli, including epigenetic changes, oxidative stress, telomere shortening, mitochondrial dysfunction and inflammation [1]. Senescent cells secrete a variety of inflammatory cytokines, growth factors, chemokines and matrix remodeling factors, collectively known as the senescence-associated secretory phenotype (SASP), which can alter the local tissue environment. This phenomenon has been observed both in vivo and in vitro [2].

In young individuals, the SASP recruits immune cells that help clear out senescent cells and restore tissue homeostasis. However, with aging, decreased immune function and increased tissue damage lead to the accumulation of senescent cells, contributing to age-related diseases. Removing these senescent cells from aged tissues holds potential for improving healthspan.

Longevity.Technology: Most senolytic strategies for eliminating senescent cells have focused on small-molecule drugs, which face limitations such as poorly defined targets on senescent cells and the need for repeated administration. Recent research has turned towards chimeric antigen receptor (CAR) T cells, where T cells are engineered to target cells expressing specific surface antigens. Unlike small molecules, CAR T cells have a precise target and can provide long-lasting effects after a single treatment.

A recent study published in Nature Aging explored the efficacy and safety of CAR T cells in eliminating senescent cells in aged mice, aiming to regulate healthspan. The researchers used 3-4 month-old, 18-month-old and 6-week-old mice for various tests, including glucose tolerance, exercise capacity, histological analysis, insulin tolerance, pathological analysis and blood measurements [3].

The team focused on the senescence-associated protein urokinase plasminogen activator receptor (uPAR), known for its role in extracellular matrix remodeling, tumorigenesis and wound healing. Prior studies indicated that CAR T cells could target uPAR on senescent cells across different types, promoting their removal from young mice tissues without harming normal cells. The current study observed an age-related increase in uPAR protein in the liver, adipose tissue, skeletal muscle and pancreas, alongside an increase in senescence-associated beta-galactosidase (SA-β-gal)-positive cells .

Further analysis revealed that endothelial and myeloid cells were the most prominent uPAR-expressing populations in the liver, with preadipocytes, myeloid cells, and dendritic cells in adipose tissue, and fibroblasts, myeloid cells, dendritic cells and endothelial cells in the pancreas. These uPAR-positive cells were associated with gene signatures linked to inflammation, growth factor-beta signaling, the coagulation cascade, and the complement pathway, and the senescent cell types were found to be the most significant in tissues where uPAR-positive cells were higher.

Administering CAR T cells resulted in a reduction of SA-β-gal-positive and uPAR-positive cells in the adipose tissue, pancreas, and liver. The CAR T cell dose used was well tolerated in both young and aged mice, and treated older mice exhibited improvements in metabolic function and exercise capacity [3].

Additionally, uPAR CAR T cells, particularly cytotoxic CD8+ T cells, persisted and expanded over the lifespan of the mice, limiting metabolic decline with age. In young mice fed a high-fat diet, uPAR CAR T cells improved metabolic dysfunction and delayed the onset of metabolic disorders, with effects lasting for at least 5.5 months post-treatment despite continual high-fat diet intake.

This study demonstrates that uPAR CAR T cells significantly improve metabolic function, exercise capacity, and physiological aging in both aged mice and young mice on high-fat diets [3]. A single administration was sufficient for long-term preventive effects, suggesting potential therapeutic applications for CAR T cells in enhancing human longevity.

While this is still early days for therapeutic avenues, possible future applications for CAR T cell therapy could include age-related metabolic disorders (targeting and eliminating senescent cells that contribute to metabolic diseases such as type 2 diabetes, obesity and metabolic syndrome) and reversal of age-related tissue dysfunction (clearing senescent cells from specific tissues and restoring function and vitality in organs commonly affected by aging, such as the liver, pancreas and adipose tissue).

Wider therapies could include enhancement of physical performance in the elderly (thereby reducing sarcopenia and frailty), prevention of age-related chronic diseases (the long-term preventive effects of CAR T cells indicate their potential in delaying or preventing the onset of chronic conditions associated with aging, such as cardiovascular diseases, neurodegenerative disorders and certain cancers) and support for weight management (preventing obesity-related complications).

[1] https://www.frontiersin.org/articles/10.3389/fcell.2021.645593/full
[2] https://inflammregen.biomedcentral.com/articles/10.1186/s41232-022-00197-8
[3] https://www.nature.com/articles/s43587-023-00560-5