bims-caglex 2025-11-30 papers

Nat Aging. 2025 Nov 25.

Anti-uPAR CAR T cells reverse and prevent aging-associated defects in intestinal regeneration and fitness.

Intestinal stem cells (ISCs) drive the rapid regeneration of the gut epithelium. However, during aging, their regenerative capacity wanes, possibly through senescence and chronic inflammation, albeit little is known about how aging-associated dysfunction arises in the intestine. We previously identified the urokinase plasminogen activator receptor (uPAR) as a senescence-associated protein and developed CAR T cells able to efficiently target it. Harnessing them, here, we identify the accumulation of mostly epithelial uPAR-positive cells in the aging gut and uncover their detrimental impact on ISC function in aging. Thus, both therapeutic and prophylactic treatment with anti-uPAR CAR T cells improved barrier function, regenerative capacity, inflammation, mucosal immune function and microbiome composition in aged mice. Overall, these findings reveal the deleterious role of uPAR-positive cells on intestinal aging in vivo and provide proof of concept for the potential of targeted immune-based cell therapies to enhance tissue regeneration in aging organisms.

DOI: https://doi.org/10.1038/s43587-025-01022-w

Cell Commun Signal. 2025 Nov 26. 23(1): 509

Extracellular vesicles for delivery of functional telomerase.

Yingying He, Yumeng Cui, Lijuan Wang, Wen Yang, Ruping Wang, Yanghua Li, Yue Ma, Yanli Lin, Xiaojie Wu, Long Cheng, Chengjiang Zhou, Youliang Wang.

BACKGROUND: Telomerase, essential for maintaining chromosomal telomere integrity and preventing cellular senescence, represents a promising therapeutic target. However, the inherent risks associated with existing treatments for telomerase deficiency-related diseases necessitate the development of safe and precise targeted delivery systems capable of reaching specific cell populations. Extracellular vesicles (EVs), nanoscale membrane-bound particles naturally secreted by cells, mediate intercellular communication by transporting bioactive molecules, including proteins and nucleic acids. We hypothesized that EVs could function as intrinsic vehicles for telomerase delivery.
METHODS: To investigate this, we demonstrated the effective encapsulation of functional telomerase components, specifically TERT and TERC, within EVs. Furthermore, we observed that enhanced TERT expression led to increased telomerase activity within the EVs, as confirmed by TRAP assay results.
RESULTS: These telomerase-loaded EVs, leveraging their inherent targeting capabilities and unique vesicular structure, efficiently delivered the active enzyme to recipient cells. In aged mice, delivery of telomerase via EVs restored endogenous telomerase activity, preserved telomere integrity, and attenuated senescence across multiple tissues. We observed that the internalized telomerase modulated the expression of senescence-associated markers, thereby delaying cellular aging and promoting cellular proliferation.
CONCLUSIONS: These findings support the feasibility of EV-mediated intercellular telomerase delivery, suggesting a potential avenue for developing therapeutic interventions for pathologies associated with telomerase deficiency.

Keywords: Cellular senescence; Extracellular vesicles; TERT; Telomerase

DOI: https://doi.org/10.1186/s12964-025-02524-1

NPJ Aging. 2025 Nov 24.

Human plasma-derived eNAMPT-containing extracellular vesicles promote NAD+ biosynthesis and thermogenesis in mice.

Kiyoshi Yoshioka, Takumi Sugimoto, Mamoru Oyabu, Naoki Ito, Aoi Kodama, Yasutomi Kamei, Shin-Ichiro Imai.

Age-associated decline in tissue NAD+ levels contribute to functional impairments, recognized as aging. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme crucial for NAD+ biosynthesis in mammals, is encapsulated in extracellular vesicles (EVs) and secreted into the bloodstream. The importance of extracellular NAMPT-containing EVs (eNAMPT-EVs) in hypothalamic NAD+ biosynthesis has been demonstrated in several mouse models. However, whether eNAMPT-EVs derived from human plasma can also act as a physiological NAD+ booster remains unclear. Here we show that administration of human plasma-derived, highly purified eNAMPT-EVs can elevate hypothalamic NAD+ levels in mice. Furthermore, eNAMPT-EV administration led to an increase in body temperature and suppression of hypothalamic Npy gene expression. These responses were negated by pharmacological NAMPT inhibition. We also found that exercise increases in plasma eNAMPT and hypothalamic NAD+ levels. These findings suggest that enhancing circulating eNAMPT-EVs can be an effective strategy for NAD+ boosting and potentially an effective anti-aging intervention in humans.

DOI: https://doi.org/10.1038/s41514-025-00297-y

Aging (Albany NY). 2025 Nov 25. 17

REVIVE: a computational platform for systematically identifying rejuvenating chemical and genetic perturbations.

Sascha Jung, Javier Arcos Hodar, Tejwasi Venkata S Badam, Antonio Del Sol.

Great efforts have been devoted to discovering rejuvenation strategies that counteract age-related functional decline and improve cellular functions in humans. However, new discoveries are currently driven by expert knowledge and require large amounts of resources. Here, we present REVIVE (Rejuvenation Estimation Via Insightful Virtual Experiments), the first computational framework for systematically predicting chemical and genetic perturbations that can restore a youthful transcriptional state based on gene expression data. REVIVE leverages age predictions to detect significant rejuvenating effects and quantifies the impact of perturbations on the hallmarks of aging. When applied to a large-scale in silico screen of more than 10000 compounds and genetic perturbations, REVIVE recapitulates known interventions as well as 477 novel compounds that restore a more youthful transcriptional state improving multiple aging hallmarks. Finally, we demonstrate the utility of REVIVE for repurposing perturbations to revert aged transcriptional states.

Keywords: aging; computational modeling; drug repurposing; machine learning; rejuvenation

DOI: https://doi.org/10.18632/aging.206342