# Harnessing CAR T cells to deconstruct the interconnectivity among hallmarks of aging

> **NIH NIH R01** · COLD SPRING HARBOR LABORATORY · 2024 · $528,215

## Abstract

SUMMARY
To date nine hallmarks of the aging process have been described, which can be grouped into three major
categories: primary hallmarks or cause of damage (genomic instability, telomere attrition, epigenetic alterations
and loss of proteostasis), antagonist hallmarks or responses to damage (cellular senescence, mitochondrial
dysfunction and deregulated nutrient sensing) and integrative hallmarks or manifestations of the aging phenotype
(stem cell exhaustion and altered intercellular communication). Despite intensive research on each individual
hallmark, little is known about their interconnectivity and the hierarchies governing those interactions. A limiting
factor in these studies is the time and resources needed for developing, breeding and aging mouse models that
would allow to untangle the interactions as well as the lack of highly selective small molecules that would enable
somatic approaches. In this regard, our recent work showed for the first time the feasibility of employing cellular
therapy to eliminate cells that have entered a specific cellular program such as cellular senescence. In a proof-
of-concept study we identified uPAR as a surface molecule upregulated in cellular senescence and developed
CAR T cells able to eliminate senescent cells with high potency and specificity. CAR T cells have the advantage
that they can be administered somatically and are highly effective at exclusively targeting cells expressing a
specific antigen. In addition, they offer the possibility of spatial and temporal control making them highly versatile
tools. Herein we leverage our team’s expertise in senescence biology and cell engineering technology to shed
light into the interactions among the hallmarks of aging. Our goals are to characterize in depth the impact of
senolytic CAR T cells on the antagonistic and integrative hallmarks of aging; develop tissue specific senolytic
CAR T cells that would allow us to untangle hierarchies among the hallmarks across physiological lifespan and
study the therapeutic potential of modulating the interactions for the treatment of age-related pathologies.
Preliminary data strongly supports the feasibility of the proposed work: we have successfully and safely
employed senolytic CAR T cells in naturally aged mice and showed their high potency at eliminating target
positive cells in the tissues over long periods of time. Importantly, treatment with senolytic CAR T cells results in
significant improvements in healthspan. In our application, we continue to characterize in a systematic way the
effects across hallmarks and harness the flexibility of cellular therapy to untangle the hierarchies governing the
interactions. Overall, we expect our studies will lead to versatile tools to interrogate aging biology as well as to
the development of new therapies for a range of age-related pathologies.

## Key facts

- **NIH application ID:** 10924067
- **Project number:** 5R01AG082800-02
- **Recipient organization:** COLD SPRING HARBOR LABORATORY
- **Principal Investigator:** Corina Amor Vegas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $528,215
- **Award type:** 5
- **Project period:** 2023-09-15 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10924067

## Citation

> US National Institutes of Health, RePORTER application 10924067, Harnessing CAR T cells to deconstruct the interconnectivity among hallmarks of aging (5R01AG082800-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10924067. Licensed CC0.

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