Letting up senescence and inflammaging through T cells

Información del proyecto

Let T Be

Identificador del acuerdo de subvención: 101044248

DOI

10.3030/101044248

Fecha de la firma de la CE 12 Diciembre 2022

Fecha de inicio 1 Marzo 2023

Fecha de finalización 29 Febrero 2028

Financiado con arreglo a

• European Research Council (ERC)

Coste total

€ 1 999 944,00

Aportación de la UE

€ 1 999 944,00

Coordinado por

AGENCIA ESTATAL CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS
Spain

Periodic Reporting for period 1 - Let T Be (Letting up senescence and inflammaging through T cells)

Período documentado: 2023-03-01 hasta 2025-08-31

Resumen del contexto y de los objetivos generales del proyecto

With the increase in human life expectancy, there is an urgent need to understand the common molecular pathways by which aging results in a progressively higher susceptibility to chronic morbidity, disability, and frailty. In the last years, immunometabolism has emerged as a new field to boost immune responses for cancer immunotherapies as well as to dampen autoimmune diseases. A recent discovery from my lab has revealed the critical role of T cell metabolism in accelerating the onset of age-associated diseases and multimorbidity. This finding has opened a new path to investigate the diverse T cell intrinsic and external stimuli that instruct T cell differentiation towards a dysfunctional state during aging, with the final goal of designing effective strategies to promote healthy aging. LetTBe will address the hypothesis that the time-dependent deterioration of T lymphocytes contributes not only to immunosenescence but also to the general aging process. The LetTBe project proposes to use multidisciplinary approaches to target age-associated T cells for preventing inflammaging, senescence and age-associated multimorbidity. Our central goals are: 1) To define age-associated T cells heterogeneity with special focus in their cellular origin, clonality, metabolic vulnerabilities and transcriptomic signatures; 2) To decode the environmental signals that are imprinted on age-associated T cells and contribute to their development; 3) To identify new strategies to targeting age-associated T cells for slowing down immunosenescence, and for boosting resilience to inflammaging, systemic senescence and age-related multimorbidity. In sum, LetTBe puts forward an ambitious but feasible program with the wide purpose of understanding the specific molecular mechanisms and metabolic requirements of age-associated T cells, with the final goal to guide new strategies to improve healthy aging.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

Aim 1A. Using spectral flow cytometry, we have mapped the distribution of various TAA-specific T cells across lymphoid and non-lymphoid organs, including bone marrow, liver, brain, gut, and skin. Importantly, we have found a subset of CD4+ T cells with a cytotoxic phenotype (CD4+ CTLs) producing the chemokine CCL5 and harbouring dysfunctional mitochondria, infiltrate the bone marrow and induce granulopoiesis in aged mice. These findings suggest that age-associated alterations in T cells reduce health outcomes by remodelling the bone marrow niche and enhancing neutrophil generation. These results are presented in a New Manuscript by Gabande-Rodriguez et al that is currently in 2nd revision in Nature.
Aim 1C. We have combined our spectral flow cytometry panel of 20 antibodies to resolve Taa heterogeneity with mitochondrial probes to asses mitochondrial function at singe cell resolution. These results are presented in Soto-Heredero et al Nature Aging, in press
Aim 2A. We have studied the crosstalk between an aged-environment and Taas. part of this results are currently presented Gabande-Rodriguez et al that is currently in 2nd revision in Nature.
Aim 2B. We have studied the Crosstalk between microbiota from aged mice and Taas. These results are presented Gomez de las Heras et al 2nd revision in Science Immunology.
We are actively working in AIM 3B. Boosting T cell metabolism to delay immunosenescence and improve resilience to inflammaging and we have preliminary data that support that PPAR agonist could improve immunometabolism to delay immunosenescence (Delgado et al, working in progress)

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

The project has generated significant progress, including in the role of T cells in aging.

The potential impacts of these results are substantial. Scientifically, they contribute to advancing the state of the art in immunosenescence, and they can enable future developments in developing strategies for preventing or delaying immunosenescene and by this control inflammaging and many age-associated diseases. From a broader perspective, the results may support future translational applications by improving adaptive immunity at the short term and at the long term, increase resilence to aging and many age-associated disorders

To ensure further uptake and long-term success, several elements will be important:

Further research: Additional experimental will be needed to expand and validate the strategies that we are proposing to rejuvenate the immune system, validate the findings in complementary models, and deepen mechanistic understanding.



By the end of the project, we expect to have generated a comprehensive set of results, including proposing different strategis to delay immune aging, all of which will be made available to the scientific community through publications, data repositories, and dissemination activities. These outcomes will create a strong basis for continued research and potential applications beyond the duration of the ERC project.