SubsidieMeestersTargeting telomeric DNA damage response as a new strategy to fight immunosenescence and improve vaccine response
The project aims to evaluate the effectiveness of telomeric antisense oligonucleotides in rejuvenating the immune response and enhancing vaccine efficacy in aged mice.
Projectdetails
Introduction
The immune system is remodeled with age, going through a series of changes known as immunosenescence. This includes:
- The involution of primary lymphoid organs
- The contraction of the immune repertoire
- A progressive lineage skewing towards the myeloid lineage
- A low-grade pro-inflammatory status
A consequence of immunosenescence impacting the morbidity and mortality of infectious diseases is a dramatically reduced vaccine response in the elderly. Thus, reducing the burden of immunosenescence has the potential to impact the effectiveness of vaccine response.
Telomere Dysfunction
An established hallmark and driver of age-associated functional decline is telomere dysfunction. Dysfunctional telomeres are actively transcribed to generate telomeric non-coding RNAs (tncRNA), which are essential to recruit DNA Damage Response (DDR) factors at damaged telomeres. This process fuels DDR and causes cellular senescence initiation and maintenance.
Telomeric Antisense Oligonucleotides
Sequence-specific telomeric antisense oligonucleotides (tASOs) target these tncRNAs and effectively inhibit DDR activation. This intervention ameliorates age-related phenotypes in mouse models.
Mouse Model
The telomerase-deficient (Terc-/-) mouse model causes telomere shortening and dysfunction, recapitulating features of immunosenescence, such as:
- Immune system reactivity reduction
- Decreased long-term renewal of hematopoietic stem cells and lymphocyte numbers
- Increased neutrophil count
tASOs treatment has a beneficial long-term effect in this model by decreasing immunosenescence and counteracting inflammation.
Future Plans
We now plan to test the efficacy of tASOs treatment on rejuvenating the immune system of aged wild type mice, which represents a physiological setting for aging.
Goals
The final goal will be to assess if tASOs impact vaccine response in both models:
- Young Terc-/- mice
- Aged WT mice
In summary, we plan to determine the efficacy of tASOs to improve immune responses, including vaccines, in the elderly.
Financiële details & Tijdlijn
Financiële details
| Subsidiebedrag | € 150.000 |
| Totale projectbegroting | € 150.000 |
Tijdlijn
| Startdatum | 1-9-2023 |
| Einddatum | 28-2-2025 |
| Subsidiejaar | 2023 |
Partners & Locaties
Projectpartners
- IFOM-ISTITUTO FONDAZIONE DI ONCOLOGIA MOLECOLARE ETSpenvoerder
Land(en)
Vergelijkbare projecten binnen European Research Council
| Project | Regeling | Bedrag | Jaar | Actie |
|---|---|---|---|---|
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Elucidating and targeting the mechanisms encoded in the genome of long-lived individuals to improve healthy ageingThis project aims to identify and validate rare genetic variants linked to longevity using CRISPR/Cas9 and high-throughput screening to promote healthy aging and extend lifespan. | ERC Starting... | € 1.500.000 | 2022 | Details |
Letting up senescence and inflammaging through T cells
LetTBe aims to investigate T cell metabolism and its role in aging to develop strategies that prevent immunosenescence and promote healthy aging.
In vivo metabolic determinants of T cell aging trajectories
This project aims to uncover how aging microenvironments affect T cell immunity and explore methods to rejuvenate T cells to combat age-related diseases.
Harnessing senescence to improve cell-based therapies against cancer
This project aims to enhance cancer therapy by combining senescence induction with CAR T and NK cell strategies to improve treatment outcomes and understand immune interactions in tumors.
Late life-applicable enhancement of longevity and fitness.
This project aims to identify molecular solutions to restore adaptive stress responses and promote healthy aging in late life using multi-omics and functional tests across various model organisms.
Elucidating and targeting the mechanisms encoded in the genome of long-lived individuals to improve healthy ageing
This project aims to identify and validate rare genetic variants linked to longevity using CRISPR/Cas9 and high-throughput screening to promote healthy aging and extend lifespan.