Targeting telomeric DNA damage response as a new strategy to fight immunosenescence and improve vaccine response

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:

1. Immune system reactivity reduction
2. Decreased long-term renewal of hematopoietic stem cells and lymphocyte numbers
3. 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.