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

The immune system is remodeled with age, going through a series of changes known as “immunosenescence’, including the involution of primary lymphoid organs, the contraction of the immune repertoire, a progressive lineage skewing towards the myeloid lineage and 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. 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, thus fueling DDR and causing cellular senescence initiation and maintenance.

Sequence-specific telomeric antisense oligonucleotides (tASOs) target these tncRNAs and effectively inhibit DDR activation, ameliorating age-related phenotypes in mouse models.

The telomerase-deficient (Terc-/-) mouse model, causes telomere shortening and dysfunction, recapitulating features of immunosenescence: immune system reactivity reduction, decreased long term renewal of hematopoietic stem cells and lymphocytes numbers, increased neutrophil count. tASOs treatment has beneficial long-term effect in this model, by decreasing immunosenescence and counteracting inflammation.

We now plan to test the efficacy of tASOs treatment on ‘rejuvenating’ the immune system of aged wild type mice, a ‘physiological’ setting for aging.

The final goal will be to assess if tASOs impact on vaccine response in both models: young Terc-/- mice and aged WT mice. In summary, we plan to determine the efficacy of tASOs to improve immune responses, including vaccines, in the elderly.