Adrenergic regulation of immunosenescence and cognitive decline across the life course

Heightened sympathetic nervous system (SNS) activity and raised systemic adrenaline and noradrenaline levels (A/NA) are found in many age-related morbidities including cognitive decline, cardiovascular disease and metabolic disorders.

SNS activity, chronic stress and adrenergic signalling are known to increase systemic inflammation and suppress activation-induced immune functions in human primary cells in vitro and in animal in vivo models.

Loss of antigen-specific immune responses and increased inflammation are the two hallmarks of the aged immune system, also called immunosenescence.

We have shown that β-adrenergic stimulation can induce senescence signalling, ROS expression and DNA damage in vitro, demonstrating that adrenergic signalling can induce senescence features within T cells.

Understanding the relationship between adrenergic-induced immune senescence and reduced cognitive function and increased inflammatory and metabolic diseases will help us to design interventions to improve healthy lifespan.

The primary aim of this proposal is to determine whether the negative regulation of immunity by SNS activity and adrenergic signalling is due to adrenergic-driven immunosenescence in humans.

The primary objectives of the project are: • To determine whether heightened systemic A/NA levels are associated with an aged-immune phenotype e.g. reduced numbers of naïve cells, T cell differentiation and increased expression of senescence markers • To determine whether heightened systemic A/NA levels are associated with reduced immune response to challenge and/ or increased systemic inflammation • To investigate whether the adverse effect of heightened adrenergic regulation of immunity is enhanced by ageing.

A secondary objective is to: • Assess the correlation between systemic A/NA levels, immunosenescence and impaired cognitive function Methodology A human in vivo cross-sectional study design in healthy adults with either low or high systemic adrenaline and noradrenaline (A/NA) will be used to determine adrenergic associated differences in immunosenescence as determined by cell differentiation and senescence phenotype, the functional response to activation, the level of systemic inflammation, and cognitive function.

To assess the interaction between age and adrenergic regulation of immunosenescence and cognitive function, results in young (<​35-years old) and old (>65-years old) low and high A/NA individuals will be compared. Latest technologies in immune profiling will be used to characterise the immune response.

First, advanced flow cytometry using full fluorescent spectrum technology (Cytek Aurora) will be used for high dimensional immune phenotyping to determine 1) participant Imm-AGE score, which is a clinically relevant measure of immune aging and a predictor of all-cause mortality, and expression of classical senescence markers (e.g.

CD57, KLRG1) and signalling molecules (e.g. p16 and p38) and 2) cellular functional responses ex-vivo including pro- and anti-inflammatory markers and accessory molecule expression. Second, the systemic inflammatory profile will be determined by the IsoPlexis multiplex Secretome platform. A/NA will be determined by ELISA.

An unbiased assessment of cognitive function will be made using a test battery to identify interactions between cognitive functions, immunosenescence and systemic adrenergic activity.

The cognitive test battery will include a range of tests to probe different domains including memory, processing speed, attention, and reaction time.

A strict inclusion and exclusion criteria will be utilised to exclude participants with underlying health issues that may impact adrenergic activity or immune function.

Deliverable impact This work will determine if high SNS activity and raised adrenergic levels associate with immunosenescence in vivo, and how this links to loss of immune function, systemic inflammation and cognitive decline in ageing.

This data will advance our understanding of the important role played by psycho-neuro-immunological interactions and how they manifest across the life course and is critical to demonstrate the need for clinical trials assessing: 1) the immunological benefits of stress reduction or sympathetic nervous system inhibition interventions on immunological health, cognitive function and ageing; and 2) whether inhibiting adrenergic signalling using beta-blockers in older adults may improve antigen-specific immune responses, for example to vaccination.

The immediate impact of this work will be the training of one postdoc, two MSci and at least five BSc students in immunological and ageing research.

Importantly, it will support the development of an early career PI and research fellow, the lead investigators on this proposal, by strengthening their research esteem, and supporting the development of innovative, original, multi-disciplinary ageing research.