Accelerating novel treatments for ageing and age-related disease: Gaining biological insights and biomarkers in healthy, multimorbid, and frail elders

Active: 2020.03.01 - 2021.09.30
UK SPINE Scientific Liaison: Monica Spisar

Clinical expression of poor health in older age presents as multimorbidity (accumulation of diseases) and/or frailty (a phenotype of adverse ageing). Multimorbidity occurs with clustering of specific diseases, suggesting common mechanisms driving cluster-specific pathology. Data suggests the main clusters are 1) cardiovascular and metabolic diseases, 2) psychiatric and neurological diseases, and 3) musculoskeletal diseases.

Using a well characterised cohort of older people, this work will elucidate the role of fundamental drivers of ageing in relation to disease clusters via comparative analysis of samples from two subgroups: those expressing 'unsuccessful’ ageing vs those expressing ‘healthy’ ageing.

Samples will be evaluated for pro- and anti-inflammatory cytokines by multiplex technology; systemic markers of senescent cell load (senescent cell derived exosomes) by NanoView cytometer; telomere length and DNA damage markers (nuclear and mitochondrial) in peripheral blood mononuclear cells (PBMCs) by qPCR.

Cross-sectional frailty and multimorbidity clusters in the cohort data will be identified by correlating cytokine, DNA damage, and cell senescence measures with clinical characterisations via network analysis and association rules. Categorical classifications will be defined using the phenotype model of frailty (non-frail, pre-frail, and frail). Latent class analysis will be used to compare disease clusters and risk factors for multimorbidity and frailty. Further multivariate discriminating techniques will include partial least-squares discriminant analysis (PLS-DA) and principal component discriminant analysis.

Samples indicative of the main multimorbidity clusters, frailty, and healthy older people will be selected to test the associations of mechanisms of ageing cross-sectionally and over a one year trajectory.

Outcomes of this research will support design of clinical trials and development of novel therapeutics targeting frailty and age-associated multimorbidity. The researchers further aim to establish a wider consortium to validate findings in other datasets (Newcastle 85+, UK biobank) and investigate trajectories of biological and clinical markers of frailty.

Note: The cohort (CARE75+) is an experimental frailty research cohort designed using Trial within Cohorts (TwiCs) methodology, to align applied epidemiological research with clinical trial evaluation of interventions to improve the health and well-being of older people living with frailty. The existing biological phenotyping repertoire of the CARE75+ cohort includes banked samples of PBMCs, plasma and serum; in this work, a sub-cohort would be developed to include immune cell functional assays and tissue biopsy to measure the broader mechanisms of ageing (autophagy, senescence, epigenetic changes).