Advancing age is a major risk factor for chronic diseases such as cancer, cardiovascular disease, and neurodegeneration and, since the mean life expectancy is still increasing, we face massive challenges from the social and economic costs of diseases associated with ageing. Therefore, we should focus on approaches aimed at identification of mechanisms that compress morbidity and thereby contribute to healthy ageing.
Genetics of healthy ageing and extended lifespan
One such approach is identification of the genetic mechanisms underlying healthy ageing and extended lifespan in humans. Thus far, the majority of the genetic research into extended lifespan in humans has been focused on common genetic variants (minor allele frequency >1%) that are detectable using genome-wide association studies (GWAS). However, we, and others, have had limited success in identifying genetic variants associated with this trait using GWAS (PMID: 21418511; PMID: 24688116), even when combining most of the available genetic datasets on longevity worldwide (PMID: 31413261). The only genetic locus to show robust, genome-wide significance across many population studies is apolipoprotein E (APOE), where the ApoE ε4 variant is associated with early mortality and the ApoE ε2 variant with survival to late age. To further increase the power of our GWAS, we combined large GWAS using different age-related phenotypes (i.e. healthspan, parental lifespan and extended lifespan) and identified several novel loci associated with healthy ageing (PMID: 32678081). These loci will now be taken forward to functional studies.
One of the main aims of our research group is to study the effect of rare protein-altering genetic variants, identified using whole-genome sequencing data of long-lived individuals. To this end, we make use of the CRISPR/Cas9 system to generate transgenic cell lines and animals harbouring the identified variants. We subsequently measure the in vitro (haploid mouse embryonic stem cells) and in vivo (mice and fruit flies) effects of the genetic variants on the functioning of the genes.
Biomarkers of healthy ageing
Another approach to identify mechanisms that contribute to healthy ageing is by studying biomarkers. To this end, we have previously looked at different serum parameters and identified glucose, insulin, triglycerides and telomere length as potential biomarkers of healthy ageing (PMID: 24425829; PMID: 27374409). In our most recent study, we studied the association between metabolomics and prospective survival and identified a set of 14 metabolic biomarkers that are predictive of future mortality (PMID: 31431621). However, the utility of these, and most other, identified biomarkers of healthy ageing in clinical settings still has to be determined.
Another main aim of our research group is therefore to establish novel human ageing studies in Cologne to determine the efficacy of previously identified biomarkers of healthy ageing, including the ones originating from studies in model organisms, in clinical studies.