Abstract
In animal models, single-gene mutations in genes involved in insulin/IGF and target of rapamycin signalling pathways extend lifespan to a considerable extent. The genetic, genomic and epigenetic influences on human longevity are expected to be much more complex. Strikingly however, beneficial metabolic and cellular features of long-lived families resemble those in animals for whom the lifespan is extended by applying genetic manipulation and, especially, dietary restriction. Candidate gene studies in humans support the notion that human orthologues from longevity genes identified in lower species do contribute to longevity but that the influence of the genetic variants involved is small. Here we discuss how an integration of novel study designs, labour-intensive biobanking, deep phenotyping and genomic research may provide insights into the mechanisms that drive human longevity and healthy ageing, beyond the associations usually provided by molecular and genetic epidemiology. Although prospective studies of humans from the cradle to the grave have never been performed, it is feasible to extract life histories from different cohorts jointly covering the molecular changes that occur with age from early development all the way up to the age at death. By the integration of research in different study cohorts, and with research in animal models, biological research into human longevity is thus making considerable progress.
Highlights
Genomic studies into human longevity are inspired by the fact that, in animal models, healthy lifespan has proved to be remarkably plastic, and major pathways of lifespan regulation have been identified
This observation is in contrast with a previous Ashkenazi Jewish Centenarian Study from which it was concluded that owing to reduced IGF-1R signalling, IGF-1 levels were increased in female offspring of centenarians with a concomitant lower height [20], potentially explained by rare genetic variants in the IGF-1R gene
We investigated in nonagenarians from the family-based Leiden Longevity Study and octogenarians from the population-based Leiden 85 plus Study the frequency of a set of alleles currently known to increase the risk of coronary artery disease, cancer and type-2 diabetes as identified by genome-wide association studies (GWASs)
Summary
Genomic studies into human longevity are inspired by the fact that, in animal models, healthy lifespan has proved to be remarkably plastic, and major pathways of lifespan regulation have been identified. 2. DESIGNS TO STUDY PARAMETERS OF HEALTHY AGEING, MORBIDITY, MORTALITY AND LONGEVITY Human cohorts may vary considerably in their morbidity, mortality and longevity characteristics and yet they have shown a common increase in mean life expectancy in the past two centuries [5]. DESIGNS TO STUDY PARAMETERS OF HEALTHY AGEING, MORBIDITY, MORTALITY AND LONGEVITY Human cohorts may vary considerably in their morbidity, mortality and longevity characteristics and yet they have shown a common increase in mean life expectancy in the past two centuries [5] This is mainly due to improved hygiene, nutrition and healthcare. The study design (figure 1) shows that, in crosssectional studies, phenotypes can be compared between familial nonagenarians and sporadic elderly from the population (such as from the Leiden 85 plus Study) to distinguish familial longevity markers from parameters marking all long-lived individuals. In addition to more classical parameters, e.g. parameters of glucose and lipid metabolism, the ongoing phenotyping includes lifestyle questionnaires, photographs, imaging (magnetic resonance imaging of the brain, X-ray of joints), metabonomics (NMR- and massspec-based) and proteomics
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