Genetic and molecular determinants of human ageing and longevity
Twin studies show that genetic factors contribute to the variation in human life span by approximately 25%, an effect which is minimal before age 60 years and most profound from age 85 years. The number of candidate genes of relevance to ageing and longevity has increased markedly over the past few years; they encode proteins involved in a variety of biological processes including insulin signalling, oxidative stress and DNA repair, underlining that ageing is a complex and multifactorial trait. In order to obtain a better understanding of ageing and longevity, the oldest old are a useful as study populations. Investigation of the variation in gene sequences of these individuals and molecular biological studies of the biological consequence of the gene variations can, hence, be expected to elucidate the role of genetic variation in ageing and longevity.
Subproject 1: To identify genetic variations of importance for ageing (the cognitive and physical capacity of the elderly and the presence of age-related diseases) and to identify genetic variations of importance for longevity.
Subproject 2: Via molecular and biochemical studies to investigate the biological consequence of selected genetic variations.
Subproject 1: The identification of genetic variations of importance for ageing and longevity will be conducted both via a longitudinal and via a cross sectional study. For the former register data and DNA from the Danish 1905 cohort (1650 individuals), which are all Danes born in 1905 and being alive in 1998, will be used. In the cross sectional study 800 younger (age 65-80 years) control individuals, selected from the Study of middle aged Danish twins, will be included.
The candidate genes will primarily be genes involved in insulin signalling, DNA repair and oxidative stress, since these biological processes are believed to have great importance for ageing and longevity. The genes will be based on literature searches: i.e. genes previously identified as being associated with ageing, age-related diseases (e.g. dementia, Alzheimer’s disease, diabetes type II, cancer or myocardial infarction), and/or longevity and genes identified via premature ageing syndromes, functional studies or animal studies. Single nucleotide polymorphisms in every gene will be chosen based on the genetic variation in Caucasians (identified via the international HapMap project).
Subproject 2: In order to investigate the biological consequence of some of the genetic variations, a number of molecular biological and biochemical studies will be conducted. It will be investigations of the gene expression levels in individuals of different genotype (via RT-PCR) or investigations of variations in the coding regions of the genes. For the latter the enzyme activity of the encoded proteins will be investigated via blood extracts or via the generation of recombinant proteins.