Genetics and genomics of human ageing

Heather E. Wheeler¹ and Stuart K. Kim^1,^2,^*

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Abstract

Ageing in humans is typified by the decline of physiological functions in various organs and tissues leading to an increased probability of death. Some individuals delay, escape or survive much of this age-related decline and live past age 100. Studies comparing centenarians to average-aged individuals have found polymorphisms in genes that are associated with long life, including APOE and FOXOA3, which have been replicated many times. However, the associations found in humans account for small percentages of the variance in lifespan and many other gene associations have not been replicated in additional populations. Therefore, ageing is probably a highly polygenic trait. In humans, it is important to also consider differences in age-related decline that occur within and among tissues. Longitudinal data of age-related traits can be used in association studies to test for polymorphisms that predict how an individual will change over time. Transcriptional and genetic association studies of different tissues have revealed common and unique pathways involved in human ageing. Genomic convergence is a method that combines multiple types of functional genomic information such as transcriptional profiling, expression quantitative trait mapping and gene association. The genomic convergence approach has been used to implicate the gene MMP20 in human kidney ageing. New human genetics technologies are continually in development and may lead to additional breakthroughs in human ageing in the near future.

Keywords: human ageing, centenarians, tissue ageing, longitudinal studies, genomic convergence

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1. Introduction

Ageing is characterized by a decline of multiple physiological functions leading to an increasing probability of death. Some ageing-related changes affect appearance, such as wrinkled skin and grey hair, whereas others affect organ function, such as decreased kidney filtration rate and decreased muscular strength. Ageing is a major risk factor in most human diseases, including heart disease and cancer. Average lifespan has increased at a steady pace of almost three months per year in both males and females since 1840 []. Japanese women have a life expectancy of 85 years, the highest in the developed world []. Initially, this increase in lifespan was probably attributed to decreases in juvenile mortality through treatment of infectious diseases []. In the latter half of the twentieth century, improvements in survival after age 65, due in part to improved treatments for ageing-related diseases, propelled the rise in lifespan []. For Japanese women, the chance of surviving from age 65 to 100 soared from less than 1 in 1000 in 1950 to 1 in 20 in 2002 []. Centenarians now constitute the fastest-growing segment of the US population, increasing in number from 3700 in 1940 to roughly 61 000 in 2006 [3]. Finding differences in genes between centenarians and average-aged individuals may point to molecular pathways important in the ageing process.