Commentary: Life course epidemiology embraces geroscience

In this issue of the Journal, Yoav Ben Shlomo, Rachel Cooper and Diana Kuh present a comprehensive and state-of-the-art review of life course epidemiology; they describe their own unique scientific contributions and offer a much needed update on conceptual and methodological advancements that have occurred in this field over the past few years.1 Of relevance for this commentary, Ben Shlomo et al. observe that the focus of life course epidemiology has broadened from simply identifying early life predictors of disease development to depicting physiological and functional trajectories over the entire lifespan and seeking explanatory models for heterogeneous pathways. A corollary to this expanded focus is the need to distinguish between chronological and biological ageing, which represents a radical departure from traditional epidemiology and opens a window of opportunity to the study of ageing as a dynamic process that, perhaps, one day may be modulated through specific interventions.2 Right from the first day of training, epidemiologists learn that ageing is a powerful risk factor for chronic disease, disability and mortality. The effect of ageing on health is so strong that the only possible way of dealing with it … is by ignoring it or, more precisely, by dissecting it out from the analyses. ‘Adjusting for age and sex’ remains a mantram today, a sine qua non of any study that aims to connect specific risk factors to a disease outcome and pass the peer review process. There are, of course, good reasons for this approach. Up to very recently, the mechanisms of ageing completely escaped our understanding and there was little hope that the ageing process and its phenotypic consequences could be modified. However, something has changed in recent years. We have witnessed extraordinary progress in ageing research that challenges some of the most rooted assumptions.3 In particular, research in several laboratory species points to specific biological mechanisms that drive many of the phenotypic manifestations of ageing.4 In other words, the idea of slowing down ageing is no longer considered the delirium of creative novelists, such as Dorian Grey for Oscar Wilde, but rather a hypothesis that could be scientifically tested.5 Research has shown that the longevity of yeast, worms and even small mammals can be extended through genetic manipulation, dietary restriction or pharmacological intervention.6–9 Recently, López-Otín and colleagues conducted an extensive review of this literature and outlined the major mechanisms hypothesized to drive ageing and likely to be the targets of these intervention. These mechanisms include genomic instability, telomere(definition) attrition, epigenetic alterations, loss of proteostasis(definition), deregulated nutrient sensing, mitochondrial dysfunction(definition), cellular senescence(definition), stem cell exhaustion and altered intercellular communication.10 Methodologies are available or in advanced stages of development that permit evaluation of some of these mechanisms in humans. Telomere length, epigenetic DNA methylation changes, mitochondrial function and inflammation already have been assessed in large epidemiological studies11–14 and genomic instability and DNA damage repair capacity can be effectively assessed in blood mononuclear cells using high-throughput sequencing.15,16 Although detection of senescent cells in humans is still problematic, P164ink, a specific biomarker of senescence, can be easily measured in circulating lymphocytes and has been found to be associated with ageing and negative health outcomes.17 Chaperone and other proteins involved in proteostasis can be assessed by liquid chromatography/mass spectrometry (LC-MS), but whether their quantification has biological and clinical meaning is still under investigation.18 Problems with many of these assays remain: they are expensive, time consuming, mostly limited to blood cells and have unknown sensitivity to changes over time and with environmental stresses. History tells us that changes in technology will help overcome these limitations, for example by substantially reducing the cost of sequencing, extensive use of robotics and developing micro-methods that can assess multiple biomarkers from small quantities of biological material. Introducing these assays in epidemiological studies should facilitate testing the hypothesis that change in biomarkers of ageing track the basic ageing phenotypes, such as muscle strength decline or loss of aerobic fitness, above and beyond chronological ageing, and may also help stimulate new hypotheses about the biological nature of ageing in humans and its relationship with disease and the ageing phenotype. Understanding the mechanisms underpinning the ageing process opens the door to research aimed at modulating this process and preventing its phenotypic manifestations. Theoretically, slowing down ageing would reduce age-specific incidence and prevalence of major chronic diseases and delay age-associated cognitive and physical decline and perhaps even push the debilitating consequences much closer to the end of life. Thus, slowing the rate of ageing could substantially improve the health of the global population and reduce health care needs.19 There is still a long journey before we can translate basic research findings to clinical applications. To reconcile research findings on basic biological mechanisms of ageing with what we are learning from epidemiological studies will require the development of new methodology tailored to this new purpose. In this regard, integrating geroscience in the design of life course epidemiological studies offers a particularly promising perspective. Indeed, geroscience aims at understanding the molecular and cellular mechanisms through which ageing becomes the major risk factor for chronic disease. Most of what we know about human ageing comes from either cross-sectional studies that compare individuals of different ages or from longitudinal studies that assess multiple p