Ageing. Mother nature’s curse, but a plastic surgeon’s blessing.
All humans age. But how we age and most importantly how fast we age, differs considerably. For example, Werner syndrome is an extreme example of accelerated ageing. The deviation in apparent age and chronological age is typically known as ‘biological age’. Until recently, robust tools to study biological age have been limited. ‘Epigenetic clocks’ are beginning to change this.
In this blog, we explore what epigenetic clocks are and their current and potential future applications in human health and disease.
What are epigenetic clocks?
The epigenome is emerging as a fundamental component of biological age. Epigenetic processes, including DNA methylation, chromatin modifications and noncoding RNAs are well-known to impact early development and cellular memory. Researchers have also recently shown that the epigenome not only changes as we age but often does so in a highly predictable manner. These predictable age-associated changes within the epigenome have now been utilised to design a set of tools to study ageing across the lifespan. These tools are known as ‘epigenetic clocks’.
These clocks, typically based on DNA methylation, were initially designed to predict chronological age and have since proven accurate. On the other hand, they also are able to capture fundamental molecular processes linked to biological age that are still not well understood. They outperform other measures, including chronological age, in predicting a range of age-related health outcomes. This includes cancer and menopause, as well as all-cause mortality. Now, newer epigenetic clocks are being explicitly trained on other age-related biological and health measures such as leukocyte telomere length.
Most well-known epigenetic clocks are constructed using supervised machine learning methods. This kind of clock construction entails a training and testing stage. One of the most well-studied clocks was designed by Steve Horvath, human geneticist and biostatistician at UCLA. Horvath trained his clock using data from many different tissues. Therefore, his clock showed remarkable accuracy across a range of contexts and tissue types. Other clocks have been derived using the strongest correlations between DNA methylation and chronological age from epigenome-wide association studies (EWAS). Such clocks can be more economical and also do not require technical bioinformatic skills to use. However, it is not known whether these clocks exhibit the same accuracy and robustness across contexts as clocks using a larger number of CpG sites.
There are several established applications of epigenetic clocks for research in human biology and aligned fields.
Predicting chronological age
Epigenetic clocks trained on chronological age have proven to be the most accurate marker of chronological age. This is highly desirable for forensics or for estimating chronological age within isolated populations. Additionally, the discrepancy between an individual’s actual and predicted chronological age (‘error’ in the clock) can capture a range of normal and pathological variations in biological ageing and development.
Predicting morbidity and mortality
Researchers are often concerned about the long-term health of their study population. Epigenetic clocks can be used to predict morbidity and mortality in advance of the study’s clinical endpoints. For example, both Horvath and Hannum clocks can predict all-cause mortality and accurately predict leading causes of morbidity and mortality.
Predicting growth, development and maturation
Epigenetic clocks can also track early growth, development and maturity, making them useful to researchers interested in life history trade-offs. For example, Horvath’s clock begins ‘ticking’ just weeks after conception, with the onset of cellular differentiation. Researchers have developed several clocks that capture gestational and paediatric epigenetic age, to more precisely model epigenetic changes during childhood. The next step is to link early exposures that affect epigenetic clocks during childhood with health and functional decline during adulthood.
Surrogates for other biomarkers
Epigenetic clocks can be trained on any feature that is accompanied by predictable changes in DNA methylation. This includes using DNA methylation as a surrogate predictor for age-related changes. For example, researchers have developed an epigenetic clock for leukocyte telomere length. Leukocyte telomere length is a measure for genome stability and cellular senescence and a biomarker for a range of health and age-related risk factors. The clock was able to predict time-to-death and time-to-coronary heart disease. While the causal relationships between clinical biomarkers and their DNA methylation surrogate clocks remain to be elucidated, these clocks may provide exciting opportunities for human biologists.
Epigenetic clocks are showing promise in certain applications that are of particular relevance to human biologists.
Studying impact of nutrition and lifestyle
Individual trajectories in epigenetic ageing appear to take place quite early. These variations in the ‘ticking’ of the clock are likely set prenatally by genetic variation. Epigenetic clocks appear to demonstrate flexibility, showing sensitivity to nutritional, behavioural, ecological and social factors that affect the ageing process. For example, findings have shown that consumption of fish, fruit and vegetables are associated with lower AgeAccelGrim (predicts hypertension, type II diabetes, poorer physical functioning, time-to-cancer and time-to-coronary heart disease). Smoking status also predicts more rapid AgeAccel (epigenetic age acceleration) for mortality-trained clocks, whereas exercise predicts slower AgeAccel for these measures.
Studying reproductive investment
Breastfeeding and pregnancy result in massive alterations in metabolism, immune function and hormone levels. Investment in reproduction leads to trade-offs with somatic maintenance which manifests as accelerated biological age. Evidence supporting the relationship between these costs of reproduction and epigenetic clocks is accumulating. However, there is little known about epigenetic clocks and men’s reproductive health and investment. Therefore, further work examining the relationship between testosterone and epigenetic clocks is warranted.
Studying psychological stress and resilience
Chronic stress is thought to accelerate biological age. Hannum, PhenoAge and GrimAge clocks are accelerated among individuals with lower household income and education levels. These effects may be partly due to diet and lifestyle, but trauma and stress may also mediate these effects. Furthermore, other studies have also found that apparent resilience to stress may actually come at a cost of accelerated epigenetic age.
Studying environmental and ecological variation
Epigenetic ageing rate for several clocks varies across socio-ecological contexts. Clocks that display divergent age-related trends depending on the context, can provide insight into how environmental and ecological variations affect the ageing process. For example, the Horvath Intrinsic Epigenetic AgeAccel clock was slower for African forest-dwelling hunter-gatherers, but not urban-dwelling. Importantly, more work needs to be done to establish the impact of early life infectious environments on the trajectory of epigenetic ageing.
Epigenetic clocks are ground-breaking tools. They are changing how researchers study human development, ageing and health. Additionally, they are providing key insights into fundamental molecular processes underpinning health and ageing. The pace of ageing and how it plays out is complex. It is an interaction between evolutionary, social and cultural forces.
There are several important diseases associated with accelerated ageing, including Alzheimer’s and Huntington’s disease, where epigenetic clocks can provide key insight. For example, researchers recently developed an epigenetic clock to help study brain ageing and development. The team hope this clock will provide insight into how accelerated ageing in the brain could be associated with brain disorders such as Alzheimer’s. The development and refinement of these clocks will increase their accuracy and continue to help explore important biological questions.
Image credit: By drobotdean – www.freepik.com