Epigenetics in ageing and development

The idea that a universal epigenetic program, which is reset during embryogenesis and influenced by diet and other environmental factors, can drive not only development but also ageing is gaining recognition, and embodies the idea that this is a major target for the future development of therapeutic strategies to improve health and longevity. Indeed, multiple and progressive epigenetic changes have emerged as key hallmarks of ageing. These changes include patterns of DNA methylation and histone posttranslational modifications, altered noncoding RNA expression, replacement of canonical histones with histone variants and reduced bulk levels of the core histones (Pal and Tyler, 2016). While part of these changes act like an epigenetic clock and are tightly related to chronological age (Horvath, 2013), others diverge (age-dependently) from chronological age likely reflecting the increasing inter-individual variation in health of old organisms (Slieker and van Iterson, 2016). Reasons for these variations, are not well understood, but they seem to occur in all tissues and cells regardless of their developmental potential. The impact of epigenetic changes in reflected by altered gene expression, reactivation of endogenous retroelements and genomic instability that can have systemic effects on ageing from cellular to the organismal level. In this special issue of Mechanisms of Ageing and Development, the hot topics around the role of epigenetic changes in ageing and development are covered by critical reviews or original research manuscripts provided by major experts in the field. While DNA methylation is currently the most promising biomarker of ageing, the mechanisms underlying age-related DNA methylation changes remain mostly undiscovered. A focused review shows how the dynamics of chromatin structure and histone posttranslational modifications are related to variations of methylcytosine and its oxidative modifications (Ciccarone and Tagliatesta, 2017). How epigenetic clock signature could be used as a lifestyle management tool to monitor healthy ageing, as well as to evaluate the effects of interventions against chronic ageing disorders and to extend healthy lifespan is the focus of another manuscript of this special issue (Declerck and Vanden Berghe, 2018). CpG DNA methylation is among the epigenetic control mechanisms used by the cell to counteract the risk of genomic instability represented by endogenous retroelements. Indeed, these repetitive elements carry most of the methylated CpG sites of our genome. A dedicated manuscript (Cardelli, 2018) describes how epigenetic changes and endogenous retroelements are tightly related and discuss the relevance of their interaction in ageing research. How nutrition affects global DNA methylation and how these changes can be transmitted to successive generation (epigenetic inheritance) is a highly discussed topic in ageing research. An original research manuscript (Guarasci and D’Aquila, 2018) provide here evidence that a low-calorie diet in rats affect the offspring’s epigenetic status, in particular when administered during the maternal pre-gestational period. Fetal epigenetics has a key impact on telomere lengths and telomere loss dynamics, and both can control health and lifespan. A review describes how different nutrients and oxygen supplied to the fetus can impact the length and dynamicity of telomeres, highlighting the way in which early environmental factors can have long term effects on healthy and unhealthy ageing (Ravlić and Škrobot Vidaček, 2017). An interesting manuscript explains ferrosenescence; how iron can promote neurodegeneration and ageing. Early biomarkers in iron dyshomeostasis has been identified, and new strategies to control iron levels suggested. To this aim the microRNA-29 family might lower neuronal iron and could represent a new strategy in the control of ferrosenenscene (Sfera and Bullock, 2017). Another two review manuscripts describe how nutrition and physical exercise can be included among those interventions able to modulate epigenetic changes with a potential benefit in cardiovascular health (Wallace and Twomey, 2017) and in particular neurodegenerative diseases (e.g. Alzhiemer) (Robinson and Grabowski, 2017). Studies on centenarians highlight how genetic and epigenetic modulation go hand in hand for a successful ageing. However, the epigenetic responses to the environment in centenarians seems more plastic and powerful then in people that have a less longer life (Puca and Spinelli, 2017). Two reviews focus on age-related diseases; one describes the differences in monozygotic twin pairs underlining the role of epigenetics in amyotrophic lateral sclerosis. The authors summarize some studies that show increased DNA methylation and progressive ageing in some twins affected by amyotrophic lateral sclerosis compared to age-matched controls. Furthermore, similarities in epigenetic biomarkers have been suggested between amyotrophic lateral sclerosis and Alzheimer’s disease (Dolinar and Ravnik-Glavač, 2018). Another review highlights how RYBP nuclear protein, controlling the polycomb group and trithorax group proteins, can influence chromatin condensation in response to stress and growth-related signals. During embryogenesis RYBP modulates the neural tube, neocortex and retinal development, as well as cardiomyocytes differentiation. RYBP has been described capable of influencing normal and pathological development through microRNA regulation and protein ubiquitylation. Interesting are also the evidences supporting the non-epigenetic control of apoptotic activity in mammalian cancer cells (Simoes da Silv and Simón, 2018). A complex scenario can be described, and early epigenetics plasticity together with environmental epigenetic control throughout life can affect significantly the progression toward a healthy or unhealthy ageing. A graphical scheme resuming the hot topics around epigenetics covered by this special issue is provided in Fig. 1.