Epigenetic regulation of ageing: linking environmental inputs to genomic stability

Abstract

Ageing is affected by both genetic and non-genetic factors. Here, we review the chromatin-based epigenetic changes that occur during ageing, the role of chromatin modifiers in modulating lifespan and the importance of epigenetic signatures as biomarkers of ageing. We also discuss how epigenome remodelling by environmental stimuli affects several aspects of transcription and genomic stability, with important consequences for longevity, and outline epigenetic differences between the 'mortal soma' and the 'immortal germ line'. Finally, we discuss the inheritance of characteristics of ageing and potential chromatin-based strategies to delay or reverse hallmarks of ageing or age-related diseases.

Figure 1. Environmental inputs that impact longevity can also affect the chromatin landscape

Environmental signals that modulate lifespan might do so by modulating chromatin. Dietary restriction increases lifespan in a range of organisms, and DR has also been linked to changes in the chromatin landscape. Those include changes in the expression of chromatin modifiers, for example increased expression of several sirtuins, or an increased maintenance of heterochromatin. Robust circadian light cycles also promote health and lifespan and are linked to circadian epigenomic changes (for example, periodic increases in H3K14 acetylation of circadian promoters by the CLOCK protein) and the modulation of the activity of chromatin modifiers such as SIRT1. Physical activity is also beneficial to health and lifespan, and has been associated with changes in chromatin modifications (for example, increased H3K36ac in human skeletal muscle) and with the regulation of chromatin modifiers (for example, induced nuclear exclusion of HDAC4 and HDAC5 in human skeletal muscle). Recent work has shown that, in C. elegans, pheromones may increase lifespan, through a mechanism requiring chromatin-modifying enzymes (for example, SIR-2.1 is required for lifespan extension following exposure to ascarosides #2 or #3). Finally, in women, the strong decrease in production of sex steroid hormones with age, such as estrogens, contributes to age-related diseases, and estrogens can directly remodel chromatin at target genes through their receptor. Whether there is a linear pathway from the environmental output to the changes in chromatin and, ultimately, to lifespan extension, remains untested.

Figure 2. Model for the possible cross-talk between chromatin changes and transcriptional and genomic instability during ageing

A possible model is the following: in cells from young organisms (top left), transcriptional programs are robustly defined and precise between cells (depicted by consistent mRNA levels). The genomic integrity is maintained (depicted by intact chromosomes), because mutations are rare or correctly repaired. As a result, ‘normal’ chromatin states are found throughout the genome. With increased age (bottom left), transcriptional instability is increased between cells of a tissue (depicted by variable mRNA levels between cells). Genomic instability is also a hallmark of ageing and is increased at both a macro level (for example, aneuploidies depicted by partial chromosome duplication), increased transposable element insertions and, more locally by DNA mutations in the form of single nucleotide mutations, small insertions or deletions (indels). DNA damage can trigger the recruitment of chromatin modifiers, and the acquisition of abnormal chromatin states. Thus, genomic instability could modify the epigenetic landscape of old cells. Reciprocally, aberrant changes in epigenetic marks, known as ‘epimutations’, can further promote the accumulation of DNA mutations in a feedback loop mechanism. The epigenetic changes acquired during ageing could also decrease the transcriptional precision of neighboring genes.