Key Points
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Widespread epigenomic remodelling, at the level of DNA or histone protein modification, has been observed during ageing across species and cell types. Some epigenetic states can function as 'molecular clocks'.
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The experimental perturbation of chromatin modifiers can influence the lifespan of model organisms.
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Environmental inputs, such as diet, physical activity, hormones or pheromones, have been linked to remodelling of the epigenome as well as to changes in lifespan. Chromatin may thus act as a molecular integrator of environmental exposures.
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Random epigenetic changes, or epimutations, throughout life may trigger increases in transcriptional and genomic instability.
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The unique regulation of chromatin in germline cells might protect these cells more than somatic cells during ageing.
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Some ageing or age-related phenotypes, such as lifespan, fertility and stress resistance, may be inherited through successive generations in model organisms, through non-genetic mechanisms.
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The use of epigenetic drugs or epigenome-editing technologies may be a promising avenue for age-related therapeutics.
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.
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Acknowledgements
The authors apologize to those whose work could not be cited owing to space constraints. B.A.B., E.A.P and A.B. wrote the review together. The authors thank Aaron Daugherty, Elizabeth Schroder and Kévin Contrepois, as well as the anonymous reviewers, for helpful comments on the manuscript. B.A.B. is supported by K99 AG049934. E.A.P. is supported by US National Science Foundation GRFP and US National Institutes of Health (NIH) F31 AG043232 graduate fellowships. A.B. is supported by NIH DP1 AG044848, P01 AG036695, and the Glenn Laboratories for the Biology of Aging.
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Supplementary information
Supplementary information S1 (box)
Targeted and global methods of epigenome mapping. (PDF 69 kb)
Supplementary information S2 (table)
Epigenetic changes observed during ageing (referenced table) (PDF 140 kb)
Supplementary information S3 (table)
Modulation of lifespan by components and modifiers of chromatin (referenced) (PDF 137 kb)
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Glossary
- Lifespan
-
The time elapsed between birth and death in time units. In yeast, lifespan can be measured in two ways: chronological lifespan, which corresponds to the length of time a non-dividing cell can survive; and replicative lifespan, which corresponds to the number of mitotic cell divisions a mother cell has undergone.
- Healthspan
-
The duration of disease-free physiological health within the lifespan of an individual. In humans, for instance, this corresponds to the period of high cognitive abilities, immune competence and peak physical condition.
- Isogenic
-
Characterized by essentially identical genetic material. Highly inbred populations are usually considered to be isogenic.
- Epigenetic
-
The broad definition of the term corresponds to modes of genomic regulation that are not directly encoded in DNA. We use it specifically to refer to chromatin-level regulation. According to its strictest definition, epigenetics encompasses strictly heritable changes without changes in the underlying gene sequence.
- Chromatin
-
A complex of DNA and histone proteins that packages genetic information. Chromatin can be broadly stratified in two states: euchromatin, which is a loose and transcription-permissive compartment; and heterochromatin, which is a dense and compact compartment that contains repressed DNA.
- Epigenomes
-
The epigenetic landscapes of cells, including the genome-wide distributions of chromatin marks such as histone modifications or DNA methylation.
- Replicative senescence
-
A limitation in the number of time a cell can divide. Replicative senescence has sometimes been used as an in vitro proxy for ageing in dividing mammalian cells such as fibroblasts or stem cells.
- CpG islands
-
Clusters of CpG dinucleotides, which are usually found in the promoter regions of some genes. CpG islands are typically defined by a minimum length (∼200–500 bp) and an unusual enrichment of CpG (>60%). They are usually unmethylated in the germline or pluripotent state.
- Chronological age
-
The time elapsed since the birth of an individual. Chronological age is often compared to biological age.
- Biological age
-
The age of the average population that is most similar to the individual under observation. Younger biological ages are linked to high performance and health, whereas older biological ages correlate with disease onset. Biological age is used as a proxy for individual health.
- Histone chaperone
-
A protein that aids the folding or dimerization of histones, as well as their loading onto the chromatin fibre. Different histones have different chaperones.
- Sirtuin
-
A member of the family of class III histone deacetylases (HDACs). The first sirtuin to be discovered was the yeast protein Sir2p. The defining characteristic of these HDACs is their dependency on NAD+ as a cofactor to catalyse deacetylation or other enzymatic reactions, including ADP-ribosylation.
- Dietary restriction
-
A reduction in food intake without malnutrition. There are many types of dietary restriction regimen, such as intermittent fasting, global caloric restriction or specific reduction of a nutrient type.
- Position variegation effect
-
Variability in the activation state of a gene depending on its proximity to a heterochromatin domain.
- Insulin and insulin-like growth factor (IGF) signalling pathways
-
Important conserved signalling pathways that are sensitive to nutrient levels and that have been linked to longevity and stress resistance across Metazoa. Primary components that are relevant to ageing include the insulin and IGF1 receptors, the activation of which triggers a phosphorylation cascade involving PI3K, AKT and ultimately the forkhead box protein O (FOXO) transcription factors.
- Genomic instability
-
Random loss of integrity of genetic material, whether through large-scale rearrangements (such as chromosomal translocations, large inversions and deletions, and so on), site-specific changes (such as single- nucleotide changes) or transposon insertions. Genomic instability may be a driver of ageing and of age-related diseases such as cancer.
- Pheromones
-
Secreted chemical factors that can trigger a response in other members of a given species. Pheromone signalling has been linked to sexual behaviour, feeding and stress.
- Epimutations
-
Aberrant or atypical changes in epigenetic states, which are often stochastic.
- Transposable elements
-
Endogenous DNA elements that change their position or amplify their copy number within a host genome. There are two main types of transposable elements. Type I elements function through an RNA intermediate, such as long interspersed nuclear elements or long tandem repeats (copy–paste mechanism). Type II elements function through a DNA intermediate (cut–paste mechanism). They usually occupy a large portion of eukaryotic genomes.
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Benayoun, B., Pollina, E. & Brunet, A. Epigenetic regulation of ageing: linking environmental inputs to genomic stability. Nat Rev Mol Cell Biol 16, 593–610 (2015). https://doi.org/10.1038/nrm4048
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DOI: https://doi.org/10.1038/nrm4048
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