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The role of epigenetics in renal ageing

Nature Reviews Nephrology volume 13, pages 471–482 (2017)Cite this article

Subjects

Key Points

  • The incidence of deaths owing to renal dysfunction is increasing globally in parallel with the ageing population

  • The epigenetic landscape of ageing is mediated by dynamic changes in the methylome and in chromatin structure, along with coordinated regulation of a complex range of molecular processes by noncoding RNAs in response to environmental changes

  • A mechanistic link is emerging between the epigenetic landscape of ageing and renal dysfunction based on regulation of ageing processes that are common across taxa

  • Epigenetic regulation of biological ageing in the kidney is influenced directly by nutrition, inflammation, the gut microbiome, psychosocial factors and lifestyle factors

  • Models of progeria provide important hypothesis-generating insights for future therapies designed to modify the epigenetic landscape in ageing and disease

  • Epigenetic interventions could potentially improve renal health, but caution is warranted given the potential for intergenerational and transgenerational effects

Abstract

An ability to separate natural ageing processes from processes specific to morbidities is required to understand the heterogeneity of age-related organ dysfunction. Mechanistic insight into how epigenetic factors regulate ageing throughout the life course, linked to a decline in renal function with ageing, is already proving to be of value in the analyses of clinical and epidemiological cohorts. Noncoding RNAs provide epigenetic regulatory circuits within the kidney, which reciprocally interact with DNA methylation processes, histone modification and chromatin. These interactions have been demonstrated to reflect the biological age and function of renal allografts. Epigenetic factors control gene expression and activity in response to environmental perturbations. They also have roles in highly conserved signalling pathways that modulate ageing, including the mTOR and insulin/insulin-like growth factor signalling pathways, and regulation of sirtuin activity. Nutrition, the gut microbiota, inflammation and environmental factors, including psychosocial and lifestyle stresses, provide potential mechanistic links between the epigenetic landscape of ageing and renal dysfunction. Approaches to modify the renal epigenome via nutritional intervention, targeting the methylome or targeting chromatin seem eminently feasible, although caution is merited owing to the potential for intergenerational and transgenerational effects.

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Figure 1: The epigenetic landscape mediates the interplay between stressors and renal dysfunction.
Figure 2: Environmental factors and epigenomic alterations.
Figure 3: Ageing and epigenomic changes in the kidney.

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Acknowledgements

P.S. has received research funding from the Swedish Medical Research Council. D.McG. has received funding from Darlinda's Charity for Renal Research The authors thank Ognian Neytchev (University of Glasgow) for assistance in formatting the references and Colin Selman (University of Glasgow) for critical reading of the manuscript prior to submission.

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Authors and Affiliations

  1. Section of Epigenetics, Institute of Cancer Sciences, Wolfson Wohl Translational Research Centre, University of Glasgow, Garscube Estate, Switchback Road, Glasgow, G61 1QH, Bearsden, UK

    Paul G. Shiels & Dagmara McGuinness

  2. Department of Biosciences and Nutrition (BioNut), H2, Eriksson, Novum 141, 83, Huddinge, Sweden

    Maria Eriksson

  3. Department of Internal Medicine, Division of Nephrology, Maastricht University Medical Center, PO Box 5800, Maastrich, 6202 AZ, Netherlands

    Jeroen P. Kooman

  4. Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska University Hospital, Huddinge, Karolinska Institutet, Stockholm, SE-14157, Sweden

    Peter Stenvinkel

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  1. Paul G. Shiels
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  4. Jeroen P. Kooman
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Contributions

All authors researched the data for the article, made a substantial contribution to discussion of the content, wrote the article and reviewed and, or edited the manuscript before submission.

Corresponding author

Correspondence to Paul G. Shiels.

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Competing interests

P.G.S. has received research funding from GlaxoSmithKline. J.P.K. has received research funding from Fresenius. The other authors declare no competing interests.

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Glossary

Diverticula

Cystic cavities that are lined by transitional epithelium and contain urine.

Epigenotype

A stable pattern of gene expression that is not encoded by the genomic sequence of the associated DNA.

Segmental progeroid syndrome

A syndrome in which certain tissues and cell types in the body display an accelerated ageing phenotype.

Epigenetic clock

A biological clock based on the levels of DNA methylation at a number of defined loci that is used to estimate the biological age of a tissue, cell type, organ or individual.

Epigenetic drift

Age-associated divergence of the epigenome owing to stochastic alteration of DNA methylation.

Metabolic memory

An epigenetic effect that results in the persistence of poor metabolic control after an episode of hyperglycaemia despite a return to normal glycaemic control.

Archetypal miRNAs

Reference miRNA sequences listed in miRNA databases.

Imprinted gene

A gene that is expressed in a manner that is epigenetically determined by the sex of the parent who contributed the gene, typically through methylation-based gene silencing.

Methyl-donor nutrient

Dietary methyl groups derived from foods that contain methionine, one-carbon units and choline (or the choline metabolite betaine).

Metastable epialleles

Genomic regions in which DNA methylation is established stochastically during embryogenesis and then maintained stably in differentiated cells and tissues, leading to inter-individual epigenetic variation.

Antagonistic pleiotropy

A genetic effect that controls for at least one trait that is beneficial to and at least one trait that is detrimental to the fitness of the organism.

Segmental ageing

Variability in the age of onset and the rate of development of accelerated ageing characteristics in different tissues and organs.

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Shiels, P., McGuinness, D., Eriksson, M. et al. The role of epigenetics in renal ageing. Nat Rev Nephrol 13, 471–482 (2017). https://doi.org/10.1038/nrneph.2017.78

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