DNA methylation-based biomarkers and the epigenetic clock theory of ageing

Horvath, Steve; Raj, Kenneth

doi:10.1038/s41576-018-0004-3

Cited by 2,174 publications

(2,296 citation statements)

References 146 publications

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“…From the perspective of cell biology, obesity is associated with 240‐bp shortened telomere length, corresponding to 8.8 years of ageing . Additionally, as estimated by all measures of epigenetic clocks, obesity is linked to the acceleration of epigenetic age in different tissues . Broadly speaking, obesity and ageing share a similar spectrum of phenotypes—redox imbalance, mitochondrial dysfunction, accumulation of macromolecules, weakened immunity, and systemic inflammation.…”

Section: Introductionmentioning

confidence: 99%

Obesity and ageing: Two sides of the same coin

2020

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Summary Conditions and comorbidities of obesity mirror those of ageing and age‐related diseases. Obesity and ageing share a similar spectrum of phenotypes such as compromised genomic integrity, impaired mitochondrial function, accumulation of intracellular macromolecules, weakened immunity, shifts in tissue and body composition, and enhanced systemic inflammation. Moreover, it has been shown that obesity reduces life expectancy by 5.8 years in men and 7.1 years in women after the age of 40. Shorter life expectancy could be because obesity holistically accelerates ageing at multiple levels. Besides jeopardizing nuclear DNA and mitochondrial DNA integrity, obesity modifies the DNA methylation pattern, which is associated with epigenetic ageing in different tissues. Additionally, other signs of ageing are seen in individuals with obesity including telomere shortening, systemic inflammation, and functional declines. This review aims to show how obesity and ageing are “two sides of the same coin” through discussing how obesity predisposes an individual to age‐related conditions, illness, and disease. We will further demonstrate how the mechanisms that perpetuate the early‐onset of chronic diseases in obesity parallel those of ageing.

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Section: Introductionmentioning

confidence: 99%

Obesity and ageing: Two sides of the same coin

2020

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“…aDMPs are generally located within the promoter or first exon of a gene (Bekaert, Kamalandua, Zapico, Voorde, & Decorte, ; Grönniger et al, ; Horvath, ; Sziráki, Tyshkovskiy, & Gladyshev, ; Zbieć‐Piekarska et al, ). Epigenetic drift is thought to occur due to a decline or imperfect replication of DNAm by an epigenetic maintenance system with increasing age (Horvath, ; Horvath & Raj, ). However, the mechanisms for specific “clock‐type” aDMP change have not yet been characterized.…”

Section: Introductionmentioning

confidence: 99%

Age estimation in a long‐lived seabird (Ardenna tenuirostris) using DNA methylation‐based biomarkers

Paoli-Iseppi

Deagle

Polanowski

et al. 2019

Molecular Ecology Resources

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Age structure is a fundamental aspect of animal population biology. Age is strongly related to individual physiological condition, reproductive potential and mortality rate. Currently, there are no robust molecular methods for age estimation in birds. Instead, individuals must be ringed as chicks to establish known‐age populations, which is a labour‐intensive and expensive process. The estimation of chronological age using DNA methylation (DNAm) is emerging as a robust approach in mammals including humans, mice and some non‐model species. Here, we quantified DNAm in whole blood samples from a total of 71 known‐age Short‐tailed shearwaters (Ardenna tenuirostris) using digital restriction enzyme analysis of methylation (DREAM). The DREAM method measures DNAm levels at thousands of CpG dinucleotides throughout the genome. We identified seven CpG sites with DNAm levels that correlated with age. A model based on these relationships estimated age with a mean difference of 2.8 years to known age, based on validation estimates from models created by repeated sampling of training and validation data subsets. Longitudinal observation of individuals re‐sampled over 1 or 2 years generally showed an increase in estimated age (6/7 cases). For the first time, we have shown that epigenetic changes with age can be detected in a wild bird. This approach should be of broad interest to researchers studying age biomarkers in non‐model species and will allow identification of markers that can be assessed using targeted techniques for accurate age estimation in large population studies.

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“…This is more evident from a recent study published when our study was conducted [42]. The methylation changes in the numerous CpGs that belong to DNA sequences coding for hypothetical proteins could be considered as markers of the functional deterioration of at least some of the enzymes responsible for the maintenance of methylation during aging.…”

Section: Discussionmentioning

confidence: 78%

Age-dependent methylation in epigenetic clock CpGs is associated with G-quadruplex, co-transcriptionally formed RNA structures and tentative splice sites

et al. 2018

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Horvath’s epigenetic clock consists of 353 CpGs whose methylation levels can accurately predict the age of individuals. Using bioinformatics analysis, we investigated the conformation, energy characteristics and presence of tentative splice sites of the sequences surrounding the epigenetic clock CpGs, in relation to the median methylation changes in different ages, the presence of CpG islands and their position in genes. Common characteristics in the 100 nt sequences surrounding the epigenetic clock CpGs are G-quadruplexes and/or tentative splice site motifs. Median methylation increases significantly in sequences which adopt less stable structures during transcription. Methylation is higher when CpGs overlap with G-quadruplexes than when they precede them. Median methylation in epigenetic clock CpGs is higher in sequences expressed as single products rather than in multiple products and those containing single donors and multiple acceptors. Age-related methylation variation is significant in sequences without G-quadruplexes, particularly those producing low stability nascent RNA and those with splice sites. CpGs in sequences close to transcription start sites and those which are possibly never expressed (hypothetical proteins) undergo similar extent of age-related median methylation decrease and increase. Preservation of methylation is observed in CpG islands without G-quadruplexes, contrary to CpGs far from CpG islands (open sea). Sequences containing G-quadruplexes and RNA pseudoknots, determining the recognition by H3K27 histone methyltransferase, are hypomethylated. The presented structural DNA and co-transcriptional RNA analysis of epigenetic clock sequences, foreshadows the association of age-related methylation changes with the principle biological processes of DNA and histone methylation, splicing and chromatin silencing.

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DNA methylation-based biomarkers and the epigenetic clock theory of ageing

Cited by 2,174 publications

References 146 publications

Obesity and ageing: Two sides of the same coin

Obesity and ageing: Two sides of the same coin

Age estimation in a long‐lived seabird (Ardenna tenuirostris) using DNA methylation‐based biomarkers

Age-dependent methylation in epigenetic clock CpGs is associated with G-quadruplex, co-transcriptionally formed RNA structures and tentative splice sites

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