Methylation and death

It is testament to the cheerful company that I keep that I receive emails entitled “methylation and death” and am expected to evince pleasure in such communications, or at least greater pleasure than normally accompanies finding the sawn-off head of one’s prize race horse lolling between the bed sheets.

Are people trying to tell me things? The paper is something of monster, with more authors than genes reliably associated with any human behaviour, drawn from notable institutions across the globe, or at least that part of it pacified, ordered, nurtured and guided by Albion’s seed. This is the way to assemble massive data sets, a virtuous aim, though it must make for fraught conference calls when responding to reviewer’s comments. On a general point, as regards multi-author papers we need to improve the dull practice of merely listing the names. I think every big team should have project titles, of the sort that come so easily to the military or management teams. Academia should identify each name as being, for example: writer, checker, data cruncher, table and figure maker, polisher, and “contributed nothing but data”. What’s wrong with full disclosure, transparency, and openness, after all?

Here I must pause a moment to explain that I describe all epigenetics as “the fluff on the toffee”. This paper is not about the DNA toffee itself, but about the fluff of methylation sticking to the genomic toffee:

Epigenetic mechanisms such as DNA methylation, characterised by the addition of a methyl group to a cytosine nucleotide primarily at cytosine-phosphate-guanine (CpG) sites, play essential roles during development, acting through the regulation of gene expression. Unlike genomic variants, such as single nucleotide polymorphisms (SNPs), levels of DNA methylation vary across the life course. DNA methylation levels are influenced by lifestyle and environmental factors, as well as by genetic variation.

What the authors have found is that if they calculate methylation age acceleration then such acceleration predicts accelerated mortality. That is, people are most likely to die at the ages predicted by their methylation age than any other lifestyle variables, including smoking.

We found that two heritable DNA methylation-based measures of the difference
between epigenetic age and chronological age are significant predictors of mortality in our meta-analysis of four independent cohorts of older people. Individual genetic or environmental exposures that drive the associations are not yet known, but they appear not to be clearly linked to classic life-course risk factors. The difference between DNA methylation age and chronological age predicts mortality risk over and above a combination of smoking, education, childhood IQ, social class, APOE genotype, cardiovascular disease, high blood pressure, and diabetes. It may therefore be possible to think of DNA methylation predicted age as an 'epigenetic clock' [11] that measures biological age and runs alongside, but not always in parallel with chronological age, and may inform life expectancy predictions. Our results imply that epigenetic marks, such as gene methylation, are like other complex traits: influenced by both genetic and environmental factors and associated with major health related outcomes.

This potentially provides a clock function which is interesting in itself, and acts as a benchmark against which other effects can be measured.

https://drive.google.com/file/d/0B3c4TxciNeJZSW5uMVdNeHE4UU0/view?usp=sharing

Naturally, the next paper makes exactly that point, showing the link to physical and cognitive fitness.

Background: The DNA methylation-based ‘epigenetic clock’ correlates strongly with chronological age, but it is currently unclear what drives individual differences. We examine cross-sectional and longitudinal associations between the epigenetic clock and four mortality-linked markers of physical and mental fitness: lung function, walking speed, grip strength and cognitive ability.
Methods: DNA methylation-based age acceleration (residuals of the epigenetic clock estimate regressed on chronological age) were estimated in the Lothian Birth Cohort 1936 at ages 70 (n¼920), 73 (n¼299) and 76 (n¼273) years. General cognitive ability, walking speed, lung function and grip strength were measured concurrently. Cross-sectional correlations between age acceleration and the fitness variables were calculated.
Longitudinal change in the epigenetic clock estimates and the fitness variables were assessed via linear mixed models and latent growth curves. Epigenetic age acceleration at age 70 was used as a predictor of longitudinal change in fitness. Epigenome-wide association studies (EWASs) were conducted on the four fitness measures.
Results: Cross-sectional correlations were significant between greater age acceleration and poorer performance on the lung function, cognition and grip strength measures All of the fitness variables declined over time but age acceleration did not correlate with subsequent change over 6 years. There were no EWAS hits for the fitness traits.
Conclusions: Markers of physical and mental fitness are associated with the epigenetic clock (lower abilities associated with age acceleration). However, age acceleration does not associate with decline in these measures, at least over a relatively short follow-up.

https://drive.google.com/file/d/0B3c4TxciNeJZT1hoZmFjOW81aDQ/view?usp=sharing

 

These authors have done us proud: here is a new metric which may possibly transform the debate about ageing.