Fight Aging!

Is epigenetic change a cause or consequence of aging, and are epigenetic clocks measuring a cause or consequence of aging? In today's open access preprint, researchers build a model of the epigenetic contribution to aging, and propose that the answer is "both", with different epigenetic marks on the genome being either cause or consequence of aging.

Epigenetic marks such as DNA methylation, the attachment of methyl groups to the genome at specific locations called CpG sites, alter gene expression. They do so by altering the structure of packaged DNA, either hiding regions from transcriptional machinery or exposing those same regions to allow RNA to be produced. The activity of RNA and proteins in a cell in turn alters epigenetic marks, a feedback loop that integrates contributions of the epigenome, cell machinery, and the impact of the surrounding extracellular environment.

A cell is thus a dynamic system, but nonetheless the advent of epigenetic clocks has demonstrated that certain epigenetic marks are characteristic of aging. Why is this the case? It was widely thought that the epigenome reacted to the accumulating damage and dysfunction of aging, and thus was much more a downstream consequence than an important contributing cause of aging. In recent years, however, new studies have suggested that at least some epigenetic change may be closer to the fundamental causes of aging. For example, recall the research indicating that repeated cycles of DNA double strand break repair directly provoke age-related epigenetic changes.

Given (a) the present popularity of intervening at the epigenetic level, (b) the billions in funding for organizations attempting to do this, and (c) the demonstrated ability to rejuvenate the aged epigenome via partial reprogramming technologies, it seems clear that hypotheses and models regarding epigenetic aging will be earnestly tested in the years ahead. While epigenetic rejuvenation clearly cannot fix issues that a young body cannot fix, such as aggregation of persistent metabolic waste, cross-links that cannot be broken down effectively by our biochemistry, or localized excess cholesterol, these are nonetheless exciting times.

Epigenetic fidelity in complex biological systems and implications for ageing

It has been proposed that epigenetic changes are causative in ageing, and a recent study has suggested that DNA damage response-induced loss of epigenetic information drives ageing. More broadly, the information theory of ageing has suggested that loss of epigenetic information with age is a major driver of the ageing process. It has also been suggested that pre-programmed shifts in epigenetic information states with age are a major determinant of ageing phenotypes. As such, understanding the basis of epigenetic clocks, and how epigenetic changes could impact ageing is a major and important open question. Moreover, despite efforts to understand the informatic character of ageing, there has been comparatively little research on what makes mammalian ageing inevitable.

In this work, we develop a conceptual model to explain the ageing process based on first principles. We demonstrate that the epigenetic system has unique inherent informatic properties that progressively acquire informatic corruption, meaning that with age epigenetic information fidelity cannot be maintained. In this work we set out to break down the nature of epigenetic damage and characterise biological ageing as a failure of repair fidelity.

To do this, we began by showing that chronological age correlates to the progressive deviation within certain classes of CpG loci. It seems that there are three variables that control the correlation to age: those values representing fluke correlation to cellular regulation, those representing genes that are being regulated increasingly as age increases (senescence, DNA repair, stress response, etc) and those peaks describing epigenetic systems becoming deregulated with age. We suggest that epigenetic clocks are measuring both of the latter classes of CpG and that the answer to the question 'Are epigenetic clocks measuring cause or consequence' is 'both', depending on the CpGs used.

Genes that change in response to age represent the effect of age and the epigenetic stochastic noise represents biological age itself. We propose that this epigenetic damage would result in a feedback cycle, in which deregulation would lead to further deregulation through the disruption of maintenance and repair of the epigenetic regions, and to the phenotype of age through the general deregulation of cellular systems. This would fit the profile of ageing as a robust, gradual process, with slow, reliable progress made as deregulation accumulates, accelerating toward network failure as the feedback cycle picks up pace.

We can see in the gene ontology results that in all organisms and tissues, those genes regulated by the loci in which deregulation correlates to age are genes governing promotors and enhancers. We suggest that this is because promotors and enhancers have a unique feature that precludes polarising their regional control for regulation: they need to regularly reconfigure the local methylation state consequent to the current state of transcription.

We suggest this makes them tautologically defined, in that the definition of the epigenetic signal of a promotor/enhancer modulator relies in part on its own current state (such that any damage results in damage to any rule from which the signal could be corrected), and thus representing a class of loci in which epigenetic regional control cannot be correctly defined once epigenetic damage has occurred. We suggest damage accrues in these regions and the global deregulation of transcription that occurs consequent to this gives rise to the general phenotype of age.