Considering Epigenetic Drift in Aging

Epigenetics is the study of mechanisms that cause changes in gene expression. Genes encode proteins, and gene expression is the complex multi-step process by which proteins are built from that blueprint. Changes in the amount of any specific protein in circulation or in a specific location in a cell can result in significant changes in the operation of metabolism, altering the operation of cellular machinery that in turn feeds back to further change gene expression. Our biology is a massively complex web of feedback loops and linkages between genes and proteins.

DNA methylation is of the mechanisms by which gene expression is altered. It involves the addition of a chemical tag to a gene. The pattern of DNA methylation changes with aging, a process sometimes called epigenetic drift, and some of those changes are characteristic enough to be used as a measure of age.

While a number of key signalling pathways (e.g. mTOR signalling) and biological processes (e.g. telomere attrition) affecting lifespan have been identified, other theories have argued that aging results mainly from accumulated molecular damage. Most likely, aging is determined by a complex cross-talk between multiple biological effects. Molecular damage itself can take many forms, including somatic DNA mutations and copy-number changes.

The advent of novel biotechnologies, allowing routine genome-wide quantitative measurement of epigenetic marks, specially DNA methylation, have recently demonstrated that age-associated changes in DNA methylation, a phenomenon now known as "epigenetic drift", may play an equally important role in contributing to the aging phenotype. Indeed, like telomere attrition, epigenetic drift has been associated with stem cell dysfunction, disease risk factors and common age-related diseases, such as cancer and Alzheimer's. Apart from extensive experimental work supporting a role for DNA methylation in aging, computational network biology approaches have recently shed further light into the potential role of epigenetic drift. For instance, one study has shown that drift appears to target WNT signalling, a key pathway in stem-cell differentiation and already known to be deregulated with age.

A more recent study mapped epigenetic drift occurring in gene promoters onto a human protein interactome and observed that most of the changes happen at genes which occupy peripheral network positions, i.e. those of relatively low connectivity. Although developmental transcription factors make up a significant proportion of "drift genes", the observed topological effect was not entirely driven by this enrichment. Crucially, the topological properties of genes undergoing epigenetic drift were highly distinctive from those which have been associated with modulating longevity, those undergoing age-related changes in expression, or those somatically mutated in age-related diseases like cancer. Moreover, essential housekeeping genes, many of which occupy highly central positions in the interactome, appear protected from epigenetic drift.

Although the overall functional significance of epigenetic drift remains to be established, a few instances of epigenetic drift causing silencing of key transcription factors have already been reported. Thus, it is plausible that epigenetic drift may gradually affect differentiation programs through functional deregulation of key lineage determining transcription factors, leading to well-known observations such as neoplastic formation.



"one study has shown that drift appears to target [...]" What? How can "drift" target anything? Isn't that almost a contradiction in terms? I'm not disputing the reality of the underlying phenomenon, but the terminology is certainly confusing and I don't see evidence for drift as it's more conventionally understood.

As always when discussing aging mechanisms the question of causality, and in particular the direction thereof, looms large. For instance, a dysregulated tissue environment (polluted by extra-cellular junk, littered with cells expressing SASP) generates "noise" or unproductive extra-cellular communications that cells may respond to by changing their commitments to suit the aberrant signals they're receiving.

One can make out a circumstantial case for the above alternate interpretation using the reported findings. Speaking in the broadest terms, cells adjust the activity of housekeeping programs in response to intracellular conditions such as the abundance of relevant substrates in the cytoplasm, etc. On the contrary, the local niche is paramount in determining the outcome of cellular differentiation and extra-cellular signals are correspondingly more important. Bearing that in mind, consider that the article states "essential housekeeping genes [...] appear protected from epigenetic drift" and that "drift appears to target WNT signalling, a key pathway in stem-cell differentiation."

Those findings comport exactly with what would be expected if the cause of the epigenetic changes was to be found in altered extra-cellular conditions!

Posted by: José at October 26th, 2013 2:08 AM

Altered extra-cellular conditions must have some effect, since repopulating young extra-cellular matrix with senescent cells can restore their juvenile phenotype -
"Restoration of senescent human diploid fibroblasts by modulation of the extracellular matrix"
Maybe, the senescent "secretory phenotype" partly reflects a cell's futile attempt to break the matrix cross-links by releasing inflammatory proteases?
Perhaps also related is -
"Age related changes of the extracellular matrix and stem cell maintenance"
And, also maybe inter-/intra-cellular debris (e.g., misfolded proteins) also affect epigenetics.

Posted by: Lou Pagnucco at October 27th, 2013 6:10 PM

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.