Epigenetic aging: insights from network biology

signalling) and biological processes (e.g. telomere attrition) affecting lifespan have been identified [1,2], other theories have argued that aging results mainly from accumulated molecular damage [1]. 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 [3,4]. Indeed, like telomere attrition, epigenetic drift has been associated with stem cell dysfunction [5], disease risk factors and common age-related diseases, such as cancer and Alzheimer's [3]. 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 [3]. 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 [6]. 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 (Figure 1). 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 Editorial silencing of key transcription factors have already been reported [5]. 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 myeloid skewing of the aged hematopoietic system [5]. Epigenetic drift affecting key transcription factors may further increase predisposition to age-related diseases like cancer, by locking stem cells into states of self-renewal, and causing tissues to exhibit an …