A HIERARCHICAL MODEL FOR THE CONTROL OF EPIGENETIC AGING IN MAMMALS.

Abstract Regulatory mechanisms range from a single level of control in simple metazoans to multi-level hierarchical control networks in higher animals. Organismal regulation encompasses homeostatic and circadian networks that are interconnected, with no documented exceptions. The epigenetic clock is a highly accurate biomarker of age in humans, defined by a mathematical algorithm based on the methylation of a subset of age-related CpG sites on DNA. Experimental evidence suggests the existence of an underlying regulatory mechanism. By analogy with other integrative systems as the neuroendocrine-immune network and the circadian clocks, a hierarchical organization in the control of the ticking rate of the epigenetic clock is hypothesized here. The hierarchical organization of the neuroendocrine, immune and circadian systems is briefly reviewed. This is followed by a brief review of the epigenetic clock at cell level. Finally, different lines of indirect evidence, consistent with the existence of a central pacemaker controlling the ticking rate of the epigenetic clock at organismal level are discussed. The concluding remarks put the hierarchical model proposed for the control of the clock into an evolutionary perspective. Within this perspective, the present hypothesis is intended as a conceptual outline based on designs consistently favored by evolution in higher animals.