Abstract
The view of aging has evolved in parallel with the advances in biomedical sciences. Long considered as an irreversible process where interventions were only aimed at slowing down its progression, breakthrough discoveries like animal cloning and cell reprogramming have deeply changed our understanding of postnatal development, giving rise to the emerging view that the epigenome is the driver of aging. The idea was significantly strengthened by the converging discovery that DNA methylation (DNAm) at specific CpG sites could be used as a highly accurate biomarker of age defined by an algorithm known as the Horvath clock. It was at this point where epigenetic rejuvenation came into play as a strategy to reveal to what extent biological age can be set back by making the clock tick backwards. Initial evidence suggests that when the clock is forced to tick backwards in vivo, it is only able to drag the phenotype to a partially rejuvenated condition. In order to explain the results, a bimodular epigenome is proposed, where module A represents the DNAm clock component and module B the remainder of the epigenome. Epigenetic rejuvenation seems to hold the key to arresting or even reversing organismal aging.
Highlights
Age is defined as the period that spans from birth to a given point in time
The field of endocrinology was born from experiments -- aimed at testing a theory of aging -- reported at the end of the XIX century, by Charles E
The hypothesis proposing the epigenome as the driver of aging was significantly strengthened by the converging discovery that DNA methylation at specific CpG sites could be used as a highly accurate biomarker of age defined by the Horvath clock [5]
Summary
Age is defined as the period that spans from birth to a given point in time. Despite the promise offered by partial cell reprogramming for safe rejuvenation in vivo, it should be pointed out that the OSKM genes are unlikely to have evolved as a physiological mechanism to regulate the epigenetic clock during adult life, rather their most plausible role seems to be the resetting of epigenetic age to zero in the zygote [31]. The middle diagram (path 2) illustrates the hypothesis that several cycles of partial reprogramming can progressively rejuvenate cells by erasing all epigenetic marks of age without affecting cell type identity marks. This means that in principle, the strategy could lead to major phenotype rejuvenation in vivo. In this particular case a more complete interpretation of results requires a refinement of the model by assuming a trimodular epigenome, where module A encompasses the clock component, module B, represents a non-clock component that is responsive to elixir, and module C represents the portion of the epigenome that is insensitive to the rejuvenating effect of elixir
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