Epigenetic chaperoning of aging

Abstract

Who wants to live forever? Lifespan extension is a long-standing human desire. And sure enough, a longer lifespan is expected to also extend the time without diseases and frailty. But should we take for granted that lifespan and healthspan are inherently linked? Meaning, does increased lifespan also extend the time without unfavorable health conditions? It is not well understood to which extend lifespan and healthspan are indeed linked. Recent studies provide increasing evidence that epigenetic factors may play a pivotal role in connecting aging and healthspan regulation. Epigenetic factors control gene expression by regulating modifications and structure of chromatin. Loss of specific chromatin regulators can cause defects and diseases such as cancer and neurodegeneration. Also, histone demethylases maintain muscle stem cells and Sirtuins with histone deacetylation activity control organismal aging [1]. Another type of chromatinregulating proteins are histone chaperones. They are required for nuclear import of histone proteins, their assembly into nucleosomes and genomic localization, as well as for the post-translational modifications of histones. Histone chaperones interact with different chromatin-regulating factors to provide gene regulatory functions with a broad spectrum of physiological functions such as cell fate safeguarding and blocking reprogramming of cell identities [2]. Recently, it was found that the histone chaperone LIN-53 in the nematode Caenorhabditis elegans (C. elegans), known as RBBP4 and RBBP7 in humans, is important for lifespan as well as healthspan regulation [3]. Interestingly, a previous study in humans revealed that RBBP4/7 are implicated in aging and age-related memory loss [4,5]. Therefore, it is conceivable that LIN-53 represents and evolutionarily conserved link of lifespan and healthspan regulation. The histone chaperone LIN-53 and its mammalian homologs RBBP4/7 (older names: CAF-1p48, RbAp46/48) are found in different chromatin-regulating complexes including Polycomb Repressive Complex 2 (PRC2, histone methyltransferase activity), CAF1 histone chaperone complex, Sin3 histone deacetylase complex (HDAC), nucleosome remodeling complex (NuRD), and DRM (Dp/Rb/Muv) complex [6]. Recently, LIN-53 and the RBBP4/7-containing CAF1 complex have been identified as reprogramming barriers in the nematode C. elegans and in mouse fibro-www.aging-us.com