Abstract
Whether extension of lifespan provides an extended time without health deteriorations is an important issue for human aging. However, to which degree lifespan and aspects of healthspan regulation might be linked is not well understood. Chromatin factors could be involved in linking both aging aspects, as epigenetic mechanisms bridge regulation of different biological processes. The epigenetic factor LIN‐53 (RBBP4/7) associates with different chromatin‐regulating complexes to safeguard cell identities in Caenorhabditis elegans as well as mammals, and has a role in preventing memory loss and premature aging in humans. We show that LIN‐53 interacts with the nucleosome remodeling and deacetylase (NuRD) complex in C. elegans muscles to ensure functional muscles during postembryonic development and in adults. While mutants for other NuRD members show a normal lifespan, animals lacking LIN‐53 die early because LIN‐53 depletion affects also the histone deacetylase complex Sin3, which is required for a normal lifespan. To determine why lin‐53 and sin‐3 mutants die early, we performed transcriptome and metabolomic analysis revealing that levels of the disaccharide trehalose are significantly decreased in both mutants. As trehalose is required for normal lifespan in C. elegans, lin‐53 and sin‐3 mutants could be rescued by either feeding with trehalose or increasing trehalose levels via the insulin/IGF1 signaling pathway. Overall, our findings suggest that LIN‐53 is required for maintaining lifespan and muscle integrity through discrete chromatin regulatory mechanisms. Since both LIN‐53 and its mammalian homologs safeguard cell identities, it is conceivable that its implication in lifespan regulation is also evolutionarily conserved.
Highlights
The decline of physical condition and the onset of diseases such as cancer, diabetes, or dementia are important issues during aging
Since it is well established that metabolome alterations have a significant impact on aging (reviewed in Peleg, Feller, Ladurner, and Imhof (2016) and Finkel (2015)), we propose that LIN‐53 is required for normal lifespan of C. elegans because it is maintaining the expression of genes that ensure a wild‐type metabolome
Should we expect that animals or humans with longer lifespans would be healthy for a longer time? Interestingly, a recent study by the research group of Heidi Tissenbaum suggests that lifespan and healthspan can be unlinked in C. elegans (Bansal, Zhu, Yen, & Tissenbaum, 2015)
Summary
The decline of physical condition and the onset of diseases such as cancer, diabetes, or dementia are important issues during aging. Similar results were obtained when comparing lifespans of the double sin‐3(tm1276); daf‐2(e1370) animals with the respective single mutants (Figure 6b) These observations suggested that the previously reported increase of trehalose levels in daf‐2 mutants (Honda et al, 2010) might compensate for the diminished trehalose levels upon loss of LIN‐53 and SIN‐3. Loss of LIN‐53 or SIN‐3 leads to diminished levels of the disaccharide trehalose, which is required for a normal lifespan (Honda et al, 2010; Seo et al, 2018) These findings suggest that the histone chaperone LIN‐53 is a critical chromatin regulator linking the epigenetic regulation of lifespan with muscle development and integrity, which is an important aspect of healthspan maintenance
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