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bioRxiv · 10.1101/539015

The conserved histone chaperone LIN-53 links lifespan and healthspan regulation in C. elegans

Muethel, S.·Uyar, B.·He, M.·Krause, A.·Vitrinel, B.·Bulut, S.·Vasiljevic, D.·Akalin, A.·Kempa, S.·Tursun, B.
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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 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) is required for safeguarding cell identities in Caenorhabditis elegans as well as mammals and for preventing memory loss and premature aging in humans. LIN-53 is a histone chaperone that associates with different chromatin-regulating complexes. We show that LIN-53 interacts with the Nucleosome remodeling and deacteylase (NuRD)-complex in C. elegans muscles to promote healthy locomotion during aging. 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 metabolome analysis and found 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 promoting healthspan through discrete chromatin regulatory mechanisms. Since both LIN-53 and its mammalian homologs safeguard cell identities, it is conceivable that its implication in lifespan and healthspan regulation is also evolutionarily conserved.

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Muethel, S., Uyar, B., He, M., Krause, A., Vitrinel, B., Bulut, S., Vasiljevic, D., Akalin, A., Kempa, S., Tursun, B.. 2019-02-02. The conserved histone chaperone LIN-53 links lifespan and healthspan regulation in C. elegans. https://doi.org/10.1101/539015

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