Inactivating histone deacetylase HDA promotes longevity by mobilizing trehalose metabolism

Area of Science:

• Epigenetics
• Molecular Biology
• Aging Research

Background:

• Histone acetylations are crucial epigenetic markers for gene transcription, responding to metabolic shifts and environmental stresses.
• Histone deacetylases (HDACs) play key roles in regulating gene expression and cellular processes.

Purpose of the Study:

• To investigate the role of the HDA complex, a class-II HDAC, in regulating aging and stress responses.
• To identify the specific epigenetic targets and molecular mechanisms by which HDA influences lifespan.

Main Methods:

• Utilized the SEquencing-Based Yeast replicative Lifespan screen (SYLS) method.
• Employed the yeast knockout collection to screen for genes affecting lifespan.
• Analyzed H3K18 acetylation levels and gene expression in the trehalose metabolic pathway.
• Investigated HDA homologs in C. elegans and Drosophila.

Main Results:

• Disruption of the HDA complex significantly extends yeast lifespan.
• HDA deficiency confers resistance to DNA damage and osmotic stress.
• Increased H3K18 acetylation at storage carbohydrate genes, particularly trehalose pathway genes, underlies these effects.
• The longevity effect of HDA is independent of the Cyc8-Tup1 repressor complex.
• Silencing HDA homologs in C. elegans and Drosophila also increases lifespan and delays aging phenotypes.

Conclusions:

• The HDA complex acts as a negative regulator of longevity through epigenetic control of carbohydrate metabolism.
• HDA-mediated epigenetic regulation of H3K18 acetylation is a conserved mechanism controlling lifespan across species.
• Targeting HDACs offers a potential therapeutic strategy for age-related diseases and promoting longevity.