Abstract
Some genes are essential for survival, while other genes play modulatory roles on health and survival. Genes that play modulatory roles may promote an organism’s survival and health by fine-tuning physiological processes. An unbiased search for genes that alter an organism’s ability to maintain aspects of health may uncover modulators of lifespan and healthspan. From an unbiased screen for Caenorhabditis elegans mutants that show a progressive decline in motility, we aimed to identify genes that play a modulatory role in maintenance of locomotor healthspan. Here we report the involvement of hda-3, encoding a class I histone deacetylase, as a genetic factor that contributes in the maintenance of general health and locomotion in C. elegans. We identified a missense mutation in HDA-3 as the causative mutation in one of the isolated strains that show a progressive decline in maximum velocity and travel distance. From transcriptome analysis, we found a cluster of genes on Chromosome II carrying BATH domains that were downregulated by hda-3. Furthermore, downregulation of individual bath genes leads to significant decline in motility. Our study identifies genetic factors that modulate the maintenance of locomotor healthspan and may reveal potential targets for delaying age-related locomotor decline.
Highlights
Locomotor ability is a key determinant of quality of life in the elderly (Groessl et al 2007).Age-related declines in locomotor ability are predictors of loss of independence, depressive symptoms, morbidity, and mortality (Trombetti et al 2016)
We refer to this mutation site as dys-1(ix259), since later we found that this mutation site is not involved in the progressive decline in locomotor ability
In this study, we found that proper HDA-3 function is required for the full maintenance of locomotor ability in C. elegans
Summary
Locomotor ability is a key determinant of quality of life in the elderly (Groessl et al 2007).Age-related declines in locomotor ability are predictors of loss of independence, depressive symptoms, morbidity, and mortality (Trombetti et al 2016). A combination of genetic and environmental factors contribute to how well a person can maintain locomotor ability during adulthood. The specific genetic factors that contribute to the maintenance of locomotor ability are largely unknown. A better understanding of the genetic factors that work to maintain locomotor ability may enable novel approaches to prevent or delay agerelated declines in locomotor ability. In order to identify genetic factors that regulate adult locomotor ability, we previously carried out a forward genetic screen for C. elegans mutants that show progressive declines in adult locomotor ability (Kawamura and Maruyama 2019). Characterization of one of the isolated strains led to the identification of a nonsense mutation in elpc-2 and implicated the Elongator complex and tRNA modifications as factors that regulate locomotor healthspan in
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