Authors: Van Nostrand EL; Sánchez-Blanco A; Wu B; Nguyen A; Kim SK
Abstract: The normal aging process is associated with stereotyped changes in gene expression, but the regulators responsible for these age-dependent changes are poorly understood. Using a novel genomics approach, we identified HOX co-factor (Homothorax) as a developmental regulator that binds proximal to age-regulated genes and modulates lifespan. Although is expressed in diverse tissues, its functions in the intestine play a particularly important role in modulating lifespan, as intestine-specific knockdown of by RNAi increases lifespan. An alternatively-spliced, tissue-specific isoform of is expressed exclusively in the intestine and declines with age. Through analysis of the downstream consequences of knockdown, we identify multiple effects linked to aging. First, RNAi decreases the expression of yolk proteins (vitellogenins) that aggregate in the body cavity in old age. Second, RNAi results in a broad increase in expression of intestinal genes that typically decrease expression with age, suggesting that activity balances intestinal resource allocation between yolk protein expression and fertility on the one hand and somatic functions on the other. Finally, in old age, the intestine shows increased expression of several aberrant genes; these UNC-62 targets are expressed predominantly in neuronal cells in developing animals, but surprisingly show increased expression in the intestine of old animals. Intestinal expression of some of these genes during aging is detrimental for longevity; notably, increased expression of insulin limits lifespan by repressing activity of insulin pathway response factor DAF-16/FOXO in aged animals. These results illustrate how regulation of intestinal gene expression is responsible for limiting lifespan during the normal aging process.
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Journal: PLoS genetics Volume: 9 Issue: 2 Pages: e1003325 Date: March 8, 2013 PMID: 23468654 |
Van Nostrand EL, Sánchez-Blanco A, Wu B, Nguyen A, Kim SK (2013) Roles of the Developmental Regulator unc-62/Homothorax in Limiting Longevity in Caenorhabditis elegans. PLoS genetics 9: e1003325.
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