Roles of the developmental regulator unc-62/homothorax in limiting longevity in Caenorhabditis elegans

This is an open-access article distributed under the terms of the Creative Commons Attribution License.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 unc-62 (Homothorax) as a developmental regulator that binds proximal to age-regulated genes and modulates lifespan. Although unc-62 is expressed in diverse tissues, its functions in the intestine play a particularly important role in modulating lifespan, as intestine-specific knockdown of unc-62 by RNAi increases lifespan. An alternatively-spliced, tissue-specific isoform of unc-62 is expressed exclusively in the intestine and declines with age. Through analysis of the downstream consequences of unc-62 knockdown, we identify multiple effects linked to aging. First, unc-62 RNAi decreases the expression of yolk proteins (vitellogenins) that aggregate in the body cavity in old age. Second, unc-62 RNAi results in a broad increase in expression of intestinal genes that typically decrease expression with age, suggesting that unc-62 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 ins-7 limits lifespan by repressing activity of insulin pathway response factor DAF-16/FOXO in aged animals. These results illustrate how unc-62 regulation of intestinal gene expression is responsible for limiting lifespan during the normal aging process.ELVN has been supported by the Stanford Genome Training Program and the Smith Fellowship (Stanford Graduate Fellowships program). Research in the laboratory of SKK is supported by the NHGRI, NIGMS, NIA, and the Glenn Foundation. Some strains were provided by the Caenorhabditis Genetics Center, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440).Peer Reviewe

Roles of the Developmental Regulator <em>unc-62/</em>Homothorax in Limiting Longevity in <em>Caenorhabditis elegans</em>

<div><p>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 <i>unc-62</i> (Homothorax) as a developmental regulator that binds proximal to age-regulated genes and modulates lifespan. Although <i>unc-62</i> is expressed in diverse tissues, its functions in the intestine play a particularly important role in modulating lifespan, as intestine-specific knockdown of <i>unc-62</i> by RNAi increases lifespan. An alternatively-spliced, tissue-specific isoform of <i>unc-62</i> is expressed exclusively in the intestine and declines with age. Through analysis of the downstream consequences of <i>unc-62</i> knockdown, we identify multiple effects linked to aging. First, <i>unc-62</i> RNAi decreases the expression of yolk proteins (vitellogenins) that aggregate in the body cavity in old age. Second, <i>unc-62</i> RNAi results in a broad increase in expression of intestinal genes that typically decrease expression with age, suggesting that <i>unc-62</i> 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 <i>ins-7</i> limits lifespan by repressing activity of insulin pathway response factor DAF-16/FOXO in aged animals. These results illustrate how <i>unc-62</i> regulation of intestinal gene expression is responsible for limiting lifespan during the normal aging process.</p> </div