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. Author Summary The normal aging process in Caenorhabditis elegans involves coordinated changes in expression of about a thousand genes. In order to find upstream regulators responsible for these aging genes, we used a genomics approach to screen for transcription factors that bind to them. We focused on one such regulator, unc-62/Homothorax , that encodes a co-factor for a Hox transcription factor. Although essential for development, expression of unc-62 in adults limits lifespan. We find that unc-62 is a transcriptional activator of yolk protein genes, which are synthesized in the intestine and encode essential nutrients for progeny but accumulate to toxic levels with age. Additionally, analysis of unc-62 knockdown indicates that when vitellogenin transcription is decreased, transcription of intestinal genes with somatic functions increases. Thus, activation of yolk protein gene expression by unc-62 is both a burden on maternal health and a necessary resource for embryonic growth. Surprisingly, we also found that the intestine of old worms has novel expression of non-intestinal proteins that are toxic when expressed in the intestine and are activated by unc-62 in old age. Our work on transcriptional regulation of intrinsic gene expression differences during normal aging has revealed insights into the mechanisms that limit lifespan.
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