A Transcription Elongation Factor That Links Signals from the Reproductive System to Lifespan Extension in Caenorhabditis elegans Arjumand Ghazi, Sivan Henis-Korenblit, Cynthia Kenyon* Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California, United States of America Abstract In Caenorhabditis elegans and Drosophila melanogaster, the aging of the soma is influenced by the germline. When germline-stem cells are removed, aging slows and lifespan is increased. The mechanism by which somatic tissues respond to loss of the germline is not well-understood. Surprisingly, we have found that a predicted transcription elongation factor, TCER-1, plays a key role in this process. TCER-1 is required for loss of the germ cells to increase C. elegans’ lifespan, and it acts as a regulatory switch in the pathway. When the germ cells are removed, the levels of TCER-1 rise in somatic tissues. This increase is sufficient to trigger key downstream events, as overexpression of tcer-1 extends the lifespan of normal animals that have an intact reproductive system. Our findings suggest that TCER-1 extends lifespan by promoting the expression of a set of genes regulated by the conserved, life-extending transcription factor DAF-16/FOXO. Interestingly, TCER-1 is not required for DAF-16/FOXO to extend lifespan in animals with reduced insulin/IGF-1 signaling. Thus, TCER-1 specifically links the activity of a broadly deployed transcription factor, DAF-16/FOXO, to longevity signals from reproductive tissues. Citation: Ghazi A, Henis-Korenblit S, Kenyon C (2009) A Transcription Elongation Factor That Links Signals from the Reproductive System to Lifespan Extension in Caenorhabditis elegans. PLoS Genet 5(9): e1000639. doi:10.1371/journal.pgen.1000639 Editor: Stuart K. Kim, Stanford University Medical Center, United States of America Received June 24, 2009; Accepted August 10, 2009; Published September 11, 2009 Copyright: 2009 Ghazi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: AG was supported by the Larry Hillblom Foundation for Aging Research postdoctoral grant. SHK was supported by a Human Frontier Science Program fellowship. This work was funded by National Institute of Health grant RO1 AG020932 to CK, who is an American Cancer Society Research Professor, director of University of California San Francisco’s Hillblom Center for the Biology of Aging, and a founder and director of Elixir Pharmaceuticals. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: cynthia.kenyon@ucsf.edu Introduction When the germline of C. elegans is removed, either by laser ablation or by mutations that block germline-stem cell prolifera- tion, the animals live approximately 60% longer than normal [1,2]. This longevity is not a simple consequence of sterility, as removing the entire gonad (the germ cells as well as the somatic reproductive tissues) does not extend lifespan [1]. These and other findings suggest that both the germline cells and the somatic reproductive tissues influence lifespan [3,4]. A link between reproductive tissues and aging may be widespread in nature, as removing germline-stem cells during adulthood increases the lifespan of flies [5], as well as worms, and transplanting ovaries of young mice into older animals can increase lifespan as well [6]. The mechanism by which loss of the germline extends lifespan is not well understood. At least two transcription factors, the FOXO- family transcription factor DAF-16/FOXO [7–9] and the nuclear hormone receptor DAF-12 [10], are required for germ-cell loss to extend lifespan in C. elegans [1]. When germ cells are removed, DAF-16/FOXO accumulates in nuclei, primarily in the animal’s intestine [11]. The intestine, which functions as the worm’s entire endoderm, including its fat tissue, appears to play a key role in this pathway, as expressing DAF-16/FOXO only in the intestine completely restores the lifespan extension of germline-defective daf-16(2) animals [12]. DAF-16/FOXO nuclear localization requires an ankyrin-repeat, intestinal protein called KRI-1 [13]. In addition, full DAF-16/FOXO nuclear localization requires DAF-12/NHR [10,13], as well as DAF-9, a cytochrome P450 protein that synthesizes a DAF-12/NHR ligand [13–15]. DAF-16/FOXO is particularly interesting because of its evolutionarily-conserved role in another lifespan regulatory path- way, the insulin/IGF-1 endocrine pathway [16–18]. In wild-type worms, the insulin/IGF-1 receptor DAF-2 activates a series of conserved kinases that ultimately phosphorylate and inactivate DAF-16/FOXO [19–21]. When insulin/IGF-1 signaling is inhib- ited, DAF-16/FOXO accumulates in nuclei, where it regulates the transcription of downstream antioxidant, chaperone, innate- immunity, and metabolic genes that more directly affect lifespan [8,9,11,22–25]. Insulin/IGF-1 signaling and FOXO proteins influence lifespan in worms, flies and mice [16,26,27]. The pathway appears to affect human longevity as well, as variants in the human Foxo3a gene have been linked to longevity in several human populations [28–32], and functionally significant IGF-1 receptor mutations are overrepresented in populations of centenarians [33]. In an effort to better understand how reproductive cues trigger lifespan extension, we carried out a genetic screen for RNAi clones that prevent germline loss from extending lifespan. Surprisingly, in our screen we identified a gene, tcer-1, that encodes the homolog of the human transcription elongation factor TCERG1. Loss of tcer-1 in C. elegans sharply curtails the lifespan extension produced by removal of the germline, but has little or no effect on wild-type lifespan. Thus, TCER-1 is not likely to be a general component of the transcriptional machinery; instead, it has a much more specific function in the animal. PLoS Genetics | www.plosgenetics.org 1 September 2009 | Volume 5 | Issue 9 | e1000639