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The study tests whether combining daf-2 hypomorphs with ant-1.1 knockdown yields stronger effects than single interventions. Results show a four-fold lifespan increase with a matching healthspan improvement, not reliant on the mitochondrial unfolded protein response, and supported by a distinctive transcriptional signature.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/combined-downregulation-of-insulin-and-mitochondrial-signaling-leads-to-synergistic-life-and-healthspan-extension-in-caenorhabditis-elegans/427255/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/combined-downregulation-of-insulin-and-mitochondrial-signaling-leads-to-synergistic-life-and-healthspan-extension-in-caenorhabditis-elegans/427255.png","ImageObject",300,407,{"name":92,"@type":93},"Olivia Brown","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-04","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":81},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What signaling pathway is central to this work in C. elegans?","Question",{"text":112,"@type":113},"The study centers on the insulin/IGF-1 signaling (IIS) pathway, which regulates nutrient response and influences lifespan and healthspan.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What combination strategy produces the main results?",{"text":117,"@type":113},"Combining a daf-2 hypomorph with adenine nucleotide translocase 1.1 (ant-1.1) knockdown leads to a four-fold increase in lifespan and a concurrent healthspan increase.",{"name":119,"@type":110,"acceptedAnswer":120},"Does the lifespan/healthspan gain require the mitochondrial unfolded protein response?",{"text":121,"@type":113},"No. The increased lifespan and healthspan improvement are demonstrated to be not dependent on the mitochondrial unfolded protein response.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},427255,1790793044,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":81,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":8,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":81},16904993612988,"https://ap-avatar.wpscdn.com/davatar_a8503ba1806abce46bf441b54a3ca4cd","288 Innovation in Aging, 2025, Vol. 9, No. S2  \nAbstract citation ID: igaf122.968  \nCOMBINED DOWNREGULATION OF INSULIN AND MITOCHONDRIAL SIGNALING LEADS TO SYNERGISTIC LIFE-AND HEALTHSPAN EXTENSION IN CAENORHABDITIS ELEGANS  \nSinclair Emans1, Nicole Sthur2, Sophia DiPaola3, Zoe Nathwani4, and Alexander Soukas5, 1. Harvard Medical School, Boston, Massachusetts, United States, 2. University of Southern California, Los Angeles, California, United States, 3. Eckerd College, St.  \nPetersburg, Florida, United States, 4. Harvard University, Boston, Massachusetts, United States, 5. Massachusetts General Hospital, Boston, Massachusetts, United States  \nThe Caenorhabditis elegans insulin/IGF-1 signaling (IIS) pathway functions as both a rheostat for nutrient levels and as an evolutionarily conserved mechanism likely to shed light on its functions and regulation in higher organisms. Early studies in C. elegans demonstrated that IIS receptor homolog daf-2 downregulation led to a drastic increase in lifespan, from a maximum of 25 to 60 days. Over the following decades many other manipulations were shown to increase lifespan in worms including interventions in diet,AMPK, mTOR signaling, and mitochondrial homeostasis, to name just a few. However, combinatorial lifespan studies still remain few and far between. Herein, we demonstrate that combining a daf-2 hypomorph with adenine nucleotide translocase 1.1 (ant-1.1) knockdown leads to a four-fold increase in lifespan and a concomitant healthspan increase.We further demonstrate that this increase is not dependent on the mitochondrial unfolded protein response. Moreover, we showthat a distinctive transcriptional signature could explain this distinctive synergistic phenomenon. In sum, we describe a combinatorial treatment that can quadruple lifespan and produce a similar healthspan increase through a potentially unique transcriptional program.","cbCaitDPmNQ0QufJ","https://ap.wps.com/l/cbCaitDPmNQ0QufJ","pdf",304739,"English","# Abstract\n## IIS and lifespan regulation\n## Combined daf-2 and ant-1.1 effects\n## Independence from mitochondrial unfolded protein response\n## Transcriptional signature and conclusions","[{\"question\":\"What signaling pathway is central to this work in C. elegans?\",\"answer\":\"The study centers on the insulin/IGF-1 signaling (IIS) pathway, which regulates nutrient response and influences lifespan and healthspan.\"},{\"question\":\"What combination strategy produces the main results?\",\"answer\":\"Combining a daf-2 hypomorph with adenine nucleotide translocase 1.1 (ant-1.1) knockdown leads to a four-fold increase in lifespan and a concurrent healthspan increase.\"},{\"question\":\"Does the lifespan/healthspan gain require the mitochondrial unfolded protein response?\",\"answer\":\"No. The increased lifespan and healthspan improvement are demonstrated to be not dependent on the mitochondrial unfolded protein response.\"}]","COMBINED DOWNREGULATION OF INSULIN AND MITOCHONDRIAL SIGNALING LEADS TO SYNERGISTIC LIFE- AND HEALTHSPAN EXTENSION IN CAENORHABDITIS ELEGANS | PDF",1790643326]