Activated Interferon Signaling Suppresses Age-Dependent Liver Cancer

Activated Interferon Signaling Suppresses Age-Dependent Liver Cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Biological Sciences - Article Activated Interferon Signaling Suppresses Age-Dependent Liver Cancer Peter Adams, Aaron Havas, Kathryn Lande, Adarsh Rajesh, K. Evensen, and 23 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4838839/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Age is a major risk factor for liver cancer, as is the case for most adult human cancers. However, the underlying mechanisms are not well defined. A better understanding of the role of aging in liver and other cancers can facilitate approaches for risk assessment, early detection and prevention. We hypothesize that age-driven changes render aged liver more sensitive to oncogenic stress and hence tumorigenesis. To investigate how the liver changes with age, we documented the immune profile, transcriptome and epigenome of healthy livers from both young and aged mice, revealing pronounced alterations with aging. Notably, in aged hepatocytes, we identified heightened interferon (IFN) signaling, as well as simultaneous tumor suppressor and oncogene signaling at both bulk and single cell level, suggestive of an aged liver that is poised for neoplasia. To challenge this seemingly poised state, we employed adeno-associated virus (AAV)-mediated expression of a c-Myc oncogene in young and aged mouse liver hepatocytes in vivo. Analysis of aged hepatocytes expressing c-Myc revealed further elevated expression of IFN Stimulated Genes (ISGs). This ISG upregulation was evident in multiple models of oncogenic stress and transformation in older mice and also observed in aged humans with Metabolic dysfunction-Associated Steatohepatitis (MASH). We determined that Stat1 is both necessary and sufficient for the age specific elevated ISG expression in old wild type mice. Remarkably, inhibiting Jak/Stat signaling alongside ectopic c-Myc expression led to high-grade hepatocyte dysplasia and tumor formation, selectively in aged mice. Together, these results suggest that an aged liver is in a state of “precarious balance”, due to concurrent activation of oncogenic and tumor suppressor pathways, but protected against neoplastic progression by IFN-signaling. Age-dependent activation of IFN signaling has been observed in many tissues and recent studies have demonstrated its detrimental consequences on aging, raising the question as to why IFN signaling is activated during aging. We propose that aged tissues are intrinsically at higher risk of cancer and age-dependent activation of IFN-signaling is an adaptive process to protect from tumorigenesis, but one that also has maladaptive consequences. Biological sciences/Cell biology/Mechanisms of disease Biological sciences/Cancer/Oncogenes Biological sciences/Cancer/Tumour-suppressor proteins Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4838839","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":338242840,"identity":"af7138da-56b4-4839-92fb-ad26ab7fc116","order_by":0,"name":"Peter Adams","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA70lEQVRIiWNgGAWjYHACAyC2AZEGB0jRkka6lsNgLcSpN2c/vPHTjT/n7c2lmzce/FFjk9gvfcaA4eOeWpxaLHvSiqVz224n7pxzrOAwz7G0xJl9OQaMM54dx+2qAzkG0rkNtxMMbuQYHGZsOGxscIbHgJnnwDHcWs6/Mf6d8+ecPUjLwZ9ALfYEtdzIMZPOYTvAuAGo5QBvw2E5Ax6wlhrcfpnxrMw6ty0Z7hc5iTNsBQdnHDiAU4s5f/Lm2zl/7EAhtvkjMMR4+HuYNz74cKAOt8PgLAk4iwMUp4dJ0sL+AEjgtmUUjIJRMApGHAAAptddNdjjouQAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-0684-1770","institution":"Sanford Burnham Prebys Medical Discovery Institute","correspondingAuthor":true,"prefix":"","firstName":"Peter","middleName":"","lastName":"Adams","suffix":""},{"id":338242841,"identity":"1d962a17-b334-426e-9b2d-124bf4b1f1ef","order_by":1,"name":"Aaron Havas","email":"","orcid":"https://orcid.org/0000-0003-4291-8015","institution":"Sanford Burnham Prebys Medical Discovery Institute","correspondingAuthor":false,"prefix":"","firstName":"Aaron","middleName":"","lastName":"Havas","suffix":""},{"id":338242842,"identity":"d0ca3e80-caed-426a-9ff4-50c7372e37ff","order_by":2,"name":"Kathryn Lande","email":"","orcid":"","institution":"The Salk Institute for Biological Studies","correspondingAuthor":false,"prefix":"","firstName":"Kathryn","middleName":"","lastName":"Lande","suffix":""},{"id":338242843,"identity":"9501a778-3f12-4920-ae0a-6548b575d336","order_by":3,"name":"Adarsh Rajesh","email":"","orcid":"","institution":"Sanford Burnham Prebys Medical Discovery Institute","correspondingAuthor":false,"prefix":"","firstName":"Adarsh","middleName":"","lastName":"Rajesh","suffix":""},{"id":338242844,"identity":"e9da2b95-d87b-4f6d-98e8-ea2d0468d1eb","order_by":4,"name":"K. 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However, the underlying mechanisms are not well defined. A better understanding of the role of aging in liver and other cancers can facilitate approaches for risk assessment, early detection and prevention. We hypothesize that age-driven changes render aged liver more sensitive to oncogenic stress and hence tumorigenesis. To investigate how the liver changes with age, we documented the immune profile, transcriptome and epigenome of healthy livers from both young and aged mice, revealing pronounced alterations with aging. Notably, in aged hepatocytes, we identified heightened interferon (IFN) signaling, as well as simultaneous tumor suppressor and oncogene signaling at both bulk and single cell level, suggestive of an aged liver that is poised for neoplasia. To challenge this seemingly poised state, we employed adeno-associated virus (AAV)-mediated expression of a c-Myc oncogene in young and aged mouse liver hepatocytes in vivo. Analysis of aged hepatocytes expressing c-Myc revealed further elevated expression of IFN Stimulated Genes (ISGs). This ISG upregulation was evident in multiple models of oncogenic stress and transformation in older mice and also observed in aged humans with Metabolic dysfunction-Associated Steatohepatitis (MASH). We determined that Stat1 is both necessary and sufficient for the age specific elevated ISG expression in old wild type mice. Remarkably, inhibiting Jak/Stat signaling alongside ectopic c-Myc expression led to high-grade hepatocyte dysplasia and tumor formation, selectively in aged mice. Together, these results suggest that an aged liver is in a state of “precarious balance”, due to concurrent activation of oncogenic and tumor suppressor pathways, but protected against neoplastic progression by IFN-signaling. Age-dependent activation of IFN signaling has been observed in many tissues and recent studies have demonstrated its detrimental consequences on aging, raising the question as to why IFN signaling is activated during aging. We propose that aged tissues are intrinsically at higher risk of cancer and age-dependent activation of IFN-signaling is an adaptive process to protect from tumorigenesis, but one that also has maladaptive consequences.","manuscriptTitle":"Activated Interferon Signaling Suppresses Age-Dependent Liver Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-12 03:57:47","doi":"10.21203/rs.3.rs-4838839/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-aging","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nataging","sideBox":"Learn more about [Nature Aging](https://www.nature.com/nataging/)","snPcode":"","submissionUrl":"","title":"Nature Aging","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"49baaeea-8c7e-46e7-a7bb-c9534453464c","owner":[],"postedDate":"December 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":35837000,"name":"Biological sciences/Cell biology/Mechanisms of disease"},{"id":35837001,"name":"Biological sciences/Cancer/Oncogenes"},{"id":35837002,"name":"Biological sciences/Cancer/Tumour-suppressor proteins"}],"tags":[],"updatedAt":"2024-12-12T03:57:47+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-12 03:57:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4838839","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4838839","identity":"rs-4838839","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}