{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:54:37Z","timestamp":1790747677011,"version":"4.1.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Nutr."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Frailty is a degenerative geriatric syndrome characterized by declining muscle mass and function, unintentional weight loss, and fatigue. It is a key risk factor for many geriatric diseases and poor postoperative outcomes. Currently, pathogenesis remains unclear, and apart from nutritional support and exercise, no pharmacological interventions are available. Notably, the frailty phenotype is also a major feature in patients with advanced-stage cancer, and both frailty and advanced cancer are characterized by dysregulation of nutritional and energy metabolism. Consequently, cancer serves as a novel accelerated model for investigating the mechanisms underlying frailty development.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The phenome-wide association study (PheWAS) framework was employed to systematically analyze the causal relationship between 264 cancer types and frailty, and to identify candidate cancer types directly causally associated with frailty. A large-scale analysis was conducted to assess the causal relationship between \u201ccandidate cancer- Icelandic peripheral blood proteome-frailty\u201d and to further explore the characteristics and patterns of the key proteins mediating cancer-induced frailty using the two-sample Mendelian randomization method. Finally, the correlation between key candidate proteins and frailty was verified using peripheral blood from a 100-case colorectal cancer (CRC) cohort.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The PheWAS analysis identified 21 cancer types with significant causal associations with frailty among the 264 cancers examined. An in-depth analysis of the top 5 cancer types revealed that the mechanisms by which they induce frailty exhibit both prominent shared features and distinct characteristics. Shared signaling pathways included stress responses, immune processes, and metabolic pathways. Among these, immune-related pathways involving complement component C3 (C3), lipocalin-2 (LCN2), and coagulation factor V (F5) emerged as key shared mechanisms across multiple cancer types. Finally, validation in an independent clinical cohort of patients with CRC (\n                      <jats:italic>n<\/jats:italic>\n                      \u202f=\u202f100) demonstrated that circulating C3 levels were positively correlated with frailty severity and the frailty-related comorbidity index, and negatively correlated with serum albumin levels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study systematically elucidated the causal relationships between cancer and frailty, identified multiple candidate proteins that may drive frailty progression, and demonstrated that complement C3 is associated with frailty development. Furthermore, we propose that cancer serves as a novel accelerated model for investigating the mechanisms underlying frailty. These findings provide new insights into the biological mechanisms underlying frailty and identify a series of promising molecular targets for future mechanistic studies and therapeutic interventions.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnut.2026.1953476","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:56:06Z","timestamp":1790744166000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Complement C3 is associated with cancer-induced frailty: genetic and clinical evidence"],"prefix":"10.3389","volume":"13","author":[{"given":"Chaobao","family":"Zhang","sequence":"first","affiliation":[{"name":"Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai Institute of Geriatrics and Gerontology, Huadong Hospital, Shanghai Medical College, Fudan University","place":["Shanghai, China"]},{"name":"National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Huadong Hospital, Shanghai Medical College, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiyi","family":"Li","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai Institute of Geriatrics and Gerontology, Huadong Hospital, Shanghai Medical College, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhan","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Oncology, Huadong Hospital, Shanghai Medical College, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijun","family":"Bao","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai Institute of Geriatrics and Gerontology, Huadong Hospital, Shanghai Medical College, Fudan University","place":["Shanghai, China"]},{"name":"National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"101498","DOI":"10.1016\/j.arr.2021.101498","article-title":"Prevalence of multidimensional frailty and pre-frailty in older people in different settings: a systematic review and meta-analysis","volume":"72","author":"Veronese","year":"2021","journal-title":"Ageing Res 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Res"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1038\/s41598-017-00099-7","article-title":"Complement C3 of the innate immune system secreted by muscle adipogenic cells promotes myogenic differentiation","volume":"7","author":"Rouaud","year":"2017","journal-title":"Sci Rep"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1186\/s12877-024-04720-z","article-title":"Complement component C3 is associated with body composition parameters and sarcopenia in community-dwelling older adults: a cross-sectional study in Japan","volume":"24","author":"Nakamura","year":"2024","journal-title":"BMC Geriatr"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"E232","DOI":"10.1152\/ajpendo.00476.2010","article-title":"Acute injection of ASP in the third ventricle inhibits food intake and locomotor activity in rats","volume":"301","author":"Roy","year":"2011","journal-title":"Am J Physiol Endocrinol 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