Pub Date : 2026-03-12DOI: 10.1038/s41591-026-04278-w
Max Rollwage, Jessica McFadyen, Keno Juchems, Annamaria Balogh, Sashank Pisupati, Margareta-Theodora Mircea, Tobias U. Hauser, George Prichard, Ross Harper
Clinician–patient conversations form the cornerstone of mental healthcare. Large language models (LLMs) could hold promise for this domain but their effectiveness in patient-facing interactions remains largely unproven. Here we introduce a cognitive layer architecture that enhances general-purpose LLMs with specialized clinical psychotherapeutic reasoning capabilities. In a randomized, double-blind evaluation, 227 human participants generated naturalistic mental well-being session transcripts by interacting with different therapy agents. A consortium of 22 expert clinicians assessed these transcripts, finding that LLMs augmented with this architecture consistently outperformed both standalone state-of-the-art LLMs and human clinicians across key clinical competencies required for delivering high-quality cognitive-behavioral therapy. We validated these results in an analysis of 19,674 transcripts from a large-scale, real-world deployment where an LLM embedded within this cognitive layer architecture was used as part of healthcare delivery to support 8,920 users seeking mental well-being assistance. Increased cognitive layer activation was associated with greater symptom improvement and a higher likelihood of long-term clinical recovery (~10 weeks). Our findings demonstrate that a cognitive layer architecture can enable LLMs to deliver high-quality cognitive-behavioral therapy interactions, with continued research warranted into mechanisms and clinical efficacy of AI-assisted therapeutics.
{"title":"A cognitive layer architecture to support large-language model performance in psychotherapy interactions","authors":"Max Rollwage, Jessica McFadyen, Keno Juchems, Annamaria Balogh, Sashank Pisupati, Margareta-Theodora Mircea, Tobias U. Hauser, George Prichard, Ross Harper","doi":"10.1038/s41591-026-04278-w","DOIUrl":"https://doi.org/10.1038/s41591-026-04278-w","url":null,"abstract":"Clinician–patient conversations form the cornerstone of mental healthcare. Large language models (LLMs) could hold promise for this domain but their effectiveness in patient-facing interactions remains largely unproven. Here we introduce a cognitive layer architecture that enhances general-purpose LLMs with specialized clinical psychotherapeutic reasoning capabilities. In a randomized, double-blind evaluation, 227 human participants generated naturalistic mental well-being session transcripts by interacting with different therapy agents. A consortium of 22 expert clinicians assessed these transcripts, finding that LLMs augmented with this architecture consistently outperformed both standalone state-of-the-art LLMs and human clinicians across key clinical competencies required for delivering high-quality cognitive-behavioral therapy. We validated these results in an analysis of 19,674 transcripts from a large-scale, real-world deployment where an LLM embedded within this cognitive layer architecture was used as part of healthcare delivery to support 8,920 users seeking mental well-being assistance. Increased cognitive layer activation was associated with greater symptom improvement and a higher likelihood of long-term clinical recovery (~10 weeks). Our findings demonstrate that a cognitive layer architecture can enable LLMs to deliver high-quality cognitive-behavioral therapy interactions, with continued research warranted into mechanisms and clinical efficacy of AI-assisted therapeutics.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"61 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147394056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-12DOI: 10.1038/s41591-026-04252-6
Luyang Luo,Sung Eun Kim,Xiaoman Zhang,Julius M Kernbach,Roshan Kenia,Julian N Acosta,Larry A Nathanson,Adrian D Haimovich,Adam Rodman,Ethan Goh,Jonathan H Chen,Nigam H Shah,David A Kim,James Zou,Faisal Mahmood,Jakob Nikolas Kather,Matthew Lungren,Vivek Natarajan,Eric J Topol,Pranav Rajpurkar
Clinical evaluation of large language models (LLMs) currently relies on static datasets and isolated scenarios that fail to capture the cascading effects of healthcare decisions. We propose the Clinical Environment Simulator (CES), a framework that evaluates clinical LLMs within digital hospital environments where every decision dynamically alters future states. The CES would use a parallel simulation architecture: a 'hospital engine' that tracks bed availability, staff workloads and equipment status in real time, and a 'patient engine' that simulates disease progression and treatment responses based on LLM interventions. Unlike current benchmarks, the CES framework requires clinical LLMs to execute decisions through realistic electronic health record interfaces, while managing trade-offs between individual patient optimization and system-wide efficiency. The CES enables three critical evaluations absent from current benchmarks: temporal reasoning under evolving constraints, where delayed diagnostics can lead to patient deterioration; resource-aware decision-making, where aggressive workups for one patient may exhaust capacity needed by others; and operational resilience, through adversarial testing with simultaneous emergencies and system failures. By scoring LLM performance on both clinical outcomes and operational metrics, the CES represents a shift toward evaluating clinical LLMs as a dynamic and integrated component of healthcare delivery systems.
{"title":"A clinical environment simulator for dynamic AI evaluation.","authors":"Luyang Luo,Sung Eun Kim,Xiaoman Zhang,Julius M Kernbach,Roshan Kenia,Julian N Acosta,Larry A Nathanson,Adrian D Haimovich,Adam Rodman,Ethan Goh,Jonathan H Chen,Nigam H Shah,David A Kim,James Zou,Faisal Mahmood,Jakob Nikolas Kather,Matthew Lungren,Vivek Natarajan,Eric J Topol,Pranav Rajpurkar","doi":"10.1038/s41591-026-04252-6","DOIUrl":"https://doi.org/10.1038/s41591-026-04252-6","url":null,"abstract":"Clinical evaluation of large language models (LLMs) currently relies on static datasets and isolated scenarios that fail to capture the cascading effects of healthcare decisions. We propose the Clinical Environment Simulator (CES), a framework that evaluates clinical LLMs within digital hospital environments where every decision dynamically alters future states. The CES would use a parallel simulation architecture: a 'hospital engine' that tracks bed availability, staff workloads and equipment status in real time, and a 'patient engine' that simulates disease progression and treatment responses based on LLM interventions. Unlike current benchmarks, the CES framework requires clinical LLMs to execute decisions through realistic electronic health record interfaces, while managing trade-offs between individual patient optimization and system-wide efficiency. The CES enables three critical evaluations absent from current benchmarks: temporal reasoning under evolving constraints, where delayed diagnostics can lead to patient deterioration; resource-aware decision-making, where aggressive workups for one patient may exhaust capacity needed by others; and operational resilience, through adversarial testing with simultaneous emergencies and system failures. By scoring LLM performance on both clinical outcomes and operational metrics, the CES represents a shift toward evaluating clinical LLMs as a dynamic and integrated component of healthcare delivery systems.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"81 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147439607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-12DOI: 10.1038/s41591-026-04265-1
Aurélie Ploquin, Rosemarie D. Mason, LaSonji A. Holman, Myra Happe, Alicia T. Widge, Laura Novik, Ana M. Ortega-Villa, Galina V. Yamshchikov, Ingelise J. Gordon, Abidemi Ola, Anita Arthur, Pamela J. M. Costner, Floreliz Mendoza, Jamie Saunders, Xioalin Wang, William R. Whalen, Joanna Utoh, Jennifer Cunningham, Lorin N. Loftus, Ashley Heimann, Katia Korzeniwsky, Shayne F. Andrew, Evan Lamb, Shruthi Shyam Sunder, Amelia Thompson, Mary McDonald, Kathryn E. Foulds, Nancy J. Sullivan, Jessica Bahorich, Emily E. Coates, Rebecca J. Loomis, Barney S. Graham, Karin Bok, Sunny Himansu, Brett Leav, Walla Dempsey, John H. Beigel, Mario Roederer, Lesia K. Dropulic, The VRC 322 study team
Nipah virus (NiV) is a highly pathogenic, zoonotic paramyxovirus with pandemic potential. No licensed vaccines or treatments are available. Therefore, we conducted a phase 1, first-in-human, open-label, dose-escalation trial of a lipid nanoparticle mRNA vaccine, mRNA-1215, encoding a chimeric pre-fusion F (Pre-F) protein linked to glycoprotein G of a NiV Malaysian strain. Forty healthy adults, who met eligibility criteria, were enrolled into the 10-, 25-, 50- or 100-μg dose groups with ten participants per group. Each participant received two doses of mRNA-1215, intramuscularly, at a 4-week interval except for one participant in the 10-μg dose group who received only the first dose. All participants remained in the study until their final study visit. The primary outcome of vaccine safety and tolerability was determined by prespecified end points: the frequency and severity of solicited local and systemic adverse events (AEs), unsolicited AEs, safety laboratory measures, medically attended AEs, AEs of special interest, new chronic medical conditions and serious AEs. The most frequently reported local and systemic AEs were mild pain and tenderness at the injection site (n = 33; 82%) and mild malaise (n = 16; 40%), respectively. Overall, the vaccine was well tolerated. No serious AEs occurred during the study. mRNA-1215 elicited robust Pre-F and G binding antibody titers, the prespecified secondary end points. An exploratory analysis found that mRNA-1215 elicited neutralizing titers by 2 weeks after the prime in all dose groups. Responses increased after the boost and remained elevated for at least 1 year after vaccination. These findings demonstrate an initial overall favorable safety profile and immunogenicity results for a first-in-human, structure-based, chimeric mRNA Nipah virus vaccine. mRNA-1215 is a promising vaccine candidate for continued clinical development for populations at risk for regional and potentially larger outbreaks caused by Nipah virus. ClinicalTrials.gov identifier: NCT05398796.
{"title":"A structure-based mRNA vaccine for Nipah virus in healthy adults: a phase 1 trial","authors":"Aurélie Ploquin, Rosemarie D. Mason, LaSonji A. Holman, Myra Happe, Alicia T. Widge, Laura Novik, Ana M. Ortega-Villa, Galina V. Yamshchikov, Ingelise J. Gordon, Abidemi Ola, Anita Arthur, Pamela J. M. Costner, Floreliz Mendoza, Jamie Saunders, Xioalin Wang, William R. Whalen, Joanna Utoh, Jennifer Cunningham, Lorin N. Loftus, Ashley Heimann, Katia Korzeniwsky, Shayne F. Andrew, Evan Lamb, Shruthi Shyam Sunder, Amelia Thompson, Mary McDonald, Kathryn E. Foulds, Nancy J. Sullivan, Jessica Bahorich, Emily E. Coates, Rebecca J. Loomis, Barney S. Graham, Karin Bok, Sunny Himansu, Brett Leav, Walla Dempsey, John H. Beigel, Mario Roederer, Lesia K. Dropulic, The VRC 322 study team","doi":"10.1038/s41591-026-04265-1","DOIUrl":"https://doi.org/10.1038/s41591-026-04265-1","url":null,"abstract":"Nipah virus (NiV) is a highly pathogenic, zoonotic paramyxovirus with pandemic potential. No licensed vaccines or treatments are available. Therefore, we conducted a phase 1, first-in-human, open-label, dose-escalation trial of a lipid nanoparticle mRNA vaccine, mRNA-1215, encoding a chimeric pre-fusion F (Pre-F) protein linked to glycoprotein G of a NiV Malaysian strain. Forty healthy adults, who met eligibility criteria, were enrolled into the 10-, 25-, 50- or 100-μg dose groups with ten participants per group. Each participant received two doses of mRNA-1215, intramuscularly, at a 4-week interval except for one participant in the 10-μg dose group who received only the first dose. All participants remained in the study until their final study visit. The primary outcome of vaccine safety and tolerability was determined by prespecified end points: the frequency and severity of solicited local and systemic adverse events (AEs), unsolicited AEs, safety laboratory measures, medically attended AEs, AEs of special interest, new chronic medical conditions and serious AEs. The most frequently reported local and systemic AEs were mild pain and tenderness at the injection site (n = 33; 82%) and mild malaise (n = 16; 40%), respectively. Overall, the vaccine was well tolerated. No serious AEs occurred during the study. mRNA-1215 elicited robust Pre-F and G binding antibody titers, the prespecified secondary end points. An exploratory analysis found that mRNA-1215 elicited neutralizing titers by 2 weeks after the prime in all dose groups. Responses increased after the boost and remained elevated for at least 1 year after vaccination. These findings demonstrate an initial overall favorable safety profile and immunogenicity results for a first-in-human, structure-based, chimeric mRNA Nipah virus vaccine. mRNA-1215 is a promising vaccine candidate for continued clinical development for populations at risk for regional and potentially larger outbreaks caused by Nipah virus. ClinicalTrials.gov identifier: NCT05398796.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"15 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147394060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-11DOI: 10.1038/s41591-026-04284-y
Gabriel Baldanzi,Anna Larsson,Sergi Sayols-Baixeras,Koen F Dekkers,Ulf Hammar,Diem Nguyen,Tíscar Graells,Shafqat Ahmad,Camila Gazolla Volpiano,Guillaume Meric,Josef D Järhult,Thomas Tängdén,Jonas F Ludvigsson,Lars Lind,Johan Sundström,Karl Michaëlsson,Johan Ärnlöv,Beatrice Kennedy,Marju Orho-Melander,Tove Fall
Disruptions in gut microbiome are implicated in cardiometabolic disorders and other health outcomes. Antibiotics are known gut microbiome disruptors, but their long-term consequences remain underexplored. Here we combined individual-level data from the Swedish Prescribed Drug Register with fecal metagenomes of 14,979 adults to examine the association between oral antibiotic use over 8 years and gut microbiome. In multivariable confounder-adjusted regression models, antibiotic use <1 year before fecal sampling was associated with the greatest reduction in species diversity, but significant associations were also observed for use 1-4 and 4-8 years earlier. Clindamycin, fluoroquinolones and flucloxacillin accounted for most of the associations with the abundance of individual species. Use of these antibiotics 4-8 years earlier was associated with altered abundance of 10-15% of the species studied; penicillin V, extended-spectrum penicillins and nitrofurantoin were associated with only a few species. Similar results were found comparing one antibiotic course 4-8 years before sampling versus none in the past 8 years. These findings indicate that antibiotics may have long-lasting consequences for the gut microbiome.
{"title":"Antibiotic use and gut microbiome composition links from individual-level prescription data of 14,979 individuals.","authors":"Gabriel Baldanzi,Anna Larsson,Sergi Sayols-Baixeras,Koen F Dekkers,Ulf Hammar,Diem Nguyen,Tíscar Graells,Shafqat Ahmad,Camila Gazolla Volpiano,Guillaume Meric,Josef D Järhult,Thomas Tängdén,Jonas F Ludvigsson,Lars Lind,Johan Sundström,Karl Michaëlsson,Johan Ärnlöv,Beatrice Kennedy,Marju Orho-Melander,Tove Fall","doi":"10.1038/s41591-026-04284-y","DOIUrl":"https://doi.org/10.1038/s41591-026-04284-y","url":null,"abstract":"Disruptions in gut microbiome are implicated in cardiometabolic disorders and other health outcomes. Antibiotics are known gut microbiome disruptors, but their long-term consequences remain underexplored. Here we combined individual-level data from the Swedish Prescribed Drug Register with fecal metagenomes of 14,979 adults to examine the association between oral antibiotic use over 8 years and gut microbiome. In multivariable confounder-adjusted regression models, antibiotic use <1 year before fecal sampling was associated with the greatest reduction in species diversity, but significant associations were also observed for use 1-4 and 4-8 years earlier. Clindamycin, fluoroquinolones and flucloxacillin accounted for most of the associations with the abundance of individual species. Use of these antibiotics 4-8 years earlier was associated with altered abundance of 10-15% of the species studied; penicillin V, extended-spectrum penicillins and nitrofurantoin were associated with only a few species. Similar results were found comparing one antibiotic course 4-8 years before sampling versus none in the past 8 years. These findings indicate that antibiotics may have long-lasting consequences for the gut microbiome.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"26 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147393916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-11DOI: 10.1038/s41591-026-04272-2
Stephan A Kaeser,Stephanie A Schultz,Anna Hofmann,Lisa M Häsler,Ying Xu,Marius Lambert,Ulrike Obermüller,Kathrin Brockmann,Johan Bijzet,Hans Nienhuis,Mario Nuvolone,Laura Obici,Giovanni Palladini,Ute Hegenbart,Stefan O Schönland,Mathias Jucker
Elevated blood levels of phosphorylated tau (p-tau) are diagnostic of Alzheimer disease and are associated with the deposition of amyloid-β in the cerebral neuropil. Elevated p-tau levels have also been associated with cerebral deposition of Danish amyloid and prion protein amyloid. Here we analyzed p-tau in serum from four different cohorts of people with the most common types of systemic amyloidosis, transthyretin (ATTR) amyloidosis and immunoglobulin light chain (AL) amyloidosis. We found higher levels of serum p-tau181 in the AL and ATTR groups than in controls. Subsequent analyses revealed that these effects were more pronounced in the presence of polyneuropathy (PNP) and in AL compared to ATTR amyloidosis. Individuals with different forms of PNP that were not due to amyloidosis did not exhibit elevated p-tau181 levels. In cases of presymptomatic (genetic) ATTR, p-tau181 levels increased as a function of predicted years from symptom onset. Additional measurement of p-tau217 in one cohort revealed similar increases, and discriminated people with AL and those with ATTR from controls equally as well as p-tau181. These findings suggest that elevated serum p-tau levels are not specific to Alzheimer disease and may also serve as a diagnostic tool of ATTR and AL amyloidosis, with potential utility in distinguishing amyloidosis-related PNP from PNP of other etiologies.
{"title":"Blood phosphorylated tau elevation as a biomarker in immunoglobulin light chain and transthyretin amyloidosis.","authors":"Stephan A Kaeser,Stephanie A Schultz,Anna Hofmann,Lisa M Häsler,Ying Xu,Marius Lambert,Ulrike Obermüller,Kathrin Brockmann,Johan Bijzet,Hans Nienhuis,Mario Nuvolone,Laura Obici,Giovanni Palladini,Ute Hegenbart,Stefan O Schönland,Mathias Jucker","doi":"10.1038/s41591-026-04272-2","DOIUrl":"https://doi.org/10.1038/s41591-026-04272-2","url":null,"abstract":"Elevated blood levels of phosphorylated tau (p-tau) are diagnostic of Alzheimer disease and are associated with the deposition of amyloid-β in the cerebral neuropil. Elevated p-tau levels have also been associated with cerebral deposition of Danish amyloid and prion protein amyloid. Here we analyzed p-tau in serum from four different cohorts of people with the most common types of systemic amyloidosis, transthyretin (ATTR) amyloidosis and immunoglobulin light chain (AL) amyloidosis. We found higher levels of serum p-tau181 in the AL and ATTR groups than in controls. Subsequent analyses revealed that these effects were more pronounced in the presence of polyneuropathy (PNP) and in AL compared to ATTR amyloidosis. Individuals with different forms of PNP that were not due to amyloidosis did not exhibit elevated p-tau181 levels. In cases of presymptomatic (genetic) ATTR, p-tau181 levels increased as a function of predicted years from symptom onset. Additional measurement of p-tau217 in one cohort revealed similar increases, and discriminated people with AL and those with ATTR from controls equally as well as p-tau181. These findings suggest that elevated serum p-tau levels are not specific to Alzheimer disease and may also serve as a diagnostic tool of ATTR and AL amyloidosis, with potential utility in distinguishing amyloidosis-related PNP from PNP of other etiologies.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"15 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147393917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-11DOI: 10.1038/s41591-026-04288-8
Jiyeon Oh,Soeun Kim,Yesol Yim,Min Seo Kim, ,Simon I Hay,Jae Il Shin,Dong Keon Yon
{"title":"Author Correction: Global, regional, and national burden of chronic respiratory diseases and impact of the COVID-19 pandemic, 1990-2023: a Global Burden of Disease study.","authors":"Jiyeon Oh,Soeun Kim,Yesol Yim,Min Seo Kim, ,Simon I Hay,Jae Il Shin,Dong Keon Yon","doi":"10.1038/s41591-026-04288-8","DOIUrl":"https://doi.org/10.1038/s41591-026-04288-8","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"196 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147393915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-09DOI: 10.1038/s41591-026-04285-x
Sumanta K Pal, Diwakar Davar
{"title":"Microbiome modulation in cancer immunotherapy.","authors":"Sumanta K Pal, Diwakar Davar","doi":"10.1038/s41591-026-04285-x","DOIUrl":"https://doi.org/10.1038/s41591-026-04285-x","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147390456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-09DOI: 10.1038/s41591-026-04239-3
Sidong Li,Rikuta Hamaya,Haidong Zhu,Brian H Chen,Alexandre C Pereira,Kerry L Ivey,Pamela M Rist,JoAnn E Manson,Yanbin Dong,Howard D Sesso
Large-scale randomized trials have found that multivitamin-multimineral (MVM) supplements and cocoa flavanols may benefit several age-related chronic conditions among older adults, but it remains unclear whether these two supplements directly slow the biological aging process. This prespecified ancillary study evaluated the 2-year effect of a daily MVM (Centrum Silver) and cocoa extract (500 mg cocoa flavanols per day, including 80 mg (-)-epicatechin) on five DNA methylation measures of biological aging (PCHannum, PCHorvath, PCPhenoAge, PCGrimAge and DunedinPACE) among 958 participants (482 women and 476 men) in the COcoa Supplement and Multivitamin Outcomes Study (COSMOS). Compared with placebo, daily MVM supplementation modestly reduced the rate of increase of second-generation epigenetic clocks, with a between-group difference in yearly change of -0.113 years (95% confidence interval (CI) -0.205 to -0.020; P = 0.017) for PCGrimAge and -0.214 years (-0.410 to -0.019; P = 0.032) for PCPhenoAge. MVM had a stronger effect on PCGrimAge among those with accelerated biological aging at baseline (-0.236 [-0.380 to -0.091]) compared with those with normal or decelerated biological aging (-0.013 [-0.130 to 0.104]; P = 0.018 for interaction). Cocoa extract did not have an effect on the five epigenetic clocks tested. Although the statistically significant but small effects of daily MVM supplementation on slowing biological aging are encouraging, additional studies are needed to determine the clinical relevance of daily MVM supplementation on epigenetic clocks and whether such effects can help explain the beneficial effects of MVM supplementation on aging-related chronic conditions.
{"title":"Effects of daily multivitamin-multimineral and cocoa extract supplementation on epigenetic aging clocks in the COSMOS randomized clinical trial.","authors":"Sidong Li,Rikuta Hamaya,Haidong Zhu,Brian H Chen,Alexandre C Pereira,Kerry L Ivey,Pamela M Rist,JoAnn E Manson,Yanbin Dong,Howard D Sesso","doi":"10.1038/s41591-026-04239-3","DOIUrl":"https://doi.org/10.1038/s41591-026-04239-3","url":null,"abstract":"Large-scale randomized trials have found that multivitamin-multimineral (MVM) supplements and cocoa flavanols may benefit several age-related chronic conditions among older adults, but it remains unclear whether these two supplements directly slow the biological aging process. This prespecified ancillary study evaluated the 2-year effect of a daily MVM (Centrum Silver) and cocoa extract (500 mg cocoa flavanols per day, including 80 mg (-)-epicatechin) on five DNA methylation measures of biological aging (PCHannum, PCHorvath, PCPhenoAge, PCGrimAge and DunedinPACE) among 958 participants (482 women and 476 men) in the COcoa Supplement and Multivitamin Outcomes Study (COSMOS). Compared with placebo, daily MVM supplementation modestly reduced the rate of increase of second-generation epigenetic clocks, with a between-group difference in yearly change of -0.113 years (95% confidence interval (CI) -0.205 to -0.020; P = 0.017) for PCGrimAge and -0.214 years (-0.410 to -0.019; P = 0.032) for PCPhenoAge. MVM had a stronger effect on PCGrimAge among those with accelerated biological aging at baseline (-0.236 [-0.380 to -0.091]) compared with those with normal or decelerated biological aging (-0.013 [-0.130 to 0.104]; P = 0.018 for interaction). Cocoa extract did not have an effect on the five epigenetic clocks tested. Although the statistically significant but small effects of daily MVM supplementation on slowing biological aging are encouraging, additional studies are needed to determine the clinical relevance of daily MVM supplementation on epigenetic clocks and whether such effects can help explain the beneficial effects of MVM supplementation on aging-related chronic conditions.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"26 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147381169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-09DOI: 10.1038/s41591-026-04249-1
Daniel W Belsky,Calen P Ryan
{"title":"A daily multivitamin slows the ticking of epigenetic clocks.","authors":"Daniel W Belsky,Calen P Ryan","doi":"10.1038/s41591-026-04249-1","DOIUrl":"https://doi.org/10.1038/s41591-026-04249-1","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"77 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147381168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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