{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T05:37:18Z","timestamp":1781501838123,"version":"3.54.1"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T00:00:00Z","timestamp":1741046400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T00:00:00Z","timestamp":1741046400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"NHMRC Investigator Grant","award":["APP1175405"],"award-info":[{"award-number":["APP1175405"]}]},{"name":"NHMRC Investigator Grant","award":["2010072"],"award-info":[{"award-number":["2010072"]}]},{"name":"Global STEM Professorship Scheme","award":["P0046113"],"award-info":[{"award-number":["P0046113"]}]},{"DOI":"10.13039\/501100001782","name":"University of Melbourne","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001782","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["GeroScience"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>The aim of this study is to investigate the association between retinal age gap and multimorbidity. Retinal age gap was calculated based on a previously developed deep learning model for 45,436 participants. The number of age-related conditions reported at baseline was summed and categorized as zero, one, or at least two conditions at baseline (multimorbidity). Incident multimorbidity was defined as having two or more age-related diseases onset during the follow-up period. Linear regressions were fit to examine the associations of disease numbers at baseline with retinal age gaps. Cox proportional hazard regression models were used to examine associations of retinal age gaps with the incidence of multimorbidity. In the fully adjusted model, those with multimorbidity and one disease both showed significant increases in retinal age gaps at baseline compared to participants with zero disease number (<jats:italic>\u03b2<\/jats:italic> = 0.254, 95% CI 0.154, 0.354; P &lt; 0.001; <jats:italic>\u03b2<\/jats:italic> = 0.203, 95% CI 0.116, 0.291; <jats:italic>P<\/jats:italic> &lt; 0.001; respectively). After a median follow-up period of 11.38 (IQR, 11.26\u201311.53; range, 0.02\u201311.81) years, a total of 3607 (17.29%) participants had incident multimorbidity. Each 5-year increase in retinal age gap at baseline was independently associated with an 8% increase in the risk of multimorbidity (HR = 1.08, 95% CI 1.02, 1.14, <jats:italic>P<\/jats:italic> = 0.008). Our study demonstrated that an increase of retinal age gap was independently associated with a greater risk of incident multimorbidity. By recognizing deviations from normal aging, we can identify individuals at higher risk of developing multimorbidity. This early identification facilitates patients\u2019 self-management and personalized interventions before disease onset.<\/jats:p>","DOI":"10.1007\/s11357-025-01581-1","type":"journal-article","created":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T11:18:12Z","timestamp":1741087092000},"page":"4291-4300","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Accelerated retinal ageing and multimorbidity in middle-aged and older adults"],"prefix":"10.1007","volume":"47","author":[{"given":"Ruiye","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomin","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyi","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepak","family":"Jeyarajan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongyuan","family":"Ge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianwen","family":"Shang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingguang","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9897-1192","authenticated-orcid":false,"given":"Zhuoting","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,4]]},"reference":[{"key":"1581_CR1","doi-asserted-by":"publisher","first-page":"4","DOI":"10.15256\/joc.2013.3.22","volume":"3","author":"J Almirall","year":"2013","unstructured":"Almirall J, Fortin M. The coexistence of terms to describe the presence of multiple concurrent diseases. J Comorb. 2013;3:4\u20139.","journal-title":"J Comorb"},{"issue":"7","key":"1581_CR2","doi-asserted-by":"publisher","first-page":"e102149","DOI":"10.1371\/journal.pone.0102149","volume":"9","author":"C Violan","year":"2014","unstructured":"Violan C, Foguet-Boreu Q, Flores-Mateo G, et al. Prevalence, determinants and patterns of multimorbidity in primary care: a systematic review of observational studies. PLoS One. 2014;9(7):e102149.","journal-title":"PLoS One"},{"key":"1581_CR3","unstructured":"United Nations, Department of economic and social affairs, population division. World population ageing 2017, 2017. Accessed 10 June 2024. https:\/\/www.un.org\/en\/development\/desa\/population\/publications\/pdf\/ageing\/WorldPopulationAgeing2019-Highlights.pdf."},{"key":"1581_CR4","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.ebiom.2017.03.046","volume":"21","author":"J Jylhava","year":"2017","unstructured":"Jylhava J, Pedersen NL, Hagg S. Biological AGE PREDICTors. EBioMedicine. 2017;21:29\u201336.","journal-title":"EBioMedicine."},{"key":"1581_CR5","doi-asserted-by":"publisher","first-page":"101743","DOI":"10.1016\/j.arr.2022.101743","volume":"81","author":"R Duan","year":"2022","unstructured":"Duan R, Fu Q, Sun Y, Li Q. Epigenetic clock: a promising biomarker and practical tool in aging. Ageing Res Rev. 2022;81:101743.","journal-title":"Ageing Res Rev"},{"key":"1581_CR6","doi-asserted-by":"publisher","first-page":"630186","DOI":"10.3389\/fgene.2020.630186","volume":"11","author":"A Vaiserman","year":"2020","unstructured":"Vaiserman A, Krasnienkov D. Telomere length as a marker of biological age: state-of-the-art, open issues, and future perspectives. Front Genet. 2020;11:630186.","journal-title":"Front Genet"},{"issue":"12","key":"1581_CR7","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1016\/j.tins.2017.10.001","volume":"40","author":"JH Cole","year":"2017","unstructured":"Cole JH, Franke K. Predicting age using neuroimaging: innovative brain ageing biomarkers. Trends Neurosci. 2017;40(12):681\u201390.","journal-title":"Trends Neurosci"},{"issue":"4","key":"1581_CR8","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1136\/bjophthalmol-2021-319807","volume":"107","author":"Z Zhu","year":"2023","unstructured":"Zhu Z, Shi D, Guankai P, et al. Retinal age gap as a predictive biomarker for mortality risk. Br J Ophthalmol. 2023;107(4):547\u201354.","journal-title":"Br J Ophthalmol"},{"key":"1581_CR9","doi-asserted-by":"crossref","unstructured":"Yu Z, Chen R, Gui P, et al. Retinal age estimation with temporal fundus images enhanced progressive label distribution learning. paper presented at: medical image computing and computer assisted intervention \u2013 MICCAI 2023; 2023\/\/, 2023; Cham.","DOI":"10.1007\/978-3-031-43990-2_59"},{"issue":"17","key":"1581_CR10","doi-asserted-by":"publisher","first-page":"1270","DOI":"10.1093\/eurheartj\/eht023","volume":"34","author":"J Flammer","year":"2013","unstructured":"Flammer J, Konieczka K, Bruno RM, Virdis A, Flammer AJ, Taddei S. The eye and the heart. Eur Heart J. 2013;34(17):1270\u20138.","journal-title":"Eur Heart J"},{"issue":"1","key":"1581_CR11","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/nrneurol.2012.227","volume":"9","author":"A London","year":"2013","unstructured":"London A, Benhar I, Schwartz M. The retina as a window to the brain-from eye research to CNS disorders. Nat Rev Neurol. 2013;9(1):44\u201353.","journal-title":"Nat Rev Neurol"},{"issue":"11","key":"1581_CR12","doi-asserted-by":"publisher","first-page":"3320","DOI":"10.1161\/STROKEAHA.122.038809","volume":"53","author":"Z Zhu","year":"2022","unstructured":"Zhu Z, Chen Y, Wang W, et al. Association of retinal age gap with arterial stiffness and incident cardiovascular disease. Stroke. 2022;53(11):3320\u20138.","journal-title":"Stroke"},{"issue":"1","key":"1581_CR13","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1186\/s12916-022-02620-w","volume":"20","author":"Z Zhu","year":"2022","unstructured":"Zhu Z, Hu W, Chen R, et al. Retinal age gap as a predictive biomarker of stroke risk. BMC Med. 2022;20(1):466.","journal-title":"BMC Med"},{"issue":"3","key":"1581_CR14","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1111\/1753-0407.13364","volume":"15","author":"Z Zhu","year":"2023","unstructured":"Zhu Z, Liu D, Chen R, et al. The association of retinal age gap with metabolic syndrome and inflammation. J Diabetes. 2023;15(3):237\u201345.","journal-title":"J Diabetes"},{"key":"1581_CR15","doi-asserted-by":"publisher","unstructured":"Hu W, Wang W, Wang Y, et al. Retinal age gap as a predictive biomarker of future risk of Parkinson\u2019s disease. Age Ageing. 2022;51(3). https:\/\/doi.org\/10.1093\/ageing\/afac062","DOI":"10.1093\/ageing\/afac062"},{"key":"1581_CR16","doi-asserted-by":"crossref","unstructured":"Zhang S, Chen R, Wang Y, et al. Association of retinal age gap and risk of kidney failure: a UK biobank study. Am J Kidney Dis. 2023;81(5):537-544.e531.","DOI":"10.1053\/j.ajkd.2022.09.018"},{"issue":"1","key":"1581_CR17","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1038\/s41572-022-00376-4","volume":"8","author":"ST Skou","year":"2022","unstructured":"Skou ST, Mair FS, Fortin M, et al. Multimorbidity. Nat Rev Dis Primers. 2022;8(1):48.","journal-title":"Nat Rev Dis Primers"},{"issue":"6","key":"1581_CR18","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1093\/ageing\/afx150","volume":"46","author":"AJ Yarnall","year":"2017","unstructured":"Yarnall AJ, Sayer AA, Clegg A, Rockwood K, Parker S, Hindle JV. New horizons in multimorbidity in older adults. Age Ageing. 2017;46(6):882\u20138.","journal-title":"Age Ageing"},{"issue":"3","key":"1581_CR19","doi-asserted-by":"publisher","first-page":"e1001779","DOI":"10.1371\/journal.pmed.1001779","volume":"12","author":"C Sudlow","year":"2015","unstructured":"Sudlow C, Gallacher J, Allen N, et al. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 2015;12(3):e1001779.","journal-title":"PLoS Med"},{"issue":"2","key":"1581_CR20","doi-asserted-by":"publisher","first-page":"e025077","DOI":"10.1136\/bmjopen-2018-025077","volume":"9","author":"SYL Chua","year":"2019","unstructured":"Chua SYL, Thomas D, Allen N, et al. Cohort profile: design and methods in the eye and vision consortium of UK Biobank. BMJ Open. 2019;9(2):e025077.","journal-title":"BMJ Open"},{"key":"1581_CR21","unstructured":"Fu H, Wang B, Shen J, et al. Evaluation of retinal image quality assessment networks in different color-spaces. Paper presented at: Medical Image Computing and Computer Assisted Intervention\u2013MICCAI 2019: 22nd International Conference, Shenzhen, China, October 13\u201317, 2019, Proceedings, Part I 222019"},{"issue":"1","key":"1581_CR22","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1093\/pubmed\/fdh193","volume":"27","author":"J Adams","year":"2005","unstructured":"Adams J, Ryan V, White M. How accurate are Townsend deprivation scores as predictors of self-reported health? A comparison with individual level data. J Public Health (Oxf). 2005;27(1):101\u20136.","journal-title":"J Public Health (Oxf)"},{"issue":"1","key":"1581_CR23","doi-asserted-by":"publisher","first-page":"3570","DOI":"10.1038\/s41467-020-17312-3","volume":"11","author":"P Timmers","year":"2020","unstructured":"Timmers P, Wilson JF, Joshi PK, Deelen J. Multivariate genomic scan implicates novel loci and haem metabolism in human ageing. Nat Commun. 2020;11(1):3570.","journal-title":"Nat Commun"},{"issue":"2","key":"1581_CR24","doi-asserted-by":"publisher","first-page":"R24","DOI":"10.1186\/gb-2014-15-2-r24","volume":"15","author":"CI Weidner","year":"2014","unstructured":"Weidner CI, Lin Q, Koch CM, et al. Aging of blood can be tracked by DNA methylation changes at just three CpG sites. Genome Biol. 2014;15(2):R24.","journal-title":"Genome Biol"},{"issue":"1","key":"1581_CR25","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1186\/s13059-018-1599-6","volume":"19","author":"JG Fleischer","year":"2018","unstructured":"Fleischer JG, Schulte R, Tsai HH, et al. Predicting age from the transcriptome of human dermal fibroblasts. Genome Biol. 2018;19(1):221.","journal-title":"Genome Biol"},{"key":"1581_CR26","doi-asserted-by":"publisher","first-page":"8570","DOI":"10.1038\/ncomms9570","volume":"6","author":"MJ Peters","year":"2015","unstructured":"Peters MJ, Joehanes R, Pilling LC, et al. The transcriptional landscape of age in human peripheral blood. Nat Commun. 2015;6:8570.","journal-title":"Nat Commun"},{"key":"1581_CR27","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/j.neuroimage.2016.11.005","volume":"148","author":"F Liem","year":"2017","unstructured":"Liem F, Varoquaux G, Kynast J, et al. Predicting brain-age from multimodal imaging data captures cognitive impairment. Neuroimage. 2017;148:179\u201388.","journal-title":"Neuroimage"},{"issue":"5","key":"1581_CR28","doi-asserted-by":"publisher","first-page":"1385","DOI":"10.1038\/mp.2017.62","volume":"23","author":"JH Cole","year":"2018","unstructured":"Cole JH, Ritchie SJ, Bastin ME, et al. Brain age predicts mortality. Mol Psychiatry. 2018;23(5):1385\u201392.","journal-title":"Mol Psychiatry"},{"issue":"10","key":"1581_CR29","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1038\/s41366-023-01345-x","volume":"47","author":"R Chen","year":"2023","unstructured":"Chen R, Zhang J, Shang X, Wang W, He M, Zhu Z. Central obesity and its association with retinal age gap: insights from the UK Biobank study. Int J Obes (Lond). 2023;47(10):979\u201385.","journal-title":"Int J Obes (Lond)"},{"issue":"3","key":"1581_CR30","doi-asserted-by":"publisher","first-page":"1511","DOI":"10.1007\/s11357-023-00743-3","volume":"45","author":"R Chen","year":"2023","unstructured":"Chen R, Xu J, Shang X, et al. Association between cardiovascular health metrics and retinal ageing. Geroscience. 2023;45(3):1511\u201321.","journal-title":"Geroscience"},{"issue":"4","key":"1581_CR31","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1111\/j.1469-7580.2005.00395.x","volume":"206","author":"N Patton","year":"2005","unstructured":"Patton N, Aslam T, Macgillivray T, Pattie A, Deary IJ, Dhillon B. Retinal vascular image analysis as a potential screening tool for cerebrovascular disease: a rationale based on homology between cerebral and retinal microvasculatures. J Anat. 2005;206(4):319\u201348.","journal-title":"J Anat"},{"issue":"6","key":"1581_CR32","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","volume":"153","author":"C Lopez-Otin","year":"2013","unstructured":"Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194\u2013217.","journal-title":"Cell"},{"key":"1581_CR33","doi-asserted-by":"crossref","unstructured":"Gao H, Hollyfield JG. Aging of the human retina. Differential loss of neurons and retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 1992;33(1):1-17.","DOI":"10.1167\/iovs.61.1.1"},{"issue":"12","key":"1581_CR34","doi-asserted-by":"publisher","first-page":"1853","DOI":"10.1016\/S0161-6420(95)30784-1","volume":"102","author":"S Panda-Jonas","year":"1995","unstructured":"Panda-Jonas S, Jonas JB, Jakobczyk-Zmija M. Retinal photoreceptor density decreases with age. Ophthalmology. 1995;102(12):1853\u20139.","journal-title":"Ophthalmology"},{"issue":"7","key":"1581_CR35","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1016\/S0895-4356(00)00363-2","volume":"54","author":"R Gijsen","year":"2001","unstructured":"Gijsen R, Hoeymans N, Schellevis FG, Ruwaard D, Satariano WA, van den Bos GA. Causes and consequences of comorbidity: a review. J Clin Epidemiol. 2001;54(7):661\u201374.","journal-title":"J Clin Epidemiol"},{"key":"1581_CR36","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1186\/1477-7525-2-51","volume":"2","author":"M Fortin","year":"2004","unstructured":"Fortin M, Lapointe L, Hudon C, Vanasse A, Ntetu AL, Maltais D. Multimorbidity and quality of life in primary care: a systematic review. Health Qual Life Outcomes. 2004;2:51.","journal-title":"Health Qual Life Outcomes"},{"issue":"4","key":"1581_CR37","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1007\/s11606-013-2659-y","volume":"29","author":"K Uhlig","year":"2014","unstructured":"Uhlig K, Leff B, Kent D, et al. A framework for crafting clinical practice guidelines that are relevant to the care and management of people with multimorbidity. J Gen Intern Med. 2014;29(4):670\u20139.","journal-title":"J Gen Intern Med"},{"issue":"6","key":"1581_CR38","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1001\/jama.294.6.716","volume":"294","author":"CM Boyd","year":"2005","unstructured":"Boyd CM, Darer J, Boult C, Fried LP, Boult L, Wu AW. Clinical practice guidelines and quality of care for older patients with multiple comorbid diseases: implications for pay for performance. JAMA. 2005;294(6):716\u201324.","journal-title":"JAMA"},{"issue":"9","key":"1581_CR39","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1093\/aje\/kwx246","volume":"186","author":"A Fry","year":"2017","unstructured":"Fry A, Littlejohns TJ, Sudlow C, et al. Comparison of sociodemographic and health-related characteristics of UK biobank participants with those of the general population. Am J Epidemiol. 2017;186(9):1026\u201334.","journal-title":"Am J Epidemiol"}],"container-title":["GeroScience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11357-025-01581-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11357-025-01581-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11357-025-01581-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,21]],"date-time":"2025-06-21T13:02:46Z","timestamp":1750510966000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11357-025-01581-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,4]]},"references-count":39,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["1581"],"URL":"https:\/\/doi.org\/10.1007\/s11357-025-01581-1","relation":{},"ISSN":["2509-2723"],"issn-type":[{"value":"2509-2723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,4]]},"assertion":[{"value":"25 September 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 February 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 March 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}