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Here, we investigate the relationship between cognitive fatigue (CF, fatigue resulting from mental work) and two types of aging\u2014chronological age and brain age\u2014in 85 participants ranging in age from 20 to 84\u00a0years. Whereas chronological age is simply participants\u2019 absolute age, brain age is derived from a comparison of participants\u2019 brain morphology relative to a normative model. CF was induced using a working memory paradigm that participants repeatedly performed, reporting their instantaneous level of CF at baseline and after each successive block of the task. Chronological age was associated with a decrease in the CF reported at baseline (the intercept of a regression line fit to the CF ratings), whereas brain age was related to the rate at which fatigue was induced (the slope of the regression line fit to the CF ratings). Behaviorally, the decrease in CF as a function of chronological age was mirrored by a more liberal response bias, providing more evidence that response bias represents an objective behavioral index of CF. Additionally, areas of the insula showed a relationship between CF and chronological age, suggesting that the role of the insula may change across the lifespan. These results represent the first well-powered study to investigate the relationship between CF and chronological age as well as brain age and suggests that CF may be an important indicator of brain age across the lifespan.<\/jats:p>","DOI":"10.1007\/s00415-025-13584-1","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T10:47:24Z","timestamp":1767782844000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The differential effect of chronological age and brain age on cognitive fatigue: new metrics, new insights"],"prefix":"10.1007","volume":"273","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7061-6658","authenticated-orcid":false,"given":"G. R.","family":"Wylie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. A. 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