Reduced counterfactual (“What-If”) thinking (CFT) in late life is believed to reflect successful adaptation to limited resources for overcoming missed opportunities, thereby preventing feelings of regret. We propose that this adaptation becomes critical from midlife onwards, affects emotional regulation, and is mediated by the preserved functionality of the ventromedial prefrontal cortex (vmPFC). To test this, an epidemiological sample from the Hamburg City Health Study (N = 494), aged 48 to 75, completed a sequential risk-taking task presenting missed opportunities to induce CFT, and was assessed for life satisfaction, depressive symptoms, emotion regulation, and resting-state functional connectivity of the vmPFC. In line with the ‘paradox of aging,’ our cross-sectional data indicate a positive linear relationship between age and life satisfaction from midlife onward, alongside a negative association between age and depressive symptoms. Crucially, counterfactual thinking (CFT) was also lower in older compared to younger adults; however, reduced CFT in later life was restricted to individuals free of significant depressive symptoms, suggesting that a lack of disengagement from regrets specifically in older age enhances the risk for depression. Mediation models suggest that reduced what-if-thinking improves emotional well-being in late life by facilitating positive reappraisal and depends on preserved vmPFC connectivity with the dorsolateral PFC. Our findings underscore the increasing role of CFT and intra-prefrontal connectivity in emotional adaptation in the second half of life. Equipping middle-aged adults with strategies to address missed opportunities may significantly enhance resilience in aging populations. Graphical Abstract

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