Stress from early life to adulthood: Is there a protective role of cognitive control?

Early life events can have long-lasting effects that may impact the quality of life into adulthood. The link between childhood adversities and adult mental and physical health is well documented, however, the underlying mechanisms remain poorly understood. Executive functions are assumed to be a key factor in successfully dealing with cognitive-emotional challenges thereby contributing to stress resilience and mental health across the lifespan. Here, we examined whether cognitive control moderates the link between early life adversity and depression. Data was available from a sample of 424 participants aged 20-70 years (Clinicaltrials.gov: NCT05155397). They performed in the Stroop task and behavior as well as frontal theta power were recorded. Negative childhood experiences were assessed with the Childhood Trauma Questionnaire (CTQ), chronic stress was measured with the Trier Inventory for Chronic Stress (TICS) and depression symptoms with Beck's Depression Inventory (BDI). The CTQ predicted symptoms of chronic stress and depression. Regression models pointed to the TICS as a crucial mediator in the relationship between CTQ and BDI. However, parameters of cognitive control demonstrated a rather weak effect as moderators. These results indicate that chronic stress is an important mediator linking childhood trauma to depression but suggest only a limited role for cognitive control.

Phenotyping in clinical laterality research: a comparison of commonly used methods to determine mixed-handedness and ambidexterity.

An increased prevalence of mixed-handedness has been reported in several neurodevelopmental and psychiatric disorders. Unfortunately, there is high between-study variability in the definition of mixed-handedness, leading to a major methodological problem in clinical laterality research and endangering replicability and comparability of research findings. Adding to this challenge is the fact that sometimes researchers use the concepts of mixed-handedness and ambidexterity interchangeably. Therefore, having a consensus on how to determine mixed-handedness and how to distinguish it from ambidexterity is crucial for clinical laterality research. To this end, hand preference and hand performance data from more than 600 participants from the Dortmund Vital Study (Trial registration: ClinicalTrials.gov NCT05155397), a population-based study in Germany, was analyzed to ascertain an optimal classification to determine mixed-handedness and ambidexterity. Using a combination of latent class analyses, effect size determination, and comparisons with the existing literature, we establish that an LQ cut-off criterion of +/-60 for mixed-handedness is optimal for future clinical laterality studies. Moreover, we show that mixed-handedness and ambidexterity are not identical and that the terms should not be used interchangeably. We further highlight the need for a consensus on how to mathematically determine ambidexterity as results of existing categorization schemes largely differ.Trial registration: ClinicalTrials.gov NCT05155397; https://clinicaltrials.gov/ct2/show/NCT05155397.

The impact of physical fitness, social life, and cognitive functions on work ability in middle-aged and older adults.

OBJECTIVE: Demographic changes encompass societies to maintain the work ability (WA) of aging workforces. The present study explored the relationship between modifiable lifestyle factors, cognitive functions, and their influence on WA, using a multi-group structural equation approach. METHOD: Cross-sectional data from 247 middle-aged and 236 older employees from the Dortmund Vital Study were included in this analysis. We proposed a model with three exogenous variables (Physical Fitness, Cognitive Functions, and Social Life), and with WA as the endogenous variable. WA was measured with the Work Ability Index (WAI), which considers job demands and individual physical and mental resources. Multi-group analyses were based on the principles of invariance testing and conducted using robust estimation methods. RESULTS: Results revealed that Social Life outside work had significant positive effects on WA in both, middle-aged and older adults. Physical Fitness had a significant effect on WA only in middle-aged adult, and Cognitive Functions had no significant influence on WA in either group. In older adults, Physical Fitness correlated with Cognitive Functions, whereas in middle-aged adults, Cognitive Functions marginally correlated with Social Life. CONCLUSIONS: Our results underline the importance of an active social life outside the workplace for WA, regardless of the employees' age. The influence of Physical Fitness on WA changes with increasing age, indicating the necessity to have a differentiated view of age effects and interacting influencing factors. Our research contributes to the knowledge of how WA could be most effectively promoted in different age groups. CLINICALTRIALS: gov NCT05155397; https://clinicaltrials.gov/ct2/show/NCT05155397 .

Stress exposure, hand preference, and hand skill: A deep phenotyping approach.

ABSTRACTStress exposure and reactivity may show differential associations with handedness, but shallow phenotyping may influence the current knowledge. Importantly, different handedness measures do not necessarily show high correlations with each other and should not be used interchangeably as they may reflect different dimensions of laterality. Here, data on handedness from 599 participants in the population-based, longitudinal Dortmund Vital Study was used to determine various asymmetry indices. Hand preference was assessed with the Edinburgh Handedness Inventory (EHI) and the lateral preference inventory (LPI) measuring handedness, footedness, earedness, and eyedness. Hand performance was determined using the pegboard test. In addition, data on several dimensions of stress exposure and reactivity, including hair cortisol, and mental well-being was analysed to determine associations with handedness. All handedness measures correlated significantly with each other, with the strongest correlation between the EHI and the LPI handedness score. The EHI and LPI hand measures resulted in the highest effect sizes and most consistent correlations with stress or mental well-being. In contrast, the pegboard test only showed very little association with the stress and mental well-being measures. This highlights the importance of handedness phenotyping. Including preference measures is recommended to disentangle the link between handedness and mental health.

From Immunosenescence to Aging Types-Establishing Reference Intervals for Immune Age Biomarkers by Centile Estimation.

Immunological aging type definition requires establishing reference intervals from the distribution of immunosenescence biomarkers conditional on age. For 1605 individuals (18-97 years), we determined the comprehensive immune age index IMMAX from flow-cytometry-based blood cell sub-populations and identified age-specific centiles by fitting generalized additive models for location, scale, and shape. The centiles were uncorrelated with age and facilitated the categorization of individuals as immunologically slow or fast aging types. Using its 50th percentile as a reference, we rescaled the IMMAX to equivalent years of life (EYOL) and computed the immunological age gap as the difference between EYOL and chronological age. Applied to preliminary baseline and follow-up measurements from 53 participants of the Dortmund Vital Study (Clinical-Trials.gov Identifier: NCT05155397), the averaged changes in the IMMAX and EYOL conformed to the 5-year follow-up period, whereas no significant changes occurred concerning IMMAX centiles and age gap. This suggested that the participants immunologically adapted to aging and kept their relative positions within the cohort. Sex was non-significant. Methodical comparisons indicated that future confirmatory analyses with the completed follow-up examinations could rely on percentile curves estimated by simple linear quantile regression, while the selection of the immunosenescence biomarker will greatly influence the outcome, with IMMAX representing the preferable choice.

When long appears short: Effects of auditory distraction on event-related potential correlates of time perception.

Attentional models of time perception assume that the perceived duration of a stimulus depends on the extent to which attentional resources are allocated to its temporal information. Here, we studied the effects of auditory distraction on time perception, using a combined attentional-distraction duration-discrimination paradigm. Participants were confronted with a random sequence of long and short tone stimuli, most of which having a uniform (standard) pitch and only a few a different (deviant) pitch. As observed in previous studies, pitch-deviant tones impaired the discrimination of tone duration and triggered a sequence of event-related potentials (ERPs) reflecting a cycle of deviance detection, involuntary attentional distraction and reorientation (MMN, P3a, RON). Contrasting ERPs of short and long tone durations revealed that long tones elicited a more pronounced fronto-central contingent negative variation (CNV) in the time interval after the expected offset of the short tone as well as a more prominent centro-parietal late positive complex (LPC). Relative to standard-pitch tones, deviant-pitch tones especially impaired the correct discrimination of long tones, which was associated with a reduction of the CNV and LPC. These results are interpreted within the theoretical framework of resource-based models of time perception, in which involuntary distraction due to a deviant event led to a withdrawal of attentional resources from the processing of time information.

Stroop task performance across the lifespan: High cognitive reserve in older age is associated with enhanced proactive and reactive interference control.

Susceptibility to interference increases with age but there is large inter-individual variability in interference control in older adults due to a number of biological and environmental factors. The present study aims at analyzing behavior and ERPs in a Stroop interference task with increasing difficulty in a sample of 246 young, middle-aged and healthy old participants. The old age group was divided into three subgroups based on performance scores. The results show a gradual performance reduction with increasing age and task difficulty. However, old high performers reached a performance level comparable to middle-aged subjects. The contingent negative variation (CNV) reflecting preparation and proactive task control and the target-locked P2/N2 complex associated with retrieval and implementation of S-R mappings during reactive task control were larger in the old high than low performers and similar to middle-aged or even young participants. High performance was limited to executive control tasks, while other cognitive functions were less affected. In addition, high performance was associated with higher level of education, usage of foreign languages and higher IQ. Thus, the performance differences in old age were discussed in the framework of cognitive reserve that constitutes individual differences in neural networks underlying task performance.

ERP and Behavioral Effects of Physical and Cognitive Training on Working Memory in Aging: A Randomized Controlled Study.

Working memory (WM) performance decreases with age. A promising method to improve WM is physical or cognitive training. The present randomized controlled study is aimed at evaluating the effects of different training methods on WM. A sample of 141 healthy older adults (mean age 70 years) was assigned to one of four groups: physical training, cognitive training, a social control group, and a no-contact control group. The participants trained for four months. Before and after the training, n-back task during an EEG recording was applied. The results show that cognitive training enhanced the target detection rate in the 2-back task. This was corroborated by an increased number of repeated digits in the backward digit-span test but not in other memory tests. The improvement of WM was supported by an increased P3a prior to a correct target and an increased P3b both in nontarget and target trials. No ERP effects in the physical and no-contact control groups were found, while a reduction of P3a and P3b was found in the social control group. Thus, cognitive training enhances frontal and parietal processing related to the maintenance of a stored stimulus for subsequent matching with an upcoming stimulus and increases allocation of cognitive resources. These results indicate that multidomain cognitive training may increase WM capacity and neuronal activity in older age.

Long-term habitual physical activity is associated with lower distractibility in a Stroop interference task in aging: Behavioral and ERP evidence.

Aging is associated with compromised executive control functions. Several lines of evidence point to beneficial effects of physical activity on cognition which indicate that regular physical activity may counteract the age-related decline of some executive functions. Here, we investigate the effects of lifelong physical activity (about 50 years) on interference processing in two matched groups of 20 physically high active and 20 low active healthy older men using event-related potentials (ERPs). In a low interference block of the Stroop task, participants had to indicate the meaning of color-words, while color was either compatible or incompatible with the meaning. In the high interference block, participants were asked to respond according to the ink color of the word and to ignore its meaning. Physically active seniors showed faster reaction times, lower individual variability in reaction times, and higher accuracy compared to low active seniors, particularly in the high interference block. This result was confirmed in the classic paper-and-pencil version of the Stroop task showing higher interference score in the low active than high active individuals. ERPs revealed a shorter latency of the P2 and generally more negative amplitudes of the fronto-central N2 and N450 components in the high active group compared to the low active group. The amount of interference was negatively correlated with objectively measured fitness and self-reported physical activity. The positive effect of physical fitness on interference processing in the behavioral data was related to N2 and N450 amplitudes. Taken together, this suggests that seniors reporting long-term physical activity may exhibit generally enhanced activity in the frontal cortex which enables more efficient interference resolution in the Stroop task.

The ultra-slow NAT2*6A haplotype is associated with reduced higher cognitive functions in an elderly study group.

N-Acetyltransferase 2 (NAT2) genotype is associated with age-related declines in basic sensory hearing functions. However, the possible modulatory role of NAT2 for higher cognitive functions has not yet been studied. We tested auditory goal-directed behavior and attentional control in 120 NAT2 genotyped subjects (63-88 years), using an auditory distraction paradigm in which participants responded to the duration of long and short tone stimuli. We studied involuntary shifts in attention to task-irrelevant deviant stimuli and applied event-related potentials (ERPs) to examine which cognitive subprocesses are affected by NAT2 status on a neurophysiological level. Relative to the standard stimuli, deviant stimuli decreased performance in the recently described ultra-slow acetylators (NAT2*6A and *7B): The increase in error-corrected reaction times (a combined measure of response speed and accuracy) in ultra-slow acetylators (254 ms increase) was more than twice as high as in the rapid acetylator reference group (111 ms increase; p < 0.01). The increase was still higher than in the other slow acetylators (149 ms increase, p < 0.05). In addition, clear differences were found in the ERP results: Ultra-slow acetylators showed deficits specifically in the automatic detection of changes in the acoustic environment as evidenced by reduced mismatch negativity (MMN, p < 0.005 compared to rapid acetylators). Refocussing of attention after a distracting event was also impaired in the ultra-slow acetylators as evidenced by a reduced re-orienting negativity (RON, p < 0.01 compared to rapid acetylators). In conclusion, the ultra-slow acetylation status was associated with reduced higher cognitive functions.

Toxoplasma gondii impairs memory in infected seniors.

Almost 30% of humans present a Toxoplasma gondii positive antibody status and its prevalence increases with age. The central nervous system is the main target. However, little is known about the influence of asymptomatic i.e. latent Toxoplasmosis on cognitive functions in humans. To investigate neurocognitive dysfunctions in asymptomatic older adults with T. gondii positive antibody status a double-blinded neuropsychological study was conducted. The participants were classified from a population-based sample (N=131) of healthy participants with an age of 65 years and older into two groups with 42 individuals each: Toxoplasmosis positive (T-pos; IgG>50 IU/ml) and Toxoplasmosis negative (T-neg; IgG=0 IU/ml). The outcome measures were a computer-based working-memory test (2-back) and several standardized psychometric tests of memory and executive cognitive functions. T-pos seniors showed an impairment of different aspects of memory. The rate of correctly detected target symbols in a 2-back task was decreased by nearly 9% (P=0.020), corresponding to a performance reduction of about 35% in working memory relative to the T-neg group. Moreover, T-pos seniors had a lower performance in a verbal memory test, both regarding immediate recall (10% reduction; P=0.022), delayed recognition (6%; P=0.037) and recall from long-term memory assessed by the word fluency tests (12%; P=0.029). In contrast, executive functions were not affected. The effects remained mostly unchanged after controlling for medication. The impairment of memory functions in T-pos seniors was accompanied by a decreased self-reported quality of life. Because of the high prevalence of asymptomatic Toxoplasmosis and an increasing population of older adults this finding is of high relevance for public health.

Auditory distraction, time perception, and the role of age: ERP evidence from a large cohort study.

Cognitive aging is typically associated with a higher susceptibility to distraction by concurrent, but task-irrelevant stimuli. Here, we studied the cognitive sub-processes involved in a sample of 484 healthy adults aged 20-70 years from the Dortmund Vital Study (Clinicaltrials.gov NCT05155397). Participants judged the duration of tone stimuli of a random sequence of long and short tones, having either a regular (standard) pitch or rare (deviant) pitch. Deviance-related ERPs were explored, reflecting neuro-cognitive correlates of pre-attentive deviance detection (MMN), attention allocation toward (P3a) and processing of (P3b) the deviance, and re-orienting toward the task-relevant stimulus feature (RON). Accuracy was reduced for deviant long tones, possibly due to withdrawing attention from processing the time information, making long stimuli appear shorter. This effect increased with age, and cluster-based permutation tests on the correlation of ERPs and age as well as linear mixed modeling indicated a decrease in MMN, an increase in P3a with long tones, and decreases in P3b and RON. This suggests a greater attentional orienting to the deviant stimulus feature and a reduced re-orienting to the task-relevant feature with increasing age.

Resting-state EEG data before and after cognitive activity across the adult lifespan and a 5-year follow-up.

This dataset consists of 64-channels resting-state EEG recordings of 608 participants aged between 20 and 70 years, 61.8% female, as well as follow-up measurements after approximately 5 years of 208 participants, starting 2021. The EEG was measured for three minutes with eyes open and eyes closed before and after a 2-hour block of cognitive experimental tasks. The data set is part of the Dortmund Vital Study, a prospective study on the determinants of healthy cognitive aging. The dataset can be used for (1) analyzing cross-sectional resting-state EEG of healthy individuals across the adult life span; (2) generating normalization data sets for comparison of resting-state EEG data of patients with clinically relevant disorders; (3) studying effects of performing cognitive tasks on resting-state EEG and age; (4) exploring intra-individual changes in resting-state EEG and effects of task performance over a time period of about 5 years. The data are provided in Brain Imaging Data Structure (BIDS) format and are available on OpenNeuro.

Chronic Toxoplasma gondii Infection Modulates Hearing Ability across the Adult Life Span.

While several studies have shown associations between hearing disorders and congenital toxoplasmosis, the present study investigated the impact of chronic, latent Toxoplasma gondii (T. gondii) infection on hearing loss. We used a regression analysis to explore whether latent T. gondii infection modulates changes in hearing thresholds over an age range from 20 to 70 years. We analyzed audiometric data of 162 T. gondii IgG-positive and 430 T. gondii-negative participants, collected in the Dortmund Vital Study (DVS, ClinicalTrials.gov Identifier: NCT05155397), a prospective study on healthy cognitive aging. The regression analysis indicated that latent toxoplasmosis was associated with an accelerated development in hearing loss over the observed age range. Hearing loss was less frequent in IgG-positive than in IgG-negative participants up to the age of about 40 for a low (0.125-1 kHz)-frequency range. For high (2-8 kHz) frequencies, this pattern reversed for ages above 65 years. We discuss these findings on hearing function in the context of a recently proposed model, suggesting that latent toxoplasmosis can differentially affect brain functions across a lifespan.

BDNF Val66Met polymorphism and goal-directed behavior in healthy elderly - evidence from auditory distraction.

Aging affects the ability to focus attention on a given task and to ignore distractors. These functions subserve response control processes for which fronto-striatal networks have been shown to play an important role. Within these networks, the brain-derived-neurotrophic-factor (BDNF), which is known to underlie aging effects, plays a pivotal role. We investigated how cognitive subprocesses constituting a cycle of distraction, orientation and refocusing of attention are affected by the functional BDNF Val66Met polymorphism using event-related potentials (ERPs) in 122 healthy elderly. Using an auditory distraction paradigm we found that the Val/Val genotype confers a disadvantage to its carriers. This disadvantage was partly compensated by intensified attentional shifting mechanisms. It could be based on response selection processes being more vulnerable against interference from distractors in this genotype group. Processes reflecting transient sensory memory processes, or the re-orientation of attention were not affected by the BDNF Val66Met polymorphism, suggesting a higher importance of BDNF for mechanisms related to response control, than stimulus processing. The results add on recent literature showing that the Met allele confers some benefit to its carriers. We suggest an account for unifying different results of BDNF Val66Met association studies in executive functions, based on the role of BDNF in fronto-striatal circuits.

Effects of cognitive and stress management training in middle-aged and older industrial workers in different socioeconomic settings: a randomized controlled study.

Introduction: The demographic change requires longer working lifetime. However, fear of job loss may lead to chronic stress whereas aging and unchallenging work may accelerate cognitive decline and early retirement. Long-time repetitive work led to impairments of cognitive functions in middle-aged and older employees, as demonstrated in a previous study conducted in a large car manufacturer. In the present study, a training concept was implemented to enhance the cognitive and emotional competence of these employees. Methods: A first group of employees received a trainer-guided cognitive training only, whereas a wait list control group received a cognitive training and stress management training. This design was applied in two independent samples separated by one year either during or after a socioeconomically tense situation of the factory. Results: In sample 1, with a tense occupational situation, the cognitive training effects occurred with a delay of three months. In contrast, in sample 2, with less critical socioeconomic situation, the training effects occurred immediately and persisted three months later. Stress management training showed reduction of subjectively and objectively measured stress level. Discussion: The results indicate that effects of cognitive interventions are diminished under chronic stress which can be reduced after a short stress management training. This leads also to enhanced attention and memory in daily life. In contrast, in Sample 2 with less chronic stress, effects of cognitive training were stronger and persisted at least three months later, whereas stress management training had less impact. This suggests that cognitive learning in occupational settings is only efficient at lower stress levels.

Cognitive aging at work and in daily life-a narrative review on challenges due to age-related changes in central cognitive functions.

Demographic change is leading to an increasing proportion of older employees in the labor market. At the same time, work activities are becoming more and more complex and require a high degree of flexibility, adaptability, and cognitive performance. Cognitive control mechanism, which is subject to age-related changes and is important in numerous everyday and work activities, plays a special role. Executive functions with its core functions updating, shifting, and inhibition comprises cognitive control mechanisms that serve to plan, coordinate, and achieve higher-level goals especially in inexperienced and conflicting actions. In this review, influences of age-related changes in cognitive control are demonstrated with reference to work and real-life activities, in which the selection of an information or response in the presence of competing but task-irrelevant stimuli or responses is particularly required. These activities comprise the understanding of spoken language under difficult listening conditions, dual-task walking, car driving in critical traffic situations, and coping with work interruptions. Mechanisms for compensating age-related limitations in cognitive control and their neurophysiological correlates are discussed with a focus on EEG measures. The examples illustrate how to access influences of age and cognitive control on and in everyday and work activities, focusing on its functional role for the work ability and well-being of older people.

Chronic stress is associated with specific path integration deficits.

Repeated exposure to stress (chronic stress) can cause excess levels of circulating cortisol and has detrimental influences on various cognitive functions including long-term memory and navigation. However, it remains an open question whether chronic stress affects path integration, a navigational strategy that presumably relies on the functioning of grid cells in the medial entorhinal cortex. The entorhinal cortex is a brain region in the medial temporal lobe, which contains multiple cell types involved in spatial navigation (and episodic memory), and a high number of corticosteroid receptors, predisposing it as a potential target of cortisol effects. Here, our goal was to investigate the association between chronic stress and path integration performance. We assessed chronic stress via hair cortisol concentration (physiological measure) and the Perceived Stress Questionnaire (subjective measure) in 52 female participants aged 22-65 years. Path integration was measured using a virtual homing task. Linear mixed models revealed selective impairments associated with chronic stress that depended on error type and environmental features. When focusing on distance estimations in the path integration task, we observed a significant relationship to hair cortisol concentrations indicating impaired path integration particularly during trials with higher difficulty in participants with high hair cortisol concentrations. This relationship especially emerged in the absence of spatial cues (a boundary or a landmark), and particularly in participants who reported high levels of subjectively experienced chronic stress. The findings are in line with the hypothesis that chronic stress compromises path integration, possibly via an effect on the entorhinal grid cell system.

Does physical fitness affect cognitive functions differently across adulthood? An advantage of being older.

Introduction: There is a large interindividual variability in cognitive functioning with increasing age due to biological and lifestyle factors. One of the most important lifestyle factors is the level of physical fitness (PF). The link between PF and brain activity is widely accepted but the specificity of cognitive functions affected by physical fitness across the adult lifespan is less understood. The present study aims to clarify whether PF is basically related to cognition and general intelligence in healthy adults, and whether higher levels of PF are associated with better performance in the same or different cognitive functions at different ages. Methods: A sample of 490 participants (20-70 years) was analyzed to examine this relationship. Later, the sample was split half into the young to middle-aged group (YM; 20-45 years; n = 254), and the middleaged to older group (MO; 46-70 years; n = 236). PF was measured by a quotient of maximum power in a bicycle ergometry test PWC-130 divided by body weight (W/kg), which was supported by a self-reported level of PF. Cognitive performance was evaluated by standardized neuropsychological test batteries. Results: Regression models showed a relationship between PF and general intelligence (g-factor) and its subcomponents extracted using structural equation modeling (SEM) in the entire sample. This association was moderated by age, which also moderated some specific cognitive domains such as attention, logical reasoning, and interference processing. After splitting the sample into two age groups, a significant relationship was found between cognitive status, as assessed by the Mini Mental State Examination (MMSE), and PF in both age groups. However, apart from cognitive failures in daily life (CFQ), no other association between PF and specific cognitive functions was found in the YM group. In contrast, several positive associations were observed in the MO group, such as with selective attention, verbal memory, working memory, logical reasoning, and interference processing. Discussion: These findings show that middle-aged to older adults benefit more from PF than younger to middle-aged adults. The results are discussed in terms of the neurobiological mechanisms underlying the cognitive effects of PF across the lifespan. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT05155397, identifier NCT05155397.

A Systematic Analysis of Biological, Sociodemographic, Psychosocial, and Lifestyle Factors Contributing to Work Ability Across the Working Life Span: Cross-sectional Study.

BACKGROUND: As employees age, their physical and mental abilities decline and work ability decreases, enhancing the risk for long-term sick leave or even premature retirement. However, the relative impact of biological and environmental determinants on work ability with increasing age is poorly understood in terms of their complexity. OBJECTIVE: Previous research has shown relationships between work ability and job and individual resources, as well as specific demographic and lifestyle-related variables. However, other potentially important predictors of work ability remain unexplored, such as personality traits and biological determinants, including cardiovascular, metabolic, immunological, and cognitive abilities or psychosocial factors. Our aim was to systematically evaluate a wide range of factors to extract the most crucial predictors of low and high work ability across the working life span. METHODS: As part of the Dortmund Vital Study, 494 participants from different occupational sectors, aged between 20 and 69 years, completed the Work Ability Index (WAI) assessing employee's mental and physical resources. A total of 30 sociodemographic variables were grouped into 4 categories (social relationships, nutrition and stimulants, education and lifestyle, and work related), and 80 biological and environmental variables were grouped into 8 domains (anthropometric, cardiovascular, metabolic, immunologic, personality, cognitive, stress related, and quality of life) and have been related to the WAI. RESULTS: Using the analyses, we extracted important sociodemographic factors influencing work ability, such as education, social activities, or sleep quality, and identified age-dependent and age-independent determinants of work ability. Regression models explained up to 52% of the WAI variance. Negative predictors of work ability were chronological and immunological age, immunological inefficiency, BMI, neuroticism, psychosocial stress, emotional exhaustion, demands from work, daily cognitive failures, subclinical depression, and burnout symptoms. Positive predictors were maximum heart rate during ergometry, normal blood pressure, hemoglobin and monocyte concentration, weekly physical activity, commitment to the company, pressure to succeed, and good quality of life. CONCLUSIONS: The identified biological and environmental risk factors allowed us to evaluate work ability in its complexity. Policy makers, employers, and occupational safety and health personnel should consider the modifiable risk factors we identified to promote healthy aging at work through focused physical, dietary, cognitive, and stress-reduced preventive programs, in addition to well-balanced working conditions. This may also increase the quality of life, commitment to the job, and motivation to succeed, which are important factors to maintain or even enhance work ability in the aging workforce and to prevent early retirement. TRIAL REGISTRATION: ClinicalTrials.gov NCT05155397; https://clinicaltrials.gov/ct2/show/NCT05155397. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/32352.