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Exercise training is an important strategy to counteract cognitive and brain health decline during aging. Evidence from systematic reviews and meta-analyses supports the notion of beneficial effects of exercise in cognitively unimpaired and impaired older individuals. However, the effects are often modest, and likely influenced by moderators such as exercise training parameters, sample characteristics, outcome assessments, and control conditions. Here, we discuss evidence on the impact of exercise on cognitive and brain health outcomes in healthy aging and in individuals with or at risk for cognitive impairment and neurodegeneration. We also review neuroplastic adaptations in response to exercise and their potential neurobiological mechanisms. We conclude by highlighting goals for future studies, including addressing unexplored neurobiological mechanisms and the inclusion of under-represented populations., Competing Interests: Declaration of interests The authors declare no competing interests in relation to this work., (Copyright © 2024. Published by Elsevier Ltd.)

Objectives: Physical activity (PA) and total sleep time (TST) are each associated with cognition; however, whether these relationships vary by age and biological sex is unclear. We examined the relationships of PA or TST with cognition, and whether age and sex moderated these relationships, using baseline data from the Canadian Longitudinal Study on Aging (CLSA; 2010-2015)., Study Design: A cross-sectional analysis of participants from the Comprehensive cohort of the CLSA with complete PA and sleep data (n = 20,307; age range 45-86 years)., Main Outcome Measures: PA and TST were measured using the Physical Activity Scale for the Elderly (PASE) and self-reported TST over the past month. Cognition was indexed using a three-factor structural equation model (i.e., memory, executive function, and verbal fluency)., Results: Non-linear restricted cubic spline models indicated that PA and TST explained statistically significant (p < 0.01) but modest variance of each cognitive domain (<1 % of 23-24 % variance). Age and sex did not moderate associations of PA with any cognitive domain. However, age and sex moderated relationships of TST with cognition, whereby: 1) associations of TST with memory decreased with age for males and females; and 2) males and females had different age-associated relationships of TST with executive function and verbal fluency., Conclusions: PA and TST modestly contribute to multiple domains of cognition across middle and older adulthood. Importantly, the association of PA with cognition does not appear to vary across middle or older adulthood, nor does it vary by biological sex; however, TST appears to have a complex relationship with multiple domains of cognition which is both age- and sex-dependent., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Sex differences are well-established in Alzheimer's disease (AD) frequency and pathogenesis, but are not mechanistically understood. Accelerated epigenetic age has been associated with both cognitive aging and AD pathophysiology, but has not been studied by sex in AD or related cognitive impairment. Using the ADNI cohort, we found that none of sex, cognitive impairment diagnosis, nor load of APOEε4 alleles (strongest genetic AD risk factor) were associated with epigenetic age acceleration (DNAmAge, Intrinsic DNAmAge, PhenoAge, or GrimAge), although females exhibit more accelerated epigenetic aging using the Skin & Blood clock in the transition from normal cognition to cognitive impairment than males., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism may be an important source of heterogeneity seen in cognitive aging, although the specific relationship between this polymorphism and cognition remains controversial and may depend on the sex of participants. We assessed 2668 older black and white adults and fit linear mixed models to digit symbol substitution test (DSST) performance assessed in years 0 (baseline), 4, 7, and 9 to examine the interaction between sex and BDNF genotype on the intercept (i.e., estimated baseline DSST) and change in DSST over 9 years, adjusted for covariates. Sex interacted with BDNF genotype to predict DSST intercept (F[1,1599] = 7.4, p < 0.01) and 9-year change (F[1,1183] = 4.1, p = 0.04) in white participants only. Initially, white male Val/Val carriers had lower DSST scores (37.6, SE = 0.8) in comparison with male Met carriers (difference, -1.7; 95% CI, -3.2 to -0.3) and female Val/Val carriers (difference, -5.6; 95% CI, -6.8 to -4.3). White female Met carriers showed a slower rate of change (annual rate of change = -0.6, SE = 0.1) in comparison with female Val/Val carriers (difference, -0.2; 95% CI, -0.4 to -0.02) and male Met carriers (difference, -0.3; 95% CI, -0.5 to -0.02). Our findings suggest that BDNF Val66Met and sex should be considered in future endeavors aimed at treating or preventing neurodegenerative disorders., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Research in humans indicates that women may show greater cognitive benefits from aerobic training (AT) than men. To determine whether this sex difference extends to rodents, we conducted a systematic review and meta-analysis of studies in healthy, older rodents. Results indicate that compared to controls, AT improved hippocampus-dependent and -independent learning and memory. A sex difference was found with males showing larger benefits from AT on conditioned-avoidance and non-spatial memory tasks. AT also increased brain-derived neurotrophic factor compared to controls, with larger effects in females. As an exploratory analysis, sex differences in voluntary AT were examined separately from forced AT. Voluntary AT enhanced non-spatial memory to a greater extent in males. Forced AT enhanced hippocampus-dependent learning and memory more so in females. These findings suggest that sex is an important factor to consider, and studies directly assessing sex differences in the ability of exercise to improve brain function are needed., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Exercise is a non-pharmacological strategy to mitigate the deleterious effects of aging on brain health. However, a large amount of variation exists in its efficacy. Sex of participants and exercise type are two possible factors contributing to this variation. To better understand this, we conducted a concurrent systematic review and meta-analysis of cognitively healthy older adults. Executive functions, episodic memory, visuospatial function, word fluency, processing speed and global cognitive function were examined for exercise- and sex-dependent effects. For executive functions, three types of exercise interventions - aerobic training, resistance training, and multimodal training (i.e., both aerobic and resistance training) - were associated with larger effect sizes in studies comprised of a higher percentage of women compared to studies with a lower percentage of women. This suggests that women's executive processes may benefit more from exercise than men. Regardless of sex, compared to control, all three exercise training approaches enhanced visuospatial function, but only multimodal training enhanced episodic memory. Overall, aerobic training led to greater benefits than resistance training in global cognitive function and executive functions, while multimodal combined training led to greater benefits than aerobic training for global cognitive function, episodic memory, and word fluency. Possible underlying mechanisms, including brain-derived neurotrophic factor and sex steroid hormones, are discussed., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Life history theory (LHT) predicts a trade-off between reproductive effort and the pace of biological aging. Energy invested in reproduction is not available for tissue maintenance, thus having more offspring is expected to lead to accelerated senescence. Studies conducted in a variety of non-human species are consistent with this LHT prediction. Here we investigate the relationship between the number of surviving children born to a woman and telomere length (TL, a marker of cellular aging) over 13 years in a group of 75 Kaqchikel Mayan women. Contrary to LHT's prediction, women who had fewer children exhibited shorter TLs than those who had more children (p = 0.045) after controlling for TL at the onset of the 13-year study period. An "ultimate" explanation for this apparently protective effect of having more children may lay with human's cooperative-breeding strategy. In a number of socio-economic and cultural contexts, having more chilren appears to be linked to an increase in social support for mothers (e.g., allomaternal care). Higher social support, has been argued to reduce the costs of further reproduction. Lower reproductive costs may make more metabolic energy available for tissue maintenance, resulting in a slower pace of cellular aging. At a "proximate" level, mechanisms involved may include the actions of the gonadal steroid estradiol, which increases dramatically during pregnancy. Estradiol is known to protect TL from the effects of oxidative stress as well as increase telomerase activity, an enzyme that maintains TL. Future research should explore the potential role of social support as well as that of estradiol and other potential biological pathways in the trade-offs between reproductive effort and the pace of cellular aging within and among human as well as in non-human populations.

Adult neurogenesis exists in most mammalian species, including humans, in two main areas: the subventricular zone (new cells migrate to the olfactory bulbs) and the dentate gyrus of the hippocampus. Many factors affect neurogenesis in the hippocampus and the subventricular zone, however the focus of this review will be on factors that affect hippocampal neurogenesis, particularly in females. Sex differences are often seen in levels of hippocampal neurogenesis, and these effects are due in part to differences in circulating levels of steroid hormones such as estradiol, progesterone, and corticosterone during the estrous cycle, in response to stress, with reproduction (including pregnancy and lactation), and aging. Depletion and administration of these same steroid hormones also has marked effects on hippocampal neurogenesis in the adult female, and these effects are dependent upon reproductive status and age. The present review will focus on current research investigating how hippocampal neurogenesis is altered in the adult female rodent across the lifespan.

BackgroundOlder females show greater cognitive gains from physical activity (PA) than males, which may be related to long-term consequences of female-specific reproductive events (eg, pregnancy) on cognitive health.MethodsTo determine whether previous parity could moderate the relationship between PA and cognitive decline in older women, we conducted secondary analyses of data from the Health, Aging, and Body Composition Study. We tested whether the association between average PA over 10 years and cognition (Modified Mini-Mental State Examination [3MS]) and executive functioning (digit symbol substitution test [DSST]) over 10 years varied by previous parity (nulliparity, low parity, medium parity, and grand multiparity). An analysis of covariance was performed with cognition (average and change over 10 years) as the dependent variables, parity as a categorical predictor, average PA as a continuous predictor, and a set of relevant covariates.ResultsSignificant interactions were found between PA and parity group for all 4 comparisons: average 3MS (p = .014), average DSST (p = .032), change in 3MS (p = .016), and change in DSST (p = .017). Simple slope analyses indicated the positive relationship between PA and average 3MS and DSST was only significant in the nulliparity and grand multiparity groups, and the positive relationship between PA and change in 3MS and DSST was only significant in the grand multiparity group.ConclusionThe findings suggest the relationship between self-reported walking and cognitive performance was strongest in the groups at risk for cognitive decline and dementia, the nulliparous and grand multiparous groups.

BackgroundPhysical activity (PA) is a promising strategy for the promotion of brain health, although substantial variation exists in the effects of PA at the individual level. Given the greater prevalence and faster progression of Alzheimer's disease in women compared to men, and known sex differences in brain architecture, analysis of sex differences in the relationship between PA, cognition, and brain region volumes is warranted.MethodsTo address this, we conducted secondary analyses of data from the Health, Aging, and Body Composition study. To determine whether longitudinal changes in PA over 10 years predicted declines in global cognitive functioning and executive functions and processing speed differently in males and females, latent growth curve modeling was utilized. Magnetic resonance imaging was performed at year 10, and the hippocampus and dorsolateral prefrontal cortex were identified as regions of interest.ResultsMaintaining PA over 10 years predicted less declines in executive functions and processing speed in females but not males. Maintaining PA over 10 years was significantly associated with greater volume of the left dorsolateral prefrontal cortex, a brain region involved in executive functions, in year 10 in females only. Maintaining physical activity was associated with better global cognitive function in both males and females, and also predicted volume of the left hippocampus, albeit in different directions with females showing a negative relationship and males showing a positive relationship.ConclusionsThese findings suggest that the relationship of PA with cognition and its neurobiological correlates differ by sex, with females apparently benefiting from PA to a greater extent than males. Development of personalized, tailored exercise recommendations to promote healthy brain aging should account for sex differences.

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism may be an important source of heterogeneity seen in cognitive aging, although the specific relationship between this polymorphism and cognition remains controversial and may depend on the sex of participants. We assessed 2668 older black and white adults and fit linear mixed models to digit symbol substitution test (DSST) performance assessed in years 0 (baseline), 4, 7, and 9 to examine the interaction between sex and BDNF genotype on the intercept (i.e., estimated baseline DSST) and change in DSST over 9 years, adjusted for covariates. Sex interacted with BDNF genotype to predict DSST intercept (F[1,1599] = 7.4, p < 0.01) and 9-year change (F[1,1183] = 4.1, p = 0.04) in white participants only. Initially, white male Val/Val carriers had lower DSST scores (37.6, SE = 0.8) in comparison with male Met carriers (difference, -1.7; 95% CI, -3.2 to -0.3) and female Val/Val carriers (difference, -5.6; 95% CI, -6.8 to -4.3). White female Met carriers showed a slower rate of change (annual rate of change = -0.6, SE = 0.1) in comparison with female Val/Val carriers (difference, -0.2; 95% CI, -0.4 to -0.02) and male Met carriers (difference, -0.3; 95% CI, -0.5 to -0.02). Our findings suggest that BDNF Val66Met and sex should be considered in future endeavors aimed at treating or preventing neurodegenerative disorders.

The number of older people worldwide living with cognitive impairment and neurodegenerative diseases is growing at an unprecedented rate. Despite accumulating evidence that engaging in physical activity is a promising primary behavioral strategy to delay or avert the deleterious effects of aging on brain health, a large degree of variation exists in study findings. Thus, before physical activity and exercise can be prescribed as "medicine" for promoting brain health, it is imperative to understand how different biological factors can attenuate or amplify the effects of physical activity on cognition at the individual level. In this review article, we briefly discuss the current state of the literature, examining the relationship between physical activity and brain health in older adults and we present the argument that biological sex is a potent moderator of this relationship. Additionally, we highlight some of the potential neurobiological mechanisms underlying this sex difference for this relatively new and rapidly expanding line of research. [ABSTRACT FROM AUTHOR]

Physical activity is a promising strategy for dementia prevention and disease modification. Here, we provide a narrative review of the current evidence from epidemiological and intervention studies on the role of physical activity and exercise in promoting cognitive health in older adults both without and with cognitive impairment. We highlight some of the potential underlying mechanisms and discuss biological sex as a potential moderating factor. We conclude with limitations and future directions for this rapidly expanding line of research. [ABSTRACT FROM AUTHOR]

Psychological challenges, including traumatic events, have been hypothesized to increase the age-related pace of biological aging. Here we test the hypothesis that psychological challenges can affect the pace of telomere attrition, a marker of cellular aging, using data from an ongoing longitudinal-cohort study of Kaqchikel Mayan women living in a population with a high frequency of child mortality, a traumatic life event. Specifically, we evaluate the associations between child mortality, maternal telomere length and the mothers’ hypothalamic-pituitary-adrenal axis (HPAA), or stress axis, activity. Child mortality data were collected in 2000 and 2013. HPAA activity was assessed by quantifying cortisol levels in first morning urinary specimens collected every other day for seven weeks in 2013. Telomere length (TL) was quantified using qPCR in 55 women from buccal specimens collected in 2013. Results: Shorter TL with increasing age was only observed in women who experienced child mortality (p = 0.015). Women with higher average basal cortisol (p = 0.007) and greater within-individual variation (standard deviation) in basal cortisol (p = 0.053) presented shorter TL. Non-parametric bootstrapping to estimate mediation effects suggests that HPAA activity mediates the effect of child mortality on TL. Our results are, thus, consistent with the hypothesis that traumatic events can influence cellular aging and that HPAA activity may play a mediatory role. Future large-scale longitudinal studies are necessary to confirm our results and further explore the role of the HPAA in cellular aging, as well as to advance our understanding of the underlying mechanisms involved. [ABSTRACT FROM AUTHOR]

Menopause is associated with cognitive decline, and previous parity can increase or delay the trajectory of cognitive aging. Furthermore, parity enables the hippocampus to respond to estrogens in middle age. The present study investigated how previous parity and estrogens influence cognition, neurogenesis, and neuronal activation in response to memory retrieval in the hippocampus of middle-aged females. Multiparous and nulliparous rats were ovariectomized (OVX) or received sham surgery and were treated with vehicle, 17β-estradiol, 17α-estradiol, or estrone. Rats were trained on the spatial working and reference memory versions of the Morris water maze. Multiparous rats had a significantly greater density of immature neurons in the hippocampus, enhanced acquisition of working memory, but poorer reference memory compared with nulliparous rats. Furthermore, OVX increased, while treatment with estrogens reduced, the density of immature neurons, regardless of parity. OVX improved reference memory only in nulliparous rats. Thus, motherhood has long-lasting effects on the neuroplasticity and function of the hippocampus. These findings have wide-ranging implications for the treatment of age-associated decline in women. [ABSTRACT FROM AUTHOR]