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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]

Background: Worldwide, the population is aging and the number of individuals diagnosed with dementia is rising rapidly. Currently, there are no effective pharmaceutical cures. Hence, identifying lifestyle approaches that may prevent, delay, or treat cognitive impairment and dementia in older adults is becoming increasingly important. Computerized Cognitive Training (CCT) is a promising strategy to combat cognitive decline. Yet, the underlying mechanisms of the effect of CCT on cognition remain poorly understood. Hence, the primary objective of this systematic review was to examine peer-reviewed literature ascertaining the effect of CCT on both structural and functional neuroimaging measures among older adults to gain insight into the underlying mechanisms by which CCT may benefit cognitive function.Methods: In accordance with PRISMA guidelines, we used the following databases: MEDLINE, EMBASE, and CINAHL. Two independent reviewers abstracted data using pre-defined terms. These included: main study characteristics such as the type of training (i.e., single- versus multi-domain), participant demographics (age ≥ 50 years; no psychiatric conditions), and the inclusion of neuroimaging outcomes. The Physiotherapy Evidence Database (PEDro) scale was used to assess quality of all studies included in this systematic review.Results: Nine studies were included in this systematic review, with four studies including multiple MRI sequences. Results of this systematic review are mixed: CCT was found to increase and decrease both brain structure and function in older adults. In addition, depending on region of interest, both increases and decreases in structure and function were associated with behavioural performance.Conclusions: Of all studies included in this systematic review, results from the highest quality studies, which were two randomized controlled trials, demonstrated that multi-domain CCT could lead to increases in hippocampal functional connectivity. Further high quality studies that include an active control, a sample size calculation, and an appropriate training dosage, are needed to confirm these findings and their relation to cognition. [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]

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. [ABSTRACT FROM AUTHOR]

Estrogens are known to exert significant structural and functional effects in the hippocampus of adult rodents. In particular, 17β-estradiol can improve, impair, or have no effect on hippocampus-dependent learning and memory depending on dose and time of administration. The effects of other forms of estrogen, such as estrone and 17α-estradiol, on hippocampus-dependent learning have not been as thoroughly investigated. Therefore, the purpose of this study was to investigate the effects of 17β-estradiol, estrone, and 17α-estradiol at three different doses on two different tasks: hippocampus-dependent contextual fear conditioning and hippocampus-independent cued fear conditioning. Adult ovariectomized female rats were injected with one of the estrogens at one of the three doses 30 mins before conditioning to assess the rapid effects of these estrogens on acquisition. Twenty-four hours later memory for the context was examined and 1 h later memory for the cue (tone) was assessed. Levels of synaptophysin were examined in the dorsal hippocampus of rats to identify a potential synaptic correlate of hormonal effects on contextual fear conditioning. Low 17β-estradiol and 17α-estradiol enhanced, whereas high 17β-estradiol and 17α-estradiol impaired, contextual fear conditioning. Only the middle dose of estrone severely impaired contextual fear conditioning. Estrogens did not alter performance in the hippocampus-independent cued task. Synaptophysin expression was increased by estrone (at a middle and high dose) and 17β-estradiol (at a middle dose) in the CA3 region of the hippocampus and was not correlated with cognition. The results of this study indicate that estradiol can positively or negatively influence hippocampus-dependent learning and memory, whereas estrone impairs hippocampus-dependent learning and memory in a dose-dependent manner. These results have important therapeutic implications, as estrone, a main component of a widely used hormone replacement therapy, was shown to have either a negative effect or no effect on learning and memory. It may be possible to use 17α-estradiol and lower doses of estrogens as potential alternatives in hormone replacement therapies. [ABSTRACT FROM AUTHOR]

Engaging in targeted exercise interventions is a promising, non-pharmacological strategy to mitigate the deleterious effects of aging and disease on brain health. However, despite its therapeutic potential, a large amount of variation exists in exercise efficacy in older adults aged 55 and older. In this review, we present the argument that biological sex may be an important moderator of the relationship between physical activity and cognition. Sex differences exist in dementia as well as in several associated risk factors, including genetics, cardiovascular factors, inflammation, hormones and social and psychological factors. Different exercise interventions, such as aerobic training and resistance training, influence cognition and brain health in older adults and these effects may be sex-dependent. The biological mechanisms underlying the beneficial effects of exercise on the brain may be different in males and females. Specifically, we examine sex differences in neuroplasticity, neurotrophic factors and physiological effects of exercise to highlight the possible mediators of sex differences in exercise efficacy on cognition. Future studies should address the potential sex difference in exercise efficacy if we are to develop effective, evidence-based exercise interventions to promote healthy brain aging for all individuals.

Antidepressant drugs are too often ineffective, the exact mechanism of efficacy is still ambiguous, and there has been a paucity of novel targets for pharmacotherapy. In an attempt to understand the pathogenesis of depression and subsequently develop more efficacious antidepressant drugs, multiple theories have been proposed, including the modulation of neurotransmission, the upregulation of neurogenesis and neurotrophic factors, normalizing hypothalamic-pituitary-adrenal reactivity, and the reduction of neuroinflammation; all of which have supporting lines of evidence. Therefore, an ideal molecular target for novel pharmaceutical intervention would function at the confluence of these theories. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) functions broadly, serving to mediate synaptic plasticity, neurogenesis, neurotrophic factor signaling, and inflammatory signaling throughout the brain; all of which are associated with the pathophysiology and treatment of depression. Moreover, the expression of PSA-NCAM is reduced by depression, and conversely enhanced by antidepressant treatment, particularly within the hippocampus. Here we demonstrate that selectively cleaving the polysialic acid moiety, using the bacteriophage-derived enzyme endoneuraminidase N, completely inhibits the antidepressant efficacy of the selective-serotonin reuptake inhibitor fluoxetine (FLX) in a chronic unpredictable stress model of depression. We also observe a corresponding attenuation of FLX-induced hippocampal neuroplasticity, including decreased hippocampal neurogenesis, synaptic density, and neural activation. These data indicate that PSA-NCAM-mediated neuroplasticity is necessary for antidepressant action; therefore PSA-NCAM represents an interesting, and novel, target for pharmacotherapy.