Effects of growth hormone releasing hormone on rat ovarian steroidogenesis

During the last decade, it has been shown that each part ofthe somatotrophic axis can influence granulosa cell function.Growth hormone releasing hormone (GHRH) may be effective throughthe release of hypophyseal growth hormone (GH) and the subsequentincrease of insulin-like growth factors (IGF). There is alsosome evidence that GHRH could act directly on ovarian function.The aim of this study was to determine the mechanism throughwhich GHRH affects granulosa cell steroidogenesis in the ovary.Granulosa cells were obtained from immature, oestrogen-treatedrats supplemented with or without follicle stimulating hormone(FSH) in vivo and were cultured for 48 h to evaluate steroidproduction. GHRH was administered either in vivo at the sametime as FSH, or in vitro in the presence or absence of testosteroneand FSH. Our results show that co-treatment with GHRH and FSHin vivo induced significant increases in plasma IGF-I concentrationsand steroid production by cultured granulosa cells. The additionof GHRH to culture medium did not significantly alter steroidproduction by either non-differentiated (no FSH in vivo) ordifferentiated (FSH in vivo) granulosa cells. In contrast, treatmentin vitro with IGF-I significantly increased steroidogenesisha both cases. Our results suggest that any physiologicallysignificant effect of GHRH on ovarian function is probably tobe exerted via activation of the somatotrophic axis and thesubsequent amplification of ovarian FSH responsiveness by IGF-I.     

Relationships between macular pigment optical density and cognitive function in unimpaired and mildly cognitively impaired older adults

Low carotenoid status (especially of the xanthophylls, lutein [L], and zeaxanthin [Z]) is common in older adults and has been associated with a number of degenerative diseases of the central nervous system ranging from retina (e.g., macular degeneration) to brain (e.g., Alzheimer's disease). In this study, we tested whether retinal measures of L + Z (macular pigment optical density [MPOD]), used as a surrogate for brain L + Z levels, were related to cognitive function when comparing healthy older adults with mildly cognitively impaired older adults. Twenty-four subjects with mild cognitive impairment were compared with 24 matched controls. Subjects were matched with respect to age, body mass index, ethnicity, sex, and smoking status. Degree of cognitive impairment and cognitive ability was determined via structured clinical interview. MPOD was measured psychophysically. In healthy older adults, MPOD was only related to visual-spatial and constructional abilities (p = 0.04). For subjects with mild cognitive impairment (MCI), however, MPOD was broadly related to cognition including the composite score on the mini-mental state examination (p = 0.02), visual-spatial and constructional abilities (p = 0.04), language ability (p = 0.05), attention (p = 0.03), and the total scale on the Repeatable Battery for the Assessment of Neuropsychological Status (p = 0.03). It is possible that L/Z status may be more strongly related to cognition when individuals are considered with established onset of cognitive decline.     

Subcortical hyperintensities impact cognitive function among a select subset of healthy elderly.

Previous studies have examined the impact of subcortical hyperintensities (SH), a proxy measure of cerebrovascular disease, on the cognitive abilities of otherwise healthy older adults. However, there remains a limited understanding as to what extent this MRI marker of pathological processes explains the decline in specific cognitive functions that occur nearly ubiquitously with advanced age, especially in relation to other age-related imaging markers. In the present study we compared cognitive abilities between a sample of 53 older healthy adults (age range=50-79) and a sample of 53 younger adults (age range=21-40). As expected, the older group performed significantly worse on most cognitive measures compared to the younger group. Frontal volume and total grey matter volume were also significantly reduced among the older individuals compared to the younger individuals. SH volume was consistently associated with cognitive function in older adults, though, this relationship was evident only for a relatively small subset of older individuals with the most severe SH. These data suggest that the relationship between SH and cognition in the elderly is driven by a subset of individuals who may be in the earliest stages of vascular cognitive impairment. Further, the findings suggest that cognitive aging is largely determined by factors other than SH for most older adults.     

The effects of aerobic exercise and transcranial direct current stimulation on cognitive function in older adults with and without cognitive impairment: A systematic review and meta-analysis

BackgroundAerobic exercise (AE) may slow age-related cognitive decline. However, such cognition-sparing effects are not uniform across cognitive domains and studies. Transcranial direct current stimulation (tDCS) is a form of non-invasive brain stimulation and is also emerging as a potential alternative to pharmaceutical therapies. Like AE, the effectiveness of tDCS is also inconsistent for reducing cognitive impairment in ageing. The unexplored possibility exists that pairing AE and tDCS could produce synergistic effects and reciprocally augment cognition-improving effects in older individuals with and without cognitive impairments.Previous research found such synergistic effects on cognition when cognitive training is paired with tDCS in older individuals with and without mild cognitive impairment (MCI) or dementia.AimThe purpose of this systematic review with meta-analysis was to explore if pairing AE with tDCS could augment singular effects of AE and tDCS on global cognition (GC), working memory (WM) and executive function (EF) in older individuals with or without MCI and dementia.MethodsUsing a PRISMA-based systematic review, we compiled studies that examined the effects of AE alone, tDCS alone, and AE and tDCS combined on cognitive function in older individuals with and without mild cognitive impairment (MCI) or dementia. Using a PICOS approach, we systematically searched PubMed, Scopus and Web of Science searches up to December 2021, we focused on ‘MoCA’, ‘MMSE’, ‘Mini-Cog’ (measures) and ‘cognition’, ‘cognitive function’, ‘cognitive’, ‘cognitive performance’, ‘executive function’, ‘executive process’, ‘attention’, ‘memory’, ‘memory performance’ (outcome terms). We included only randomized controlled trials (RTC) in humans if available in English full text over the past 20 years, with participants’ age over 60. We assessed the methodological quality of the included studies (RTC) by the Physiotherapy Evidence Database (PEDro) scale.ResultsOverall, 68 studies were included in the meta-analyses. AE (ES = 0.56 [95% CI: 0.28–0.83], p = 0.01) and tDCS (ES = 0.69 [95% CI: 0.12–1.26], p = 0.02) improved GC in all three groups of older adults combined (healthy, MCI, demented). In healthy population, AE improved GC (ES = 0.46 [95% CI: 0.22–0.69], p = 0.01) and EF (ES = 0.27 [95% CI: 0.05–0.49], p = 0.02). AE improved GC in older adults with MCI (ES = 0.76 [95% CI: 0.21–1.32], p = 0.01). tDCS improved GC (ES = 0.69 [90% CI: 0.12–1.26], p = 0.02), all three cognitive function (GC, WM and EF) combined in older adults with dementia (ES = 1.12 [95% CI: 0.04–2.19], p = 0.04) and improved cognitive function in older adults overall (ES = 0.69 [95% CI: 0.20–1,18], p = 0.01).ConclusionOur systematic review with meta-analysis provided evidence that beyond the cardiovascular and fitness benefits of AE, pairing AE with tDCS may have the potential to slow symptom progression of cognitive decline in MCI and dementia. Future studies will examine the hypothesis of this present review that a potentiating effect would incrementally improve cognition with increasing severity of cognitive impairment.     

Growth hormone administration to aged animals reduces disulfide glutathione levels in hippocampus

Systemic growth hormone (GH) and insulin-like growth factor-1 (IGF-1), potent anabolic hormones, decrease with age. In humans and animal models, administration of growth hormone or IGF-1 to aged subjects improves learning and memory, suggesting that the age-related decline in cognitive performance results, in part, from peripheral GH/IGF-1 deficiency. However, the cellular mechanisms by which GH/IGF-1 effect cognitive function are unknown. We propose that the effects of these hormones may be mediated by increasing cellular redox potential resulting in reduced oxidative stress. Because the most abundant endogenous antioxidant is glutathione (GSH), we assessed GSH and disulfide glutathione (GSSH) levels in hippocampus and frontal cortex of young (4-month-old) and aged (30-month-old) male Fisher 344xBrown Norway rats treated with porcine growth hormone (200microg/animal, twice/daily) or vehicle. We report that hippocampal levels of GSSG increase with age (0.54+/-0.08 to 1.55+/-0.24nmolGSSG/mgprotein, p<0.05) and growth hormone treatment ameliorates both the age-related rise in GSSG (1.55+/-0.24 to 0.87+/-0.24nmolGSSG/mgprotein, p<0.05) and the decline in GSH/GSSG ratios. Analysis of GSSG reductase activity in aged animals indicated no effect of either age or growth hormone treatment (p=0.81). Although similar age-related increases in GSSG and decreases in GSH/GSSG ratios were evident in frontal cortex, growth hormone had no effect. Subsequently, we assessed whether the effects of age and growth hormone treatment result from modulating trace metal accumulation. Thirteen metals were analyzed in hippocampus and frontal cortex by inductive coupled plasma mass spectrometry. Aluminum, copper, iron, manganese and zinc levels increased with age (p<0.05 each) but growth hormone replacement had no effect on metal accumulation. Our results indicate that growth hormone replacement attenuates the age-related increase in oxidative stress in hippocampus without effects on glutathione reductase or trace metal accumulation. We conclude that the age-related decline in circulating growth hormone and IGF-1 contribute to increased oxidative stress in hippocampus with age.     

Effect of gonadotrophin-releasing hormone agonist treatment on growth hormone secretion in women with polycystic ovarian syndrome

The suppression of the pituitary-gonadal axis by the administration of gonadotrophin-releasing hormone agonists (GnRH-a) is used occasionally as an adjunct therapy with gonadotrophins for ovulation induction in women with polycystic ovarian syndrome (PCOS). A number of recent clinical studies have suggested that women with polycystic ovaries (PCO) may have disturbances of normal growth hormone (GH) kinetics and alterations in the GH/insulin-like growth factor (IGF)-I system. The purpose of this study was to determine the effect of GnRH-a administration on GH-releasing hormone (GHRH)-stimulated GH release in women with PCOS. Eight women with PCO and six control women were studied before and after 2 months of treatment with the long acting GnRH-a triptoreline (3.75 mg monthly injections). GHRH was given as a single i.v. injection and blood samples for GH measurements were obtained at -15, 0, 30, 60, 90 and 120 min. The GH responses were expressed as the area under the curve (AUC) or the differences from the basal value (delta(max)). The GH response to GHRH (mean +/- SEM) was lower in women with PCO (AUC 114.9 +/- 43.1 versus 206.2 +/- 28.7 ng/ml/120 min, P < 0.05 and delta(max) 31.6 +/- 8.2 versus 49.4 +/- 5.8 ng/ml, P < 0.05). After treatment with the GnRH-a, the GH response to GHRH was significantly smaller than before treatment in both groups (PCO AUC 34.6 +/- 9.0 ng/ml/120 min and delta(max) 12.4 +/- 3.1 ng/ml; controls AUC 148.8 +/- 28.4 ng/ml/120 min and delta(max) 31.2 +/- 6.1 ng/ml), but the PCO group had a significantly smaller response. These data demonstrate that women with PCO have a reduced GH response to GHRH compared with normal controls and that GnRH-a administration causes a further GH reduction in both groups. Women with PCO have a greater suppression of GH response to GHRH during treatment with GnRH-a. This suggests that a different level of sensitivity in the somatotrophic axis exists in PCOS.      

Growth hormone-releasing hormone expression in pituitary somatotroph adenomas, studied by immunohistochemistry and in situ hybridization using catalyzed signal amplification system

Growth hormone-releasing hormone (GHRH) is a well-known hypothalamic hormone that stimulates the synthesis and release of growth hormone (GH) as well as the proliferation of GH-producing cells in the anterior pituitary gland. Recent reports have shown GHRH synthesis in pituitary somatotroph adenomas, but GHRH immunoreactivity has not been shown in previous studies. To confirm the role of locally generated GHRH for the progression of somatotroph adenomas, we investigated the expression of GHRH in 25 pituitary somatotroph adenomas immunohistochemically, through the use of both conventional avidin-biotin-complex (ABC) method and novel catalyzed signal amplified (CSA) system. In addition, we investigated the expression of GHRH mRNA and GHRH receptor mRNA with in situ hybridization (ISH) using the CSA system. The weak immunopositivity of GHRH was observed in only 2 adenomas (8.0%) of 25 somatotroph adenomas using the ABC method. In contrast, 15 adenomas (60.0%) of 25 somatotroph adenomas were immunopositive for GHRH, as shown by CSA system. Very few of nonsomatotroph adenomas were immunopositive for GHRH using the CSA system. The expression of GHRH mRNA was confirmed, using the CSA-ISH system in 13 adenomas (72.2%) of 18 somatotroph adenomas. In 11 adenomas (61.1%) of 18 somatotrophic adenomas, the expression of GHRH receptor mRNA was demonstrated using the CSA-ISH system. This is a first report that clarified histopathologically GHRH production in pituitary somatotrophic adenomas. The demonstration of GHRH and its receptor expression is meaningful in clarifying the autocrine or paracrine regulation of GHRH in GH production and progression of pituitary somatotroph adenomas.     

Cognitive and neural plasticity in old age: A systematic review of evidence from executive functions cognitive training

Cognitive training is a popular intervention aimed at attenuating age-related cognitive decline, however, the effects of this intervention on brain structure and function have not been thoroughly explored. Core executive functions (working memory, inhibition, cognitive flexibility) are dependent upon prefrontal brain regions—one of the most vulnerable areas of age-related decline. They are also implicated in numerous cognitive processes and higher-order functions. Training executive functions should therefore promote cognitive and neural enhancements in old age. This systematic review examined the effects of executive functions training on brain and cognition amongst healthy older adults across 20 studies. Behavioral performance consistently improved on trained cognitive tasks, though mixed findings were reported for untrained tasks. Training-related structural changes were reported, evidenced through increases in grey matter and cortical volume. Functional changes were not consistent, though a general pattern of increased subcortical and decreased frontal and parietal activation emerged across studies, indicating that training may potentially reduce reliance on compensatory neural mechanisms. Training executive functions appears to promote cognitive and neural plasticity in old age, though further research is required to develop a more comprehensive framework which connects and elucidates the mechanisms underlying cognitive training, cognitive transfer, and cognitive aging.     

Difference in growth hormone response to growth hormone-releasing hormone (GHRH) testing following GHRH subacute treatment in normal aging and growth hormone-deficient adults: Possible perspectives for therapeutic use of GHRH or its analogs in elderly subjects?

The somatotroph axis function shows a decline in the elderly (somatopause). In particular growth hormone (GH) response to GH-releasing hormone (GHRH) is reduced in aged man but less than that observed in GH-deficient adults (GHDAs). Plasma GH response to GHRH (1 µg/kg BW) was significantly lower in four GHDAs than in seven healthy aged men 30, 60, and 90?min after acute GHRH administration. To verify whether a priming regimen might be able to increase the reduced GH response to GHRH, both healthy aged men and GHDA patients underwent repetitive administration of GHRH (100 µg GHRH intravenously as a single morning dose, every 2 days for 12 days). After the GHRH-priming regimen, plasma GH values 30, 60, and 90?min after the acute GHRH test were significantly higher than values at the corresponding time points before priming regimen in healthy aged men but not in GHDA patients. These findings confirmed that somatotroph cells become less sensitive to GHRH with normal aging and demonstrate that repetitive administration of GHRH restores the attenuated response only in healthy aged men but not in GHDA patients. This could support the possible use of GHRH or its analogs instead of recombinant human GH in elderly patients with the advantage of preserving the endogenous pulses of GH with the secretion of the different isoforms of GH. However, concerns arise about the possible role of these molecules in tumorigenesis and tumor growth promotion.     

Abnormalities in parathyroid hormone secretion and 1,25-dihydroxyvitamin D3 formation in women with osteoporosis

We investigated the parathyroid hormone-1,25-dihydroxyvitamin D3 (1,25(OH)2D) axis in osteoporosis by administering phosphate to 8 postmenopausal women with osteoporosis (49 to 78 years old) and to 10 normal women matched for age (50 to 74 years). All subjects responded with a similar increase in the serum phosphorus concentration (women with osteoporosis, 1.15 +/- 0.06 to 1.79 +/- 0.09 mmol per liter; controls, 1.14 +/- 0.05 to 1.73 +/- 0.08 mmol per liter) and a fall in the ionized calcium concentration (women with osteoporosis, 1.12 +/- 0.03 to 1.06 +/- 0.03 mmol per liter; controls, 1.17 +/- 0.01 to 1.11 +/- 0.02 mmol per liter). Parathyroid hormone levels rose 2.5-fold in the control group (15.4 +/- 2.2 to 37.9 +/- 6.1 pg per milliliter) but increased by only 43 percent in the group with osteoporosis (14.8 +/- 2.8 to 21.2 +/- 4.1 pg per milliliter), an increase similar to that previously reported in young normal subjects (53 percent). In healthy older and younger subjects, the levels of 1,25(OH)2D did not change; in the subjects with osteoporosis, however, they decreased significantly (50 percent). We conclude that older women require a greater parathyroid hormone stimulus than younger women to maintain vitamin D homeostasis, because of an age-related decline in the formation of 1,25(OH)2D in response to parathyroid hormone, and that in osteoporosis the age-appropriate parathyroid hormone response to the same hypocalcemic signal is diminished. Our results are consistent with the presence of an abnormality in parathyroid hormone secretory function in osteoporosis in addition to the universal decline in 1,25(OH)2D responsiveness associated with aging.     

Effects of sustained cognitive activity on white matter microstructure and cognitive outcomes in healthy middle-aged adults: A systematic review

Adults who remain cognitively active may be protected from age-associated changes in white matter (WM) and cognitive decline. To determine if cognitive activity is a precursor for WM plasticity, the available literature was systematically searched for Region of Interest (ROI) and whole-brain studies assessing the efficacy of cognitive training (CT) on WM microstructure using Diffusion Tensor Imaging (DTI) in healthy adults (> 40 years). Seven studies were identified and included in this review. Results suggest there are beneficial effects to WM microstructure after CT in frontal and medial brain regions, with some studies showing improved performance in cognitive outcomes. Benefits of CT were shown to be protective against age-related WM microstructure decline by either maintaining or improving WM after training. These results have implications for determining the capacity for training-dependent WM plasticity in older adults and whether CT can be utilised to prevent age-associated cognitive decline. Additional studies with standardised training and imaging protocols are needed to confirm these outcomes.     

Age-associated losses of brain volume predict longitudinal cognitive declines over 8 to 20 years

Absolute differences in global brain volume predict differences in cognitive ability among healthy older adults. However, absolute differences confound lifelong differences in brain size with amounts of age-related shrinkage. Measurements of cerebrospinal fluid (CSF) volume were made to estimate age-related shrinkage in 93 healthy volunteers aged 63 to 86 years. Their current levels of brain shrinkage predicted their amounts of decline over the previous 8 to 20 years on repeated assessments during a longitudinal study on the Cattell "Culture Fair" Intelligence Test, on two tests of information processing speed, and marginally on the Wechsler Adult Intelligence Scale (D. Wechsler, 1981), but not on three memory tests. Loss of brain volume is an effective marker both for current cognitive status and for amounts and rates of previous age-related cognitive losses.     

Postmenopausal hormone therapy, timing of initiation, APOE and cognitive decline

Associations between postmenopausal hormone therapy (HT) and cognitive decline may depend on apolipoprotein E (APOE) status or timing of initiation. We included 16,514 Nurses' Health Study participants aged 70-81 years who were followed since 1976 and completed up to 3 telephone cognitive assessments (2 years apart), between 1995 and 2006. The tests assessed general cognition (Telephone Interview of Cognitive Status; TICS), verbal memory, and category fluency. We used longitudinal analyses to estimate differences in cognitive decline across hormone groups. APOE genotype was available in 3697 participants. Compared with never users, past or current HT users showed modest but statistically significant worse rates of decline in the TICS: the multivariable-adjusted difference in annual rate of decline in the TICS among current estrogen only users versus never users was -0.04 (95% confidence interval, -0.07 to -0.004); for current estrogen + progestin users, the mean difference was -0.05 (95% confidence interval, -0.10 to -0.002). These differences were equivalent to those observed in women who are 1-2 years apart in age. We observed no protective associations with early timing of hormone initiation. We found suggestive interactions with APOE e4 status (e.g., on TICS, p interaction, 0.10), where the fastest rate of decline was observed among APOE e4 carriers who were current HT users. Regardless of timing of initiation, HT may be associated with worse rates of decline in general cognition, especially among those with an APOE e4 allele.     

The more the better? A meta-analysis on effects of combined cognitive and physical intervention on cognition in healthy older adults

Both cognitive intervention and physical exercise benefit cognitive function in older adults. It has been suggested that combined cognitive and physical intervention may induce larger effects than cognitive or physical intervention alone, but existing literature has shown mixed results. This meta-analysis aimed at assessing the efficacy of combined intervention on cognition by comparing combined intervention to control group, cognitive intervention and physical exercise. Eligible studies were controlled trials examining the effects of combined intervention on cognition in older adults without known cognitive impairment. Twenty interventional studies comprising 2667 participants were included. Results showed that the overall effect size for combined intervention versus control group was 0.29 (random effects model, p = 0.001). Compared to physical exercise, combined intervention produced greater effects on overall effect size (0.22, p < 0.01), while no significant difference was found between combined intervention and cognitive intervention. Effects of combined intervention were moderated by age of participants, intervention frequency and setting. The findings suggest that combined intervention demonstrates advantages over control group and physical exercise, while evidence is still lacking for superiority when compared combined intervention to cognitive intervention. More well-designed studies with long follow-ups are needed to clarify the potential unique efficacy of combined intervention for older adults.     

Self-reported cognition in older adults with insomnia: Associations with sleep and domain specific cognition

Poor subjective evaluation of cognition and sleep are associated with cognitive decline in older adults. Relationships among self-reported cognition, sleep, and cognitive domains remain unclear. We evaluated the interactive associations of objective cognition and subjective sleep with self-reported cognition in older adults with insomnia. Fifty-one older adults (M_age = 69.19, SD = 7.95) with insomnia completed 14 days of self-reported cognition ratings (0-very poor, 100-very good), sleep (total sleep time (TST), sleep onset latency (SOL), wake after sleep onset (WASO), sleep efficiency), and daily cognitive tasks: Letter series (reasoning), word list delayed recall (verbal memory), Symbol Digit Modalities Test (SDMT) (attention/processing speed), and number copy (processing speed). Multiple regressions for each cognitive task determined whether average objective cognition or sleep were independently/interactively associated with average self-reported cognition, controlling for age, education, and depression. The interaction between SDMT performance and TST was associated with self-reported cognition. Specifically, the relationship between scores and self-reported cognition was congruent in those with the shortest TST. Similarly, the interactions between SDMT and WASO, as well as sleep efficiency, were associated with self-reported. Specifically, the relationship between scores and self-reported cognition was congruent in those with longest and average WASO, as well as shortest and average sleep efficiency. The findings suggest, in an older adult population with insomnia, a congruent association exists between attention/processing speed and self-reported cognition in those with worse subjective sleep (shorter TST, longer WASO, and lower SE). Insomnia symptoms should be taken into consideration when examining the relationship between objective cognition and self-reported cognition.     

Hormonal changes and their impact on cognition and mental health of ageing men

Demographic changes resulting in ageing of the world's population have major implications for health. As men grow older, circulating levels of the principal androgen or male sex hormone testosterone (T) decline, while the prevalence of ill-health increases. Observational studies in middle-aged and older men have shown associations between lower levels of T and poorer mental health in older men, including worse cognitive performance, dementia and presence of depressive symptoms. The role of T metabolites, the more potent androgen dihydrotestosterone (DHT) and the oestrogen receptor ligand estradiol (E2) in the pathophysiology of cognitive decline are unclear. Studies of men undergoing androgen deprivation therapy in the setting of prostate cancer have shown subtle detrimental effects of reduced T levels on cognitive performance. Randomised trials of T supplementation in older men have been limited in size and produced variable results, with some studies showing improvement in specific tests of cognitive function. Interventional data from trials of T therapy in men with dementia are limited. Lower levels of T have also been associated with depressive symptoms in older men. Some studies have reported an effect of T therapy to improve mood and depressive symptoms in men with low or low-normal T levels. T supplementation should be considered in men with a diagnosis of androgen deficiency. Beyond this clinical indication, further research is needed to establish the benefits of T supplementation in older men at risk of deteriorating cognition and mental health.     

Testosterone levels and cognition in elderly men: a review

Average testosterone levels and many cognitive functions show a decline with age. There is evidence to suggest that this association is not just age related. Results from cell culture and animal studies provide convincing evidence that testosterone could have protective effects on brain function. Alzheimer's disease (AD) is characterised by brain pathology affecting cognitive function and AD prevalence increases with age. Testosterone levels are lower in AD cases compared to controls, and some studies have suggested that low free testosterone (FT) may precede AD onset. Men with AD may show accelerated endocrinological ageing, characterised by an earlier lowering of thyroid stimulating hormone, an earlier increase in sex hormone binding globulin (SHBG), a subsequent earlier decrease in FT and an earlier increase in gonadotropin levels in response to this. Positive associations have been found between testosterone levels and global cognition, memory, executive functions and spatial performance in observational studies. However, non-significant associations were also reported. It may be that an optimal level of testosterone exists at which some cognitive functions are improved. This may be modified with an older age, with a shifting of the optimal testosterone curve to maintain cognition to the left and a lower optimal level thus needed to be beneficial for the brain. Genetic factors, such as APOE and CAG polymorphisms may further interact with testosterone levels in their effects on cognition. The roles of SHBG, gonadotropins, thyroid hormones and estrogens in maintaining cognitive function and preventing dementia in men are also not completely understood and should be investigated further. Hypogonadal men do not seem to benefit from testosterone supplementation but small scale, short term intervention studies in eugonadal men with and without cognitive impairments have shown promising results. Larger randomised, controlled trials are needed to further investigate testosterone treatment in protecting against cognitive decline and/or dementia.     

Insulin-like Growth Factor 1 (IGF-1) as a marker of cognitive decline in normal ageing: A review

Insulin-like Growth Factor 1 (IGF-1) and its signaling pathway play a primary role in normal growth and ageing, however serum IGF-1 is known to reduce with advancing age. Recent findings suggest IGF-1 is essential for neurogenesis in the adult brain, and this reduction of IGF-1 with ageing may contribute to age-related cognitive decline. Experimental studies have shown manipulation of the GH/GF-1 axis can slow rates of cognitive decline in animals, making IGF-1 a potential biomarker of cognition, and/or its signaling pathway a possible therapeutic target to prevent or slow age-related cognitive decline. A systematic literature review and qualitative narrative summary of current evidence for IGF-1 as a biomarker of cognitive decline in the ageing brain was undertaken. Results indicate IGF-1 concentrations do not confer additional diagnostic information for those with cognitive decline, and routine clinical measurement of IGF-1 is not currently justified. In cases of established cognitive impairment, it remains unclear whether increasing circulating or brain IGF-1 may reverse or slow down the rate of further decline. Advances in neuroimaging, genetics, neuroscience and the availability of large well characterized biobanks will facilitate research exploring the role of IGF-1 in both normal ageing and age-related cognitive decline.     

A systematic literature review and meta-analysis of real-world interventions for cognitive ageing in healthy older adults

Activities running in community-based-settings offer a method of delivering multimodal interventions to older adults beyond cognitive training programmes. This systematic review and meta-analysis investigated the impact of randomised controlled trials (RCTs) of ‘real-world’ interventions on the cognitive abilities of healthy older adults. Database searches were performed between October 2016 and September 2018. Forty-three RCTs were eligible for inclusion with 2826 intervention participants and 2234 controls. Interventions to enhance cognitive ability consisted of participation in activities that were physical (25 studies), cognitive (9 studies), or mixed (i.e., physical and cognitive; 7 studies), and two studies used other interventions that included older adults assisting schoolchildren and engagement via social network sites. Meta-analysis revealed that Trail Making Test (TMT) A, p = 0.05, M = 0.43, 95% CI [-0.00, 0.86], digit symbol substitution, p = 0.05, M = 0.30, 95% CI [0.00, 0.59], and verbal fluency, p = 0.04, M = 0.31, 95% CI [0.02, 0.61], improved after specific types of interventions versus the control groups (which were either active, wait-list or passive controls). When comparing physical activity interventions against all control groups, TMT A, p = 0.04, M = 0.25, 95% CI [0.01, 0.48], and digit span forward, p = 0.05, M = 0.91, 95% CI [-0.00, 1.82], significantly improved. Results remained non-significant for all outcomes when comparing cognitive activity interventions against all control groups. Results therefore suggest that healthy older adults are more likely to see cognitive improvements when involved in physical activity interventions. In addition, TMT A was the only measure that consistently showed significant improvements following physical activity interventions. Visuospatial abilities (as measured by TMT A) may be more susceptible to improvement following physical activity-based interventions, and TMT A may be a useful tool for detecting differences in that domain.     

Hormone therapy is associated with preserved smooth muscle structure and dilation in the arterial vasculature of the leg in older women

Long-term hormone therapy (HT) is associated with reduced intima-medial thickness (IMT), an established risk factor for atherosclerotic disease, in the femoral artery of healthy older women relative to age-matched non-hormone users. However, the influence of continuous, long-term HT on the relation between age, IMT, and smooth muscle dilation has not been investigated in the popliteal artery, an artery prone to stiffening and calcification. In the present study, popliteal artery IMT and smooth muscle dilation (the increase in diameter to sublingual nitroglycerin, NTG) were assessed with Doppler ultrasound in young (Y: n=16; age 23+/-1 [mean+/-S.E.M.]), older non-HT (O non-HT: n=14; age 69+/-1), and older HT (O HT: n=8; age 67+/-1) healthy women. The approximately 0.5 mm increase in resting diameter observed in older non-HT women relative to young women was absent in older HT women, as was the age-related increase in IMT (Y: 0.52+/-0.02 mm; O non-HT: 0.63+/-0.02 mm; O HT: 0.56+/-0.02 mm; p<0.05 for age and hormone comparisons). NTG dilation (percent change above rest) was similarly attenuated in older non-HT women (Y: 8.6+/-1%; O non-HT: 3.0+/-0.7%; O HT: 7.4+/-1.7%; p<0.05 for age and hormone comparisons), and NTG dilation was inversely related to IMT (p<0.01). Collectively, these results suggest that long-term, continuous HT may alleviate the detrimental effects of aging on both structural changes and smooth muscle dilation of the popliteal artery in healthy women.