DHEA and cognitive function in the elderly.

The adrenal prohormone dehydroepiandrosterone (DHEA) and its sulphate conjugate (DHEAS) steadily decrease with age by 10% per decade reaching a nadir after the age of 80. Both DHEA and DHEAS (DHEA/S) exert many biological activities in different tissues and organs. In particular, DHEA and DHEAS are produced de novo in the brain, hence their classification as neurosteroids. In humans, the brain-to-plasma ratios for DHEA and DHEAS are 4-6.5 and 8.5, respectively, indicating a specific neuroendocrine role for these hormones. DHEA/S stimulates neurite growth, neurogenesis and neuronal survival, apoptosis, catecholamine synthesis and secretion. Together with antioxidant, anti-inflammatory and anti-glucocorticoid properties, it has been hypothesized a neuroprotective effect for DHEA/S. We conducted an accurate research of the literature using PubMed. In the period of time between 1994 and 2013, we selected the observational human studies testing the relationship between DHEA/S and cognitive function in both sexes. The studies are presented according to the cross-sectional and longitudinal design and to the positive or neutral effects on different domains of cognitive function. We also analysed the Clinical Trials, available in the literature, having cognitive domains as the main or secondary outcome. Although the cross-sectional evidence of a positive association between DHEA/S and cognitive function, longitudinal studies and RCTs using DHEA oral treatment (50mg/day) in normal or demented adult-older subjects, have produced conflicting and inconsistent results. In summary, the current data do not provide clear evidence for the usefulness of DHEA treatment to improve cognitive function in adult-older subjects. This article is part of a Special Issue entitled 'Essential role of DHEA'.

Effects of transdermal testosterone treatment on inflammatory markers in elderly males.

OBJECTIVE: During the male aging process, testosterone (T) levels progressively fall and inflammatory biomarkers increase. Although a relationship between these 2 phenomena has been tested in previous clinical trials, there is inconclusive evidence about the potential anti-inflammatory action of T. METHODS: A total of 108 healthy males >65 years with serum T concentration <475 ng/dL were recruited by direct mailings to alumni of the University of Pennsylvania and Temple University and randomized to 60-cm2 T or a placebo patch for 36 months. Ninety-six subjects completed the trial. Information and stored serum specimens from this trial were used to test the hypothesis of the inhibitory effect of T on inflammation. We evaluated 70 males (42 in the T group) who had banked specimens from multiple time points available for assays of T, C-reactive protein (CRP), tumor necrosis factor (TNF)-α, soluble TNF-α receptor-1 (TNFR1), interleukin-6 (IL-6), and soluble IL-6 receptors (sIL6r and sgp130). RESULTS: The mean age ± SD at baseline was 71.8 ± 4.9 years. Testosterone replacement therapy for 36 months did not induce significant decreases in inflammatory markers. A trend toward a significant increase was observed in the placebo group for TNF-α (P = .03) and sgp130 (P = .01). Significant differences in estimated means of TNFR1 (but not other inflammatory markers), with lower levels in the T group, were observed at the 36-month time point. In T-treated subjects we found an almost significant treatment x time interaction term TNFR1 (P = .02) independent of total body fat content as assessed by dual energy X-ray absorptiometry (DXA). No serious adverse effect was observed. CONCLUSIONS: Transdermal T treatment of older males for 36 months is not associated with significant changes in inflammatory markers.

Stress hormones, sleep deprivation and cognition in older adults.

Cognition can be deteriorated in older persons because of several potential mechanisms including the hormonal changes occurring with age. Stress events cause modification in hormonal balance with acute and chronic changes such as increase in cortisol and thyroid hormones, and simultaneous alterations in dehydroepiandrosterone sulphate, testosterone and insulin like growth factor-1 levels. The ability to cope with stress and regain previous healthy status, also called resiliency, is particularly impaired in older persons Thus, stressful conditions and hormonal dysregulation might concur to the onset of cognitive impairment in this population. In this review we address the relationship between stress hormones and cognitive function in older persons focusing on the role of one of the main stress factors, such as sleep deprivation (SD). We extracted and cross-checked data from 2000 to 2013 March and selected 112 full-text articles assessed for eligibility. In particular we considered 68 studies regarding the contribution of hormonal pathway to cognition in older adults, and 44 regarding hormones and SD both in rats and humans. We investigated how the activation of a stress-pattern response, like the one evoked from SD, can influence cognitive development and worsen cognitive status in the elderly. We will show the limited number of studies targeting the effects of SD and the consequent changes in stress hormones on cognitive function in this age group. We conclude that the current literature is not strong enough to give definitive answers on the role of stress hormonal pathway to the development of cognitive impairment in older individuals.

Thyroid status and 6-year mortality in elderly people living in a mildly iodine-deficient area: the aging in the Chianti Area Study.

OBJECTIVES: To test the hypothesis that, in older adults, living in a mildly iodine-deficient area, thyroid dysfunction may be associated with mortality independent of potential confounders. DESIGN: Longitudinal. SETTING: Community-based. PARTICIPANTS: Nine hundred fifty-one individuals aged 65 and older. MEASUREMENTS: Plasma thyrotropin, free thyroxine, and free triiodothyronine concentrations and demographic features were evaluated in participants of the Invecchiare in Chianti Study aged 65 and older. Participants were classified according to thyroid function test. Kaplan-Meier survival and Cox proportional hazards models adjusted for confounders were used in the analysis. RESULTS: Eight hundred nineteen participants were euthyroid, 83 had subclinical hyperthyroidism (SHyper), and 29 had subclinical hypothyroidism (SHypo). Overt hypo- and hyperthyroidism were found in five and 15 subjects, respectively. During a median of 6 years of follow-up, 210 deaths occurred (22.1%), 98 (46.6%) of which were from cardiovascular causes. Kaplan-Meier analysis revealed higher overall mortality for SHyper (P = .04) than euthyroid subjects. After adjusting for multiple confounders, participants with SHyper (hazard ratio (HR) = 1.65, 95% confidence interval (CI) = 1.02-2.69) had significantly higher all-cause mortality than those with normal thyroid function. No significant association was found between SHyper and cardiovascular mortality. In euthyroid subjects, thyrotropin was found to be predictive of lower risk of all-cause mortality (HR = 0.76, 95% CI = 0.57-0.99). CONCLUSION: SHyper is an independent risk factor for all-cause mortality in older adults. Low to normal circulating thyrotropin should be carefully monitored in elderly euthyroid individuals.

Effects of testosterone supplementation on clinical and rehabilitative outcomes in older men undergoing on-pump CABG.

Testosterone levels decrease with age. This decline is steeper during "critical illnesses". Cardiac surgery is a particular representative model of major clinical condition producing stress responses similar to those observed during severe nonsurgical illness. Cardiac revascularization with extracorporeal circulation is characterized by marked postoperative complications such as insulin resistance, a pro-inflammatory state, acute anemia and renal dysfunction. These phenomena are more evident in older subjects, who are particularly vulnerable in the post-operative state, a condition that has been recently termed as "acute postoperative frailty". We recently showed that in older men with low ejection fraction undergoing cardiac revascularization with extracorporeal circulation, there is a profound decline in anabolic hormones, including testosterone. After surgery testosterone concentration frequently declines to less than 200 ng/dl, a situation suggestive of overt hypogonadism. Since men with low testosterone levels have a high probability of developing mobility limitations, we considered this a rationale for the perioperative use of testosterone treatment in older men undergoing cardiac revasularization surgery. We hypothesized that testosterone supplementation at this time might attenuate the impressive post-surgical catabolic hormonal milieu. The aim of this manuscript is to elucidate an ongoing randomized clinical trial in older men (70+ years old) undergoing elective cardiovascular revascularization with extracorporeal circulation. This randomized clinical trial will evaluate the effects of intramuscular testosterone administration on clinical and functional outcomes in this population. The study will also address potential mechanisms underlying the expected beneficial effects of testosterone supplementation including improvement of insulin sensitivity, markers of inflammatory status and improved hemoglobin levels.

Mild thyroid hormone excess is associated with a decreased physical function in elderly men.

INTRODUCTION: In the adult, subclinical hyperthyroidism (Shyper) may alter skeletal muscle mass and strength. However, whether these effects are present in elderly subjects is not known. We explored the relationship between mild hyperthyroidism and physical function in a population-based sample of older persons. METHODS: In a cross-sectional analysis, calf muscle cross-sectional area (CMA), handgrip strength, nerve conduction velocity (NCV), and Short Physical Performance Battery (SPPB) scores were compared between 364 euthyroid (Eut) and 28 Shyper men as well as between 502 Eut and 39 Shyper women. In a longitudinal analysis, we evaluated the relationship between baseline plasma TSH, FT3 and FT4 and the 3-year change in SPPB score in 304 men and 409 women who were euthyroid at enrolment. RESULTS: At the cross-sectional analysis, Shyper men, but not women, had a significantly (p = 0.02) lower SPPB score than Eut controls, although with comparable CMA, grip strength and NCV, and were more likely to have poor physical performance (odds ratio = 2.97, p < 0.05). Longitudinal analysis showed that in Eut men higher baseline FT4 was significantly (p = 0.02) predictive of a lower SPPB score at the 3-year follow-up. CONCLUSION: Even a modest thyroid hormone excess is associated with a reduced physical function in elderly men.

Gonadal status and physical performance in older men.

OBJECTIVE: To test the relationship between gonadal status and objective measures and determinants of physical performance in older men and their determinants. METHODS: The study included 455 ≥ 65 year older men of InCHIANTI study, Italy, with complete data on testosterone levels, hand grip strength, cross-sectional muscle area (CSMA), short physical performance battery (SPPB). Linear models were used to test the relationship between gonadal status and determinants of physical performance. RESULTS: Three different groups of older men were created: (1) severely hypogonadal (N=23), total testosterone levels ≤ 230 ng /dl; (2) moderately hypogonadal (N=88), total testosterone >230 and < 350 ng/dl) and (3) eugonadal (N=344), testosterone levels ≥ 350 ng/dl. With increased severity of hypogonadal status, participants were significantly older while their BMI was substantially similar. In the age and BMI adjusted analysis, there was a significant difference in haemoglobin levels, hand grip strength and SPPB score (p for trend < 0.001) among three groups, with severely hypogonadal men having lower values of haemoglobin, muscle strength and physical performance. We found no association between testosterone group assignment and calf muscle mass and 4 m walking speed. In the multivariate analysis grip strength (p for trend = 0.004) and haemoglobin (p for trend < 0.0001) but not SPPB and other determinants of physical performance were significantly different between the three groups. CONCLUSIONS: In older men, gonadal status is independently associated with some determinants (haemoglobin and muscle strength) of physical performance.

Aging as an allostasis condition of hormones secretion: summing up the endocrine data from the inChianti study.

Aging phenomena can be seen as a breakdown of the intercellular organisation mechanisms like those represented by endocrine secretions. Such hypothesis is decidedly supported by the analysis of endocrine data coming out from the epidemiological inChianti study. Among the age related endocrine changes a leading role is played by the decline of hormones capable of anabolic effect like Testosterone, IGF-1, DHEAS on the one hand and on the other hand by the even slight increase of the hormones capable of catabolic activity like Cortisol and thyroid hormones. The derangement of this endocrine equilibrium that can be defined with the term of "allostasis", when chronically protracted, might be seen as responsible for many aging phenomena. Consequently specific hormone supplementations might be suggested as a proper strategy to counteract the functional declines occurring in the last decades of life. Nevertheless clinical intervention trials are mandatory in order to validate the hypothesis and to properly verify the risk/benefit ratio.

The concept of multiple hormonal dysregulation.

Aging process is accompanied by hormonal changes characterized by an imbalance between catabolic hormones that remain stable and anabolic hormones (testosterone, insulin like growth factor-1 (IGF-1) and dehydroepiandrosterone sulphate (DHEAS), that decrease with age. Despite the multiple hormonal dysregulation occurring with age, the prevalent line of research in the last decades has tried to explain many age-related phenomena as consequence of one single hormonal derangement with disappointing results. In this review we will list the relationship between hormonal anabolic deficiency and frailty and mortality in older population, providing evidence to the notion that multiple hormonal dysregulation rather than change in single anabolic hormone is a powerful marker of poor health status and mortality.

Subclinical thyroid disease in elderly subjects.

Subclinical thyroid disease (STD) is defined as circulating concentrations of free T4 and free T3 within their respective reference ranges in the presence of abnormal circulating concentrations of TSH. SCD is being diagnosed more frequently in clinical practice and is reported to be more prevalent in elderly as compared to young or adult subjects. The clinical impact of subclinical thyroid dysfunction is still a matter of debate, although it has been associated with various negative clinical outcomes, such as increased cardiovascular risk, reduction in bone density, decline in cognitive function, and increased risk of overt thyroid dysfunction. The treatment of STD is controversial and there is no consensus on the TSH cutoff values which can be used as indicators for treatment, especially in elderly subjects. In the present review, we report data on the prevalence of STD and on the potential clinical consequences of these disorders. Also, data of the Literature regarding the issue of the treatment of STD in relation to the age of the patient are reported.

Update on new therapeutic options for the somatopause.

During the last decade, a significant body of evidence has accumulated, indicating that the declining activity of the GH-IGF-I axis with aging might play a role in the development of frailty and in several pathological conditions commonly seen during aging, such as atherosclerosis, cardiovascular disease, and cognitive decline. GH therapy has become widely popular as antiaging therapy in order to counteract the age-related decline in muscle mass and strength and the increase in fat mass. However there are only few proven beneficial effects of GH therapy in healthy elderly subjects and its use remains highly controversial in the scientific community. In this paper we will review the current evidence related to the use of GH and/or GH-secretagogues in normal and pathological aging.

Vitamin D in older population: new roles for this 'classic actor'?

Vitamin D is a group of lipophilic hormones with pleiotropic actions. It has been traditionally related to bone metabolism, although several studies in the last decade have suggested its role in muscle strength and falls, cardiovascular and neurological diseases, insulin-resistance and diabetes, malignancies, autoimmune diseases and infections. Vitamin D appears to be a hormone with several actions and is fundamental for many biological systems including bone, skeletal muscle, brain and heart. The estimated worldwide prevalence of vitamin D deficiency of 50% in elderly subjects underlines the importance of vitamin D deficiency for public health. In this review, we will describe changes in vitamin D levels with age in both sexes, cut off values to define Vitamin D status, the impact of vitamin D deficiency in age-related disease and finally different therapeutic options available to treat Vitamin D deficiency in older populations.

[Dehydroepiandrosterone [DHEA(S)]: anabolic hormone?]. / Deidroepiandrosterone [DHEA(S)]: ormone anabolico?

The role of dehydroepiandrosterone (DHEA) and its sulphated form (DHEAS) as anabolic hormones is still debated in the literature. In this review we describe the fundamental steps of DHEA physiological secretion and its peripheral metabolism. Moreover we will list all the observational and intervention studies conducted in humans. Many observational studies have tested the relationship between low DHEA levels and age-related changes in skeletal muscle and bone, while intervention studies underline the positive and significant effects of DHEA treatment on several parameters of body composition. Surprisingly, observational studies are not consistent with different effects in men and women. There is recent evidence of a significant role of DHEA in frailty syndrome and as predictor of mortality. However a more complete approach of the problem suggests the opportunity to not focus only on one single hormonal derangement but to analyze the parallel dysregulation of anabolic hormones including sex steroids, GH-IGF-1 system and other catabolic hormones.

Estradiol and metabolic syndrome in older italian men: The InCHIANTI Study.

The increasing prevalence of metabolic syndrome (MS) with age in older men has been linked with decreasing testosterone levels. Interestingly, while testosterone levels decline with age, estradiol (E2) levels remain relatively stable, resulting in a decreased testosterone:E2 ratio. Because E2 levels tend to be elevated in morbid obesity, insulin resistance, and diabetes, it is reasonable to hypothesize that high E2 levels are associated with MS in older men. We studied the relationship of total and free E2 with MS after adjustment for multiple confounders, including age, BMI, smoking, alcohol consumption, physical activity, interleukin-6 (IL-6), fasting insulin, and testosterone. Men 65 years or older (age range, 65-96; n = 452) had complete data on E2, testosterone, fasting insulin, sex hormone-binding globulin, IL-6, and albumin. Concentrations of free E2 and free testosterone were calculated using the mass action equations. MS was defined according to Adult Treatment Panel III (ATP-III). Participants with MS had significantly higher serum free and total E2 (P < .001) (P = .003). After adjusting for confounders, including age, smoking, alcohol consumption, physical activity, log(IL-6), and log(insulin), participants with higher log(total E2) (odds ratio [OR], 2.31; 95% confidence interval [95% CI], 1.39-4.70; P = .02) and higher log(free E2) (OR, 2.69; 1.38-5.24; P < .001) had an increased risk of having MS. Log(free E2) (P = .04) maintained significant correlation with MS, even after further adjustment for BMI. In older men, high E2 is independently associated with MS. Whether confirmed in other studies, assessment of E2 should be also considered in older men. Whether changes in this hormonal pattern play a role in the development of MS should be further tested in longitudinal studies.

Relationship between higher estradiol levels and 9-year mortality in older women: the Invecchiare in Chianti study.

OBJECTIVES: To investigate the relationship between total estradiol (E2) levels and 9-year mortality in older postmenopausal women not taking hormone replacement therapy (HRT). DESIGN: Population-based study of persons living in the Chianti geographic area (Tuscany, Italy). SETTING: Community. PARTICIPANTS: A representative sample of 509 women aged 65 and older with measures of total E2. MEASUREMENTS: Serum total E2 was measured at the University of Parma using ultrasensitive radioimmunoassay (RIA). RESULTS: Women who died (n=135) during 9 years of follow up were older; had higher total E2 levels; and were more likely to have evidence of stroke, hypertension, diabetes mellitus, and congestive heart failure at baseline than survivors. Higher E2 levels were associated with a greater likelihood of death (hazard ratio (HR)=1.03, 95% confidence interval (CI)=1.01-1.06), and the relationship was independent of age, waist:hip ratio, C-reactive protein, education, cognitive function, physical activity, caloric intake, smoking, and chronic disease (HR=1.08 pg/mL, 95% CI=1.03-1.13, P=.003). The excessive risk of death associated with higher total E2 was not attenuated after adjustment for total testosterone (HR=1.12, 95% CI=1.02-1.18, P<.001) and after further adjustment for insulin resistance evaluated using the homeostasis model assessment (HR=1.07, 95% CI=1.03-1.17, P<.001). Total E2 was highly predictive of death after more than 5 years (HR=1.42: CI 1.01-1.91, P=.04) and not predictive of death for less than 5 years (P=.78). CONCLUSION: Higher total E2 concentration predicts mortality in older women not taking HRT.

Thyroid function abnormalities and cognitive impairment in elderly people: results of the Invecchiare in Chianti study.

OBJECTIVES: To investigate thyroid function testing abnormalities in older persons and to explore the relationship between thyroid dysfunction and cognition. DESIGN: Cross-sectional. SETTING: Community-based. PARTICIPANTS: One thousand one hundred seventy-one men and women aged 23 to 102. MEASUREMENTS: Thyroid function was evaluated by measuring plasma concentrations of thyrotropin (TSH), free thyroxine (FT4), and free triiodothyronine (FT3). Cognition was evaluated using the Mini-Mental State Examination (MMSE). Prevalence of overt and subclinical thyroid dysfunction was evaluated in different age groups (<65 vs > or =65). Age trends in TSH, FT4, and FT3 were examined in euthyroid participants. The cross-sectional association between thyroid dysfunction and MMSE score was evaluated adjusting for confounders. RESULTS: Subclinical hypothyroidism and subclinical hyperthyroidism were more prevalent in older than in younger participants (subclinical hypothyroidism, 3.5% vs 0.4%, P<.03; subclinical hyperthyroidism, 7.8% vs 1.9%, P<.002). In euthyroid participants, TSH and FT3 declined with age, whereas FT4 increased. Older participants with subclinical hyperthyroidism had lower MMSE scores than euthyroid subjects (22.61+/-6.88 vs 24.72+/-4.52, P<.03). In adjusted analyses, participants with subclinical hyperthyroidism were significantly more likely to have cognitive dysfunction (hazard rate=2.26, P=.003). CONCLUSION: Subtle age-related changes in FT3, FT4, and TSH occur in individuals who remain euthyroid. Subclinical hyperthyroidism is the most prevalent thyroid dysfunction in Italian older persons and is associated with cognitive impairment.

Estradiol and inflammatory markers in older men.

BACKGROUND: Aging is characterized by a mild proinflammatory state. In older men, low testosterone levels have been associated with increasing levels of proinflammatory cytokines. It is still unclear whether estradiol (E2), which generally has biological activities complementary to testosterone, affects inflammation. METHODS: We analyzed data obtained from 399 men aged 65-95 yr enrolled in the Invecchiare in Chianti study with complete data on body mass index (BMI), serum E2, testosterone, IL-6, soluble IL-6 receptor, TNF-alpha, IL-1 receptor antagonist, and C-reactive protein. The relationship between E2 and inflammatory markers was examined using multivariate linear models adjusted for age, BMI, smoking, physical activity, chronic disease, and total testosterone. RESULTS: In age-adjusted analysis, log (E2) was positively associated with log (IL-6) (r = 0.19; P = 0.047), and the relationship was statistically significant (P = 0.032) after adjustments for age, BMI, smoking, physical activity, chronic disease, and serum testosterone levels. Log (E2) was not significantly associated with log (C-reactive protein), log (soluble IL-6 receptor), or log (TNF-alpha) in both age-adjusted and fully adjusted analyses. CONCLUSIONS: In older men, E2 is weakly positively associated with IL-6, independent of testosterone and other confounders including BMI.

Inverse relationship between scores on the quality of life questionnaire SF-12 and on the Aging Males' Symptoms scale in Italian men.

OBJECTIVES: To analyse the relation between results of the Aging Males' Symptoms (AMS) questionnaire for aging males, and of quality of life (QOL) questionnaire SF-12 and cardiovascular risk factors. METHODS: 1,927 men aged 55-85 years were interviewed by 56 general practitioners. During the interview the men were asked to fill in the AMS scale and the QOL questionnaire SF-12. RESULTS: Of 1,927 men 1,806 men filled correctly the AMS questionnaire. The mean SF-12 mental index was respectively 55.9 in men with a total AMS score indicating no impairment, 50.9 mild, 42.8 moderate, and 32.8 severe impairment. The corresponding values for the physical index were 51.2, 46.7, 40.8 and 32.3. A history of diabetes was associated with an increased risk of reporting moderate/severe impairment: in relation to the total AMS score the odds ratio, (OR), of moderate/severe impairment in comparison with no impairment was 1.6 (95%CI 1.2-2.1). A history of myocardial infarction and hypertension increased the risk (respectively OR 1.4 (95%CI 1.1-18) and 1.7 (95%CI 1.2-2.4)). CONCLUSIONS: This study shows that higher AMS scores are associated with lower SF-12 indices and suggests that elevated values of the AMS score are associated with cardiovascular risk factors or diseases.