Yeap discusses the study by Kumar et al which demonstrates the power of relatively small but well-designed clinical trials to inform understanding of mechanisms underlying biological aging by testing ...a potential intervention. The results reported by Kumar et al are an informative advance in the quest to extend the healthy life span of aging population. Many of the endpoints studied by Kumar et al. were related to muscle, inviting comparison with other interventions involving muscle with multisystem effects. Testosterone is the classical anabolic hormone, increasing muscle mass and strength in older as well as younger men.
Highlights • Psychiatric disturbance and impaired cognitive function are features of overt hypothyroidism. • Free thyroxine in the high-normal range has been associated with cognitive decline and ...incidence of dementia. • Subclinical hyperthyroidism has been associated with impairment of cognition and dementia risk. • Mood disorders, psychosis and cognitive impairment can accompany overt hyperthyroidism.
Recent advances have indicated that osteocalcin, and in particular its undercarboxylated form (ucOC), is not only a nutritional biomarker reflective of vitamin K status and an indicator of bone ...health but also an active hormone that mediates glucose metabolism in experimental studies. This work has been supported by the putative identification of G protein-coupled receptor, class C, group 6, member A (GPRC6A) as a cell surface receptor for ucOC. Of note, ucOC has been associated with diabetes and with cardiovascular risk in epidemiological studies, consistent with a pathophysiological role for ucOC in vivo. Limitations of existing knowledge include uncertainty regarding the underlying mechanisms by which ucOC interacts with GPRC6A to modulate metabolic and cardiovascular outcomes, technical issues with commonly used assays for ucOC in serum, and a paucity of clinical trials to prove causation and illuminate the scope for novel health interventions. A key emerging area of research is the role of ucOC in relation to expression of GPRC6A in muscle, and whether exercise interventions may modulate metabolic outcomes favorably in part via ucOC. Further research is warranted to clarify potential direct and indirect roles for ucOC in human health and cardiometabolic diseases.
Inclusion body myositis (IBM) is the most commonly acquired skeletal muscle disease of older adults involving both autoimmune attack and muscle degeneration. As exercise training can improve outcomes ...in IBM, this study assessed whether a combination of testosterone supplementation and exercise training would improve muscle strength, physical function and quality of life in men affected by IBM, more than exercise alone.
This pilot study was a single site randomised, double-blind, placebo-controlled, crossover study. Testosterone (exercise and testosterone cream) and placebo (exercise and placebo cream) were each delivered for 12 weeks, with a two-week wash-out between the two periods. The primary outcome measure was improvement in quadriceps isokinetic muscle strength. Secondary outcomes included assessment of isokinetic peak flexion force, walk capacity and patient reported outcomes, and other tests, comparing results between the placebo and testosterone arms. A 12-month Open Label Extension (OLE) was offered using the same outcome measures collected at 6 and 12-months.
14 men completed the trial. There were no significant improvements in quadriceps extension strength or lean body mass, nor any of the secondary outcomes. Improvement in the RAND Short Form 36 patient reported outcome questionnaire 'emotional wellbeing' sub-category was reported during the testosterone arm compared to the placebo arm (mean difference 95% CI: 6.0 points, 95% CI 1.7,10.3). The OLE demonstrated relative disease stability over the 12-month period but with a higher number of testosterone-related adverse events.
Adding testosterone supplementation to exercise training did not significantly improve muscle strength or physical function over a 12-week intervention period, compared to exercise alone. However, the combination improved emotional well-being over this period, and relative stabilisation of disease was found during the 12-month OLE. A longer duration trial involving a larger group of participants is warranted.
As men grow older, circulating testosterone declines while the incidence of cardiovascular disease increases. Thus, the role of sex hormones as biomarkers, and possibly contributing factors to ...clinical manifestations of cardiovascular disease in the increasing demographic of aging men, has attracted considerable interest. This review focuses on observational studies of endogenous androgens, namely circulating testosterone and dihydrotestosterone, which have examined their associations with cardiovascular events such as myocardial infarction and stroke. Studies which have examined the associations of endogenous estrogens, namely circulating estradiol, with these outcomes are also discussed. In large prospective cohort studies of predominantly middle-aged and older men, lower circulating testosterone consistently predicts higher incidence of cardiovascular events. Of note, both lower circulating testosterone and lower dihydrotestosterone are associated with higher incidence of stroke. These associations are less apparent when myocardial infarction is considered as the outcome. Results for estradiol are inconsistent. Lower circulating testosterone has been shown to predict higher cardiovascular disease-related mortality, as has lower circulating dihydrotestosterone. It is possible that the relationship of circulating androgens to cardiovascular events or mortality outcomes may be U-shaped rather than linear, with an optimal range defining men at lowest risk. Epidemiological studies are observational in nature and do not prove causality. Associations observed in studies of endogenous androgens need not necessarily translate into similar effects of exogenous androgens. Rigorous randomized controlled trials are needed to clarify the effects of testosterone treatment on cardiovascular risk in men.
As men grow older, circulating testosterone concentrations decline, while prevalence of cognitive impairment and dementia increase. Epidemiological studies of middle-aged and older men have ...demonstrated associations of lower testosterone concentrations with higher prevalence and incidence of cognitive decline and dementia, including Alzheimer’s disease. In observational studies, men with prostate cancer treated by androgen deprivation therapy had a higher risk of dementia. Small intervention studies of testosterone using different measures of cognitive function have provided inconsistent results, with some suggesting improvement. A randomised placebo-controlled trial of one year’s testosterone treatment conducted in 788 men aged ≥ 65 years, baseline testosterone < 9.54 nmol/L, showed an improvement in sexual function, but no improvement in cognitive function. There is a known association between diabetes and dementia risk. A randomised placebo-controlled trial of two year’s testosterone treatment in 1,007 men aged 50–74 years, waist circumference ≥ 95 cm, baseline testosterone ≤ 14 nmol/L, showed an effect of testosterone in reducing type 2 diabetes risk. There were no cognitive endpoints in that trial. Additional research is warranted but at this stage lower testosterone concentrations in ageing men should be regarded as a biomarker rather than a proven therapeutic target for risk reduction of cognitive decline and dementia, including Alzheimer’s disease.
Summary
Context
The effects of testosterone treatment on glucose metabolism and other outcomes in men with type 2 diabetes (T2D) and/or the metabolic syndrome are controversial.
Objective
To perform ...a systematic review and meta‐analysis of placebo‐controlled double‐blind randomized controlled clinical trials (RCT) of testosterone treatment in men with T2D and/or the metabolic syndrome.
Data sources
A systematic search of RCTs was conducted using Medline, Embase and the Cochrane Register of controlled trials from inception to July 2014 followed by a manual review of the literature.
Study selection
Eligible studies were published placebo‐controlled double‐blind RCTs published in English.
Data extraction
Two reviewers independently selected studies, determined study quality and extracted outcome and descriptive data.
Data synthesis
Of the 112 identified studies, seven RCTs including 833 men were eligible for the meta‐analysis. In studies using a simple linear equation to calculate the homeostatic model assessment of insulin resistance (HOMA1), testosterone treatment modestly improved insulin resistance, compared to placebo, pooled mean difference (MD) −1·58 −2·25, −0·91, P < 0·001. The treatment effect was nonsignificant for RCTs using a more stringent computer‐based equation (HOMA2), MD −0·19 −0·86, 0·49, P = 0·58). Testosterone treatment did not improve glycaemic (HbA1c) control, MD −0·15 −0·39, 0·10, P = 0·25, or constitutional symptoms, Aging Male Symptom score, MD −2·49 −5·81, 0·83, P = 0·14).
Conclusions
This meta‐analysis does not support the routine use of testosterone treatment in men with T2D and/or the metabolic syndrome without classical hypogonadism. Additional studies are needed to determine whether hormonal interventions are warranted in selected men with T2D and/or the metabolic syndrome.
•Hearing loss is a potentially modifiable risk factor for dementia.•In our cohort, men with hearing loss had a 69% greater hazard of developing dementia than those free of hearing impairment.•The ...aggregated hazard of dementia was increased by 49% in a meta-analysis of 14 prospective studies.•The association of hearing loss and dementia is biologically and mechanistically plausible.•Efforts to modify risk through hearing correction should be encouraged.
Dementia is a major source of disability worldwide and there are currently no available disease-modifying treatments. Hearing loss may be associated with increased risk of dementia in later life and therefore could be a modifiable risk factor, given the availability of efficacious interventions. We investigated the association of hearing loss and dementia through two complementary approaches: a prospective, cohort study of 37,898 older men (mean age 72.5 ± 4.6 years) with a mean follow-up of 11.1 years, and a systematic review and meta-analysis of prospective studies. In our cohort, men with hearing loss were more likely to develop dementia (n = 6948, 18.3%) than men free of significant hearing impairment – adjusted hazard ratio 1.69, 95% CI = 1.54–1.85. In our review, the aggregated hazard of dementia was 1.49 (95% CI 1.30–1.67) in those with hearing impairment (14 included studies). Study quality, duration and dementia type did not alter the results considerably. We found an increased risk of incident dementia with hearing impairment in both our novel data and the meta-analysis. This is an important finding, particularly in light of recent suggestions that mid-life hearing loss may account for up to 9.1% of dementia cases worldwide, and efforts to reduce its impact should continue to be explored.
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