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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.

To determine if adiposity in later life increases dementia hazard. Cohort study of 12,047 men aged 65-84 years living in Perth, Australia. Adiposity exposures were baseline body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR). We used the Western Australian Data Linkage System (WADLS) to establish the presence of new cases of dementia between 1996 and 2009 according to the International Classification of Diseases (ICD). Crude and adjusted hazard ratio (HR, 95% confidence interval, 95%CI) of dementia for each adiposity marker was calculated using Cox regression models. Other measured factors included age, marital status, education, alcohol use, smoking, diet, physical activity, and prevalent hypertension, diabetes, dyslipidaemia and cardiovascular disease. Compared with men with BMI<25, participants with BMI between 25-30 had lower adjusted HR of dementia (HR = 0.82, 95% CI = 0.70-0.95). The HR of dementia for men with BMI ≥ 30 was comparable to men with BMI<25 (HR = 0.82, 95%CI = 0.67-1.01). Waist circumference showed no obvious association with dementia hazard. Men with WHR ≥ 0.9 had lower adjusted HR of dementia than men with WHR <0.9 (HR = 0.82, 95%CI  =  0.69-0.98). We found a \"J\" shape association between measures of obesity and the hazard of dementia, with the nadir of risk being in the overweight range of BMI and about 1 for WHR. Higher adiposity is not associated with incident dementia in this Australian cohort of older men. Overweight men and those with WHR ≥ 0.9 have lower hazard of dementia than men with normal weight and with WHR<0.9.

Understanding the distribution and variation in inflammatory markers is crucial for advancing our knowledge of inflammatory processes and evaluating their clinical utility in diagnosing and monitoring acute and chronic disease. 1 H NMR spectroscopy of blood plasma and serum was applied to measure a composite panel of inflammatory markers based on acute phase glycoprotein signals (GlycA and GlycB) and sub-regions of the lipoprotein derived Supramolecular Phospholipid Composite signals (SPC 1 , SPC 2 and SPC 3 ) to establish normal ranges in two healthy, predominantly white cohorts from Australia (n = 398) and Spain (n = 80; ages 20–70 years). GlycA, GlycB, SPC 1 and SPC 3 were not significantly impacted by age or sex, but SPC 2 (an HDL-related biomarker) was significantly higher in women across all age ranges by an average of 33.7%. A free-living Australian population cohort (n = 3945) was used to explore the relationship of BMI with the panel of inflammatory markers. The glycoprotein signals were directly associated with BMI with GlycB levels being significantly higher for women in all BMI classes. Conversely, SPC 2 was found to be inversely associated with BMI and differed significantly between the sexes at each BMI category (normal weight p = 3.46x10 -43 , overweight p = 3.33x10 -79 , obese p = 2.15x10 -64 ). SPC 1 and SPC 3 were markedly less affected by BMI changes. Given the significant association between SPC 2 and sex, these data suggest that men and women should be modelled independently for NMR-determined inflammatory biomarkers, or that data should be corrected for sex.

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.

While there is clear evidence that high levels of pollution are associated with increased all-cause mortality and cardiovascular mortality and morbidity, the biological mechanisms that would explain this association are less understood. We examined the association between long-term exposure to air pollutants and risk factors associated with cardiovascular disease. Air pollutant concentrations were estimated at place of residence for cohort members in the Western Australian Centre for Health and Ageing Health in Men Study. Blood samples and blood pressure measures were taken for a cohort of 4249 men aged 70 years and above between 2001 and 2004. We examined the association between 1-year average pollutant concentrations with blood pressure, cholesterol, triglycerides, C-reactive protein, and total homocysteine. Linear regression analyses were carried out, with adjustment for confounding, as well as an assessment of potential effect modification. The four pollutants examined were fine particulate matter, black carbon (BC), nitrogen dioxide, and nitrogen oxides. We found that a 2.25 μg/m 3 higher exposure to fine particulate matter was associated with a 1.1 percent lower high-density cholesterol (95% confidence interval: -2.4 to 0.1) and 4.0 percent higher serum triglycerides (95% confidence interval: 1.5 to 6.6). Effect modification of these associations by diabetes history was apparent. We found no evidence of an association between any of the remaining risk factors or biomarkers with measures of outdoor air pollution. These findings indicate that long-term PM 2.5 exposure is associated with elevated serum triglycerides and decreased HDL cholesterol. This requires further investigation to determine the reasons for this association.

An integrative multi-modal metabolic phenotyping model was developed to assess the systemic plasma sequelae of SARS-CoV-2 (rRT-PCR positive) induced COVID-19 disease in patients with different respiratory severity levels. Plasma samples from 306 unvaccinated COVID-19 patients were collected in 2020 and classified into four levels of severity ranging from mild symptoms to severe ventilated cases. These samples were investigated using a combination of quantitative Nuclear Magnetic Resonance (NMR) spectroscopy and Mass Spectrometry (MS) platforms to give broad lipoprotein, lipidomic and amino acid, tryptophan-kynurenine pathway, and biogenic amine pathway coverage. All platforms revealed highly significant differences in metabolite patterns between patients and controls (n = 89) that had been collected prior to the COVID-19 pandemic. The total number of significant metabolites increased with severity with 344 out of the 1034 quantitative variables being common to all severity classes. Metabolic signatures showed a continuum of changes across the respiratory severity levels with the most significant and extensive changes being in the most severely affected patients. Even mildly affected respiratory patients showed multiple highly significant abnormal biochemical signatures reflecting serious metabolic deficiencies of the type observed in Post-acute COVID-19 syndrome patients. The most severe respiratory patients had a high mortality (56.1%) and we found that we could predict mortality in this patient sub-group with high accuracy in some cases up to 61 days prior to death, based on a separate metabolic model, which highlighted a different set of metabolites to those defining the basic disease. Specifically, hexosylceramides (HCER 16:0, HCER 20:0, HCER 24:1, HCER 26:0, HCER 26:1) were markedly elevated in the non-surviving patient group (Cliff’s delta 0.91–0.95) and two phosphoethanolamines (PE.O 18:0/18:1, Cliff’s delta = −0.98 and PE.P 16:0/18:1, Cliff’s delta = −0.93) were markedly lower in the non-survivors. These results indicate that patient morbidity to mortality trajectories is determined relatively soon after infection, opening the opportunity to select more intensive therapeutic interventions to these “high risk” patients in the early disease stages.

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.

Type 2 diabetes mellitus (T2DM) is a common metabolic disorder characterized by chronic hyperglycaemia, with physical inactivity and excessive adiposity as predisposing factors. This clinical trial aimed to investigate the effects of an exercise intervention on the metabolome of T2DM participants, fasting and in response to an oral glucose tolerance test (OGTT) and an acute exercise stimulus. Thirteen people with T2DM (age 51 ± 7 years; body mass index 32.7 ± 4.9 kg/m2) completed 45 min of moderate‐intensity treadmill exercise on 12 days consecutively. Blood samples were collected before and after the first and last training sessions and during a pre‐ and postintervention OGTT. Fasted blood samples were collected from 198 healthy control subjects and 208 people with T2DM from an independent cohort for comparison. Samples were analysed using high‐resolution 1H nuclear magnetic resonance spectroscopy and liquid chromatography–mass spectrometry. The exercise intervention did not induce a shift towards a healthier fasted metabolome in people living with T2DM. In response to consumption of a glucose bolus (OGTT), glycolysis‐related metabolites increased and free fatty acids decreased, with no effect of the exercise intervention. In response to acute exercise, glucose and amino acids decreased and free fatty acids increased, with similar responses on the last day of training as on the first day, indicating no effect of the intervention. The clinical trial was registered prospectively in the Australian New Zealand Clinical Trials Registry ACTRN12617000286347 on 24 February 2017. What is the central question of this study? People with type 2 diabetes mellitus (T2DM) have a different metabolic phenotype and an impaired response to an oral glucose tolerance test compared with healthy individuals. It is unknown whether a short‐term exercise programme can improve this response. What is the main finding and its importance? Twelve consecutive days of moderate‐intensity exercise do not improve the fasted metabolic phenotype or oral glucose tolerance test response in people with T2DM. These findings suggest that exercise‐induced metabolic benefits in T2DM might occur only after longer‐term engagement in exercise activities.

Abstract Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a unique class of oral anti-hyperglycaemic medications that act to reduce glucose reabsorption in the renal proximal tubules, thereby enhancing urinary glucose excretion. Large randomized placebo-controlled trials in people with diabetes at high cardiovascular risk have demonstrated that SGLT2 inhibitors reduce heart failure hospitalization within months of commencing therapy. These findings are of considerable interest, as diabetes is associated with an increased risk of both heart failure with reduced ejection fraction and heart failure with preserved ejection fraction. In addition, left ventricular (LV) hypertrophy and impaired diastolic function is thought to be more prevalent in people with diabetes. Although many hypotheses have been proposed, the underlying mechanisms through which SGLT2 inhibitors reduce the risk of heart failure in people with diabetes are not fully understood. Given the rapid reduction in heart failure hospitalization, it is conceivable that the benefits of SGLT2 inhibitors are due to favourable haemodynamic and metabolic effects on LV function. Several clinical studies have been conducted to investigate the effect of SGLT2 inhibitors on LV structure and function and have found that LV mass index and diastolic function improve following SGLT2 inhibitor therapy in people with type 2 diabetes. If these findings are confirmed in future studies utilizing novel cardiac imaging modalities and large randomized controlled trials, then this will bring new hope for the prevention and management of heart failure with preserved ejection fraction, for which no current treatments have been shown to reduce mortality. At the present time, SGLT2 inhibitors are indicated for the treatment of type 2 diabetes; however, the results of ongoing trials in participants with heart failure but without diabetes are eagerly awaited. The purpose of this review is to summarize current knowledge regarding the effects of SGLT2 inhibitors on LV function, particularly the findings from clinical studies, proposed biological mechanisms, and future directions.

Background Based on the largely untested premise that it is a restorative hormone that may reverse the detrimental impacts of aging, prescription of testosterone (T) has increased in recent decades despite no new clinical indications. It is apparent that middle-aged and older men with low-normal serum T levels are considering T supplementation as an anti-aging strategy. At the same time, there is evidence that physical activity (PA) is at historical lows in the Western world. In this review, we compare the impacts of T treatment aimed at achieving physiological T concentrations in middle-aged and older men, alongside the impacts of ecologically relevant forms of exercise training. The independent, and possible combined, effects of T and exercise therapy on physiological outcomes such as aerobic fitness, body composition and muscular strength are addressed. Main Body Our findings suggest that both T treatment and exercise improve lean body mass in healthy older men. If improvement in lean body mass is the primary aim, then T treatment could be considered, and the combination of T and exercise may be more beneficial than either in isolation. In terms of muscle strength in older age, an exercise program is likely to be more beneficial than T treatment (where the dose is aimed at achieving physiological concentrations), and the addition of such T treatment does not provide further benefit beyond that of exercise alone. For aerobic fitness, T at doses aimed at achieving physiological concentrations has relatively modest impacts, particularly in comparison to exercise training, and there is limited evidence as to additive effects. Whilst higher doses of T, particularly by intramuscular injection, may have larger impacts on lean body mass and strength, this must be balanced against potential risks. Conclusion Knowing the impacts of T treatment and exercise on variables such as body composition, strength and aerobic fitness extends our understanding of the relative benefits of physiological and pharmacological interventions in aging men. Our review suggests that T has impacts on strength, body composition and aerobic fitness outcomes that are dependent upon dose, route of administration, and formulation. T treatment aimed at achieving physiological T concentrations in middle-aged and older men can improve lean body mass, whilst exercise training enhances lean body mass, aerobic fitness and strength. Men who are physically able to exercise safely should be encouraged to do so, not only in terms of building lean body mass, strength and aerobic fitness, but for the myriad health benefits that exercise training confers.