Relationship between Mitochondrial Quality Control Markers, Lower Extremity Tissue Composition, and Physical Performance in Physically Inactive Older Adults.

Altered mitochondrial quality and function in muscle may be involved in age-related physical function decline. The role played by the autophagy-lysosome system, a major component of mitochondrial quality control (MQC), is incompletely understood. This study was undertaken to obtain initial indications on the relationship between autophagy, mitophagy, and lysosomal markers in muscle and measures of physical performance and lower extremity tissue composition in young and older adults. Twenty-three participants were enrolled, nine young (mean age: 24.3 ± 4.3 years) and 14 older adults (mean age: 77.9 ± 6.3 years). Lower extremity tissue composition was quantified volumetrically by magnetic resonance imaging and a tissue composition index was calculated as the ratio between muscle and intermuscular adipose tissue volume. Physical performance in older participants was assessed via the Short Physical Performance Battery (SPPB). Protein levels of the autophagy marker p62, the mitophagy mediator BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), the lysosomal markers transcription factor EB, vacuolar-type ATPase, and lysosomal-associated membrane protein 1 were measured by Western immunoblotting in vastus lateralis muscle biopsies. Older adults had smaller muscle volume and lower tissue composition index than young participants. The protein content of p62 and BNIP3 was higher in older adults. A negative correlation was detected between p62 and BNIP3 and the tissue composition index. p62 and BNIP3 were also related to the performance on the 5-time sit-to-stand test of the SPPB. Our results suggest that an altered expression of markers of the autophagy/mitophagy-lysosomal system is related to deterioration of lower extremity tissue composition and muscle dysfunction. Additional studies are needed to clarify the role of defective MQC in human muscle aging and identify novel biological targets for drug development.

Effect of change of interleukin-6 over time on gait speed response: Results from the lifestyle interventions and independence for elders study.

Interleukin (IL)-6 is a well-accepted biomarker of chronic low-grade inflammation possibly conditioning the effect of physical activity (PA) intervention on physical performance in mobility-limited older adults. We evaluated PA intervention effects on 400 m gait speed by yearly change of IL-6 levels in a post-hoc analysis from Lifestyle Interventions and Independence for Elders (LIFE) Study, a multicenter single-blind randomized clinical trial on 1300 sedentary older adults (mean age:78.85 ± 5.23,65.85 % women) at risk for mobility disability. We compared the intervention effects on 400 m gait speed at 12 months follow-up, according to yearly IL-6 change categorized for 1 pg/ml increase or decrease, and subsequently for larger range of yearly variation. Among subjects with yearly IL-6 change between -1 and + 2 pg/ml, we observed a significant difference of gait speed in PA intervention group compared to healthy educational intervention group [0.041 m/s,95 % confidence interval (CI):0.008-0.074,p = 0.006;Cohen's d:0.26, 95 % CI:0.12-0.41). No effects were observed on 400 m gait speed for wider range of variation of plasma IL-6 levels. Limiting change of IL-6 levels under this specific hormetic window could be an important goal to achieve better benefit from PA intervention in terms of gait speed change and prevention of mobility disability.

Low muscle mass is associated with a higher risk of all-cause and cardiovascular disease-specific mortality in cancer survivors.

OBJECTIVES: Individuals with prior cancer diagnosis are more likely to have low muscle mass (LMM) than their cancer-free counterparts. Understanding the effects of LMM on the prognosis of cancer survivors can be clinically important. The aim of this study was to investigate whether risks for all-cause and cardiovascular disease (CVD)-specific mortality differ by status of LMM in cancer survivors and a matched cohort without cancer history. METHODS: We used cohort data from the 1999-2006 and 2011-2014 National Health and Nutrition Examination Survey. Participants included 946 adults surviving for ≥1 since cancer diagnosis and a matched cohort (by age, sex, and race) without cancer history (N = 1857). LMM was defined by appendicular lean mass and body height (men <7.26 kg/m2, women <5.45 kg/m2). Death was ascertained via the National Death Index and cause of death was assessed via International Classification of Diseases, Tenth Revision. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratio (aHR) and 95% confidence interval (CI) of LMM. RESULTS: The mean age of cancer survivors and matched cohort was 60.6 y (SD 15) and 60.2 y (SD 14.9), respectively. The median follow-up was 10.5 y for survivors and 10.9 y for matched cohort. Overall, 22.2% of cancer survivors and 19.7% of the matched cohort had LMM, respectively. In all, 321 survivors (33.9%) and 495 participants (26.7%) in the matched cohort died during follow-up. CVD-specific deaths were identified in 58 survivors (6.1%) and 122 participants in the matched cohort (6.6%). The multivariable Cox model suggested that LMM was positively associated with all-cause (aHR, 1.73; 95% CI, 1.31-2.29) and CVD-specific (aHR, 2.13; 95% CI, 1.14-4.00) mortality in cancer survivors. The associations between LMM and risk for all-cause (aHR, 1.24; 95% CI, 0.98-1.56) and CVD-specific (aHR, 1.21; 95% CI, 0.75-1.93) mortality were not statistically significant in the matched cohort. CONCLUSION: Cancer survivors with LMM have an increased risk for all-cause and CVD-specific mortality. This increase appears to be larger than that in counterparts without cancer history.

Frailty and risk of mortality in older cancer survivors and adults without a cancer history: Evidence from the National Health and Nutrition Examination Survey, 1999-2014.

BACKGROUND: Epidemiologic evidence reporting the role of frailty in survival among older adults with a prior cancer diagnosis is limited. METHODS: A total of 2050 older adults (≥60 years old) surviving for at least 1 year after a cancer diagnosis and 9474 older adults without a cancer history from the National Health and Nutrition Examination Survey (1999-2014) were included for analysis. The exposure variable, a 45-item frailty index (FI), was categorized on the basis of validated cutoffs (FI ≤ 0.10 [fit], 0.10 < FI ≤ 0.21 [prefrail], and FI > 0.21 [frail]). All-cause mortality was ascertained via the National Death Index. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs) and 95% confidence interval (CIs) for the FI, and this was followed by restricted cubic splines depicting dose-response curves. RESULTS: For older cancer survivors, the mean age at the baseline was 72.6 years (SD, 7.1 years); 5.9% were fit, 38.2% were prefrail, and 55.9% were frail. Older adults without a cancer history were slightly younger (mean age, 70.0 years) and less frail (47.9% were frail). At each level of the FI, cancer survivors (1.9 per 100 person-years for FI ≤ 0.10, 3.4 per 100 person-years for 0.10 < FI ≤ 0.21, and 7.5 per 100 person-years for FI > 0.21) had higher mortality than their cancer-free counterparts (1.4 per 100 person-years for FI ≤ 0.10, 2.4 per 100 person-years for 0.10 < FI ≤ 0.21, and 5.4 per 100 person-years for FI > 0.21). The multivariable model suggested a positive association between the FI and all-cause mortality for survivors (aHR for FI > 0.21 vs FI ≤ 0.10, 2.80; 95% CI, 1.73-4.53) and participants without a cancer history (aHR for FI > 0.21 vs FI ≤ 0.10, 2.75; 95% CI, 2.29-3.32). Restricted cubic splines indicated that all-cause mortality risk increased with the FI in a monotonic pattern. CONCLUSIONS: Frailty is associated with a higher risk of death in older cancer survivors and the elderly without a cancer history.

Novel insights on the role of spexin as a biomarker of obesity and related cardiometabolic disease.

Spexin (SPX) is a 14-amino acid neuropeptide, discovered recently using bioinformatic techniques. It is encoded by the Ch12:orf39 gene that is widely expressed in different body tissues/organs across species, and secreted into systemic circulation. Recent reports have highlighted a potentially important regulatory role of SPX in obesity and related comorbidities. SPX is also ubiquitously expressed in human tissues, including white adipose tissue. The circulating concentration of SPX is significantly lower in individuals with obesity compared to normal weight counterparts. SPX's role in obesity appears to be related to various factors, such as the regulation of energy expenditure, appetite, and eating behaviors, increasing locomotion, and inhibiting long-chain fatty acid uptake into adipocytes. Recent reports have also suggested SPX's relationship with novel biomarkers of cardiovascular disease (CVD) and glucose metabolism and evoked the potential role of SPX as a key biomarker/player in the early loss of cardiometabolic health and development of CVD and diabetes later in life. Data on age-related changes in SPX and SPX's response to various interventions are also emerging. The current review focuses on the role of SPX in obesity and related comorbidities across the life span, and its response to interventions in these conditions. It is expected that this article will provide new ideas for future research on SPX and its metabolic regulation, particularly related to cardiometabolic diseases.

Elevated IL-6 and CRP Levels Are Associated With Incident Self-Reported Major Mobility Disability: A Pooled Analysis of Older Adults With Slow Gait Speed.

BACKGROUND: Elevated interleukine-6 (IL-6) and C-reactive protein (CRP) are associated with aging-related reductions in physical function, but little is known about their independent and combined relationships with major mobility disability (MMD), defined as the self-reported inability to walk a quarter mile. METHODS: We estimated the absolute and relative effect of elevated baseline IL-6, CRP, and their combination on self-reported MMD risk among older adults (≥68 years; 59% female) with slow gait speed (<1.0 m/s). Participants were MMD-free at baseline. IL-6 and CRP were assessed using a central laboratory. The study combined a cohort of community-dwelling high-functioning older adults (Health ABC) with 2 trials of low-functioning adults at risk of MMD (LIFE-P, LIFE). Analyses utilized Poisson regression for absolute MMD incidence and proportional hazards models for relative risk. RESULTS: We found higher MMD risk per unit increase in log IL-6 (hazard ratio [HR] = 1.26; 95% confidence interval [95% CI] 1.13-1.41). IL-6 meeting predetermined threshold considered to be high (>2.5 pg/mL) was similarly associated with higher risk of MMD (HR = 1.31; 95% CI 1.12-1.54). Elevated CRP (CRP >3.0 mg/L) was also associated with increased MMD risk (HR = 1.38; 95% CI 1.10-1.74). The CRP effect was more pronounced among participants with elevated IL-6 (HR = 1.62; 95% CI 1.12-2.33) compared to lower IL-6 levels (HR = 1.19; 95% CI 0.85-1.66). CONCLUSIONS: High baseline IL-6 and CRP were associated with an increased risk of MMD among older adults with slow gait speed. A combined biomarker model suggests CRP was associated with MMD when IL-6 was elevated.

Altered Expression of Mitoferrin and Frataxin, Larger Labile Iron Pool and Greater Mitochondrial DNA Damage in the Skeletal Muscle of Older Adults.

Mitochondrial dysfunction and iron (Fe) dyshomeostasis are invoked among the mechanisms contributing to muscle aging, possibly via a detrimental mitochondrial-iron feed-forward loop. We quantified the labile Fe pool, Fe isotopes, and the expression of mitochondrial Fe handling proteins in muscle biopsies obtained from young and older adults. The expression of key proteins of mitochondrial quality control (MQC) and the abundance of the mitochondrial DNA common deletion (mtDNA4977) were also assessed. An inverse association was found between total Fe and the heavier Fe isotope (56Fe), indicating an increase in labile Fe abundance in cells with greater Fe content. The highest levels of labile Fe were detected in old participants with a Short Physical Performance Battery (SPPB) score ≤ 7 (low-functioning, LF). Protein levels of mitoferrin and frataxin were, respectively, higher and lower in the LF group relative to young participants and older adults with SPPB scores ≥ 11 (high-functioning, HF). The mtDNA4977 relative abundance was greater in old than in young participants, regardless of SPPB category. Higher protein levels of Pink1 were detected in LF participants compared with young and HF groups. Finally, the ratio between lipidated and non-lipidated microtubule-associated protein 1A/1B-light chain 3 (i.e., LC3B II/I), as well as p62 protein expression was lower in old participants regardless of SPPB scores. Our findings indicate that cellular and mitochondrial Fe homeostasis is perturbed in the aged muscle (especially in LF older adults), as reflected by altered levels of mitoferrin and frataxin, which, together with MQC derangements, might contribute to loss of mtDNA stability.

The relationship between interleukin-6 levels and physical performance in mobility-limited older adults with chronic low-grade inflammation: The ENRGISE Pilot study.

Previous studies have found an inverse relation between serum concentrations of interleukin (IL)-6 and physical performance in seniors, however this was limited to higher functioning older adults with low to moderate levels of inflammation. We explored the consistency of this association in a cohort of mobility limited older adults with chronic low-grade inflammation. This study included 289 participants (≥ 70 years old) with IL-6 level between 2.5 and 30 pg/mL and a walking speed < 1.0 m/sec from the ENRGISE Pilot study. Physical performance was assessed using the short physical performance battery (SPPB), usual gait speed over 400 m, grip strength, and knee extensor and flexor strength measured by isokinetic dynamometry at 60 and 180°/sec. There was a significant inverse correlation between log IL-6 and knee extensor strength at 60°/sec (r= -0.20, p = 0.002), at 180°/sec (r = -0.14, p = 0.037), and knee flexor strength at 60°/sec (r = -0.15, p = 0.021). After adjustment for potential confounders, the values of knee extensor strength at 60°/sec showed a trend toward a progressive reduction across IL-6 tertiles as IL-6 levels increased (p = 0.024). No significant association was found between IL-6 and other objectively measured physical performance. The findings were generally of smaller magnitude and less consistent than previously reported, which suggests that the associations are attenuated in those with both elevated inflammation and mobility limitations. These results have implications for planning and interpreting future intervention studies in older adults with low-grade inflammation and mobility limitations.

Predicting Weight Loss Using Psychological and Behavioral Factors: The POUNDS LOST Trial.

CONTEXT: Eating habits and food craving are strongly correlated with weight status. It is currently not well understood how psychological and behavioral factors influence both weight loss and weight regain. OBJECTIVE: To examine the associations between psychological and behavioral predictors with weight changes and energy intake in a randomized controlled trial on weight loss. DESIGN AND SETTING: The Prevention of Obesity Using Novel Dietary Strategies is a dietary intervention trial that examined the efficacy of 4 diets on weight loss over 2 years. Participants were 811 overweight (body mass index, 25-40.9 kg/m2; age, 30-70 years) otherwise healthy adults. RESULTS: Every 1-point increase in craving score for high-fat foods at baseline was associated with greater weight loss (-1.62 kg, P = .0004) and a decrease in energy intake (r = -0.10, P = .01) and fat intake (r = -0.16, P < .0001) during the weight loss period. In contrast, craving for carbohydrates/starches was associated with both less weight loss (P < .0001) and more weight regain (P = .04). Greater cognitive restraint of eating at baseline was associated with both less weight loss (0.23 kg, P < .0001) and more weight regain (0.14 kg, P = .0027), whereas greater disinhibition of eating was only associated with more weight regain (0.12 kg, P = .01). CONCLUSIONS: Craving for high-fat foods is predictive of greater weight loss, whereas craving for carbohydrates is predictive of less weight loss. Cognitive restraint is predictive of less weight loss and more weight regain. Interventions targeting different psychological and behavioral factors can lead to greater success in weight loss.

Advanced Age Is Associated with Iron Dyshomeostasis and Mitochondrial DNA Damage in Human Skeletal Muscle.

Whether disruption of iron metabolism is implicated in human muscle aging is presently unclear. We explored the relationship among iron metabolism, muscle mitochondrial homeostasis, inflammation, and physical function in older adults and young controls. Eleven young and 23 older men and women were included. Older adults were classified into high-functioning (HF) and low-functioning (LF) groups according to their Short Physical Performance Battery score. Vastus lateralis muscle biopsies were assayed for total iron content, expression of 8-oxoguanine and DNA glycosylase (OGG1), 3-nitrotyrosine (3-NT) levels, and mitochondrial DNA (mtDNA) content and damage. Circulating ferritin and hepcidin levels were also quantified. Muscle iron levels were greater in the old group. Protein expression of transferrin receptor 1, Zrt-Irt-like protein (ZIP) 8, and ZIP14 were lower in old participants. Circulating levels of ferritin, hepcidin, interleukin 6 (IL6), and C-reactive protein were higher in the old group. Old participants showed lower mtDNA content and greater mtDNA damage. OGG1 protein expression declined with age, whereas 3-NT levels were greater in old participants. Finally, a negative correlation was determined between ZIP14 expression and circulating IL6 levels in LF older adults. None of assayed parameters differed between HF and LF participants. Our findings suggest that muscle iron homeostasis is altered in old age, which might contribute to loss of mtDNA stability. Muscle iron metabolism may therefore represent a target for interventions against muscle aging.

Current Epidemiology of Surgical Sepsis: Discordance Between Inpatient Mortality and 1-year Outcomes.

OBJECTIVE: We sought to compare traditional inpatient outcomes to long-term functional outcomes and mortality of surgical intensive care unit (SICU) patients with sepsis. SUMMARY OF BACKGROUND DATA: As inpatient sepsis mortality declines, an increasing number of initial sepsis survivors now progress into a state of chronic critical illness (CCI) and their post-discharge outcomes are unclear. METHODS: We performed a prospective, longitudinal cohort study of SICU patients with sepsis. RESULTS: Among this recent cohort of 301 septic SICU patients, 30-day mortality was 9.6%. Only 13 (4%) patients died within 14 days, primarily of refractory multiple organ failure (62%). The majority (n = 189, 63%) exhibited a rapid recovery (RAP), whereas 99 (33%) developed CCI. CCI patients were older, with greater comorbidities, and more severe and persistent organ dysfunction than RAP patients (all P < 0.01). At 12 months, overall cohort performance status was persistently worse than presepsis baseline (WHO/Zubrod score 1.4 ±â€Š0.08 vs 2.2 ±â€Š0.23, P > 0.0001) and mortality was 20.9%. Of note at 12 months, the CCI cohort had persistent severely impaired performance status and a much higher mortality (41.4%) than those with RAP (4.8%) after controlling for age and comorbidity burden (Cox hazard ratio 1.27; 95% confidence interval, 1.14-1.41, P < 0.0001). Among CCI patients, independent risk factors for death by 12 months included severity of comorbidities and persistent organ dysfunction (sequential organ failure assessment ≥6) at day 14 after sepsis onset. CONCLUSIONS: There is discordance between low inpatient mortality and poor long-term outcomes after surgical sepsis, especially among older adults, increasing comorbidity burden and patients that develop CCI. This represents important information when discussing expected outcomes of surgical patients who experience a complicated clinical course owing to sepsis.

Effect of Losartan and Fish Oil on Plasma IL-6 and Mobility in Older Persons. The ENRGISE Pilot Randomized Clinical Trial.

BACKGROUND: Low-grade chronic inflammation, characterized by elevations in plasma Interleukin-6 (IL-6), is an independent risk factor of impaired mobility in older persons. Angiotensin receptor blockers and omega-3 polyunsaturated fatty acids (ω-3) may reduce IL-6 and may potentially improve physical function. To assess the main effects of the angiotensin receptor blocker losartan and ω-3 as fish oil on IL-6 and 400 m walking speed, we conducted the ENRGISE Pilot multicenter randomized clinical trial. METHODS: The ENRGISE Pilot enrolled participants between April 2016 and June 2017, who participated for 12 months. Participants were aged ≥70 years with mobility impairment, had IL-6 between 2.5 and 30 pg/mL, and were able to walk 400 m at baseline. Participants were randomized in three strata 2 × 2 factorial to: (i) losartan 50-100 mg/d or placebo (n = 43), (ii) fish oil 1,400-2,800 mg/d or placebo (n = 180), and (iii) with both (n = 66). RESULTS: Two hundred eighty-nine participants were randomized (mean age 78.3 years, 47.4% women, 17.0% black). There was no effect of losartan (difference of means = -0.065 ± 0.116 [SE], 95% confidence interval [CI]: -0.293-0.163, p = .58) or fish oil (-0.020 ± 0.077, 95% CI: -0.171-0.132, p = .80) on the log of IL-6. Similarly, there was no effect of losartan (-0.025 ± 0.026, 95% CI: -0.076-0.026, p = .34) or fish oil (0.010 ± 0.017, 95% CI: -0.025-0.044, p = .58) on walking speed (m/s). CONCLUSIONS: These results do not support the use of these interventions to prevent mobility loss in older adults at risk of disability with low-grade chronic inflammation. REGISTRATION: Clinicaltrials.gov NCT02676466.

Effects of 90 Days of Resveratrol Supplementation on Cognitive Function in Elders: A Pilot Study.

OBJECTIVE: The purpose of this trial was to study the effects of chronic resveratrol use on cognitive function in humans. DESIGN: The authors conducted a double-blind, Phase IIa randomized, placebo-controlled trial to obtain preliminary estimates of the effects of resveratrol supplementation on cognitive function over a 90-day period in older adults. LOCATION: University of Florida in Gainesville, FL. SUBJECTS: Sedentary, overweight older adults (N = 32; age range: 65-93 years, M age = 73.34 years, SD age = 7.02 years). INTERVENTION: Participants were randomized to one of three treatment groups (placebo, 300 mg/day resveratrol, 1000 mg/day resveratrol) for 90 days. OUTCOME MEASURES: Cognitive function was assessed before and after treatment using a well-characterized test battery: Trail Making, Digits Forward and Backward, Erikson-Flanker, Controlled Oral Word Association, Hopkins Verbal Learning Test-Revised, and Task Switching. RESULTS: Psychomotor speed improved on the Trail Making Test part A in participants taking 1000 mg/day of resveratrol compared with participants in both the 300 mg/day condition and the placebo condition (p = 0.02). CONCLUSION: This pilot study suggests that 90 days of resveratrol supplementation at a dose of 1000/mg per day selectively improves psychomotor speed but does not significantly affect other domains of cognitive function in older adults. These findings provide modest support to further study the effects of resveratrol on cognitive function in older adults.

Sepsis and Critical Illness Research Center investigators: protocols and standard operating procedures for a prospective cohort study of sepsis in critically ill surgical patients.

INTRODUCTION: Sepsis is a common, costly and morbid cause of critical illness in trauma and surgical patients. Ongoing advances in sepsis resuscitation and critical care support strategies have led to improved in-hospital mortality. However, these patients now survive to enter state of chronic critical illness (CCI), persistent low-grade organ dysfunction and poor long-term outcomes driven by the persistent inflammation, immunosuppression and catabolism syndrome (PICS). The Sepsis and Critical Illness Research Center (SCIRC) was created to provide a platform by which the prevalence and pathogenesis of CCI and PICS may be understood at a mechanistic level across multiple medical disciplines, leading to the development of novel management strategies and targeted therapies. METHODS: Here, we describe the design, study cohort and standard operating procedures used in the prospective study of human sepsis at a level 1 trauma centre and tertiary care hospital providing care for over 2600 critically ill patients annually. These procedures include implementation of an automated sepsis surveillance initiative, augmentation of clinical decisions with a computerised sepsis protocol, strategies for direct exportation of quality-filtered data from the electronic medical record to a research database and robust long-term follow-up. ETHICS AND DISSEMINATION: This study has been registered at ClinicalTrials.gov, approved by the University of Florida Institutional Review Board and is actively enrolling subjects. Dissemination of results is forthcoming.

ENabling Reduction of Low-grade Inflammation in SEniors Pilot Study: Concept, Rationale, and Design.

OBJECTIVES: To test two interventions to reduce interleukin (IL)-6 levels, an indicator of low-grade chronic inflammation and an independent risk factor for impaired mobility and slow walking speed in older adults. DESIGN: The ENabling Reduction of low-Grade Inflammation in SEniors (ENRGISE) Pilot Study was a multicenter, double-blind, placebo-controlled randomized pilot trial of two interventions to reduce IL-6 levels. SETTING: Five university-based research centers. PARTICIPANTS: Target enrollment was 300 men and women aged 70 and older with an average plasma IL-6 level between 2.5 and 30 pg/mL measured twice at least 1 week apart. Participants had low to moderate physical function, defined as self-reported difficulty walking one-quarter of a mile or climbing a flight of stairs and usual walk speed of less than 1 m/s on a 4-m usual-pace walk. INTERVENTION: Participants were randomized to losartan, omega-3 fish oil (ω-3), combined losartan and ω-3, or placebo. Randomization was stratified depending on eligibility for each group. A titration schedule was implemented to reach a dose that was safe and effective for IL-6 reduction. Maximal doses were 100 mg/d for losartan and 2.8 g/d for ω-3. MEASUREMENTS: IL-6, walking speed over 400 m, physical function (Short Physical Performance Battery), other inflammatory markers, safety, tolerability, frailty domains, and maximal leg strength were measured. RESULTS: Results from the ENRGISE Pilot Study will provide recruitment yields, feasibility, medication tolerance and adherence, and preliminary data to help justify a sample size for a more definitive randomized trial. CONCLUSION: The ENRGISE Pilot Study will inform a larger subsequent trial that is expected to have important clinical and public health implications for the growing population of older adults with low-grade chronic inflammation and mobility limitations.

Grip Strength as a Marker of Hypertension and Diabetes in Healthy Weight Adults.

INTRODUCTION: Muscle strength may play a role in cardiometabolic disease. We examined the relationship between hand grip strength and diabetes and hypertension in a sample of healthy weight adults. METHODS: In 2015, we analyzed the National Health and Nutrition Examination Survey 2011-2012 for adults aged ≥20 years with healthy BMIs (between 18.5 and <25) and no history of cardiovascular disease (unweighted n=1,467; weighted n=61,587,139). Hand grip strength was assessed with a dynamometer. Diabetes was based on hemoglobin A1c level and reported diabetes diagnosis. Hypertension was based on measured blood pressure and reported hypertension diagnosis. RESULTS: Individuals with undiagnosed diabetes compared with individuals without diabetes had lower grip strength (51.9 vs 69.8, p=0.0001), as did individuals with diagnosed diabetes compared with individuals without diabetes (61.7 vs 69.8, p=0.008). Mean grip strength was lower among individuals with undiagnosed hypertension compared with individuals without hypertension (63.5 vs 71.5, p=0.008) as well as among individuals with diagnosed hypertension compared with those without hypertension (60.8 vs 71.5, p<0.0001). In adjusted analyses controlling for age, sex, race, smoking status, and first-degree relative with disease, mean grip strength was lower for undiagnosed diabetes (ß=-10.02, p<0.0001) and diagnosed diabetes (ß=-8.21, p=0.03) compared with individuals without diabetes. In adjusted analyses, grip strength was lower among individuals with undiagnosed hypertension (ß=-6.6, p=0.004) and diagnosed hypertension (ß=-4.27, p=0.04) compared with individuals without hypertension. CONCLUSIONS: Among healthy weight adults, combined grip strength is lower in individuals with diagnosed and undiagnosed diabetes and hypertension.

Dietary Antioxidants as Modifiers of Physiologic Adaptations to Exercise.

INTRODUCTION: Adaptive responses to exercise training (ET) are crucial in maintaining physiologic homeostasis and health span. Exercise-induced aerobic bioenergetic reactions in the mitochondria and cytosol increase production of reactive oxygen species, where excess of reactive oxygen species can be scavenged by enzymatic and nonenzymatic antioxidants (AO) to protect against deleterious oxidative stress. Free radicals, however, have recently been recognized as crucial signaling agents that promote adaptive mechanisms to ET, such as mitochondrial biogenesis, AO enzyme activity defense system upregulation, insulin sensitivity, and glucose uptake in the skeletal muscle. Commonly used nonenzymatic AO supplements, such as vitamins C and E, α-lipoic acid, and polyphenols, in combination with ET, have been proposed as ways to prevent exercise-induced oxidative stress and hence improve adaptation responses to endurance training. METHODS: During the PubMed search, we selected studies that examined and compared ET effects with and without administration of commonly used AO supplements. RESULTS: Preclinical and clinical studies to date have shown inconsistent results indicating either positive or negative effects of endurance training combined with different blends of AO supplements (mostly vitamins C and E and α-lipoic acid) on redox status, mitochondrial biogenesis pathways, and insulin sensitivity. Preclinical reports on ET combined with resveratrol, however, have shown consistent positive effects on exercise performance, mitochondrial biogenesis, and insulin sensitivity, with clinical trials reporting mixed effects. Relevant clinical studies have been few and have used inconsistent results and methodology (types of compounds, combinations, and supplementation time). CONCLUSIONS: The future studies should investigate the effects of specific AO and other popular supplements, such as α-lipoic acid and resveratrol, on training effects in humans. Of particular importance are older adults who may be at higher risk of age-related increased oxidative stress, an impaired AO enzyme defense system, and comorbidities such as hypertension, insulin resistance, and diabetes.

Safety and metabolic outcomes of resveratrol supplementation in older adults: results of a twelve-week, placebo-controlled pilot study.

Resveratrol has been found to have potent antioxidant, anti-inflammatory, and anticarcinogenic effects. The safety and efficacy of resveratrol supplementation in older adults are currently unknown. We conducted a double-blind, randomized, placebo-controlled trial to examine the safety and metabolic outcomes in 32 overweight, older adults (mean age, 73±7years). Participants were randomized into one of three treatment groups: (1) placebo, (2) moderate dose resveratrol (300mg/day), and (3) high dose resveratrol (1000mg/day). Both resveratrol and placebo were orally ingested in capsule form twice daily for 90days. Blood chemistry values remained within the normal range, and there were no significant differences in the number of participants reporting adverse events across conditions. Compared to placebo, glucose levels were significantly lower at post-treatment among participants randomized to both resveratrol conditions, with and without adjustment for the corresponding baseline values (ps<0.05). Glucose values of participants in the treatment groups, however, were not significantly different from baseline levels. These findings suggest that short-term resveratrol supplementation at doses of 300mg/day and 1000mg/day does not adversely affect blood chemistries and is well tolerated in overweight, older individuals. These findings support the study of resveratrol for improving cardio-metabolic health in older adults in larger clinical trials.

Optimizing the benefits of exercise on physical function in older adults.

As the number of older adults continues to rise worldwide, the prevention of physical disability among seniors is an increasingly important public health priority. Physical exercise is among the best known methods of preventing disability, but accumulating evidence indicates that considerable variability exists in the responsiveness of older adults to standard training regimens. Accordingly, a need exists to develop tailored interventions to optimize the beneficial effects of exercise on the physical function of older adults at risk for becoming disabled. The present review summarizes the available literature related to the use of adjuvant or alternative strategies intended to enhance the efficacy of exercise in improving the physical function of older adults. Within this work, we also discuss potential future research directions in this area.

Obesity and diabetes as accelerators of functional decline: can lifestyle interventions maintain functional status in high risk older adults?

Obesity and diabetes are known risk factors for the development of physical disability among older adults. With the number of seniors with these conditions rising worldwide, the prevention and treatment of physical disability in these persons have become a major public health challenge. Sarcopenia, the progressive loss of muscle mass and strength, has been identified as a common pathway associated with the initial onset and progression of physical disability among older adults. A growing body of evidence suggests that metabolic dysregulation associated with obesity and diabetes accelerates the progression of sarcopenia, and subsequently functional decline in older adults. The focus of this brief review is on the contributions of obesity and diabetes in accelerating sarcopenia and functional decline among older adults. We also briefly discuss the underexplored interaction between obesity and diabetes that may further accelerate sarcopenia and place obese older adults with diabetes at particularly high risk of disability. Finally, we review findings from studies that have specifically tested the efficacy of lifestyle-based interventions in maintaining the functional status of older persons with obesity and/or diabetes.