Targeting whole body metabolism and mitochondrial bioenergetics in the drug development for Alzheimer's disease.

Aging is by far the most prominent risk factor for Alzheimer's disease (AD), and both aging and AD are associated with apparent metabolic alterations. As developing effective therapeutic interventions to treat AD is clearly in urgent need, the impact of modulating whole-body and intracellular metabolism in preclinical models and in human patients, on disease pathogenesis, have been explored. There is also an increasing awareness of differential risk and potential targeting strategies related to biological sex, microbiome, and circadian regulation. As a major part of intracellular metabolism, mitochondrial bioenergetics, mitochondrial quality-control mechanisms, and mitochondria-linked inflammatory responses have been considered for AD therapeutic interventions. This review summarizes and highlights these efforts.

Multi-modal intervention to reduce cardiovascular risk among hypertensive older adults: Design of a randomized clinical trial.

Persons aged over 65 years account for over 75% of healthcare expenditures and deaths attributable to cardiovascular disease (CVD). Accordingly, reducing CVD risk among older adults is an important public health priority. Functional status, determined by measures of physical performance, is an important predictor of cardiovascular outcomes in older adults and declines more rapidly in seniors with hypertension. To date, physical exercise is the primary strategy for attenuating declines in functional status. Yet despite the general benefits of training, exercise alone appears to be insufficient for preventing this decline. Thus, alternative or adjuvant strategies are needed to preserve functional status among seniors with hypertension. Prior data suggest that angiotensin converting enzyme inhibitors (ACEi) may be efficacious in enhancing exercise-derived improvements in functional status yet this hypothesis has not been tested in a randomized controlled trial. The objective of this randomized, double-masked pilot trial is to gather preliminary efficacy and safety data necessary for conducting a full-scale trial to test this hypothesis. Sedentary men and women ≥ 65 years of age with functional limitations and hypertension are being recruited into this 24 week intervention study. Participants are randomly assigned to one of three conditions: (1) ACEi plus exercise training, (2) thiazide diuretic plus exercise training, or (3) AT1 receptor antagonist plus exercise training. The primary outcome is change in walking speed and secondary outcomes consist of other indices of CV risk including exercise capacity, body composition, as well as circulating indices of metabolism, inflammation and oxidative stress.

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.

Creatine supplementation post-exercise does not enhance training-induced adaptations in middle to older aged males.

PURPOSE: The present study evaluated the effects of creatine monohydrate (CrM) consumption post-exercise on body composition and muscle strength in middle to older males following a 12-week resistance training program. METHODS: In a double-blind, randomized trial, 20 males aged between 55 and 70 years were randomly assigned to consume either CrM-carbohydrate (CHO) [20 g days(-1) CrM + 5 g days(-1) CHO × 7 days, then 0.1 g kg(-1) CrM + 5 g CHO on training days (average dosage of ~8.8 g)] or placebo CHO (20 g days(-1) CHO × 7 days, then 5 g CHO on training days) while participating in a high intensity resistance training program [3 sets × 10 repetitions at 75% of 1 repetition maximum (1RM)], 3 days weeks(-1) for 12 weeks. Following the initial 7-day "loading" phase, participants were instructed to ingest their supplement within 60 min post-exercise. Body composition and muscle strength measurements, blood collection and vastus lateralis muscle biopsy were completed at 0, 4, 8 and 12 weeks of the supplement and resistance training program. RESULTS: A significant time effect was observed for 1RM bench press (p = 0.016), leg press (p = 0.012), body mass (p = 0.03), fat-free mass (p = 0.005) and total myofibrillar protein (p = 0.005). A trend for larger muscle fiber cross-sectional area in the type II fibers compared to type I fibers was observed following the 12-week resistance training (p = 0.08). No supplement interaction effects were observed. CONCLUSION: Post-exercise ingestion of creatine monohydrate does not provide greater enhancement of body composition and muscle strength compared to resistance training alone in middle to older males.

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.

Protease supplementation improves muscle function after eccentric exercise.

UNLABELLED: Protease supplementation has been purported to reduce the damaging effects of eccentric exercise and accelerate recovery of muscle function, possibly by regulating inflammation. PURPOSE: To determine the effectiveness of protease supplementation in attenuating eccentric exercise-induced skeletal muscle damage and inflammation. METHODS: After standard physical and hemodynamic assessment and fasting venous blood samples, subjects performed isokinetic extension/flexion of the quadriceps group on a Biodex isokinetic dynamometer at 60°·s(-1), followed by VO2max testing. Subjects were randomly assigned to consume 5.83 g daily of either a cellulose placebo (N = 15; 22.27 ± 3.33 yr, 71.17 ± 2.91 inches, 179.4 ± 24.05 lb, 50.55 ± 5.66 mL·kg(-1)·min(-1)) or a proteolytic supplement containing fungal proteases, bromelain, and papain (N = 14; 22.85 ± 5.9 yr, 70.0 ± 2.67 inches, 173.11 ± 29.94 lb, 49.69 ± 6.15 mL·kg(-1)·min(-1)) for a period of 21 d. After the supplementation period, subjects donated blood samples before performing a 45-min downhill (-17.5%) treadmill protocol at 60% of VO2max. An additional four blood draws and three muscle function tests were performed during the next 48 h. Blood was analyzed using standard hematology and clinical chemistry, enzyme-linked immunosorbent assay, and bead array. Blood data were analyzed using multivariate analysis of variance (MANOVA) with repeated measures, whereas Biodex data were analyzed using a MANOVA on %Δ values. RESULTS: Significant group differences (T1-T3, P = 0.033; T1-T4, P = 0.043) and another strong trend (T1-3 h, P = 0.055) were observed for flexion (peak torque %Δ at 60°·s(-1)) indicating higher force production in the protease group. Significant group × time interactions (P < 0.05) were observed, including elevations in circulating eosinophils and basophils in the protease group coinciding with lower levels of serum cyclooxygenase 2, interleukin 6, and interleukin 12 in this group. CONCLUSIONS: Protease supplementation seems to attenuate muscle strength losses after eccentric exercise by regulating leukocyte activity and inflammation.

Impact of DHEA(S) and cortisol on immune function in aging: a brief review.

A decline in the human immune system that occurs with aging is known as immunosenescence. Several factors are involved in the process, including reduced neutrophil function and cytotoxic capacity of natural killer (NK) cells, thymus atrophy and reduced naïve T cell number, and lowered B cell antibody production in response to antigen. The endocrine system, specifically the hypothalamus-pituitary-adrenal axis, plays an important role in modulating immune function. With aging an imbalance occurs between two adrenal hormones, cortisol and DHEA, that have opposing actions on immune function. This brief review explores the interactions between cortisol and DHEA and their effects on immune function in aging, as well as potential methods to combat the endocrine-related contribution to immunosenescence, including DHEA supplementation and exercise.