Brain-Periphery Interactions in Huntington's Disease: Mediators and Lifestyle Interventions.

Prominent pathological features of Huntington's disease (HD) are aggregations of mutated Huntingtin protein (mHtt) in the brain and neurodegeneration, which causes characteristic motor (such as chorea and dystonia) and non-motor symptoms. However, the numerous systemic and peripheral deficits in HD have gained increasing attention recently, since those factors likely modulate disease progression, including brain pathology. While whole-body metabolic abnormalities and organ-specific pathologies in HD have been relatively well described, the potential mediators of compromised inter-organ communication in HD have been insufficiently characterized. Therefore, we applied an exploratory literature search to identify such mediators. Unsurprisingly, dysregulation of inflammatory factors, circulating mHtt, and many other messenger molecules (hormones, lipids, RNAs) were found that suggest impaired inter-organ communication, including of the gut-brain and muscle-brain axis. Based on these findings, we aimed to assess the risks and potentials of lifestyle interventions that are thought to improve communication across these axes: dietary strategies and exercise. We conclude that appropriate lifestyle interventions have great potential to reduce symptoms and potentially modify disease progression (possibly via improving inter-organ signaling) in HD. However, impaired systemic metabolism and peripheral symptoms warrant particular care in the design of dietary and exercise programs for people with HD.

Large Neutral Amino Acids Moderate the Effects of Metabolic Syndrome on Cognitive Performance in Middle-Aged Adults.

Introduction Two large neutral amino acids (LNAA), tryptophan and tyrosine, are precursors to cerebral neurotransmitters and are involved in cognitive function. Higher levels of LNAA in young adults are associated with improved cognition, although these associations appear to reverse over time. Given that exposure to metabolic syndrome (MetS) may induce premature cognitive aging, the current project aims to fill the gap in the literature by examining the effect of LNAA on cognitive performance in midlife adults with metabolic risks. Methods Eighty-eight adults, ages 40-61 years, participated in this cross-sectional study. LNAA metabolites were quantified, MetS components were measured using high-performance liquid chromatography, and MetS components were assessed in the laboratory. Composite verbal memory and executive functioning scores were computed using principal component analysis. We used linear regression models to test the interaction between LNAA and MetS while covarying for sex, age, and education. Results The kynurenine/tryptophan ratio (KTR) moderated the relation between MetS and verbal memory, even after adjusting for relevant covariates. Tyrosine metabolites were not significant moderators of the association between MetS and executive functioning. Conclusion Our findings suggest that the detected weaker memory performance in adults with a high number of MetS components may be related to relative tryptophan depletion and possible decreases in serotonin production. Further investigation is warranted to examine the potential role of LNAA in associations between cognitive performance and metabolic risks over time.

Association between Large Neutral Amino Acids and Brain Integrity in Middle-Aged Adults at Metabolic Risk.

This investigation delves into the interplay between large neutral amino acids (LNAA) and metabolic syndrome (MetS) in midlife adults, examining their collective influence on brain structure and cognitive function. While LNAA, such as tryptophan and phenylalanine, are known to bolster cognition in youth, our study hypothesizes a reversal of these benefits in older adults with MetS, potentially signaling premature cognitive aging. Eighty participants between 40-61 years underwent MetS component quantification, LNAA measurement via high-performance liquid chromatography, and brain imaging to evaluate white matter hyperintensity (WMH) volume and medial temporal lobe (MTL) cortical thickness. Our linear regression analysis, adjusting for sex, age, and education, revealed that phenylalanine levels moderated the relationship between MetS and WMH volume (F(6, 69) = 3.134, p < 0.05, R2 = 0.214), suggesting that MetS's cognitive impact may be partly due to phenylalanine catabolism byproducts. However, LNAA metabolites did not significantly modulate the MetS-MTL cortical thickness relationship. The findings suggest that LNAA metabolic dysregulation, marked by elevated levels in the presence of MetS, could correlate with brain structural compromises, particularly in the form of MTL cortical thinning and increased WMH load, detectable in midlife. This nuanced understanding of LNAA's role in cognitive health amid cardiovascular risk factors is pivotal, proposing a potential biomarker for early intervention. Further research is crucial to elucidate the longitudinal influence of LNAA and MetS on brain health, thereby informing strategies to mitigate cognitive decline.

Immune consequences of exercise in hypoxia: A narrative review.

Immune outcomes are key mediators of many health benefits of exercise and are determined by exercise type, dose (frequency/duration, intensity), and individual characteristics. Similarly, reduced availability of ambient oxygen (hypoxia) modulates immune functions depending on the hypoxic dose and the individual capacity to respond to hypoxia. How combined exercise and hypoxia (e.g., high-altitude training) sculpts immune responses is not well understood, although such combinations are becoming increasingly popular. Therefore, in this paper, we summarize the impact on immune responses of exercise and of hypoxia, both independently and together, with a focus on specialized cells in the innate and adaptive immune system. We review the regulation of the immune system by tissue oxygen levels and the overlapping and distinct immune responses related to exercise and hypoxia, then we discuss how they may be modulated by nutritional strategies. Mitochondrial, antioxidant, and anti-inflammatory mechanisms underlie many of the adaptations that can lead to improved cellular metabolism, resilience, and overall immune functions by regulating the survival, differentiation, activation, and migration of immune cells. This review shows that exercise and hypoxia can impair or complement/synergize with each other while regulating immune system functions. Appropriate acclimatization, training, and nutritional strategies can be used to avoid risks and tap into the synergistic potentials of the poorly studied immune consequences of exercising in a hypoxic state.

Short-Term Effects of Dietary Protein Supplementation on Physical Recovery in Older Patients at Risk of Malnutrition during Inpatient Rehabilitation: A Pilot, Randomized, Controlled Trial.

It is estimated that about 50% of geriatric rehabilitation patients suffer from sarcopenia. Thereby, malnutrition is frequently associated with sarcopenia, and dietary intake is the main modifiable risk factor. During hospitalization, older adults are recommended to consume more dietary protein than the current recommended dietary allowance of 0.8 g/kg body weight per day to optimize the recovery of muscular strength and physical function. This prospective pilot study examined the feasibility and preliminary efficacy of short-term protein supplementation with protein-enriched foods and drinks on the hand-grip strength, nutritional status, and physical function of older patients at risk of malnutrition during a three-week inpatient orthopedic rehabilitation stay. The Mini Nutritional Assessment (MNA) tool was used to assess malnutrition. Patients with an MNA score ≤ 23.5 points were randomly assigned to an intervention group (goal: to consume 1.2-1.5 g protein/kg body weight per day) or a control group (standard care). Both groups carried out the same rehabilitation program. Physical recovery parameters were determined at admission and discharge. A trend was recognized for participants in the intervention group to consume more protein than the control group (p = 0.058): 95.3 (SD 13.2) g/day as compared to 77.2 (SD 24.2) g/day, which corresponds to a mean protein intake of 1.6 (SD 0.3) g/kg/day vs. 1.3 (SD 0.5) g/kg/day. Dietary protein supplementation increased body weight by an average of 0.9 (SD 1.1) kg and fat mass by an average of 0.9 (SD 1.2) kg as compared to the baseline (p = 0.039 and p = 0.050, respectively). No significant change in hand-grip strength, body composition, or physical function was observed. In conclusion, short-term intervention with protein-enriched foods and drinks enabled older patients at risk of malnutrition to increase their protein intake to levels that are higher than their required intake. In these older individuals with appropriate protein intake, dietary protein supplementation did not result in a greater improvement in physical recovery outcomes during short-term inpatient rehabilitation. The intervention improved dietary protein intake, but further research (e.g., a full-scale, randomized, controlled trial with sufficient power) is required to determine the effects on physical function outcomes.

Intestinal microbiome in normal ageing, frailty and cognition decline.

PURPOSE OF REVIEW: The intestinal microbiome modulates the risk of several age-related chronic diseases and syndromes, including frailty and neurodegenerative diseases. Herein we provided an update on the influence of gut microbiota on physical and cognitive performance in older age and suggest microbiota-targeted interventions for healthy ageing. RECENT FINDINGS: Low uniqueness index of the gut microbiome and high representation of Bacteroides are independently associated with mortality in older individuals, while the centenarian microbiome is characterized by high abundance of Lactobacilli and Bifidobacteria . Frailty syndrome, sarcopenia and cognitive decline are associated with reduced faecal microbiota biodiversity, reduced abundance of bacteria able to synthetize short-chain fatty acids (SCFA), including Faecalibacterium prausnitzii , and reduced faecal butyrate levels. Dietary intervention, especially involving Mediterranean diet, and exercise training seem to be associated with improved biodiversity of the microbiota, increased capacity of SCFA synthesis and, probably, protection against the onset of frailty and cognitive decline. SUMMARY: The gut microbiota biodiversity and composition may reflect the different ageing trajectory, but further research is needed to understand potential independent and combined effects of environmental and lifestyle factors in older adults, especially from a clinical point of view.

The Impact of Training on the Loss of Cardiorespiratory Fitness in Aging Masters Endurance Athletes.

Elite masters endurance athletes are considered models of optimal healthy aging due to the maintenance of high cardiorespiratory fitness (CRF) until old age. Whereas a drop in VO2max in masters athletes has been broadly investigated, the modifying impact of training still remains a matter of debate. Longitudinal observations in masters endurance athletes demonstrated VO2max declines between -5% and -46% per decade that were closely related to changes in training volume. Here, using regression analyses, we show that 54% and 39% of the variance in observed VO2max decline in male and female athletes, respectively is explained by changes in training volume. An almost linear VO2max decrease was observed in studies on young and older athletes, as well as non-athletes, starting a few days after training cessation, with a decline of as much as -20% after 12 weeks. Besides a decline in stroke volume and cardiac output, training cessation was accompanied by considerable reductions in citrate synthase and succinate dehydrogenase activity (reduction in mitochondrial content and oxidative capacity). This reduction could largely be rescued within similar time periods of training (re)uptake. It is evident that training reduction or cessation leads to a considerably accelerated VO2max drop, as compared to the gradual aging-related VO2max decline, which can rapidly nullify many of the benefits of preceding long-term training efforts.

The Effects of Lifestyle and Diet on Gut Microbiota Composition, Inflammation and Muscle Performance in Our Aging Society.

Living longer is associated with an increased risk of chronic diseases, including impairments of the musculoskeletal and immune system as well as metabolic disorders and certain cancers, each of which can negatively affect the relationship between host and microbiota up to the occurrence of dysbiosis. On the other hand, lifestyle factors, including regular physical exercise and a healthy diet, can affect skeletal muscle and immune aging positively at all ages. Accordingly, health benefits could partly depend on the effect of such interventions that influence the biodiversity and functionality of intestinal microbiota. In the present review, we first discuss the physiological effects of aging on the gut microbiota, immune system, and skeletal muscle. Secondly, we describe human epidemiological evidence about the associations between physical activity and fitness and the gut microbiota composition in older adults. The third part highlights the relevance and restorative mechanisms of immune protection through physical activity and specific exercise interventions during aging. Fourth, we present important research findings on the effects of exercise and protein as well as other nutrients on skeletal muscle performance in older adults. Finally, we provide nutritional recommendations to prevent malnutrition and support healthy active aging with a focus on gut microbiota. Key nutrition-related concerns include the need for adequate energy and protein intake for preventing low muscle mass and a higher demand for specific nutrients (e.g., dietary fiber, polyphenols and polyunsaturated fatty acids) that can modify the composition, diversity, and metabolic capacity of the gut microbiota, and may thus provide a practical means of enhancing gut and systemic immune function.

Nutrition for Older Athletes: Focus on Sex-Differences.

Regular physical exercise and a healthy diet are major determinants of a healthy lifespan. Although aging is associated with declining endurance performance and muscle function, these components can favorably be modified by regular physical activity and especially by exercise training at all ages in both sexes. In addition, age-related changes in body composition and metabolism, which affect even highly trained masters athletes, can in part be compensated for by higher exercise metabolic efficiency in active individuals. Accordingly, masters athletes are often considered as a role model for healthy aging and their physical capacities are an impressive example of what is possible in aging individuals. In the present review, we first discuss physiological changes, performance and trainability of older athletes with a focus on sex differences. Second, we describe the most important hormonal alterations occurring during aging pertaining regulation of appetite, glucose homeostasis and energy expenditure and the modulatory role of exercise training. The third part highlights nutritional aspects that may support health and physical performance for older athletes. Key nutrition-related concerns include the need for adequate energy and protein intake for preventing low bone and muscle mass and a higher demand for specific nutrients (e.g., vitamin D and probiotics) that may reduce the infection burden in masters athletes. Fourth, we present important research findings on the association between exercise, nutrition and the microbiota, which represents a rapidly developing field in sports nutrition.

Physical Activity and Diet Shape the Immune System during Aging.

With increasing age, the immune system undergoes a remodeling process, termed immunosenescence, which is accompanied by considerable shifts in leukocyte subpopulations and a decline in various immune cell functions. Clinically, immunosenescence is characterized by increased susceptibility to infections, a more frequent reactivation of latent viruses, decreased vaccine efficacy, and an increased prevalence of autoimmunity and cancer. Physiologically, the immune system has some adaptive strategies to cope with aging, while in some settings, maladaptive responses aggravate the speed of aging and morbidity. While a lack of physical activity, decreased muscle mass, and poor nutritional status facilitate immunosenescence and inflammaging, lifestyle factors such as exercise and dietary habits affect immune aging positively. This review will discuss the relevance and mechanisms of immunoprotection through physical activity and specific exercise interventions. In the second part, we will focus on the effect of dietary interventions through the supplementation of the essential amino acid tryptophan, n-3 polyunsaturated fatty acids, and probiotics (with a special focus on the kynurenine pathway).

Role of dietary protein and exercise on biomarkers of immune activation in older patients during hospitalization.

The aim of this study was to examine the effect of short-term protein supplementation (aiming to consume 1.2 g protein/kg body weight per day) combined with moderate resistance training on 3 days of the week on tryptophan-kynurenine metabolism in 40 older patients with hip fracture. Secondary outcomes for physical recovery were hand-grip strength and chair-rise score. Older patients with hip fracture exhibited higher degrees of immune activation, detected by increased neopterin and kynurenine to tryptophan levels compared with reference values for healthy elderly with no significant differences between those who received the exercise-protein intervention compared to the control. Increasing dietary protein intake during hospitalization did not alleviate the Th1-type immune response in the elderly patient. On the other hand, muscularity per se may affect immune activation responses following injury, as improvements in maximum hand-grip strength with the intervention were related to decreases in neopterin levels.

Association Between Muscular Strength and Mortality in Clinical Populations: A Systematic Review and Meta-Analysis.

OBJECTIVES: To assess the relationship between muscular strength measures and mortality in outpatient populations with chronic diseases such as cancer, chronic obstructive pulmonary disease, renal disease, and metabolic and vascular diseases, and in critically ill hospitalized patients. DESIGN: A systematic review and random-effects meta-analysis of prospective cohort studies was performed. SETTING AND PARTICIPANTS: The databases Medline, Embase, Clinical Trial Register, and Cochrane Trial Register were searched from inception until September 30, 2018. The systematic literature review yielded 39 studies with a total of 39,852 participants. RESULTS: Lowest vs highest category of muscular strength revealed a statistically significant increased risk of all-cause mortality with a hazard ratio (HR) and 95% confidence intervals (CI) of 1.80 (95% CI 1.54-2.10). Lower muscular strength was associated with enhanced mortality in patients with cancer (HR 2.40; 95% CI 1.57-3.69), critical illness (HR 2.06; 95% CI 1.33-3.21), renal disease (HR 1.84; 95% CI 1.37-2.47), metabolic and vascular diseases (HR 1.64; 95% CI 1.26-2.14), and chronic obstructive pulmonary disease (HR 1.36; 95% CI 1.16-1.61). Conversely, a 5-kg higher level of muscular strength conferred a reduced risk of overall mortality (HR 0.72; 95% CI 0.59-0.89) and was accompanied by a reduction in mortality in patients with metabolic and vascular diseases (HR 0.52; 95% CI 0.29-0.91), critical illness (HR 0.78; 95% CI 0.61-0.99), and renal disease (HR 0.82; 95% CI 0.73-0.91). CONCLUSIONS AND IMPLICATIONS: Muscular strength is inversely associated with mortality risk in various acute and chronic conditions. Future trials should focus on developing validated cut-points for diagnosing low muscular strength and their predictive value for hard end-points.

Preparation for Endurance Competitions at Altitude: Physiological, Psychological, Dietary and Coaching Aspects. A Narrative Review.

It was the Summer Olympic Games 1968 held in Mexico City (2,300 m) that required scientists and coaches to cope with the expected decline of performance in endurance athletes and to establish optimal preparation programs for competing at altitude. From that period until now many different recommendations for altitude acclimatization in advance of an altitude competition were proposed, ranging from several hours to several weeks. Those recommendations are mostly based on the separate consideration of the physiology of acclimatization, psychological issues, performance changes, logistical or individual aspects, but there is no review considering all these aspects in their entirety. Therefore, the present work primarily focusses on the period of altitude sojourn prior to the competition at altitude based on physiological and psychological aspects complemented by nutritional and sports practical considerations.

Immunological alterations in frail older adults: A cross sectional study.

Frailty is a progressive physiologic decline in multiple body systems, characterized by loss of function, loss of physiologic reserve, and increased vulnerability to disease and death. This condition is induced by a complex and multifactorial interaction between genetic, biological, physical, psychological and environmental factors. To understand the interplay between the age-related decline of the immune response, and the upregulation of the inflammatory response, the so called inflammaging, we investigated the role of different inflammatory mediators on frailty status in the elderly. The study was performed in a population of 180 older adults (≥65 years), who were classified according to Fried's frailty phenotype. Plasma concentrations of neopterin, tryptophan, kynurenine, phenylalanine, tyrosine as well as kynurenine/tryptophan (Kyn/Trp) and phenylalanine/tyrosine (Phe/Tyr) ratios were analyzed as immune stimulation biomarkers. In addition, nitrite and C-reactive protein levels were measured as indicators of nitric oxide production and acute inflammation, respectively. Significant increases in neopterin, C-reactive protein and Kyn/Trp ratio, and decreases in tryptophan and nitrite concentrations in frail individuals compared with non-frail group were found. Both Kyn/Trp and Phe/Tyr ratios were significantly and positively correlated with neopterin. A positive correlation between kynurenine and tryptophan was also observed. Four parameters, i.e., neopterin, tryptophan, nitrite and C-reactive protein, were found to be strongly related to frailty status, although only nitrite confirmed its role of predictor after multiple regression analysis, supporting its use as a potential biomarker of frailty. Further investigation is required to strengthen the consistence and reproducibility of these findings, and to establish this parameter as a clinical biomarker of frailty.

Mediator Effect of Balance Problems on Association Between Grip Strength and Falls in Older Adults: Results From the KORA-Age Study.

Objective: To examine the association between grip strength and history of falls among older individuals, and to assess the possible mediating effect of balance problems on this relationship. Method: Data originate from KORA (Cooperative Health Research in the Region of Augsburg)-Age Study of 808 individuals (65 years and above). Follow-up assessment occurred 3 years later. Results: The risk of falls within the last 12 months was reduced on average by 3% (odds ratio [OR] 95% confidence interval [95% CI] = 0.97 [0.94, 0.99]; p value = .026) per 1-kg increase in maximum grip strength after adjusting for age and gender. There was a trend toward an indirect effect of grip strength through the mediator variable balance problems (p value = .043). Discussion: Increased muscular strength is associated with a reduced risk of falls in older age after adjustment for age and gender. The association is partially mediated by balance problems. Thus, in older adults, muscle-strengthening exercises may decrease the risk of falling.