Neuroprotective Metabolites of Hericium erinaceus Promote Neuro-Healthy Aging.

Frailty is a geriatric syndrome associated with both locomotor and cognitive decline, typically linked to chronic systemic inflammation, i.e., inflammaging. In the current study, we investigated the effect of a two-month oral supplementation with standardized extracts of H. erinaceus, containing a known amount of Erinacine A, Hericenone C, Hericenone D, and L-ergothioneine, on locomotor frailty and cerebellum of aged mice. Locomotor performances were monitored comparing healthy aging and frail mice. Cerebellar volume and cytoarchitecture, together with inflammatory and oxidative stress pathways, were assessed focusing on senescent frail animals. H. erinaceus partially recovered the aged-related decline of locomotor performances. Histopathological analyses paralleled by immunocytochemical evaluation of specific molecules strengthened the neuroprotective role of H. erinaceus able to ameliorate cerebellar alterations, i.e., milder volume reduction, slighter molecular layer thickness decrease and minor percentage of shrunken Purkinje neurons, also diminishing inflammation and oxidative stress in frail mice while increasing a key longevity regulator and a neuroprotective molecule. Thus, our present findings demonstrated the efficacy of a non-pharmacological approach, based on the dietary supplementation using H. erinaceus extract, which represent a promising adjuvant therapy to be associated with conventional geriatric treatments.

Frailty syndrome: A target for functional nutrients?

Frailty is a late life phenotype characterized by a decline in physiological reserve across several organ systems, resulting in the increased susceptibility to endogenous and/or exogenous stressors. Although the etiology of frailty remains poorly understood, an interconnected network of putative mechanisms linked to the ageing process has been proposed. However, frailty is a dynamic process that may be prevented, delayed, or even reversed. The syndromic nature of frailty requires a multidomain approach, such as proper nutrition, as part of modifiable environmental factors, and represents one of the most promising and least costly ways to prevent and reduce frailty among older adults. Nutrient deficiencies have been consistently associated with frailty; however, mounting evidence also supports the hypothesis that beyond the traditional nutritional value, specific dietary components may exert function-enhancing effects and mitigate the extent of frailty. Thus, further mechanistic studies, along with large clinical trials, are imperative to establish the exact role of functional nutrients in the clinical management of frailty. Here, we provide a contemporary discussion of how emerging functional nutrients may contribute to modify the trajectory of the frailty syndrome.

The Role of Muscle Mass Gain Following Protein Supplementation Plus Exercise Therapy in Older Adults with Sarcopenia and Frailty Risks: A Systematic Review and Meta-Regression Analysis of Randomized Trials.

Aging and frailty are associated with a high risk of lean mass (LM) loss, which leads to physical disability and can be effectively alleviated by protein supplementation (PS) and muscle strengthening exercise (MSE). In this study, the associations between LM gain and PS + MSE efficacy (measured using physical outcomes) in elderly patients with a high risk of sarcopenia or frailty were identified. A comprehensive search of online databases was performed to identify randomized controlled trials (RCTs) reporting the efficacy of PS + MSE in elderly patients with sarcopenia or frailty. The included RCTs were analyzed using meta-analysis and risk of bias assessment. We finally included 19 RCTs in this meta-analysis with a median (range/total) Physiotherapy Evidence Database score of 7/10 (5-9/10). The PS + MSE group exhibited significant improvements in the whole-body LM (standard mean difference (SMD) = 0.66; p < 0.00001), appendicular LM (SMD = 0.35; p < 0.00001), leg strength (SMD = 0.65; p < 0.00001), and walking capability (SMD = 0.33; p = 0.0006). Meta-regression analyses showed that changes in appendicular LM were significantly associated with the effect sizes of leg strength (ß = 0.08; p = 0.003) and walking capability (ß = 0.17; p = 0.04), respectively. Our findings suggest that LM gain after PS + MSE significantly contributes to the efficacy of the intervention in terms of muscle strength and physical mobility in elderly patients with a high risk of sarcopenia or frailty.

Leucine Supplementation Does Not Alter Insulin Sensitivity in Prefrail and Frail Older Women following a Resistance Training Protocol.

BACKGROUND: Frailty is a clinical condition associated with loss of muscle mass and strength (sarcopenia). Although sarcopenia has multifactorial causes, it might be partly attributed to a blunted response to anabolic stimuli. Leucine acutely increases muscle protein synthesis, and resistance training (RT) is the strongest stimuli to counteract sarcopenia and was recently shown to improve insulin sensitivity (IS) in frail older women. Discrepancies exist regarding whether chronic supplementation of leucine in conjunction with RT can improve muscle mass and IS. OBJECTIVE: The aim of this double-blinded placebo-controlled study was to determine the effects of leucine supplementation and RT on IS in prefrail and frail older women. METHODS: Using the Fried criteria, 19 nondiabetic prefrail (1-2 criteria) and frail (≥3 criteria) older women (77.5 ± 1.3 y; body mass index (kg/m2): 25.1 ± 0.9) underwent a 3-mo intervention of RT 3 times/wk with protein-optimized diet of 1.2 g·kg-1·d-1 and 7.5 g·d-1 of l-leucine supplementation compared with placebo l-alanine. Pre-/postintervention primary outcomes were fasting plasma glucose, serum insulin, and 4-h responses to a standard meal of complete liquid formula. Secondary outcomes of resting energy expenditure using indirect calorimetry and body composition using dual-energy X-ray absorptiometry were obtained. Paired t tests analyzed pooled data, and 2-factor repeated-measures ANOVA determined supplementation, training, and interaction effects. RESULTS: No significant time, group, or interaction effects were observed for postprandial areas under the curve of serum insulin or plasma glucose or for resting energy expenditure in l-leucine compared with l-alanine. Total lean body mass increased and percentage body fat decreased significantly for both groups postintervention (0.76 ± 0.13 and -0.92 ± 0.33 kg, respectively; time effect: P < 0.01). CONCLUSIONS: IS was not affected by RT and leucine supplementation in nondiabetic prefrail and frail older women. Therefore, leucine supplementation does not appear to influence IS under these conditions. This trial was registered at clinicaltrials.gov as NCT01922167.

Sarcopenia, frailty and their prevention by exercise.

Sarcopenia is a major component of the frailty syndrome, both being considered as strong predictors of morbidity, disability, and death in older people. In this review, we explore the definitions of sarcopenia and frailty and summarize the current knowledge on their relationship with oxidative stress and the possible therapeutic interventions to prevent or treat them, including exercise-based interventions and multimodal strategies. We highlight the relevance of the impairment of the nervous system and of the anabolic response (protein synthesis) in muscle aging leading to frailty and sarcopenia. We also discuss the importance of malnutrition and physical inactivity in these geriatric syndromes. Finally, we propose multimodal interventions, including exercise programs and nutritional supplementation, as the strategies to prevent and treat both sarcopenia and frailty.

Towards frailty biomarkers: Candidates from genes and pathways regulated in aging and age-related diseases.

OBJECTIVE: Use of the frailty index to measure an accumulation of deficits has been proven a valuable method for identifying elderly people at risk for increased vulnerability, disease, injury, and mortality. However, complementary molecular frailty biomarkers or ideally biomarker panels have not yet been identified. We conducted a systematic search to identify biomarker candidates for a frailty biomarker panel. METHODS: Gene expression databases were searched (http://genomics.senescence.info/genes including GenAge, AnAge, LongevityMap, CellAge, DrugAge, Digital Aging Atlas) to identify genes regulated in aging, longevity, and age-related diseases with a focus on secreted factors or molecules detectable in body fluids as potential frailty biomarkers. Factors broadly expressed, related to several "hallmark of aging" pathways as well as used or predicted as biomarkers in other disease settings, particularly age-related pathologies, were identified. This set of biomarkers was further expanded according to the expertise and experience of the authors. In the next step, biomarkers were assigned to six "hallmark of aging" pathways, namely (1) inflammation, (2) mitochondria and apoptosis, (3) calcium homeostasis, (4) fibrosis, (5) NMJ (neuromuscular junction) and neurons, (6) cytoskeleton and hormones, or (7) other principles and an extensive literature search was performed for each candidate to explore their potential and priority as frailty biomarkers. RESULTS: A total of 44 markers were evaluated in the seven categories listed above, and 19 were awarded a high priority score, 22 identified as medium priority and three were low priority. In each category high and medium priority markers were identified. CONCLUSION: Biomarker panels for frailty would be of high value and better than single markers. Based on our search we would propose a core panel of frailty biomarkers consisting of (1) CXCL10 (C-X-C motif chemokine ligand 10), IL-6 (interleukin 6), CX3CL1 (C-X3-C motif chemokine ligand 1), (2) GDF15 (growth differentiation factor 15), FNDC5 (fibronectin type III domain containing 5), vimentin (VIM), (3) regucalcin (RGN/SMP30), calreticulin, (4) PLAU (plasminogen activator, urokinase), AGT (angiotensinogen), (5) BDNF (brain derived neurotrophic factor), progranulin (PGRN), (6) α-klotho (KL), FGF23 (fibroblast growth factor 23), FGF21, leptin (LEP), (7) miRNA (micro Ribonucleic acid) panel (to be further defined), AHCY (adenosylhomocysteinase) and KRT18 (keratin 18). An expanded panel would also include (1) pentraxin (PTX3), sVCAM/ICAM (soluble vascular cell adhesion molecule 1/Intercellular adhesion molecule 1), defensin α, (2) APP (amyloid beta precursor protein), LDH (lactate dehydrogenase), (3) S100B (S100 calcium binding protein B), (4) TGFß (transforming growth factor beta), PAI-1 (plasminogen activator inhibitor 1), TGM2 (transglutaminase 2), (5) sRAGE (soluble receptor for advanced glycosylation end products), HMGB1 (high mobility group box 1), C3/C1Q (complement factor 3/1Q), ST2 (Interleukin 1 receptor like 1), agrin (AGRN), (6) IGF-1 (insulin-like growth factor 1), resistin (RETN), adiponectin (ADIPOQ), ghrelin (GHRL), growth hormone (GH), (7) microparticle panel (to be further defined), GpnmB (glycoprotein nonmetastatic melanoma protein B) and lactoferrin (LTF). We believe that these predicted panels need to be experimentally explored in animal models and frail cohorts in order to ascertain their diagnostic, prognostic and therapeutic potential.

Nutrition and Exercise in Sarcopenia.

Sarcopenia is a debilitating condition that involves loss of muscle mass and function, which affects virtually everyone as they age, and can lead to frailty and ultimately disability. In growing recognition of the importance of both muscle strength and muscle mass relative to body size in contributing to functional decline, recent definitions have now incorporated grip strength and a correction for body mass as part of the key criteria that define sarcopenia. With this new definition, a much larger population of older adults are now at risk of sarcopenia. In the present article, we reviewed the literature for studies which tested the effects of diet or exercise interventions on changes in lean mass and/or functional outcomes in individuals with either sarcopenia and/or frailty and identified 19 clinical trials. There were a few key findings. First, dietary interventions involving protein supplementation improved functional and/or strength outcomes in a few trials; however, other dietary approaches were less effective. Exercise interventions and combined diet and exercise interventions produced consistent improvements in lower body muscle strength but had less consistent effects on walking speed and grip strength. Lifestyle interventions not involving calorie restriction generally did not induce significant changes in body composition. There were a limited number of trials in which participants with sarcopenia were specifically targeted, and thus there is an important need for more research to determine the appropriate types of intervention approaches for the high risk population of sarcopenic older adults.

Beta-Hydroxy-Beta-Methyl Butyrate (HMB): From Experimental Data to Clinical Evidence in Sarcopenia.

ß-hydroxy-ß-methylbutyrate (HMB) is a metabolite derived from leucine and its ketoacid alpha- ketoisocaproate. Leucine has a role in regulating protein synthesis in muscle cells, and HMB seems to be a key active metabolite in such regulation. HMB has been shown to modulate muscle protein degradation by inhibiting the ubiquitin-proteasome proteolytic pathway, to up-regulate protein synthesis via the mTOR pathway, and to stabilize cell membranes via the rate limiting enzyme to cholesterol synthesis HMG- coenzyme A reductase. It can also decrease cell apoptosis, therefore improving cell survival; and increase proliferation and differentiation of muscle stem cell, via the MAPK/ERK and PI3K/Akt pathways. HMB is widely used as an ergogenic supplement by athletes and bodybuilders, usually combined with exercise training, to increase muscle mass and strength. Some studies have explored the role of HMB in chronic diseases associated with muscle wasting (cancer, acquired immunodeficiency syndrome, chronic obstructive pulmonary disease). This review focuses on the role of HMB in the management of sarcopenia (age or disease-related loss of muscle mass and function) in older persons. A small number of studies have shown increases in lean (muscle) mass and some muscle function and physical performance parameters in older people with or without resistance exercise, and preservation of muscle mass during bed rest. However, heterogeneous methodological approaches preclude solid conclusions, and more studies are needed to confirm the role of HMB as a promising agent to treat sarcopenia.

Redox Systems, Antioxidants and Sarcopenia.

According to the free-radical theory of aging, oxidative stress is a key contributor to the onset of age-related conditions by inducing structural and functional alterations in several cellular components. Although innate defenses exist for limiting the occurrence of such detrimental effects, their ability to counteract the continuous and large production of reactive oxygen species becomes increasingly inefficient with aging. In this context, interventions aimed at preserving the homeostatic balance between oxidant production and antioxidant protection may be beneficial on the pathophysiological modifications and clinical manifestations featuring the aging process. Sarcopenia is a clinical condition defined as the progressive age-related loss of muscle mass and function. In particular, a reduction of motor units and wasting of muscle fibers occurs during the aging process and negatively affects muscle quality. The biological mechanisms responsible for sarcopenia are complex, multifactorial and closely related to those characterizing the aging process. Among these, a pronounced unbalance between pro-oxidant and antioxidant species may play a major role. This review paper presents and discusses the possible role of the oxidant/antioxidant systems in the determination and development of the sarcopenic phenotype. Special attention will be devoted to the contribution of antioxidant agents in the maintenance of the homeostatic equilibrium for the organismal protection against the onset of age-related conditions. However, despite their popularity as beneficial compounds, there is no clear evidence in the literature about the protective effect of antioxidant supplements usage. Therefore, further research is needed to address and clarify such ambiguity.