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Tryptophan (TRP) metabolites along the kynurenine (KYN) pathway (KP) have been found to influence muscle. Proinflammatory cytokines are known to stimulate the degradation of TRP down the KP. Given that both inflammation and KP metabolites have been connected with loss of muscle, we assessed the potential mediating role of KP metabolites on inflammation and muscle mass in older men. Five hundred and five men (85.0 ± 4.2 years) from the Osteoporotic Fractures in Men cohort study with measured D3-creatine dilution (D3Cr) muscle mass, KP metabolites, and inflammation markers (C-reactive protein [CRP], alpha-1-acid glycoprotein [AGP] and a subsample [n = 305] with interleukin [IL-6, IL-1β, IL-17A] and tumor necrosis factor-α [TNF-α]) were included in the analysis. KP metabolites and inflammatory markers were measured using liquid chromatography-tandem mass spectrometry and immunoassays, respectively. 23%-92% of the inverse relationship between inflammatory markers and D3Cr muscle mass was mediated by KP metabolites (indirect effect p < .05). 3-hydroxyanthranilic acid (3-HAA), quinolinic acid (QA), TRP, xanthurenic acid (XA), KYN/TRP, 3-hydroxykynurenine (3-HK)/3-HAA, QA/3-HAA, and nicotinamide (NAM)/QA mediated the AGP relationship. 3-HAA, QA, KYN/TRP, 3-HK/XA, HKr ratio, 3-HK/3-HAA, QA/3-HAA, and NAM/QA mediated the CRP. KYN/TRP, 3-HK/XA, and NAM/QA explained the relationship for IL-6 and 3-HK/XA and QA/3-HAA for TNF-α. No mediation effect was observed for the other cytokines (indirect effect p > .05). KP metabolites, particularly higher ratios of KYN/TRP, 3-HK/XA, 3-HK/3-HAA, QA/3-HAA, and a lower ratio of NAM/QA, mediated the relationship between inflammation and low muscle mass. Our preliminary cross-sectional data suggest that interventions to alter D3Cr muscle mass may focus on KP metabolites rather than inflammation per se., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The musculoskeletal system is one of the most affected organs by aging that correlates well with an accumulation of senescent cells as for other multiple age-related pathologies. The molecular mechanisms underpinning muscle impairment because of senescent cells are still elusive. The availability of in vitro model of skeletal muscle senescence is limited and restricted to a small panel of phenotypic features of these senescent cells in vivo. Here, we developed a new in vitro model of senescent C2C12 mouse myoblasts that, when subjected to differentiation, the resulting myotubes showed sarcopenic features. To induce senescence, we used SYUIQ-5, a quindoline derivative molecule inhibitor of telomerase activity, leading to the expression of several senescent hallmarks in treated myoblasts. They had increased levels of p21 protein accordingly with the observed cell cycle arrest. Furthermore, they had enhanced SA-βgalactosidase enzyme activity and phosphorylation of p53 and histone H2AX. SYUIQ-5 senescent myoblasts had impaired differentiation potential and the resulting myotubes showed increased levels of ATROGIN-1 and MURF1, ubiquitin ligases components responsible for protein degradation, and decreased mitochondria content, typical features of sarcopenic muscles. Myotubes differentiated from senescent myoblasts cultures release increased levels of MYOSTATIN that could affect skeletal muscle cell growth. Overall, our data suggest that a greater burden of senescent muscle cells could contribute to sarcopenia. This study presents a well-defined in vitro model of muscle cell senescence useful for deeper investigation in the aging research field to discover new putative therapeutic targets and senescence biomarkers associated with the aged musculoskeletal system., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: This narrative review describes foundational and emerging evidence of how dietary protein intakes may influence muscle-related attributes of older adults., Methods: PubMed was used to identify pertinent research., Results: Among medically stable older adults, protein intakes below the recommended dietary allowance (RDA) (0.8 g/kg body weight [BW]/d) exacerbate age-related reductions in muscle size, quality, and function. Dietary patterns with total protein intakes at or moderately above the RDA, including one or preferably more meals containing sufficient dietary protein to maximize protein anabolism, promote muscle size and function. Some observational studies suggest protein intakes from 1.0 to 1.6 g/kg BW/d may promote greater muscle strength and function more so than muscle size. Experimental findings from randomized controlled feeding trials indicate protein intakes greater than the RDA (averaging ~1.3 g/kg BW/d) do not influence indices of lean body mass or muscle and physical functions with non-stressed conditions, but positively influence changes in lean body mass with purposeful catabolic (energy restriction) or anabolic (resistance exercise training) stressors. Among older adults with diagnosed medical conditions or acute illness, specialized protein or amino acid supplements that stimulate muscle protein synthesis and improve protein nutritional status may attenuate the loss of muscle mass and function and improve survival of malnourished patients. Observational studies favor animal versus plant protein sources for sarcopenia-related parameters., Conclusions: Quantity, quality, and patterning of dietary protein consumed by older adults with varied metabolic states, and hormonal and health status influence the nutritional needs and therapeutic use of protein to support muscle size and function., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Sarcopenia is an age-related condition of slow, progressive loss of muscle mass and strength, which contributes to frailty, increased risk of hospitalization and mortality, and increased health care costs. The incidence of sarcopenia is predicted to increase to >200 million affected older adults worldwide over the next 40 years, highlighting the urgency for understanding biological mechanisms and developing effective interventions. An understanding of the mechanisms underlying sarcopenia remains incomplete. Iron in the muscle is important for various metabolic functions, including oxygen supply and electron transfer during energy production, yet these same chemical properties of iron may be deleterious to the muscle when either in excess or when biochemically unshackled (eg, in ferroptosis), it can promote oxidative stress and induce inflammation. This review outlines the mechanisms leading to iron overload in muscle with aging and evaluates the evidence for the iron overload hypothesis of sarcopenia. Based on current evidence, studies are needed to (a) determine the mechanisms leading to iron overload in skeletal muscle during aging; and (b) investigate whether skeletal muscles are functionally deficient in iron during aging leading to impairments in oxidative metabolism., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Sarcopenia, the age-related loss of skeletal muscle mass and function, contributes to high morbidity and mortality in the older population. Regular exercise is necessary to avoid the initiation and progression of sarcopenia, in which the underlying molecular mechanism is still not clear. Our data revealed that the outcomes induced by sarcopenia, including muscle mass and strength loss, decreased cross-sectional area of gastrocnemius fiber, chronic inflammation, and increased dysfunctional mitochondria, were reversed by regulation exercise. Knockout or silencing of Sestrin2 (Sesn2) resulted in imbalanced mitochondrial fusion and fission, mitochondrial biogenesis, and mitophagy damage in vivo and in vitro, which was attenuated by aerobic exercise or overexpression of Sesn2. Moreover, we found that the effects of Sesn2 on mitochondrial function are dependent on AMP-activated protein kinase α2 (AMPKα2). This study indicates that aerobic exercise alleviates the negative effects resulting from sarcopenia via the Sesn2/AMPKα2 pathway and provides new insights into the molecular mechanism by which the Sesn2/AMPKα2 signaling axis mediates the beneficial impact of exercise on sarcopenia., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Although characteristic changes in amino acid concentrations occur in obesity and sarcopenia, amino acids concentrations have not been reported in sarcopenic obesity. We studied n = 831 men aged 75 years and older from the 5-year follow-up of the Concord Health and Ageing in Men Project. Sarcopenia was defined using the Foundation of the National Institutes of Health criteria and obesity was defined as >30% fat mass. There were 31 men (3.7%) who had sarcopenic obesity. Branched chain amino acids were elevated in the obese (but not sarcopenic) group (n = 348) but reduced in both the sarcopenic (but not obese) (n = 44) and the sarcopenic obese groups. Apart from this, most of the amino acid concentrations were between those for the obese and the sarcopenic groups. Yet despite low concentrations of branched chain amino acids, the sarcopenic obese group had indications of insulin resistance and diabetes mellitus (fasting glucose and insulin concentrations, homeostatic model assessment, and percentage of participants taking diabetes medications) that were similar to the obese group. In summary, sarcopenic obese participants did not have a unique amino acid signature. In obesity, elevated branched chain amino acids are not a prerequisite for insulin resistance and diabetes if obesity is associated with sarcopenia., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Anabolic resistance to a mechanical stimulus may contribute to the loss of skeletal muscle mass observed with age. In this study, young and aged mice were injected with saline or human LM-111 (1 mg/kg). One week later, the myotendinous junction of the gastrocnemius muscle was removed via myotenectomy (MTE), thus placing a chronic mechanical stimulus on the remaining plantaris muscle for 2 weeks. LM-111 increased α7B integrin protein expression and clustering of the α7B integrin near DAPI+ nuclei in aged muscle in response to MTE. LM-111 reduced CD11b+ immune cells, enhanced repair, and improved the growth response to loading in aged plantaris muscle. These results suggest that LM-111 may represent a novel therapeutic approach to prevent and/or treat sarcopenia., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Participants of the population-based Uppsala longitudinal study of adult men (ULSAM) cohort reaching more than 88 years of age (survivors, S) were investigated at age 70, 82, and 88-90 and compared at 70 years with non-survivors (NS) not reaching 82 years. Body composition, muscle mass and muscle histology were remarkably stable over 18 years of advanced aging in S. Analysis of genes involved in muscle remodeling showed that S had higher mRNA levels of myogenic differentiation factors (Myogenin, MyoD), embryonic myosin (eMyHC), enzymes involved in regulated breakdown of myofibrillar proteins (Smad2, Trim32, MuRF1,) and NCAM compared with healthy adult men (n = 8). S also had higher mRNA levels of eMyHC, Smad 2, MuRF1 compared with NS. At 88 years, S expressed decreased levels of Myogenin, MyoD, eMyHC, NCAM and Smad2 towards those seen in NS at 70 years. The gene expression pattern of S at 70 years was likely beneficial since they maintained muscle fiber histology and appendicular lean body mass until advanced age. The expression pattern at 88 years may indicate a diminished muscle remodeling coherent with a decline of reinnervation capacity and/or plasticity at advanced age., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: Evidence suggests the pivotal contribution of nutrition as a modifiable risk factor for sarcopenia. The present cross-sectional study characterized the nutritional and metabolic profile of sarcopenia through an extensive exploration of a wide array of blood biomarkers related to muscle protein metabolism and transcriptomic signatures in community-dwelling elderly adults., Methods: Among 189 older individuals with a mean age of 73.2 years, sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia criteria based on appendicular lean mass measured by dual-energy X-ray absorptiometry scan, muscle strength, and gait speed. Nutritional status was evaluated using the mini-nutritional assessment (MNA). In addition, we assessed specific blood biomarkers of nutritional status (plasma essential amino acids [EAAs], vitamins), nicotine-derived metabolites, and an extensive microarray analysis from peripheral blood mononuclear cells., Results: Malnutrition defined by low MNA score was independently associated with sarcopenia (p < .001). Sarcopenic elderly showed lower body mass index and leptin and higher adiponectin and high-density lipoproteins. Levels of EAAs including lysine, methionine, phenylalanine, threonine, as well as branched-chain AAs and choline, were inversely associated with sarcopenia. Furthermore, nicotine metabolites (cotinine and trans-3'-hydroxycotine) and vitamin B6 status were linked to one or more clinical and functional measures of sarcopenia. Differentially expressed genes and ingenuity pathway analysis supported the association of nutrition with sarcopenia., Conclusions: Herein, the characterization of a nutritional and metabolic signature of sarcopenia provides a firm basis and potential identification of specific targets and directions for the nutritional approach to the prevention and treatment of sarcopenia in aging populations., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: Essential amino acids (EAA) and aerobic exercise (AE) acutely and independently stimulate skeletal muscle protein anabolism in older adults., Objective: In this Phase 1, double-blind, placebo-controlled, randomized clinical trial, we determined if chronic EAA supplementation, AE training, or a combination of the two interventions could improve muscle mass and function by stimulating muscle protein synthesis., Methods: We phone-screened 971, enrolled 109, and randomized 50 independent, low-active, nonfrail, and nondiabetic older adults (age 72 ± 1 years). We used a 2 × 2 factorial design. The interventions were: daily nutritional supplementation (15 g EAA or placebo) and physical activity (supervised AE training 3 days/week or monitored habitual activity) for 24 weeks. Muscle strength, physical function, body composition, and muscle protein synthesis were measured before and after the 24-week intervention., Results: Forty-five subjects completed the 24-week intervention. VO2peak and walking speed increased (p < .05) in both AE groups, irrespective of supplementation type, but muscle strength increased only in the EAA + AE group (p < .05). EAA supplementation acutely increased (p < .05) muscle protein synthesis from basal both before and after the intervention, with a larger increase in the EAA + AE group after the intervention. Total and regional lean body mass did not change significantly with any intervention., Conclusions: In nonfrail, independent, healthy older adults AE training increased walking speed and aerobic fitness, and, when combined with EAA supplementation, it also increased muscle strength and EAA-stimulated muscle protein synthesis. These increases occurred without improvements in muscle mass., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Loss of skeletal muscle mass and function is a hallmark of aging. This phenomenon has been related to a dysregulation of mitochondrial function and proteostasis. Calorie restriction (CR) has been demonstrated to delay aging and preserve function until late in life, particularly in muscle. Recently, we reported the type of dietary fat plays an important role in determining life span extension with 40% CR in male mice. In these conditions, lard fed mice showed an increased longevity compared to mice fed soybean or fish oils. In this article, we analyze the effect of 40% CR on muscle mitochondrial mass, autophagy, and mitochondrial dynamics markers in mice fed these diets. In CR fed animals, lard preserved muscle fibers structure, mitochondrial ultrastructure, and fission/fusion dynamics and autophagy, not only compared to control animals, but also compared with CR mice fed soybean and fish oils as dietary fat. We focus our discussion on dietary fatty acid saturation degree as an essential predictor of life span extension in CR mice., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

To gain insight into the mechanism of sarcopenia and the protective effect of melatonin, the gastrocnemius muscles of young (3-4 months), early-aged (12 months), and old-aged (24 months) wild-type C57BL/6J female mice were examined by magnetic resonance and microscopy. Locomotor activity, lactate production, and nuclear apoptosis were also assessed. The results support the early onset of sarcopenia at 12 months of age, with reduction of muscle fiber number, muscle weight/body weight ratio, lactate, and locomotor activity. Lipid droplet infiltration and autophagosomes were also detected. These changes driven little effects on the early-aged muscle, but they got worse in old-aged animals by the progressive damage of the muscle. Old-aged muscle showed a reduction of the mitochondrial number, a destruction of the mitochondrial cristae, and swelling. Tubular aggregates and nucleic acid fragmentation were the most striking findings in old-aged muscle, reflecting a broad damage with loss of autophagy efficacy. Oral melatonin administration conserved the normal muscular architecture, weight, muscle fiber number, and activity in the old age; it stimulated lactate production, prevented mitochondrial damage and tubular aggregates, and reduced the percentage of apoptotic nuclei in aged muscles. Altogether, gastrocnemius muscle showed age-mediated signs of sarcopenia that were reduced by melatonin treatment.

The progression of age-related sarcopenia can be accelerated by impaired recovery of muscle mass following periods of disuse due to illness or immobilization. However, the mechanisms underlying poor recovery of aged muscle following disuse remain to be delineated. Recent evidence suggests that mitochondrial energetics play an important role in regulation of muscle mass. Here, we report that 22- to 24-month-old mice with low muscle mass and low glucose clearance rate also display poor early recovery of muscle mass following 10 days of hind limb unloading. We used unbiased and targeted approaches to identify changes in energy metabolism gene expression, metabolite pools and mitochondrial phenotype, and show for the first time that persistent mitochondrial dysfunction, dysregulated fatty acid β-oxidation, and elevated H2O2 emission occur concomitantly with poor early recovery of muscle mass following a period of disuse in old mice. Importantly, this is linked to more severe whole-body insulin resistance, as determined by insulin tolerance test. The findings suggest that muscle fuel metabolism and mitochondrial energetics could be a focus for mining therapeutic targets to improve recovery of muscle mass following periods of disuse in older animals.

Background: Some clinical trials suggest that protein supplementation enhances the effects of resistance exercise on skeletal muscle mass (SMM); fewer studies examine the effects of diets rich in protein-source foods on SMM and functional status among community-dwelling adults., Methods: Data from the Framingham Offspring study including diet (three-day records, exams 3 and 5), physical activity (exams 2 and 4), percent SMM (%SMM) (exams 6 and 7), and functional performance (exams 5 through 8) were used to evaluate independent and combined effects of physical activity and high-protein foods on adjusted mean %SMM (using analysis of covariance) and risk of functional decline (using Cox proportional hazard's models). Analyses were adjusted for such factors as age, education, height, smoking, and fruit and grain consumption)., Results: Higher intakes of protein-source foods (red meat, poultry, fish, dairy, and soy, nuts, seeds and legumes) were associated with higher %SMM over 9 years, particularly among women. Men and women with higher intakes of foods from animal sources had a higher % SMM regardless of activity; beneficial effects of plant-based protein foods were only evident in physically active adults. Active subjects with higher intakes of animal or plant protein-source foods had 35% lowest risks of functional decline. Among less active individuals, only those consuming more animal protein-source foods had reduced risks of functional decline (HR: 0.7l; 95% CI: 0.50-1.01)., Conclusion: Higher intake of animal-protein foods, alone and especially in combination with a physically active lifestyle, was associated with preservation of muscle mass and functional performance in older adults., (© The Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Nutritional supplementation and physical activity have been shown to positively influence muscle mass and strength in older adults. The efficacy of long-term nutritional supplementation in combination with physical activity in older adults remains unclear., Methods: Mobility-limited (short physical performance battery [SPPB] ≤9) and vitamin D insufficient (serum 25(OH) D 9-24 ng/mL) older adults were recruited for this study. All subjects participated in a physical activity program. Subjects were randomized to consume a daily nutritional supplement (150 kcal, 20 g whey protein, 800 IU vitamin D, 119 mL beverage) or placebo (30 kcal, nonnutritive, 119 mL). In a prespecified secondary analysis, we examined total-body composition (dual energy X-ray absorptiometry), thigh composition (computed tomography), and muscle strength, power, and quality before and after the 6-month intervention., Results: One hundred and forty-nine subjects were randomized into the study [mean (standard deviation, SD) age 78.5 (5.4) years; 46.3% female; mean (SD) short physical performance battery 7.9 (1.2); mean (SD) vitamin D 18.7 (6.4) ng/mL]. After the intervention period both groups demonstrated improvements in muscle strength, body composition, and thigh composition. Nutritional supplementation lead to further losses of intermuscular fat (p = .049) and increased normal muscle density (p = .018)., Conclusions: Six months of physical activity resulted in improvements in body composition, subcutaneous fat, intermuscular fat, and strength measures. The addition of nutritional supplementation resulted in further declines in intermuscular fat and improved muscle density compared to placebo. These results suggest nutritional supplementation provides additional benefits to mobility-limited older adults undergoing exercise training. ClinicalTrials.gov Identifier: NCT01542892., (© The Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Common cyclooxygenase (COX)-inhibiting drugs enhance resistance exercise induced muscle mass and strength gains in older individuals. The purpose of this investigation was to determine whether the underlying mechanism regulating this effect was specific to Type I or Type II muscle fibers, which have different contractile and metabolic profiles. Muscle biopsies (vastus lateralis) were obtained before and after 12 weeks of knee-extensor resistance exercise (3 days/week) from healthy older men who consumed either a placebo (n = 8; 64±2 years) or COX inhibitor (acetaminophen, 4 gram/day; n = 7; 64±1 years) in double-blind fashion. Muscle samples were examined for Type I and II fiber cross-sectional area, capillarization, and metabolic enzyme activities (glycogen phosphorylase, citrate synthase, β-hydroxyacyl-CoA-dehydrogenase). Type I fiber size did not change with training in the placebo group (304±590 μm(2)) but increased 28% in the COX inhibitor group (1,388±760 μm(2), p < .1). Type II fiber size increased 26% in the placebo group (1,432±499 μm(2), p < .05) and 37% in the COX inhibitor group (1,825±400 μm(2), p < .05). Muscle capillarization and enzyme activity were generally maintained in the placebo group. However, capillary to fiber ratio increased 24% (p < .1) and citrate synthase activity increased 18% (p < .05) in the COX inhibitor group. COX inhibitor consumption during resistance exercise in older individuals enhances myocellular growth, and this effect is more pronounced in Type I muscle fibers., (© The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

One of the most noticeable effects of aging is the reduction in skeletal muscle mass and strength (sarcopenia). The metabolic syndrome (MS) is also prevalent in old subjects, but its relevance to skeletal muscle characteristics has poorly been investigated. Immunohistochemical studies were performed with muscle biopsies from young (22 years) and old (73 years) men with and without MS to reveal age-dependent and MS-associated modifications of fiber-type characteristics. Atrophy of type II fibers and altered fiber shape characterized muscle aging in lean healthy men. In contrast, increased cross-sectional area of the most abundant type I and type IIA fibers, and reduced cytochrome c oxidase content in all fiber types, characterized MS. Aging and particularly MS were associated with accumulation of intramyocellular lipid droplets. Although lipids mostly accumulated in type I fibers, matrix-assisted laser desorption/ionization-mass spectrometry imaging of intramyocellular lipids did not distinguish fiber types, but clearly separated young, old, and MS subjects. In conclusion, our study suggests that MS in the elderly persons is associated with alterations in skeletal muscle at a fiber-type specific level. Overall, these fiber type-specific modifications may be important both for the age-related loss of muscle mass and strength and for the increased prevalence of MS in elderly subjects., (© The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aging is associated with a gradual loss of muscle mass termed sarcopenia, which has significant impact on quality-of-life. Because oxidative stress is proposed to negatively impact upon musculoskeletal aging, we investigated links between human aging and markers of oxidative stress, and relationships to muscle mass and strength in young and old nonsarcopenic and sarcopenic adults. Sixteen young and 16 old males (further subdivided into "old" and "old sarcopenic") were studied. The abundance of protein carbonyl adducts within skeletal muscle sarcoplasmic, myofibrillar, and mitochondrial protein subfractions from musculus vastus lateralis biopsies were determined using Oxyblot immunoblotting techniques. In addition, concentrations of recognized cytoprotective proteins (eg, heat shock proteins [HSP], αβ-crystallin) were also assayed. Aging was associated with increased mitochondrial (but not myofibrillar or sarcoplasmic) protein carbonyl adducts, independently of (stage-I) sarcopenia. Correlation analyses of all subjects revealed that mitochondrial protein carbonyl abundance negatively correlated with muscle strength ([1-repetition maximum], p = .02, r (2) = -.16), but not muscle mass (p = .13, r (2) = -.08). Abundance of cytoprotective proteins, including various HSPs (HSP 27 and 70), were unaffected by aging/sarcopenia. To conclude, these data reveal that mitochondrial protein carbonylation increases moderately with age, and that this increase may impact upon skeletal muscle function, but is not a hallmark of (stage-I) sarcopenia, per se., (© The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Aging is associated with alterations in glucose metabolism and sarcopenia that jointly contribute to a higher risk of developing type 2 diabetes. Because aging is considered as a state of low-grade inflammation, in this study we examined whether older, healthy (lean, community-dwelling) participants have altered signaling flux through toll-like receptor 4 (TLR4), a key mediator of innate and adaptive immune responses. We also examined whether a 4-month aerobic exercise program would have an anti-inflammatory effect by reducing TLR4 expression and signaling. At baseline, muscle TLR4, nuclear factor κB p50 and nuclear factor κB p65 protein content, and c-Jun N-terminal kinase phosphorylation were significantly elevated in older versus young participants. The plasma concentration of the TLR4 agonist lipopolysaccharide and its binding protein also were significantly elevated in older participants, indicative of metabolic endotoxemia, which is a recently described phenomenon of increased plasma endotoxin level in metabolic disease. These alterations in older participants were accompanied by decreased insulin sensitivity, quadriceps muscle volume, and muscle strength. The exercise training program increased insulin sensitivity, without affecting quadriceps muscle volume or strength. Muscle TLR4, nuclear factor κB, and c-Jun N-terminal kinase, and plasma lipopolysaccharide and lipopolysaccharide binding protein were not changed by exercise. In conclusion, insulin resistance and sarcopenia of aging are associated with increased TLR4 expression/signaling, which may be secondary to metabolic endotoxemia., (© The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Adequate protein ingestion-mediated stimulation of myofibrillar protein synthesis (MPS) is required to maintain skeletal muscle mass. It is currently unknown what per meal protein intake is required to maximally stimulate the response in older men and whether it differs from that of younger men., Methods: We retrospectively analyzed data from our laboratories that measured MPS in healthy older (~71 years) and younger (~22 years) men by primed constant infusion of l-ring-[(13)C6]phenylalanine after ingestion of varying amounts (0-40 g) of high-quality dietary protein as a single bolus and normalized to body mass and, where available, lean body mass (LBM)., Results: There was no difference (p = .53) in basal MPS rates between older (0.027±0.04%/h; means ± 95% CI) and young (0.028 ± 0.03%/h) men. Biphase linear regression and breakpoint analysis revealed the slope of first line segment was lower (p < .05) in older men and that MPS reached a plateau after ingestion of 0.40 ± 0.19 and 0.24 ± 0.06 g/kg body mass (p = .055) and 0.60 ± 0.29 and 0.25 ± 0.13 g/kg lean body mass (p < .01) in older and younger men, respectively., Conclusions: This is the first report of the relative (to body weight) protein ingested dose response of MPS in younger and older men. Our data suggest that healthy older men are less sensitive to low protein intakes and require a greater relative protein intake, in a single meal, than young men to maximally stimulate postprandial rates of MPS. These results should be considered when developing nutritional solutions to maximize MPS for the maintenance or enhancement of muscle mass with advancing age., (© The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: It has been hypothesized that insulin resistance plays a role in the development of the loss of skeletal muscle; however, no cohort studies on insulin resistance and low relative appendicular skeletal muscle mass (ASM) have been published to date. Thus, we examined whether insulin resistance is associated with low relative ASM after a 4.6-year follow-up period among apparently healthy older men and women participants., Methods: This is a combined retrospective-prospective cohort study, which includes 147 community-dwelling older men and women participants. ASM was measured by dual-energy x-ray absorptiometry at baseline and follow-up. Participants with a relative change in ASM below the sex-specific 15th value were classified as the low relative ASM group. Homeostatic model assessment was used to quantify insulin resistance. Logistic regression calculated odds ratios and 95% confidence intervals for development of low relative ASM, adjusted for covariates., Results: The loss of ASM in the low relative ASM and normal groups was -1.8kg and -0.35kg, respectively (p ≤ .05). The low relative ASM group was older and had higher insulin and homeostatic model assessment of insulin resistance values at baseline. The risk of developing low relative ASM at 4.6-year follow-up was 2.9 times higher (95% CI, 1.00-7.8; p = .04) among the participants with homeostatic model assessment of insulin resistance levels more than 2.3. After adjusting for age, the risk increased to 3.9 times higher (95% CI, 1.3-11.5; p = .03)., Conclusion: Insulin resistance was associated with low relative ASM at 4.6-year follow-up after accounting for several covariates in a cohort of apparently healthy, well-functioning young older men and women., (© The Author 2013. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Previously, we showed that FI34, a frailty index based on 34 health and function ability variables, is heritable and a reliable phenotypic indicator of healthy aging. We have now examined the relationship between major components of energy expenditure and the FI34 in participants of the Louisiana Healthy Aging Study. Resting metabolic rate was associated with FI34, even after adjustment for fat-free mass, fat mass, age, sex, thyroid hormones, and insulin-like growth factor 1 levels, in multiple regression analyses. In contrast, there was no association between total daily energy expenditure and FI34. Circulating creatine phosphokinase, a clinical marker of muscle damage, was also significantly associated with FI34. However, these associations of resting metabolic rate with FI34 were restricted to the oldest old (≥90 years) and absent in younger age groups. In oldest old men, the association of FI34 with creatine phosphokinase persisted, whereas in the oldest old women, only the association with resting metabolic rate pertained with the appearance of an effect of body size and composition. These results point toward an increasing metabolic burden for the maintenance of homeodynamics as health declines in nonagenarians, and this has implications for contraction of metabolic reserve that may potentially accelerate the path to disability., (© The Author 2013. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Sarcopenia is characterized by the age-related loss of muscle mass and strength. One of the mechanisms of sarcopenia is the loss in the function and number of muscle satellite cells. Royal jelly (RJ) is a health food used worldwide. To obtain better digestion and absorption than RJ, protease-treated RJ (pRJ) has been developed. RJ and pRJ have been suggested to have potential pharmacological benefits such as prolonging the life span and reducing fatigue. Because these effects may improve sarcopenia and the functions of satellite cells, we examined the effects of RJ or pRJ treatment on the skeletal muscles in an animal model using aged mice. In vivo, RJ/pRJ treatment attenuated the decrease in the muscle weight and grip strength and increased the regenerating capacity of injured muscles and the serum insulin-like growth factor-1 levels compared with controls. In vitro, using isolated satellite cells from aged mice, pRJ treatment increased the cell proliferation rate, promoted cell differentiation, and activated Akt intracellular signaling pathway compared with controls. These findings suggest that RJ/pRJ treatment had a beneficial effect on age-related sarcopenia.

The primary purpose of this study was to assess the feasibility of applying a novel approach to measure myosin heavy chain (MHC) isoform expression, glucose uptake, fiber volume, and protein abundance in single muscle fibers of adult (9 months) and old (25 months) rats. Epitrochlearis muscle fibers were successfully isolated and analyzed for MHC isoform expression, glucose uptake, fiber volume, and protein (COXIV, APPL1, IκB-β) abundance. Insulin-stimulated glucose uptake by single fibers did not differ between age groups, but there was a significant difference between fiber types (IIA > IIX > IIB/X ≈ IIB). There were also significant main effects of fiber type on APPL1 (IIX > IIB) and COXIV (IIA > IIX > IIB/X ≈ IIB) abundance, and IIB fibers were significantly larger than IIA fibers. This study established the feasibility of a new approach for assessing age-related differences in muscle at the single-fiber level and demonstrated the magnitude and rank order for fiber-type differences in insulin-stimulated glucose uptake of 9-month-old and 25-month-old rats.

Background: Aging in humans is characterized by a progressive loss of muscle mass and strength known as sarcopenia. Although considered to be a normal aspect of aging, the loss of strength can have significant effects on the health, functioning, and independence of elderly individuals. Although these aspects of sarcopenia have been well studied, the molecular mechanisms leading to its development are still unclear. The nematode Caenorhabditis elegans might be a novel animal model for sarcopenia as worms experience sarcopenia during aging and mutations affecting the daf-2/insulin-like signaling pathway are able to delay this process., Methods: Via the use of RNA interference, we screened a total of 43 genes, most of which have been shown to be required for the enhanced longevity of daf-2 mutants, to assess for the effects of these genes on muscle function and worm mobility during aging., Results: We identified 17 novel genes that are essential for the delay in the onset of sarcopenia in daf-2 mutants. The identified genes include splicing factors, vacuolar sorting proteins, transcription factors, and metabolic enzymes. Using a transgenic strain that only responds to RNA interference in the body wall muscle, we also found that most of the identified genes act in muscle to prevent the onset of sarcopenia., Conclusions: Our results demonstrate that at least in worms, specific genetic pathways that modify the development of sarcopenia can be identified. Interestingly, almost all the identified genes also have a known human homolog, and hence, our findings may offer significant leads toward the identification of genes involved in sarcopenia in people.

This study analyzed the capacity of resveratrol, a naturally occurring polyphenol, to reduce aging-induced oxidative stress and protect against sarcopenia. Middle-aged (18 months) C57/BL6 mice were randomly assigned to receive either a control diet or a diet supplemented with 0.05% trans-resveratrol for 10 months. Young (6 months) and middle-aged (18 months) mice were used as controls. Resveratrol supplementation did not reduce the aging-associated loss of muscle mass or improve maximal isometric force production, but it appeared to preserve fast-twitch fiber contractile function. Resveratrol supplementation did not improve mitochondrial content, the subcellular localization of cytochrome c protein content, or PGC1 protein content. Resveratrol increased manganese superoxide dismutase (MnSOD), reduced hydrogen peroxide(,) and lipid peroxidation levels in muscle samples, but it was unable to significantly reduce protein carbonyl levels. The data suggest that resveratrol has a protective effect against aging-induced oxidative stress in skeletal muscle, likely through the upregulation of MnSOD activity, but sarcopenia was not attenuated by resveratrol.