Kevin E. Yarasheski

Decreased Clearance of CNS β-Amyloid in Alzheimer’s Disease

Alzheimer’s disease is associated with reduced β-amyloid clearance from the brain Alzheimer’s disease is hypothesized to be caused by an imbalance between β-amyloid (Aβ) production and clearance that leads to Aβ accumulation in the central nervous system (CNS). Aβ production and clearance are key targets in the development of disease-modifying therapeutic agents for Alzheimer’s disease. However, there has not been direct evidence of altered Aβ production or clearance in Alzheimer’s disease. By using metabolic labeling, we measured Aβ42 and Aβ40 production and clearance rates in the CNS of participants with Alzheimer’s disease and cognitively normal controls. Clearance rates for both Aβ42 and Aβ40 were impaired in Alzheimer’s disease compared with controls. On average, there were no differences in Aβ40 or Aβ42 production rates. Thus, the common late-onset form of Alzheimer’s disease is characterized by an overall impairment in Aβ clearance.

Decreased clearance of CNS beta-amyloid in Alzheimer's disease.

Alzheimer’s disease is associated with reduced β-amyloid clearance from the brain Alzheimer’s disease is hypothesized to be caused by an imbalance between β-amyloid (Aβ) production and clearance that leads to Aβ accumulation in the central nervous system (CNS). Aβ production and clearance are key targets in the development of disease-modifying therapeutic agents for Alzheimer’s disease. However, there has not been direct evidence of altered Aβ production or clearance in Alzheimer’s disease. By using metabolic labeling, we measured Aβ42 and Aβ40 production and clearance rates in the CNS of participants with Alzheimer’s disease and cognitively normal controls. Clearance rates for both Aβ42 and Aβ40 were impaired in Alzheimer’s disease compared with controls. On average, there were no differences in Aβ40 or Aβ42 production rates. Thus, the common late-onset form of Alzheimer’s disease is characterized by an overall impairment in Aβ clearance.

Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo.

Certain disease states are characterized by disturbances in production, accumulation or clearance of protein. In Alzheimer disease, accumulation of amyloid-β (Aβ) in the brain and disease-causing mutations in amyloid precursor protein or in enzymes that produce Aβ indicate dysregulation of production or clearance of Aβ. Whether dysregulation of Aβ synthesis or clearance causes the most common form of Alzheimer disease (sporadic, >99% of cases), however, is not known. Here, we describe a method to determine the production and clearance rates of proteins within the human central nervous system (CNS). We report the first measurements of the fractional production and clearance rates of Aβ in vivo in the human CNS to be 7.6% per hour and 8.3% per hour, respectively. This method may be used to search for novel biomarkers of disease, to assess underlying differences in protein metabolism that contribute to disease and to evaluate treatments in terms of their pharmacodynamic effects on proposed disease-causing pathways.

Effects of Exercise Training on Frailty in Community‐Dwelling Older Adults: Results of a Randomized, Controlled Trial

OBJECTIVES: Although deficits in skeletal muscle strength, gait, balance, and oxygen uptake are potentially reversible causes of frailty, the efficacy of exercise in reversing frailty in community‐dwelling older adults has not been proven. The aim of this study was to determine the effects of intensive exercise training (ET) on measures of physical frailty in older community‐dwelling men and women.

Differential effects of resistance and endurance exercise in the fed state on signalling molecule phosphorylation and protein synthesis in human muscle.

Resistance (RE) and endurance (EE) exercise stimulate mixed skeletal muscle protein synthesis. The phenotypes induced by RE (myofibrillar protein accretion) and EE (mitochondrial expansion) training must result from differential stimulation of myofibrillar and mitochondrial protein synthesis. We measured the synthetic rates of myofibrillar and mitochondrial proteins and the activation of signalling proteins (Akt–mTOR–p70S6K) at rest and after an acute bout of RE or EE in the untrained state and after 10 weeks of RE or EE training in young healthy men. While untrained, RE stimulated both myofibrillar and mitochondrial protein synthesis, 67% and 69% (P < 0.02), respectively. After training, only myofibrillar protein synthesis increased with RE (36%, P= 0.05). EE stimulated mitochondrial protein synthesis in both the untrained, 154%, and trained, 105% (both P < 0.05), but not myofibrillar protein synthesis. Acute RE and EE increased the phosphorylation of proteins in the Akt–mTOR–p70S6K pathway with comparatively minor differences between two exercise stimuli. Phosphorylation of Akt–mTOR–p70S6K proteins was increased after 10 weeks of RE training but not by EE training. Chronic RE or EE training modifies the protein synthetic response of functional protein fractions, with a shift toward exercise phenotype‐specific responses, without an obvious explanatory change in the phosphorylation of regulatory signalling pathway proteins.

Resistance exercise decreases skeletal muscle tumor necrosis factor α in frail elderly humans

Skeletal muscle protein and function decline with advancing age but the underlying pathophysiology is poorly understood. To test the hypothesis that the catabolic cytokine tumor necrosis factor alpha (TNF‐α) contributes to this process, we studied the effects of aging and resistance exercise on TNF‐α expression in human muscle. Using in situ hybridization, TNF‐α message was localized to myocytes in sections of skeletal muscle from elderly humans. Both TNF‐α mRNA and protein levels were elevated in skeletal muscle from frail elderly (81±1 year) as compared to healthy young (23±1 year) men and women. To determine whether resistance exercise affects TNF‐α expression, frail elderly men and women were randomly assigned to a training group or to a nonexercising control group. Muscle biopsies were performed before and after 3 months. Muscle TNF‐α mRNA and protein levels decreased in the exercise group but did not change in the control group. Muscle protein synthesis rate in the exercise group was inversely related to levels of TNF‐α protein. These data suggest that TNF‐α contributes to age‐associated muscle wasting and that resistance exercise may attenuate this process by suppressing skeletal muscle TNF‐α expression.—Greiwe, J. S., Cheng, B., Rubin, D. C., Yarasheski, K. E., Semenkovich, C. F. Resistance exercise decreases skeletal muscle tumor necrosis factor α in frail elderly humans. FASEB J. 15, 475‐482 (2001)

Bacterial community structures are unique and resilient in full-scale bioenergy systems

Anaerobic digestion is the most successful bioenergy technology worldwide with, at its core, undefined microbial communities that have poorly understood dynamics. Here, we investigated the relationships of bacterial community structure (>400,000 16S rRNA gene sequences for 112 samples) with function (i.e., bioreactor performance) and environment (i.e., operating conditions) in a yearlong monthly time series of nine full-scale bioreactor facilities treating brewery wastewater (>20,000 measurements). Each of the nine facilities had a unique community structure with an unprecedented level of stability. Using machine learning, we identified a small subset of operational taxonomic units (OTUs; 145 out of 4,962), which predicted the location of the facility of origin for almost every sample (96.4% accuracy). Of these 145 OTUs, syntrophic bacteria were systematically overrepresented, demonstrating that syntrophs rebounded following disturbances. This indicates that resilience, rather than dynamic competition, played an important role in maintaining the necessary syntrophic populations. In addition, we explained the observed phylogenetic differences between all samples on the basis of a subset of environmental gradients (using constrained ordination) and found stronger relationships between community structure and its function rather than its environment. These relationships were strongest for two performance variables—methanogenic activity and substrate removal efficiency—both of which were also affected by microbial ecology because these variables were correlated with community evenness (at any given time) and variability in phylogenetic structure (over time), respectively. Thus, we quantified relationships between community structure and function, which opens the door to engineer communities with superior functions.

A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system

Accumulation of amyloid‐β (Aβ) by overproduction or underclearance in the central nervous system (CNS) is hypothesized to be a necessary event in the pathogenesis of Alzheimers disease. However, previously, there has not been a method to determine drug effects on Aβ production or clearance in the human CNS. The objective of this study was to determine the effects of a γ‐secretase inhibitor on the production of Aβ in the human CNS.

Muscle-specific mutations accumulate with aging in critical human mtDNA control sites for replication

The recently discovered aging-dependent large accumulation of point mutations in the human fibroblast mtDNA control region raised the question of their occurrence in postmitotic tissues. In the present work, analysis of biopsied or autopsied human skeletal muscle revealed the absence or only minimal presence of those mutations. By contrast, surprisingly, most of 26 individuals 53 to 92 years old, without a known history of neuromuscular disease, exhibited at mtDNA replication control sites in muscle an accumulation of two new point mutations, i.e., A189G and T408A, which were absent or marginally present in 19 individuals younger than 34 years. These two mutations were not found in fibroblasts from 22 subjects 64 to 101 years of age (T408A), or were present only in three subjects in very low amounts (A189G). Furthermore, in several older individuals exhibiting an accumulation in muscle of one or both of these mutations, they were nearly absent in other tissues, whereas the most frequent fibroblast-specific mutation (T414G) was present in skin, but not in muscle. Among eight additional individuals exhibiting partial denervation of their biopsied muscle, four subjects >80 years old had accumulated the two muscle-specific point mutations, which were, conversely, present at only very low levels in four subjects ≤40 years old. The striking tissue specificity of the muscle mtDNA mutations detected here and their mapping at critical sites for mtDNA replication strongly point to the involvement of a specific mutagenic machinery and to the functional relevance of these mutations.

Resistance exercise training increases mixed muscle protein synthesis rate in frail women and men

Muscle atrophy (sarcopenia) in the elderly is associated with a reduced rate of muscle protein synthesis. The purpose of this study was to determine if weight-lifting exercise increases the rate of muscle protein synthesis in physically frail 76- to 92-yr-old women and men. Eight women and 4 men with mild to moderate physical frailty were enrolled in a 3-mo physical therapy program that was followed by 3 mo of supervised weight-lifting exercise. Supervised weight-lifting exercise was performed 3 days/wk at 65-100% of initial 1-repetition maximum on five upper and three lower body exercises. Compared with before resistance training, the in vivo incorporation rate of [13C]leucine into vastus lateralis muscle protein was increased after resistance training in women and men ( P < 0.01), although it was unchanged in five 82 ± 2-yr-old control subjects studied two times in 3 mo. Maximum voluntary knee extensor muscle torque production increased in the supervised resistance exercise group. These findings suggest that muscle contractile protein synthetic pathways in physically frail 76- to 92-yr-old women and men respond and adapt to the increased contractile activity associated with progressive resistance exercise training.Muscle atrophy (sarcopenia) in the elderly is associated with a reduced rate of muscle protein synthesis. The purpose of this study was to determine if weight-lifting exercise increases the rate of muscle protein synthesis in physically frail 76- to 92-yr-old women and men. Eight women and 4 men with mild to moderate physical frailty were enrolled in a 3-mo physical therapy program that was followed by 3 mo of supervised weight-lifting exercise. Supervised weight-lifting exercise was performed 3 days/wk at 65-100% of initial 1-repetition maximum on five upper and three lower body exercises. Compared with before resistance training, the in vivo incorporation rate of [(13)C]leucine into vastus lateralis muscle protein was increased after resistance training in women and men (P < 0.01), although it was unchanged in five 82 +/- 2-yr-old control subjects studied two times in 3 mo. Maximum voluntary knee extensor muscle torque production increased in the supervised resistance exercise group. These findings suggest that muscle contractile protein synthetic pathways in physically frail 76- to 92-yr-old women and men respond and adapt to the increased contractile activity associated with progressive resistance exercise training.