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Since maximum anabolism occurs postprandially, we developed a simulated fed state with clamped hyperinsulinemia, physiological hyperglycemia, and hyperaminoacidemia (Hyper-3) and explored muscle cellular mechanisms. Whole body [1-[sup.13]C]leucine and [3-[sup.3]H]glucose kinetics in healthy men were compared between hyperinsulinemic, euglycemic, isoaminoacidemic (Hyper-1, n = 10) and Hyper-3 (n = 9) clamps. In Hyper-3 vs. Hyper-1, nonoxidative leucine [R.sub.d] [rate of disappearance (synthesis)] was stimulated more (45 [+ or -] 4 vs. 24 [+ or -] 4 [micro]mol/min, P < 0.01) and endogenous [R.sub.a] [rate of appearance (breakdown)] was inhibited similarly; hence net balance increased more (86 [+ or -] 6 vs. 49 [+ or -] 2 [micro]mol/min, P < 0.001). Glucose [R.sub.d] was similar; thus Hyper-3 metabolic clearance rate (331 [+ or -] 23 vs. 557 [+ or -] 41 ml/min, P < 0.0005) and [R.sub.d]/insulin (M, 0.65 [+ or -] 0.10 vs. 1.25 [+ or -] 0.10 mg x [min.sup.-1] x [pmol.sup.-1] x 1, P < 0.001) were less, despite higher insulin (798 [+ or -] 74 vs. 450 [+ or -] 24 pmol/l, P < 0.005). In vastus lateralis muscle biopsies, phosphorylation of Akt (P = 0.025), mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase (p[70.sup.S6K1]; P = 0.008), S6 (P = 0.049), and 4E-binding protein 1 (4E-BP1; P = 0.001) increased. With decreased eukaryotic initiation factor-4E (eIF4E) x 4E-BP1 complex (P = 0.01), these are consistent with increased roTOR complex 1 (mTORC1) signaling and translation initiation of protein synthesis. Although mRNA expression of ubiquitin, MAFbx 1, and MuRF-1 was unchanged, total ubiquitinated proteins decreased 20% (P < 0.01), consistent with proteolysis suppression. The Hyper-3 clamp increases whole body protein synthesis, net anabolism, and muscle protein translation initiation pathways and decreases protein ubiquitination. The main contribution of hyperaminoacidemia is stimulation of synthesis rather than inhibition of proteolysis, and it attenuates the expected increment of glucose disposal. translation initiation; ubiquitin pathway; leucine kinetics; glucose turnover; insulin resistance

Background. Although insulin resistance of glucose is often reported with aging, that of protein metabolism is still debated. We tested if the insulin sensitivity of protein metabolism parallels that of glucose and is altered with aging. Method. Whole-body [sup.13]C-leucine and [sup.13]H glucose kinetics were measured in file postabsorptive stale and during an hyperinsulinemic, euglycemic, isoaminoacidemic clamp in 12 young men (age: 27 [+ or -] 1 years: body mass index [BMI]: 23 [+ or -] 1 kg/[m.sup.2]), 11 young women (age: 25 [+ or -] 1 years: BMI: 21 [+ or -] 1 kg/[m.sup.2]), 9 elderly men (age: 70 [+ or -] 1 years: BMI: 26 [+ or -] 1 kg/[m.sup.2]), and 10 elderly women (age: 69 [+ or -] 2 years: BMI: 23 [+ or -] 1 kg/[m.sup.2]). Results. Postabsorptive leucine flux rates adjusted for fat free mass (FFM) were not different between elderly and young participants. During the clamp, leucine flux and protein synthesis rates increased less in the elderly participants, and protein breakdown decreased equally. Thus, the net anabolic (protein balance) response to hyperinsulinemia was lower in elderly versus young participants (p = .007) and was highly correlated with the clamp glucose rate of disposal (r = 0.671. p < .001), indicating insulin resistance of protein concurrent with that of glucose. From regression analysis. FFM explained 73% of the variance in the anabolic response. Age explained an additional 3%, but was accounted for by markers of adiposity. FFM and percent body fat collectively explained 79% of the variance. Conclusion. Both reduction in absolute FFM and increased adiposity, intrinsic to the aging process, are associated with an altered anabolic action of insulin in stimulating protein synthesis. This alteration may contribute to the progressive muscle loss with aging.

Recent studies reported that retinoid metabolism was influenced by long-term dietary restriction (DR) in rats. Because plasma retinol was decreased in rats subjected to DR, it was thought that this dietary manipulation may have an effect on retinol-binding protein (RBP) metabolism. Thus, the aim of this study was to assess retinoids, RBP, and transthyretin (TTR) levels in plasma and liver of young (3 months), adult (12 months), and old (22 months) female Sprague-Dawley rats fed ad libitum (AL) or subjected to a 40% DR, enriched (DR+), or not (DR), with vitamins and minerals. Results indicate that hepatic total retinoid concentrations and content increased with age in all the groups. DR+ rats showed higher hepatic retinoid concentrations than age-matched AL and DR rats. Adult and old DR and DR+ rats exhibited significantly lower plasma RBP-retinol and higher total retinoic acid levels than corresponding controls, although these parameters were not influenced by aging. Liver RBP levels were also decreased in DR and DR+ rats when compared to respective AL controls. There was a slight age-related decline in plasma TTR levels in DR and DR+ rats which was not associated with modifications in liver TTR levels. Hepatic gene expression of RBP and TTR, as evaluated by Northern blot hybridization, did not change with age or diet, suggesting that the lower levels of plasma RBP-retinol and liver RBP in vitamin A-sufficient rats subjected to DR may reflect post-transcriptional alterations and/or accelerated degradation of hepatic RBP. The elevated plasma levels of retinoic acid may represent an adaptive mechanism developed by DR rats to maintain retinoid-dependent functions.

We investigated the contribution of bile salts and glutathione (GSH) to the generation of bile flow in young, mature, and old female Sprague-Dawley rats, either fed ad libitum (AL) or subjected to a 40% dietary restriction (DR), which was supplemented or not with vitamins and minerals, starting from weaning. An age-related decline in bile flow was observed in the AL group. DR increased bile flow compared to age-matched AL rats, resulting in a twofold increase in the old animals. This was associated with a statistically significantly higher biliary GSH secretion rate and a moderate increase in the bile salt secretory rate. The apparent GSH-dependent flow was significantly increased in DR groups of all ages. Hepatic GSH concentration was closely related to the GSH secretion rate. These results indicate that the increase in biliary GSH content produced by DR is the major mediator of the increased bile flow, resulting in enhanced GSH and GSH-derived thiols supply to the intestinal lumen.

Abstract Background The optimal patient selection of frail elderly persons undergoing rehabilitation in Geriatric Day Hospital (GDH) programs remains uncertain. This study was done to identify potential predictors of rehabilitation outcomes for these patients. Methods This study is a retrospective cohort analysis of patients admitted to the rehabilitation program of our GDH, in Montreal, Canada, over a five year period. The measures considered were: Barthel Index, Older Americans Resources and Services, Folstein Mini Mental Status Exam, Timed Up & Go (TUG), 6-minute walk test (6 MWT), Gait speed, Berg Balance, grip strength and the European Quality of life - 5 Dimensions. Successful improvement with rehabilitation was defined as improvement in three or more tests of physical function. Logistic regression analysis using the Bayesian Information Criterion (BIC) was employed to select the optimal model for making predictions of rehabilitation success. Results A total of 335 patients were studied, but only 233 patients had a complete data set suitable for the predictive model. Average age was 81 years and patients attended the GDH an average of 24 visits. Significant changes were found in several measures of physical performance for many patients ranging from improved gait speed in 21.3% to improved TUG in 62.7% of the cohort. Fifty-eight percent of patients attained successful improvement with rehabilitation by our criteria. This group was characterized by lower test scores on admission. Using BIC, the best predictor model was the 6 MWT [OR: 0.994 per meter walked (95% CI: 0.990-0.997)]. Conclusions The GDH rehabilitation program is effective in improving patients' physical performance. Although no single measure was found to be sufficiently predictive to help target candidates appropriately, the 6 MWT showed a trend to significance. Further research will be done to elucidate the utility of a composite 'rehab appropriateness index' and the role of International Classification of Function concepts for targeting frail elderly to GDH rehabilitation services.