Long-term cysteine fortification impacts cysteine/glutathione homeostasis and food intake in ageing rats.

PURPOSE: Healthy ageing is associated with higher levels of glutathione. The study aimed to determine whether long-term dietary fortification with cysteine increases cysteine and glutathione pools, thus alleviating age-associated low-grade inflammation and resulting in global physiological benefits. METHODS: The effect of a 14-week dietary fortification with cysteine was studied in non-inflamed (NI, healthy at baseline) and in spontaneously age-related low-grade inflamed (LGI, prefrail at baseline) 21-month-old rats. Fifty-seven NI rats and 14 LGI rats received cysteine-supplemented diet (4.0 g/kg of free cysteine added to the standard diet containing 2.8 g/kg cysteine). Fifty-six NI rats and 16 LGI rats received a control alanine-supplemented diet. RESULTS: Cysteine fortification in NI rats increased free cysteine (P < 0.0001) and glutathione (P < 0.03) in the liver and the small intestine. In LGI rats, cysteine fortification increased total non-protein cysteine (P < 0.0007) and free cysteine (P < 0.03) in plasma, and free cysteine (P < 0.02) and glutathione (P < 0.01) in liver. Food intake decreased over time in alanine-fed rats (r² = 0.73, P = 0.0002), whereas it was constant in cysteine-fed rats (r² = 0.02, P = 0.68). Cysteine fortification did not affect inflammatory markers, mortality, body weight loss, or tissue masses. CONCLUSION: Doubling the dietary intake of cysteine in old rats increased cysteine and glutathione pools in selected tissues. Additionally, it alleviated the age-related decline in food intake. Further validation of these effects in the elderly population suffering from age-related anorexia would suggest a useful therapeutic approach to the problem.

Effect of zinc supplementation on protein metabolism in late-middle-aged men: The Zenith study.

OBJECTIVE: Zinc (Zn) is an essential trace element that is a potent enhancer of protein metabolism due to its numerous roles in metabolic processes. Protein turnover decreases with age. We determined whether a Zn supplementation, which increases serum Zn concentration and Zn exchangeable pool mass, modifies whole-body protein turnover and albumin and fibrinogen synthesis rates in late-middle-aged men. METHODS: Three groups of 16 healthy subjects 55-70 y of age participated in a randomized, doubled-blinded, placebo-controlled intervention. Each group received 0, 15, or 30 mg/d of supplemental Zn for 6 mo. At the end of the supplementation period, each subject received an intravenous infusion of L-[1-13C] leucine to quantify whole-body leucine fluxes and synthesis rates of albumin and fibrinogen. RESULTS: In the placebo group, mean +/- SEM whole-body leucine fluxes to protein synthesis, to oxidation, and from protein degradation were 1.46 +/- 0.05, 0.40 +/- 0.01, and 1.73 +/- 0.06 micromol.kg(-1).min(-1), respectively. Zn supplementation did not significantly change whole-body leucine fluxes. In the placebo group, plasma concentration and fractional rate of protein synthesis were 45 +/- 1 g/L and 8.2 +/- 0.6%/d for albumin and 3.6 +/- 0.2 g/L and 16.7 +/- 1.3%/d for fibrinogen, respectively. Zn supplementation did not significantly change these parameters or the absolute rates of synthesis of these proteins. CONCLUSION: Increasing Zn supply does not modify whole-body protein metabolism and synthesis rates of albumin and fibrinogen in late-middle-aged men.

Therapeutic paracetamol treatment in older persons induces dietary and metabolic modifications related to sulfur amino acids.

Sulfur amino acids are determinant for the detoxification of paracetamol (N-acetyl-p-aminophenol) through sulfate and glutathione conjugations. Long-term paracetamol treatment is common in the elderly, despite a potential cysteine/glutathione deficiency. Detoxification could occur at the expense of anti-oxidative defenses and whole body protein stores in elderly. We tested how older persons satisfy the extra demand in sulfur amino acids induced by long-term paracetamol treatment, focusing on metabolic and nutritional aspects. Effects of 3 g/day paracetamol for 14 days on fasting blood glutathione, plasma amino acids and sulfate, urinary paracetamol metabolites, and urinary metabolomic were studied in independently living older persons (five women, five men, mean (±SEM) age 74 ± 1 years). Dietary intakes were recorded before and at the end of the treatment and ingested sulfur amino acids were evaluated. Fasting blood glutathione, plasma amino acids, and sulfate were unchanged. Urinary nitrogen excretion supported a preservation of whole body proteins, but large-scale urinary metabolomic analysis revealed an oxidation of some sulfur-containing compounds. Dietary protein intake was 13% higher at the end than before paracetamol treatment. Final sulfur amino acid intake reached 37 mg/kg/day. The increase in sulfur amino acid intake corresponded to half of the sulfur excreted in urinary paracetamol conjugates. In conclusion, older persons accommodated to long-term paracetamol treatment by increasing dietary protein intake without any mobilization of body proteins, but with decreased anti-oxidative defenses. The extra demand in sulfur amino acids led to a consumption far above the corresponding population-safe recommendation.

Increased albumin plasma efflux contributes to hypoalbuminemia only during early phase of sepsis in rats.

The mechanisms leading to hypoalbuminemia in sepsis were explored by measuring plasma volume, albumin distribution, plasma albumin transcapillary escape rate (TER), and efflux (TER x albumin intravascular pool). These parameters were quantified in infected rats, injected intravenously with live Escherichia coli, and pair-fed and well-fed rats using an injection of (35)S-albumin and measuring plasma and whole body albumin concentrations. Animals were studied on days 1, 6, and 10 after infection. In pair-fed rats, neither albumin distribution nor exchange rate between the intra- and extravascular compartments was modified. The increase of plasma volume after infection partly explained hypoalbuminemia. Infection resulted in a reduction of the total albumin pool of the body all along the experimental period, indicating a net loss of the protein. Albumin TER (%/day) was significantly increased 1 and 6 days after infection, but the absolute efflux was increased only on day 1. Normal values were observed on day 10. Therefore, an accelerated plasma efflux contributes to hypoalbuminemia only during the early period of sepsis. During this phase, the protein was retained in the extravascular space where it was probably catabolized. Later on, other factors are probably involved.