Methionine restriction delays aging-related urogenital diseases in male Fischer 344 rats.

Dietary methionine restriction (MR) has been found to enhance longevity across many species. We hypothesized that MR might enhance longevity in part by delaying or inhibiting age-related disease processes. To this end, male Fischer 344 rats were fed control (CF, 0.86% methionine) or MR (0.17% methionine) diets throughout their life until sacrifice at approximately 30 months of age, and histopathology was performed to identify the incidence and progression of two important aging-related pathologies, namely, chronic progressive nephropathy (CPN) and testicular tumorigenesis. Although kidney pathology was observed in 87% CF rats and CPN in 62% of CF animals, no evidence of kidney disease was observed in MR rats. Consistent with the absence of renal pathology, urinary albumin levels were lower in the MR group compared to controls throughout the study, with over a six-fold difference between the groups at 30 months of age. Biomarkers associated with renal disease, namely, clusterin, cystatin C, and ß-2 microglobulin, were reduced following 18 months of MR. A reduction in testicular tumor incidence from 88% in CF to 22% in MR rats was also observed. These results suggest that MR may lead to metabolic and cellular changes providing protection against age-related diseases.

Tissue glutathione and cysteine levels in methionine-restricted rats.

OBJECTIVE: Previously, we demonstrated that lifelong methionine (Met) restriction (MR) increases lifespan, decreases the incidence of aging-related diseases, increases blood glutathione (GSH) levels, and prevents loss of GSH during aging in rats. Our present objective was to elucidate the effects of MR on GSH metabolism and transport by determining the time course and nature of GSH and cysteine changes in blood and other tissues in young and mature rats. METHODS: Male F-344 rats were placed on control (0.86% Met) or MR (0.17% Met) defined amino acid diets at age 7 wk and killed at different times thereafter. MR was also initiated in adult (12-mo-old) rats. RESULTS: Throughout the first 2 mo of MR, blood GSH levels increased 84% and liver GSH decreased 66% in relation to controls. After this period, liver GSH levels remained constant through at least 6 mo. GSH levels also decreased in the pancreas (80%) and kidney (22%) but remained unchanged in other tissues examined after 11 wk of MR. The increase in blood GSH was evident as soon as 1 wk after initiating MR and reached a plateau by 6 wk. A similar increase in erythrocyte GSH levels was observed when MR was administered to mature adult rats. Fasting decreased liver GSH in controls but had no further effect in MR animals. By 1 mo, cysteine levels had decreased in all tissues except brain. CONCLUSION: These results suggest that adaptive changes occur in the metabolism of Met, cysteine, and/or GSH as a result of MR in young and adult rats. These early metabolic changes lead to conservation of GSH levels in most extrahepatic tissues and increased GSH in erythrocytes by depleting liver GSH to a critical level.

Nutritional control of aging.

For more than 60 years the only dietary manipulation known to retard aging was caloric restriction, in which a variety of species respond to a reduction in energy intake by demonstrating extended median and maximum life span. More recently, two alternative dietary manipulations have been reported to also extend survival in rodents. Reducing the tryptophan content of the diet extends maximum life span, while lowering the content of sulfhydryl-containing amino acids in the diet by removing cysteine and restricting the concentration of methionine has been shown to extend all parameters of survival, and to maintain blood levels of the important anti-oxidant glutathione. To control for the possible reduction in energy intake in methionine-restricted rats, animals were offered the control diet in the quantity consumed by rats fed the low methionine diet. Such pair-fed animals experienced life span extension, indicating that methionine restriction-related life span extension is not a consequence of reduced energy intake. By feeding the methionine restricted diet to a variety of rat strains we determined that lowered methionine in the diet prolonged life in strains that have differing pathological profiles in aging, indicating that this intervention acts by altering the rate of aging, not by correcting some single defect in a single strain.