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

Abstract

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 β-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.

Keywords: Aging; Metabolic changes; Methionine restriction; Nephropathy; Testicular cancer.

Fig. 1

Food intake in F344 rats on Met-restricted (MR) and control (CF) diets. Rats (8–9 per group) were randomized into CF and MR groups at 7 weeks of age. Twenty-four-hour food consumption was assessed monthly during months 1–5 and 19–24 after the initiation of MR by weighing the food ration for each cage at the beginning and end of feeding. Bars represent the mean daily food consumption during the 5-month period. Error bars represent SEM values

Fig. 2

Organ weight changes in F344 rats on Met-restricted (MR) and control (CF) diets. Rats (8–9 per group) were randomized into CF and MR groups at 7 weeks of age and body and organ weights were recorded at the time of sacrifice. Both absolute weights (left panel) and weights relative to total body weight (right panel) are presented. Bars represent the mean weights and error bars represent SD values. Significant differences (P < 0.00001) between CF and MR groups are designated by asterisks

Fig. 3

MR eliminates chronic progressive nephropathy (CPN). Rats were randomized into CF (n = 8) and MR (n = 9) groups at 7 weeks of age. Upon sacrifice when rats became moribund (26–33 months for CF and 29–36 months for MR), kidneys were removed and processed for histopathologic analysis. *Significantly different from control group, P < 0.04. ^†Significantly different from control group, P < 0.02

Fig. 4

Prevention of the age-related increase in albumin excretion by MR. Rats (6 per group) were randomized into CF and MR groups at 7 weeks of age and 24-h urine samples were collected every 5 months for albumin measurement. Values are mean ± SEM. P < 0.05 for CF vs. MR at 30 months

Fig. 5

MR reduces tumor development and cell proliferation in the aging rat. Rats were randomized into CF (n = 8) and MR (n = 9) groups at 7 weeks of age. Upon sacrifice when rats became moribund (26–33 months for CF and 29–36 months for MR), testes were removed and processed for analysis of histopathology (a) and cell proliferation by PCNA immunohistochemistry (b). *Significantly different from control group, P < 0.04. ^†Significantly different from control group, P < 0.02. ^‡Significantly different from control group, P < 0.003