Genetic suppression of GH-IGF-1 activity, combined with lifelong caloric restriction, prevents age-related renal damage and prolongs the life span in rats.

Authors: Zha Y; Taguchi T; Nazneen A; Shimokawa I; Higami Y; Razzaque MS

Abstract: AIM: The aim of this study was to determine the effects of kidney pathology on overall survival and longevity and the combined effects of chronic suppression of growth hormone (GH)/insulin-like growth factor-1 (IGF-1) activity and lifelong caloric restriction on age-associated nephropathy. METHODS: We analyzed the kidneys of rats with suppressed GH activity through genetic manipulation with an antisense GH transgene. Rats were fed normally or with a 30% calorie-restricted diet for 24-26 months. The kidneys of male wild-type young (6 months) and old (24-26 months) rats were compared with male hemizygote transgenic young (6 months) and old (24-26 months) rats fed with either regular diet or 30% calorie-restricted diet for their entire life span. RESULTS: The transgenic rats had relatively less pituitary GH-secreting cells, and the plasma levels of IGF-1 were decreased by 53% in homozygote rats (tg/tg) and by 28% in hemizygote rats (tg/wt) compared to wild-type rats (wt/wt) of the same age (6 months). Wild-type rats fed the regular diet developed age-associated nephropathy as they aged, showing severe inflammatory cell infiltration, glomerulosclerosis, and tubulointerstitial fibrosis. In addition, about 83% of the wild-type rats allowed to survive naturally showed signs of nephropathy. In contrast, only 26% of the naturally surviving hemizygote rats showed features of nephropathy, despite the fact that these rats lived 8% longer (maximum survival 171 weeks) than the wild-type rats (maximum survival 158 weeks). When chronic suppression of GH/IGF-1 activity was combined with lifelong caloric restriction, however, age- associated nephropathy was nonexistent in hemizygote transgenic rats, and they showed about 30% increase in survival (maximum survival 204 weeks). There was no significant difference in the rate of neoplastic or nonneoplastic lesions (other than in the kidney) in the regularly fed wild-type rats or in the calorie-restricted hemizygote transgenic rats that survived longer. CONCLUSION: We concluded that kidney pathology is an important determinant of overall survival, and that prevention of kidney pathology by dietary restriction, combined with chronic suppression of GH/IGF-1 activity, significantly extends overall survival and longevity.

Keywords: Animals; Animals, Genetically Modified; Caloric Restriction; Growth Hormone/*genetics; Insulin-Like Growth Factor I/*genetics; Kidney/*pathology; Kidney Diseases/*prevention & control; *Longevity; Male; Rats; Rats, Wistar; Transgenes
Journal: American journal of nephrology
Volume: 28
Issue: 5
Pages: 755-64
Date: April 25, 2008
PMID: 18434714
Select reference article to upload


Citation:

Zha Y, Taguchi T, Nazneen A, Shimokawa I, Higami Y, Razzaque MS (2008) Genetic suppression of GH-IGF-1 activity, combined with lifelong caloric restriction, prevents age-related renal damage and prolongs the life span in rats. American journal of nephrology 28: 755-64.


Study
Update (Admin) | Auto-Update

Comment on This Data Unit