This study compared the effects of ad libitum (AL) overfeeding and moderate dietary restriction (DR) of 2 different diets on Sprague-Dawley (SD) rat survival and spontaneous, age-related proliferative and degenerative lesions. SD rats were fed Purina Rodent Chow 5002 or a modified Rodent Chow 5002-9 containing lower protein, fat, metabolizable energy, and increased fiber by AL or by DR at 65% of the AL amount by measurement or time (6.5 hr). At 106 wk, rats fed the 5002-9 diet AL did not have significantly improved survival over rats fed the 5002 diet AL. The 5002 diet fed DR by time (6.5 hr) improved survival for males but not females. Only DR by measurement of both diets resulted in lower mortality for both sexes. By 106 wk rats fed either diet by AL had the same brain weights as DR fed rats, but AL fed rats had greater body weight, body fat content, and increased heart, lung, kidney, liver, adrenal, thyroid, and pituitary weights that correlated with an increased incidence and severity of degenerative and/or proliferative lesions in these organs. Moderate DR delayed the progression of chronic nephropathy by delaying the early development of glomerular hypertrophy that initiates the development of glomerular sclerosis and nephron loss in AL overfed rats. Moderate DR lowered the incidence, severity, and progression of cardiomyopathy and other degenerative, age-related lesions and appeared to delay the development of reproductive senescence in SD females. The conclusion from this study is that moderate DR delayed onset and progression of degenerative lesions, and death due to cardiovascular or renal disease, and thus potentially improves the bioassay to detect compound-specific chronic toxicity.
Bidani AK, Mitchell KD, Schwartz MM, Navar LG, and Lewis EJ (1990). Absence of glomerular injury or nephron loss in a normotensive rat remnant kidney model. Kidney Int. 38: 28-38.
2.
Bray GA and York DA (1979). Hypothalamic and genetic obesity in experimental animals: An autonomic and endocrine hypothesis. Physiol. Rev . 59: 719-809.
3.
Brenner BM (1985). Nephron adaptation to renal injury or ablation . Am. J. Physiol. 249: F324-F337.
4.
Burek JD (1990). Survival experience with the Sprague-Dawley-derived rat. The Toxicology Forum, Transcript of 1990 Annual Meeting, Aspen, CO, pp. 506-518.
5.
Chapin RE, Gulati DK, Barnes LH, and Teague JL (1993). The effects of feed restriction on reproductive function in Sprague-Dawley rats. Fund. Appl. Toxicol. 20: 23-29.
6.
Corman BJ and Owen RA (1992). Normal development, growth, and aging of the kidney . In: Pathobiology of the Aging Rat, Vol. I, U Mohr, DL Dungworth , and CC Capen (eds). ILSI Press, Washington, DC, pp. 195-210.
7.
Cornwell GG, Thomas BP, and Snyder DL (1991). Myocardial fibrosis in aging germ-free and conventional Lobund-Wistar rats: The protective effect of diet restriction. J. Gerontol. 46: B167-169.
8.
Elias H. and Hyde DM (1983). A Guide to Practical Stereology. S. Karger, New York.
9.
Finch CE (1990). Longevity, Senescence and the Genome. The University of Chicago Press, Chicago, IL.
10.
Fishbein L (ed) (1991). Biological Effects of Dietary Restriction. Springer-Verlag , New York.
11.
Fogo A. and Ichikawa I. (1989). Evidence for the central role of glomerular growth promoters in the development of sclerosis. Sem. Nephrol. 9: 329-342.
12.
Frank JD, Cartwright ME, and Keenan KP (1993). Intensification of 5-bromo-2'-deoxyuridine immunohistochemistry with zinc buffered formalin post-fixation and ABC elite solution. J. Histotechnol16(4): 329-334.
13.
Fries JWU , Sandstrom DJ, Meyer TW, and Rennke HG (1989). Glomerular hypertrophy and epithelial cell injury modulate progressive glomerulosclerosis in the rat. Lab. Invest . 60: 205-218.
14.
Frisch RE (1982). Fatness, puberty, menstrual periodicity, and fertility . In: Clinical Reproductive Neuroendocrinology, JL Vaitukaitis (ed). Elsevier, New York, pp. 105-135.
15.
Garfinkel L. (1985). Overweight and cancer . Ann. Intern. Med. 103: 1034-1036.
16.
Glick Z., Yamini S., Lupien J., and Sod-Moriah U. (1990). Estrous cycle irregularities in overfed rats. Physiol. Behav. 47: 307-310.
17.
Gumprecht LA , Long CR, Soper KA, Smith PF, Has-check-Hock WM, and Keenan KP (1993). The early effects of dietary restriction on the pathogenesis of chronic renal disease in Sprague-Dawley rats at 12 months . Toxicol. Pathol . 21(6): 528-537.
18.
Harman D. (1956). Aging: A theory based on free radical and radiation chemistry. J. Gerontol. 11: 298-300.
19.
Harter HL (1961). Expected values of normal order statistics. Biometrika48: 151-165.
20.
Haseman JK and Rao GR (1992). Effects of corn-oil, time-related changes and inter-laboratory variability on tumor occurrence in control Fisher 344 (F-344/ N) rats. Toxicol. Pathol. 20(1): 52-60.
21.
Iwasaki K., Gleiser CA, Masoro EJ, McMahan CA, Seo EJ, and Yu BP (1988). The influence of dietary protein source on longevity and age-related disease processes of Fischer rats. J. Gerontol . 43: B5-12.
22.
Iwasaki K., Maeda H., Shimokawa I., Hayashida M., Yu BP, Masoro EJ, and Ikeda T. (1988). An electron microscopic examination of age-related changes in the rat liver. The influence of diet. Acta Pathol. Jpn. 38: 1119-1130.
23.
Jordan A. (1992). FDA requirements for nonclinical testing of contraceptive steroids. Contraception46: 499-509.
24.
Keenan KP, Smith PF, Ballam GC, Soper KA, and Bokelman DL (1992). The effect of diet and dietary optimization (caloric restriction) on rat survival in carcinogenicity studies-An industrial viewpoint . In: Centre for Medicines Research Workshop. The Carcinogenicity Debate, JAN McAuslane, CF Lumley, and SR Walker (eds). Quay Publishing, Lancaster, England, pp. 77-102.
25.
Keenan KP, Smith PF, Hertzog P., Soper KA, Ballam GG, and Clark RL (1994). The effects of overfeeding and dietary restriction on Sprague-Dawley rat survival and early pathology biomarkers of aging. Toxicol. Pathol. 22(3): 300-315.
26.
Keenan KP, Smith PF, and Soper KA (1994). The effects of dietary (caloric) restriction on rat aging, survival, pathology and toxicology. In: Pathobiology of the Aging Rat, Vol. II, U Mohr, DL Dungworth, and CC Capen (eds). ILSI Press, Washington, DC, pp. 609-628.
27.
Keenan KP, Soper KA, Smith PF, Ballam GC, and Clark RL (1995). Diet, overfeeding and moderate dietary restriction in control Sprague-Dawley rats: I. Effects on spontaneous neoplasms. Toxicol. Pathol. 23: 269-286.
28.
Klahr S., Levey AS, Beck GJ, Caggiula AW, Hunsicker L., Kusek JW, and Striker G. (1994). The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. N. Engl. J. Med. 330(13): 877-884.
29.
Laganiere S. and Yu BP (1989). Effect of chronic food restriction in aging rats. I. Liver subcellular membranes. Mech. Ageing & Dev. 48: 207-219.
30.
Lang PL (1989). Survival of Crl:CD®BR rats during chronic toxicology studies. Charles River Laboratories Reference Paper, pp. 1-4.
31.
Lang PL (1990). Survival of CDF®(F-344)/CrlBR rats during chronic toxicology studies. Charles River Laboratories Reference Paper, pp. 1-4.
32.
Lang PL (1991). Changes in life span of research animals leading to questions about validity of toxicologic studies. Chem. Regulation Reporter14: 1518-1520.
33.
Laganiere S. and Yu BP (1989). Effect of chronic food restriction in aging rats, II. Liver cytosolic antioxidants and related enzymes . Mech. Ageing & Dev. 48: 221-230.
34.
Lee DW and Yu BP (1990). Modulation of free radicals and superoxide dismutases by age and dietary restriction. Aging2: 357-362.
35.
Lee I.-M. , Manson JE, Hennekens CH, and Paffenbarger RS (1993). Body weight and mortality, a 27-year follow-up of middle-aged men. J. Am. Med. Assoc. 270(23): 2823-2828.
36.
Lewis DJ (1992). Nonneoplastic lesions in the cardiovascular system . In: Pathobiology of the Aging Rat, Vol. I, U Mohr, DL Dungworth , and CC Capen (eds). ILSI Press, Washington, DC, pp. 301-309.
37.
Maeda H., Gleiser CA, Masoro EJ, Murata I., McMahan CA, and Yu BP (1985). Nutritional influences on aging of Fischer 344 rats II. Pathology. J. Gerontol. 40: 671-688.
38.
Masoro EJ (1991). Biology of aging: Facts, thoughts, and experimental approaches. Lab. Invest. 65: 500-510.
39.
Masoro EJ (1991). Use of rodents as models for the study of "normal aging": Conceptual and practical issues. Neurobiol. Aging12: 639-643.
40.
Masoro EJ, Iwasaki K., Gleiser CA, McMahan CA, Seo EJ, and Yu BP (1989). Dietary modulation of the progression of nephropathy in aging rats: An evaluation of the importance of protein. Am. J. Clin. Nutr. 49: 1217-1227.
41.
Masoro EJ and McCarter RJM (1991). Aging as a consequence of fuel utilization. Aging3: 117-128.
42.
Masoro EJ, Shimokawa I., and Yu BP (1991). Retardation of the aging process in rats by food restriction. Ann. N.Y. Acad. Sci. 621: 337-352.
43.
McGinnis JM and Foege WH (1993). Actual causes of death in the United States. J. Am. Med. Assoc. 270(18): 2207-2212.
44.
McMartin DN , Sahota PS, Gunson DE, Hsu HH, and Spaet RH (1992). Neoplasms and related proliferative lesions in control Sprague-Dawley rats from carcinogenicity studies. Historical data and diagnostic considerations. Toxicol. Pathol. 20: 212-225.
45.
Meites J. (1989). Evidence that underfeeding acts via the neuroendocrine system to influence aging processes. In: Dietary Restriction and Aging, DL Snyder (ed). Alan R. Liss, Inc., New York, pp. 169-180.
46.
Merry BJ and Holehan AM (1991). The effect of dietary restriction on the endocrine control of reproduction. In: Biological Effects of Dietary Restriction, L Fishbein (ed). Springer-Verlag, New York, pp. 140-146.
47.
Miller RG Jr (1981). Simultaneous Statistical Inference , 2nd ed. Springer-Verlag, New York, pp. 90-94.
48.
Nathan DM (1993). Long-term complications of diabetes mellitus. N. Engl. J. Med. 328(23): 1676-1685.
49.
Nohynek GJ, Longeart L., Geffray B., Provost JP, and Lodola A. (1993). Fat, frail and dying young: Survival body weight and pathology of the Charles River Sprague-Dawley-derived rat prior to and since the introduction of the VAF® variant in 1988. Hum. Exp. Toxicol. 12: 87-98.
50.
Owen RA and Heywood R. (1986). Age-related variations in renal structure and function in Sprague-Dawley rats. Toxicol. Pathol. 14: 158-167.
51.
Raij L., Azar S., and Keane W. (1984). Mesangial immune injury, hypertension, and progressive glomerular damage in Dahl rats. Kidney Int. 26: 137-143.
52.
Rao GN, Edmondson J., and Elwell MR (1993). Influence of dietary protein concentration on severity of nephropathy in Fischer-344 (F-344/N) rats. Toxicol. Pathol. 21: 353-361.
53.
Rao GN, Hasemen JK, Grumbein S., Crawford DD, and Eustis SL (1990). Growth, body weight, survival, and tumor trends in F-344/N rats during an eleven-year period. Toxicol. Pathol . 18(1): 61-70.
54.
Reid JM (1980). Morphometric methods in veterinary pathology: A review. Vet. Pathol. 17: 522-542.
55.
Remuzzi G. and Bertani T. (1990). Is glomerulosclerosis a consequence of altered glomerular permeability to macromolecules? Kidney Int. 38: 384-394.
56.
Roe FJC (1991). 1200-Rat Biosure Study: Design and overview of results. In: Biological Effects of Dietary Restriction, L Fishbein (ed). Springer-Verlag, New York, pp. 287-304.
57.
Roe FJC , Lee PN, Conybeare G., Tobin G., Kelly D., Prentice D., and Matler B. (1991). Risk of premature death and cancer predicted by body weight in early life . Hum. Exp. Toxicol. 10: 285-288.
58.
Rogers AE, Zeisel SH, and Groopman J. (1993). Diet and carcinogenesis. Carcinogenesis14(11): 2205-2217.
59.
Rohr H., Oberholzer J., Bartsch G., and Keller M. (1976). Morphometry in experimental pathology: Methods, baseline data and applications. In: International Review of Experimental Pathology, RW Richter and MA Epstein (eds). Academic Press, New York, pp. 233-325.
60.
Rush GF, Gorski JR, Riple MG, Sowinski J., Bugelski P., and Hewitt WR (1985). Organic hydroperoxide-induced lipid peroxidation and cell death in isolated hepatocytes. Toxicol. Appl. Pharmacol . 78: 473-483.
61.
Sarkar DK, Gottschall PE, and Meites J. (1983). Relation of the neuroendocrine system to development of prolactin-secreting pituitary tumors. In: Neuroendocrinology of Aging, J Meites (ed). Plenum Press, New York, pp. 353-376.
62.
Shimokawa I. , Higami Y., Hubbard GB, McMahan CA, Masoro EJ, and Yu BP (1993). Diet and the suitability of the male Fischer 344 rat as a model for aging research. J. Gerontol. 48: B27-B32.
63.
Short BG, Burnett VL, Cox MG, Bus JS, and Swenberg JA (1987). Site-specific renal cytotoxicity and cell proliferation in male rats exposed to petroleum hydrocarbons. Lab. Invest . 57: 564-577.
64.
Short BG and Goldstein RS (1992). Non-neoplastic lesions in the kidney. In: Pathobiology of the Aging Rat, Vol. I, U Mohr, DL Dungworth, and CC Capen (eds). ILSI Press, Washington, DC, pp. 211-226.
65.
Snedecor GW and Cochran WG (1989). Statistical Methods, 8th ed. Iowa State University Press, Ames, IA.
66.
Snyder SL, Pollard M., Wostmann BS, and Luckert P. (1990). Life span, morphology, and pathology of diet-restricted germ-free and conventional Lobund-Wistar rats. J. Gerontol . 45: B52-58.
67.
Stadtman ER (1992). Protein oxidation and aging. Science257: 1220-1224.
68.
Stefaneann L. and Kovacs K. (1994). Changes in structure and function of the pituitary . In: Pathobiology of the Aging Rat, Vol. II, U Mohr, DL Dungworth , and CC Capen (eds). ILSI Press, Washington, DC, pp. 173-191.
69.
Tanaka K., Smith PF, Stromberg PC, Eydelloth RS, Herold EG, Grossman SJ, Frank JD, Hertzog PR, Soper KA, and Keenan KP (1992). Studies of early hepatocellular proliferation and peroxisomal prolif eration in Sprague-Dawley rats treated with tumorigenic doses of clofibrate. Toxicol. Appl. Pharmacol. 116: 71-77.
70.
Tapp DC, Wortham WG, Addison JF, Hammonds DN, Barnes JL, and Venkatachalam MA (1989). Food restriction retards body growth and prevents end-stage renal pathology in remnant kidneys of rats regardless of protein intake. Lab. Invest. 60: 184-185.
71.
van Goor H. , Fidler V., Weening JJ, and Grond J. (1991). Determinants of focal and segmental glomerulosclaerosis in the rat after renal ablation. Evidence for involvement of macrophages and lipids. Lab. Invest. 64: 754-765.
72.
Weindruch R. and Walford RL (1988). The Retardation of Aging and Disease by Dietary Restriction. Charles C Thomas, Springfield, IL.
73.
Yu BP (ed) (1993). Free Radicals in Aging. CRC Press, Boca Raton, FL.
74.
Yu BP, Laganiere S., and Kim JW (1989). Influence of life-prolonging food restriction on membrane lipoperoxidation and antioxidant status In: Oxygen Radicals in Biology and Medicine, MG Simic , KA Taylor, JF Ward, and C von Sonntag (eds). Plenum, New York, pp. 1067-1073.
75.
Yoshida Y., Fogo A., and Ichikawa I. (1989). Glomerular hemodynamic changes vs. hypertrophy in experimental glomerular sclerosis. Kidney Int. 35: 654-660.
76.
Yoshida Y., Kawamura T., Ikoma M., Fogo A., and Ichikawa I. (1989). Effects of antihypertensive drugs on glomerular morphology. Kidney Int. 36: 626-635.
77.
Yoshioka T. , Shiraga H., Yoshida Y., Fogo A., Glick AD, Deen WM, Hoyer JR, and Ichikawa T. (1988). "Intact nephrons" as the primary origin of proteinuria in chronic renal disease. Study in the rat model of subtotal nephrectomy. J. Clin. Invest. 82: 1614-1623.
