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Diet, Overfeeding, and Moderate Dietary Restriction in Control Sprague-Dawley Rats: II. Effects on Age-Related Proliferative and Degenerative Lesions
Kevin P. Keenan
Department of Safety Assessment, Merck Research Laboratories
Keith A. Soper
Department of Biometrics, Merck Research Laboratories, West Point, Pennsylvania 19486
Phillip R. Hertzog
Department of Safety Assessment, Merck Research Laboratories
Laura A. Gumprecht
Department of Safety Assessment, Merck Research Laboratories, Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Illinois, Urbana, Illinois 61801
Peter F. Smith
Department of Safety Assessment, Merck Research Laboratories, Searle Laboratories, Skokie, Illinois 60077
Britta A. Mattson
Department of Safety Assessment, Merck Research Laboratories
Gordon C. Ballam
Purina Mills, Inc., St. Louis, Missouri
Robert L. Clark
Department of Safety Assessment, Merck Research Laboratories, Rhone-Poulenc Rorer Central Research, Collegeville, Pennsylvania 19426
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.
Key Words: Caloric restriction • degenerative disease • nephropathy • cardiomyopathy • aging • reproductive senescence
Toxicologic Pathology, Vol. 23, No. 3,
287-302 (1995)
DOI: 10.1177/019262339502300306
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