Longevity, Body Weight, and Neoplasia in Ad Libitum-Fed and Diet-Restricted C57BL6 Mice Fed NIH-31 Open Formula Diet

Abstract

Groups of C57BL6 mice of each sex were assigned to one of 2 dietary regimens, ad libitum (AL) or dietary restriction (DR), to study effects of food restriction on body weight, survival, and neoplasia. The AL and DR groups were subdivided into a scheduled sacrifice group for examination at 6-mo intervals, and a lifetime group to provide longevity data. Necropsies and microscopic examinations were conducted on 911 animals. In the lifetime group food consumption averaged 33.6 and 34.4 g per week by AL males and AL females, respectively; the DR counterparts were given 40% less. The diet contained 4.35 kcal/g. The average lifetime body weights were 34.8, 26.8, 22.6, and 21.6 g for AL males, AL females, DR males, and DR females, respectively, and their age at 50% survival was 27.5, 26.9, 31.7, and 33.5 mo. Maximal lifespan was increased 18% in DR males and females. Lifetime incidence of tumor-bearing mice was 89% and 86% for AL males and females, versus 64% for each sex of DR mice. Dramatic reduction occurred in female DR mice in lymphoma (9% vs 29%), pituitary neoplasms (1% vs 37%), and thyroid neoplasms (0.4% vs 8%). In males, hepatocellular tumors were reduced to 1% from 10% by DR. In contrast, the incidence of histiocytic sarcoma was increased in DR females and unaffected in DR males. Tumor onset was delayed in DR animals; 87% of all neoplasms in males and 95% in females had occurred in the AL mice by 24 mo, whereas the DR animals had only 52% and 39% of their lifetime incidence, respectively, by that age. This study provided comparative AL and DR data from C57BL6 mice examined randomly at 6-mo intervals (cross-sectional group) in parallel with data from animals in similar cohort that was unsampled and allowed to succumb naturally (longevity group). Dietary restriction reduced the lifetime percentage of tumor-bearing animals and the number of tumors per animal, and delayed the age at onset of most neoplasms.

Suppression of thymic lymphomas and increased nonthymic lymphomagenesis in Trp53‐deficient mice lacking inducible nitric oxide synthase gene

“…All of the Trp53 and iNOS mutant mice used in our study had the same background (C57BL/6/129Sv), and we maintained them with C57BL/6, leading to the high incidence of lymphomas since the C57BL/6 strain is highly prone to spontaneous lymphomas. 30 Our study confirmed previous findings showing constitutive expression of iNOS in dendritic cells of the thymus in both Trp53 wild-type and -deficient mice. We also demonstrated increased iNOS expression in dendritic cells and macrophages of the thymus of Trp53-deficient mice.…”

Reduced in vivo hepatic proteome replacement rates but not cell proliferation rates predict maximum lifespan extension in mice

“…The degree of hepatic protein RR reduction was smallest in response to 14 ppm Rapa treatment, which is established to extend maxLS by 12%, and greatest in Snell Dwarf mice, which live 40% longer than their Het/WT counterparts, while hepatic protein RRs were reduced to an intermediate level in response to 40% CR, which extends maxLS by 18% (Fig. 4) (Blackwell et al ., 1995; Flurkey et al ., 2002; Harrison et al ., 2009; Miller et al ., 2011, 2013). These data suggest that a reduction in hepatic protein RRs may be an early BM not only qualitatively of maxLS extension but also quantitatively of the degree of maxLS extension in mice.…”

Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake

“…The only environmental variable that has been shown to markedly affect the rate of aging in a wide range of species is caloric intake: Restricting food intake to a level below that which would be consumed voluntarily results in a decrease in the rate of aging and an increase in average and maximum life span (1,2). Dietary restriction (DR) reduces cancer formation (3,4) and kidney disease (5) and increases the resistance of neurons to dysfunction and degeneration in experimental models of Alzheimer's and Parkinson's diseases as well as stroke (6)(7)(8)(9). Two different DR paradigms have proven effective in increasing life span and disease resistance in rats and mice.…”