Sci. Aging Knowl. Environ., 10 September 2003
Vol. 2003, Issue 36, p. as2
[DOI: 10.1126/sageke.2003.36.as2]

EXPERIMENTAL RODENT STRAINS

F344 Rat

Donna J. Holmes

The author is in the Department of Biological Sciences, University of Idaho, Moscow, ID 83844, USA. E-mail: electric{at}uidaho.edu

http://sageke.sciencemag.org/cgi/content/full/sageke;2003/36/as2

Key Words: F344 rat • caloric restriction • inbred mouse strain • mortality • pathologies of aging

Abstract: This document contains a summary of the biological characteristics of the F344 rat. This strain, including calorically restricted individuals, is available from the National Institute on Aging.


Strain Fischer 344 (F344). Inbred laboratory strain.
Species and taxonomy Norway rat, Rattus norvegicus. Order Rodentia; family Muridae (Old World rats and mice)
Source This strain, including calorically restricted individuals, is available from the National Institute on Aging (NIA) of the National Institutes of Health (NIH). For more information, go to http://www.nia.nih.gov/research/rodent.htm or contact Nancy Nadon at NadonN{at}nia.nih.gov.
Phenotype Albino. Lacks the brownish scales on skin of the back, genital region, and tail that characterize some other rat strains. F344 rats are larger than Brown Norways (see general comments below).
History and genetic background This strain originated at the Columbia University Institute for Cancer Research in 1920 and was procured by NIH in 1951. For additional information on strain history and inbred rat strains in general, see Festing 1998.

General comments. Considered by many to be the "standard" laboratory rat strain, this is by far the most popular inbred rat for general research use, especially for aging, cancer, and toxicology studies. Weindruch and Masoro (1991) noted that F344 rats were subjects of over half (54%) of the studies published in the Journal of Gerontology from 1985 through 1990. They also suggested that this strain has been overused and emphasized the need for a greater variety of rodent genotypes in aging studies.

F344 rats are known for good reproductive performance, big litters, and low levels of aggression toward handlers. In the NIH/Biomarkers of Aging Program (BAP) study, body weights of F344 rats averaged about 445 g (both sexes combined), which is about 17 percent higher than weights of Brown Norway rats. Both sexes reach their peak body weight by 24 to 27 months of age, with the weights of mature females being between 50 and 75% of male weights.

Caveats for researchers in the field of aging. Inbred rat strains vary considerably in terms of their longevities and aging patterns, as well as in the incidence and frequency of pathologies of aging. Life span and the incidence of tumors and other aging-related pathologies vary substantially within the F344 strain, as well as between F344 and other rat strains, as may responses to aging-related experimental manipulations such as caloric restriction (see below for a more detailed discussion of common pathologies). Researchers using F344 rats in aging-related studies should note that this strain has been shown to be especially prone to nephropathy (kidney pathology) and, at advanced ages, renal failure, as well as interstitial (Leydig) cell tumors in the testis, leukemia, and pituitary adenomas (Weindruch and Masoro 1991). The susceptibility to renal disease is reliably influenced by dietary factors, particularly total caloric intake and the protein source used in semi-synthetic laboratory rodent feed. When soy protein is used rather than casein or lactalbumin, far fewer rats (approximately 30%, versus almost 50%) had kidney pathologies, even by 27 months of age (see, for example, Iwasaki et al. 1988). Caloric restriction to 60% of ad lib food intake nearly eliminates the occurrence of nephropathy, even when casein is the protein component (Masoro et al. 1989). Caloric restriction also reduces the incidence of neoplastic lesions. These effects should be carefully considered when selecting F344 rats for studies of aging.

Rat strains also differ with respect to hypothalamic-pituitary-adrenal sensitivity and activation. For example, F344 rats have been shown to exhibit higher levels of diurnal and stress-induced corticosteroids than LEW or Sprague-Dawley rats. Hippocampal neurons are more susceptible to ischemic injury in F344s than in other strains. Some aspects of behavioral performance decline faster with aging in F344 than in Brown Norway or other rat strains.

Low rates of wheel-running activity in general have been documented in F344 females relative to other strains. In addition, F344s have been noted to lack the preference for salt that is typical of other rats, and they are resistant to sodium-induced hypertension. Susceptibilities to other aging-related and experimentally induced diseases are outlined in Festing 1998 and Lipman et al. 1999.

RESULTS OF MAJOR AGING STUDIES USING F344 RATS

The following results are from the life span study by BAP, NIA, Bethesda, MD, and the National Center for Toxicological Research (NCTR), Food and Drug Administration (FDA), Jefferson, AR (Turturro et al. 1999). Longevity statistics were calculated from data provided by NCTR (courtesy of Angelo Turturro, NCTR, FDA, Jefferson, AR).

Methodology (key aspects). BAP study: lifetime (up to 37 months) comparison of ad lib-fed (AL) controls with 40% calorie-restricted (CR) rats. Three rat strains (F344, BN, and BNF3F1 hybrids) and four mouse strains (C57BI/6NNia; D2 [DBA/2JNia]; B6D2F1; and C3H [B6C3F1] hybrids) were included in the study. All were maintained in a specific pathogen-free barrier facility. F344 rats were fed NIH-31 open-formula diet; CRs were fed a calorie-reduced, vitamin-supplemented version of NIH-31. Caloric restriction was initiated stepwise at 6 to 14 weeks of age and was increased over several weeks to 40%. (For experimental details, see Turturro et al. 1999.)

Statistical sample sizes (for entire life span study; F344 rats only). Longevity statistics were calculated for 55 ad lib-fed females (AL-F), 53 CR females (CR-F), 50 ad lib-fed males (AL-M), and 53 calorie-restricted males (CR-M).

Maximum life span in days. AL-F, 1072 (35.73 months); CR-F, 1292 (43.07 months); AL-M, 896 (29.87 months); CR-M, 1222 (40.73 months).

Mean life span (with coefficient of variation) in days. AL-F, 825.85 (27.52 months) ± 15.46; CR-F, 920.09 (30.67 months) ± 8.83; AL-M, 721.00 (24.03 months) ± 13.69; CR-M, 875.6 (29.13 months) ± 16.69.

Median life span (days). AL-F, 813.5; CR-F, 923; AL-M, 718; CR-M, 875.

Time until 80% mortality (days). AL-F, 985; CR-F, 1038; AL-M, 827; CR-M, 986.

Pathology study parameters. Data are from the BAP caloric restriction study as described above, but from individual rats other than those used to generate life span data (see Lipman et al. 1999 for the published report on pathology; this report includes F344, BN, and BNF3F1 hybrid rats only). Rats were killed at ages 12, 18, 24, 30, and 36 months, when sample sizes in the oldest groups allowed. The initial experimental groups had 30 animals in each (age x sex x diet) treatment group, and animals were shipped live by NCTR to Jean Mayer, U.S. Department of Agriculture, Human Nutrition Research Center on Aging, Tufts University, Boston, MA, where they were killed and necropsied. The organs were then fixed, and histopathological analysis was performed. (The numbers of animals necropsied in each experimental group are shown below.) The average number of lesions per rat was analyzed by strain, sex, and diet group. Lesion prevalence in each strain was analyzed for 24- and 30-month-old groups only. Only the most prevalent or reliably age-associated lesions are included here, especially those likely to be proliferative or degenerative with age.

Most frequent lesions for F344 rat strain (total n = 436 rats; both sexes and all diet groups combined). Lesions are given in descending order of frequency, and the number of cases is shown in parentheses.

Lymphoid nodule in lung* (245)

Focal mineralization in kidney* (205)

Abnormal formation of fibrous tissue in heart* (146)

Retinal degeneration (125)

Bile duct hyperplasia (107)

Leydig cell hyperplasia in testis (78)

Glomerulonephropathy* (65)

Leydig cell tumor in testis (adenoma)* (60)

Hyperplasia in C cells of thyroid* (57)

Protein casts in renal tubules* (56)

[*Indicates lesions that were also among the five most prevalent types (listed below) in either sex at 24 and 30 months.]

Most common proliferative and degenerative lesions in older age groups (by sex and diet group, expressed as percentages). Abbreviations for experimental groups are the same as used above. Percentages are shown in parentheses.

AL-F (24 and 30 months combined) (n = 59): Mineralization of kidney (61.0); fibrosis of heart (52.5); protein casts in kidney (40.7); lymphoid nodule in lung (33.9); C cell hyperplasia in thyroid (28.8); Harderian (exorbital) gland hyperplasia (percent not available).

AL-M (24 and 30 months combined) (n = 62): Glomerulonephropathy (56.5); fibrosis of heart (51.6); Leydig cell adenoma (testis) (48.4); bile duct hyperplasia (43.5); leukemia (32.3).

Lesions with frequencies reliably reduced by caloric restriction in rats <=30 months (that is, significantly associated either with diet group or age x diet group interaction, as determined by log odds-ratio linear regression analysis). Only lesions with P <= 0.005 are included. Symbols and abbreviations are as follows: P indicates the level of statistical significance. {beta} is equal to the y intercept of the regression line. Positive {beta} indicates greater prevalence in CR animals; negative {beta} indicates greater prevalence in AL animals. OR equals odds ratio; this can be used to estimate odds that an animal in a specific experimental group will have a lesion of interest. (See Lipman et al. 1999 for details.)

Harderian gland metaplasia. CR: P = 0.002, {beta} = -1.09, OR = 0.34.

Heart fibrosis (abnormal formation of fibrous tissue). CR: P = 0.001, {beta} = -1.86, OR = 0.16.

Bile duct hyperplasia. CR: P = 0.001, {beta} = -1.97, OR = 0.14.

Leukemia. CR: P = 0.001, {beta} = -1.64, OR = 0.20.

Pancreatic atrophy. CR: P = 0.001, {beta} = -1.76, OR = 0.17.

Cysts in stomach. CR: P = 0.005, {beta} = -1.25, OR = 0.29.

Leydig cell adenoma (testis). P = 0.001, {beta} = -2.27, OR = 0.10.

Thyroid C cell hyperplasia. P = 0.001, {beta} = -2.56, OR = 0.38.

Tracheal cysts. P = 0.001, {beta} = -2.60, OR = 0.08.

Focal cortical hyperplasia in adrenal gland. P = 0.001, {beta} = -0.96, OR = 0.10.

Focal cytoplasmic vacuolization in adrenal gland. P = 0.001, {beta} = -1.14, OR = 0.32.

Summary. In the entire study overall (all three rat strains combined), the total age-associated lesion burden was higher in AL than in CR diet groups at all ages, from 12 to 30 months (only CR animals were included at 36 months). The most common lesions increased in prevalence with age, and many were never seen in rats under 18 months (in F344 rats, the only exception to this was lymphoid nodules in the liver). Lesion prevalence differed significantly between the sexes, except for lung lymphoid nodules, pancreatic atrophy, retinal degeneration, thyroid C cell hyperplasia, and tracheal cysts, which were equally prevalent in both sexes in this strain. F344 females had the following lesions more often than did F344 males: Harderian gland metaplasia, stomach cysts, protein casts in the kidney, and mineral deposition and liver lymphoid nodules. More common in males were glomerulonephropathy, bile duct hyperplasia, leukemia, and necrosis in the liver. F344 rats are less prone to nine lesions commonly occurring in female BN or BNF3F1 hybrids, and 10 lesions also occur more often in males of these other two strains.

Lipman et al. (1999) also noted variation in age-related lesions within age groups and within each strain in the BAP study, despite the fact that all subjects within a strain were genetically identical and were reared under virtually identical and uniform conditions. This variability increased at older ages; declines in sample sizes with age, however, could account statistically for some of this increase. (For more details, see Lipman et al. 1999.)


September 10, 2003
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Citation: D. J. Holmes, F344 Rat. Sci. SAGE KE 2003 (36), as2 (2003).








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