Diet, cancer and aging in DNA mismatch repair deficient mice.
Diet is an important risk factor for many cancers. High fat/low calcium (HFLC) diets are associated with increased tumorigenesis, whereas caloric restriction (CR) reproducibly increases lifespan and decreases tumors. Mutations are involved in aging and cancer, and different diets may alter mutagenesis. However, a number of repair pathways normally counteract mutations by correcting errors before they can be fixed in the genome. To further understand interactions between diet, aging and cancer, mice deficient in a major repair pathway called DNA mismatch repair (MMR) were fed HFLC, CR or control diets. Mlh1 deficient mice are prone to lymphomas and intestinal adenomas and carcinomas. No significant changes in adenocarcinoma or lymphoma incidence were observed with HFLC or CR diets. Significantly more (2.2-fold) adenomas occurred with HFLC diets although adenoma numbers were unchanged with CR. Only a small increase in lifespan (116% of control) was achieved with CR. In addition, levels of microsatellite mutations in the small and large intestines were unchanged with the different diets. Our studies indicate that MMR deficiency may be epistatic to certain otherwise strong environmental influences on carcinogenesis or aging.
Tsao
Jen-Lan
JL
Department of Pathology, Molecular Biology and Surgery, Norris Cancer Center, University of Southern California School of Medicine, Los Angeles, CA 90033, USA.
Dudley
Sandra
S
Kwok
Brian
B
Nickel
Andrea E
AE
Laird
Peter W
PW
Siegmund
Kimberly D
KD
Liskay
R Michael
RM
Shibata
Darryl
D
D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics / Q000517:prevention & control; D000236:Adenoma / Q000209:etiology / Q000235:genetics / Q000517:prevention & control; D000375:Aging / Q000235:genetics*; D000821:Animal Feed / Q000032:analysis; D000818:Animals; D020137:Base Pair Mismatch; D002136:Calcium, Dietary / Q000008:administration & dosage; D002352:Carrier Proteins; D004260:DNA Repair; D004032:Diet; D004038:Diet, Reducing; D004041:Dietary Fats / Q000008:administration & dosage / Q000633:toxicity; D002149:Energy Intake; D007414:Intestinal Neoplasms / Q000209:etiology / Q000235:genetics / Q000517:prevention & control; D008136:Longevity; D008223:Lymphoma / Q000209:etiology / Q000235:genetics / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D009374:Neoplasms, Experimental / Q000209:etiology / Q000235:genetics* / Q000517:prevention & control; D009687:Nuclear Proteins
D048868:Adaptor Proteins, Signal Transducing; D002136:Calcium, Dietary; D002352:Carrier Proteins; D004041:Dietary Fats; C501485:Mlh1 protein, mouse; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1