Caloric restriction promotes genomic stability by induction of base excision repair and reversal of its age-related decline.
Caloric restriction is a potent experimental manipulation that extends mean and maximum life span and delays the onset and progression of tumors in laboratory rodents. While caloric restriction (CR) clearly protects the genome from deleterious damage, the mechanism by which genomic stability is achieved remains unclear. We provide evidence that CR promotes genomic stability by increasing DNA repair capacity, specifically base excision repair (BER). CR completely reverses the age-related decline in BER capacity (P<0.01) in all tissues tested (brain, liver, spleen and testes) providing aged, CR animals with the BER phenotype of young, ad libitum-fed animals. This CR-induced reversal of the aged BER phenotype is accompanied by a reversal in the age-related decline in DNA polymerase beta (beta-pol), a rate-limiting enzyme in the BER pathway. CR significantly reversed the age-related loss of beta-pol protein levels (P<0.01), mRNA levels (P<0.01) and enzyme activity (P<0.01) in all tissues tested. Additionally, in young (4-6-month-old) CR animals a significant up-regulation in BER capacity, beta-pol protein and beta-pol mRNA is observed (P<0.01), demonstrating an early effect of CR that may provide insight in distinguishing the anti-tumor from the anti-aging effects of CR. This up-regulation in BER by caloric restriction in young animals corresponds to increased protection from carcinogen exposure, as mutation frequency is significantly reduced in CR animals exposed to either DMS or 2-nitropropane (2-NP) (P<0.01). Overall the data suggest an important biological consequence of moderate BER up-regulation and provides support for the hormesis theory of caloric restriction.
Cabelof
Diane C
DC
Department of Nutrition and Food Science, Wayne State University, 3009 Science Hall, Detroit, MI 48202, USA.
Yanamadala
Sunitha
S
Raffoul
Julian J
JJ
Guo
ZhongMao
Z
Soofi
Abdulsalam
A
Heydari
Ahmad R
AR
D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D031204:Caloric Restriction; D004247:DNA / Q000187:drug effects; D019951:DNA Polymerase beta / Q000378:metabolism; D004260:DNA Repair / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009153:Mutagens / Q000494:pharmacology; D009154:Mutation; D009595:Nitroparaffins / Q000494:pharmacology; D011407:Propane / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013463:Sulfuric Acid Esters / Q000494:pharmacology; D015854:Up-Regulation
D009153:Mutagens; D009595:Nitroparaffins; D013463:Sulfuric Acid Esters; D004247:DNA; D019951:DNA Polymerase beta; C016617:2-nitropropane; C007482:dimethyl sulfate; D011407:Propane