Pharmacologic manipulation of the ataxia-telangiectasia mutated gene product as an intervention in age-related disease.
Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by progressive ataxia, elevated cancer incidence, and premature aging. A-T cells, Atm-deficient mice, and individuals with A-T show increased oxidant sensitivity, genomic instability, altered IGF-1 and p53 signaling, and rapid telomere shortening compared to normal controls. The gene mutated in A-T, ATM, regulates DNA repair, IGF-1 and p53 signaling, age pigment removal, antioxidant capacity, and telomere maintenance - pathways involved in and often attenuated with aging. Interestingly, flavonoids with chemopreventative effects, such as quercetin, genistein, and epigallocatechin gallate activate ATM. Since ATM activates pathways which increase genomic stability, oxidant resistance, and/or telomere stability, and since many diseases of old age (i.e., cancer, cardiovascular and neurodegenerative disease), result from attenuation of these pathways, pharmacologic manipulation of ATM activity via flavonoid intake may prove useful in slowing the appearance of age-associated disease.
Shackelford
Rodney E
RE
Lousiana State University at Shreveport, Department of Pathology, 1501 Kings Hwy, PO Box 33932, Shreveport, LA 711030-3932, USA. rdnyshac@aol.com
D000375:Aging; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D008962:Models, Theoretical; D009154:Mutation; D016877:Oxidants / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011794:Quercetin / Q000494:pharmacology; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D000975:Antioxidants; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D016877:Oxidants; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D007334:Insulin-Like Growth Factor I; D002392:Catechin; D011794:Quercetin; C045651:epigallocatechin gallate; D019833:Genistein; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases