genes known to be involved in DNA repair is altered under conditions of caloric restriction. Several agents reported to have anti-aging properties have been shown to attenuate constitutive level of mTOR signaling, an evidence of reduction of metabolic activity, and concurrently to reduce constitutive level of DNA damage induced by endogenously generated reactive oxygen species. For example, increasing the gene dosage of the gene SIR-2, which regulates DNA packaging in the nematode worm Caenorhabditis elegans, can significantly extend lifespan. The mammalian homolog of SIR-2 is known to induce downstream DNA repair factors involved in NHEJ, an activity that is especially promoted under conditions of caloric restriction. Caloric restriction has been closely linked to the rate of base excision repair in the nuclear DNA of rodents, although similar effects have not been observed in mitochondrial DNA. The C. elegans gene AGE-1, an upstream effector of DNA repair pathways, confers dramatically extended life span under free-feeding conditions but leads to a decrease in reproductive fitness under conditions of caloric restriction. This observation supports the pleiotropy theory of the biological origins of aging, which suggests that genes conferring a large survival advantage early in life will be selected for even if they carry a corresponding disadvantage late in life. Medicine and DNA repair modulation Hereditary DNA repair disorders Defects in the NER mechanism are responsible for several genetic disorders, including: Xeroderma pigmentosum: hypersensitivity to sunlight/UV, resulting in increased skin cancer incidence and premature aging Cockayne syndrome: hypersensitivity to UV and chemical agents Trichothiodystrophy: sensitive skin, brittle hair and nails Mental retardation often accompanies the latter two disorders, suggesting increased vulnerability of developmental neurons. Other DNA repair disorders include: Werner's syndrome: premature aging and retarded growth Bloom's syndrome: sunlight hypersensitivity, high incidence of malignancies (especially leukemias). Ataxia telangiectasia: sensitivity to ionizing radiation and some chemical agents All of the above diseases are often called "segmental progerias" ("accelerated aging diseases") because those affected appear elderly and experience aging-related diseases at an abnormally young age, while not manifesting all the symptoms of old age. Other diseases associated with reduced DNA repair function include Fanconi anemia, hereditary breast cancer and hereditary colon cancer. Cancer Because of inherent limitations in the DNA repair mechanisms, if humans lived long enough, they would all eventually develop cancer. There are at least 34 Inherited human DNA repair gene mutations that increase cancer risk. Many of these mutations cause DNA repair to