Cancer and Aging as Consequences of Un-Repaired DNA Damage (pp. 1-47)
Authors: (Harris Bernstein, Departments of Cell Biology and Anatomy, Arizona Cancer Center, College of Medicine, University of Arizona, Claire M. Payne, Departments of Cell Biology and Anatomy, Internal Medicine, Arizona Cancer Center, College of Medicine, University of Arizona, Carol Bernstein, Departments of Cell Biology and Anatomy, Section of Hematology/Oncology, Southern Arizona Veterans Affairs Health Care System, Tucson, Arizona, USA)
Abstract: Cancer and aging appear to be consequences of DNA damage, a pervasive,
fundamental problem for living organisms. Un-repaired DNA damages in dividing cells
can cause errors during DNA synthesis leading to mutation and ultimately to cancer.
Furthermore, un-repaired DNA damages, especially in non- or infrequently dividing
cells, can accumulate and cause progressive blockage of transcription, loss of gene
expression capability and ultimately aging at the cellular, tissue and organ level. With
respect to cancer, the likely sources of DNA damage causing the most frequent deadly
cancers are reviewed, and it is concluded that, in general, reactive oxygen species
reactions with DNA, and DNA-adduct forming molecule reactions, are the chief sources
of damage. Approximately 30 inherited genetic defects in humans have been identified
that cause reduced DNA repair. In general, these genetic defects are associated with
increased cancer risk, indicating that increased DNA damage is causally related to
cancer. Furthermore, evidence indicates that after formation of a mutation that provides a
growth or survival advantage to a cell, the succeeding steps of progression to cancer
likely involve natural selection and formation of a pre-malignant defective field of cells,
a “field defect”. With respect to aging, evidence is reviewed that DNA damages,
particularly oxidative DNA damages, accumulate with age in the brain (29 studies) and
muscle (18 studies), as well as in liver, kidney and hematopoietic stem cells. This
accumulation is associated with a decline in expression of genes associated with the
aging process. A calorie-restricted diet is known to increase lifespan in mammals and is
also associated with decreased oxidative DNA damage. Inherited syndromes such as
Werner syndrome, Hutchinson-Guilford progeria, and Cockayne syndrome are due to
reduced DNA repair capability and are also associated with early aging, indicating that
increased DNA damage is causally related to aging. The principal source of DNA
damages leading to normal aging appears to be reactive oxygen species produced as
byproducts of cellular respiration.
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