The integrity of the genome and the faithful transmission of the genetic material it contains to the next generation are important for survival of species. Similarly, the integrity of genomic and mitochondrial DNA and the transmission of the information they contain are important for the survival of individuals. DNA damage in the form of mutations or genomic instability result from genotoxic stress caused by exposure to toxic agents, including the sun’s ultraviolet rays, background ionizing radiation, chemicals in food and the environment, and highly reactive molecules produced within cells during metabolism. Similar types of DNA damage occur in response to various agents and include mutations, removal of bases and nucleotides, formation of dimers, strand breaks, cross-links, and chromosomal aberrations. Some of these types of damage accumulate in nuclear or mitochondrial DNA during aging (e.g., point mutations, single-strand breaks, DNA cross-links, additions/deletions, oxidative damage, and methylated bases). In a chapter in Hormones and Aging (1995), Suresh Rattan reviews DNA damage and repair and the evidence for genomic instability, loss of cell proliferation, production of altered proteins, and altered cellular responsiveness as a result of damage to DNA in cells and genes during aging. The ability to repair DNA damage may be related to length of the life span, since humans repair DNA faster than mice, but is not always related to maximum life span because premature aging is not always associated with a reduced capacity to repair DNA. Although there is little evidence to suggest an overall decline in the capacity of cells to repair DNA during aging, thus far only a few DNA repair pathways have been studied in any detail.
The sensitivity of cells to genotoxic stress increases during aging. Age-related deficits in protein synthesis and the responsiveness of cells to stress, decreased cell-cell communication, and inefficient signal transduction may render old cells less able to withstand stress. The ability to repair DNA may be compromised by other toxic agents, leading to loss of function in molecules and cells and shortening of life span. A decrease in the ability to repair genomic DNA may lead to increased incidence of cancer in elderly persons. Similarly, mitochondrial DNA damage and mutations increase with aging, as does susceptibility to age-related diseases such as diabetes, Parkinson’s, and Alzheimer’s disease. In 2000, Jay Robbins and colleagues at the National Cancer Institute and a European group independently established a link between faulty DNA repair caused by defects in nucleotide excision repair and neurodegeneration, a link that was proposed by Robbins twenty-five years previously. Some patients with xeroderma pigmentosum show, in addition to greatly exaggerated risks of skin cancer, premature neuron death and DNA lesions similar to those in Alzheimer’s disease. Although cancer susceptibility and neuron death can both result from defects in DNA repair, the precise mechanisms may differ. Mouse models that are deficient in nucleotide excision repair also show increased incidence of tumors in response to genotoxic stress and a decreased life span, but they have reduced neurological deficits compared with human syndromes. These mice are being used to understand the involvement of DNA repair in genotoxic sensitivity and cancer susceptibility and in the process of aging.
Studies pioneered by Richard Setlow in the 1970s showed a correlation between DNA repair and species life span, but were largely based on crude measures of DNA repair. In 1998, using improved techniques that allowed specific genes to be assessed, Arlan Richardson’s group in San Antonio, Texas, demonstrated that nucleotide excision repair of DNA in liver cells from old rats challenged with UV irradiation depended on whether the strand was actively transcribed or silent. The rate of repair of the transcribed strand of albumin DNA (transcription-coupled repair) was 40 percent less compared with young rats, but the extent of repair was not different at the end of the experiment. This was in contrast to the extent of repair of the silent strand, which was 40 percent less in old rats compared with young rats. Thus accumulation of DNA damage and mutations during aging may occur in nontranscribed regions of the genome. Richardson’s studies also showed that both age-related deficits in DNA repair could be reversed by caloric restriction, which retards aging by increasing life span and reducing or delaying many of the diseases associated with aging.
Beginning in the 1990s, modern approaches to screening for changes in the expression of genes and proteins have fueled searches for cellular responses to genotoxic stresses, which may hold clues for understanding the process of aging. Hundreds of genes are induced in mammalian cells, most of which represent general responses to cell injury (e.g., induction of the immediate early genes, c-fos and c-jun). Many DNA-damaging agents and their activated signaling pathways converge on the transcription factor p53, which functions as a sensor for DNA damage and regulates the transcription of hundreds of genes. However, changes in a few critical genes, such as those involved in DNA repair or information transfer, may underlie genomic instability during aging. Candidates are poly(ADP-ribose polymerases, or PARPs, a family of nuclear enzymes, some of which bind nicked DNA and guard the genome by regulating DNA repair and cell death. The activity of PARPs in white blood cells from thirteen mammalian species correlates with life span, yet knockout of the PARP-1 gene confers resistance to stroke and diabetes. Other candidates are helicases (DNA unwinding enzymes) or their associated proteins. Helicases are involved in DNA repair and regulation of transcription, and are mutated in premature aging syndromes. Overlapping aging phenotypes in some helicase disorders and normal aging implicate common pathways, especially transcriptional regulation. Further studies of PARPs and helicase enzymes and their functions during aging could establish a stronger link with cellular or organismal aging. Mouse models that are deficient in nucleotide excision repair also show increased incidence of tumors in response to genotoxic stress and a decreased life span, although they have reduced neurological deficits compared with human syndromes. These mice are being used to understand the involvement of DNA repair in genotoxic sensitivity and cancer susceptibility, and in the process of aging.