Special issue on DNA Aging: exploring the links between DNA damage and repair, organismal aging and aging-related disease
Long life and youth are among the oldest human dreams, and they have long inspired scientific research. Many theories of aging have been postulated, some of which sound strange to modern ears. For example, Elie Metchnikoff, who shared the Nobel prize with Paul Ehrlich in 1908, claimed that aging is caused by ‘intestinal putrefaction’ and suggested yogurt as an antidote (1). Although yogurt continues to enjoy a reputation as a health food, Metchnikoff's theory of aging has, itself, not aged well.
The prevailing modern view of aging is that it is caused by stochastic damage to cells and molecules, particularly as the result of oxidative damage (2). Genetically determined prevention and repair systems counteract this wear and tear, resulting in ‘successful aging’, defined as the longest possible unimpaired life span. These prevention and repair systems interact with each other and with systems regulating growth and development of the whole organism. A surprising recent example of such an interaction is the link between inter-strand cross-link repair pathways and the growth hormone–insulin-like growth factor signaling axis (3), which provides a mechanism whereby elevated damage might directly influence organismal growth.
Damage and repair occur at many levels. On the organismal level, the immune system plays an important role in removing damaging pathogens and other stressors. Age-related dysfunction in immune cells not only leads to lowered defense but also to damage by itself, a phenomenon termed ‘inflamm-aging’ (4). At the level of tissues and organs, stem and progenitor cells provide the capacity for repair and regeneration, which diminishes with age (5). At the levels of molecules and cells, damaged proteins, lipids, carbohydrates, and nucleic acids must be removed or, in the case of DNA and some kinds of protein damage, repaired. The efficiency of molecular repair systems may decline with age as well.
Repair of DNA damage appears to be crucial for the survival of all organisms. DNA is the essential information-storing molecule in cells, and it is the only constituent that is not turned over as a whole during the cellular life span. But is DNA really as stable, however, as this fact suggests? Estimates are that 10 000 to 100 000 damage events occur per human cell per day in vivo (6). Thus, the genome might resemble one of those magnificent Italian churches that, whenever we visit, is under restoration and reconstruction. To carry the analogy further, the order to demolish the church (or demolish the genome through apoptotic fragmentation) is given only if repair fails and its overall condition poses a major threat to visitors and neighbors.
This issue of Nucleic Acids Research contains a special collection of Surveys and Summaries, ‘DNA Aging’. The collection explores the idea that an age-dependent increase in DNA damage, accompanied by age-related decline in repair capacity, contributes to functional decline of cells, tissues and organisms and the pathogenesis of age-associated diseases. Some of the Survey and Summary articles deal specifically with the relationship between DNA aging and human diseases, including the impact of DNA damage repair on adult stem cells (7), the occurrence of oxidative DNA damage in mild cognitive impairment and Alzheimer's disease (8) and the occurrence of single-gene defects leading to human premature aging syndromes (9,10). Another article discusses yeast as a model system for investigating DNA aging (11). Proposed roles of PARP-1 in limiting DNA aging (12) and DNA inter-strand cross-linking in promoting aging are discussed (13). Several articles discuss or propose specific molecular hypotheses connecting DNA aging and organismal aging. These include how damage accumulates in the mitochondrial genome (14), a connection between DNA damage in mitochondria and telomeres (15), a theory that DNA replication stress is a main cause of DNA aging (16), a dual role of p53 in tumor suppression and aging (17), a connection between caloric reduction and delayed aging (18), changes in DNA repair capacity during aging (19), and a connection between DNA damage, cellular senescence and DNA aging (20). We hope that our readers will agree that, together, the articles in this collection form an exciting introduction to the links between DNA damage and repair, organismal aging and aging-related disease.
References
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