DNA damage and ageing: new-age ideas for an age-old problem

Garinis, George A.; Horst, Gijsbertus T. J. van der; Vijg, Jan; Hoeijmakers, Jan H.J.

doi:10.1038/ncb1108-1241

Cited by 334 publications

(279 citation statements)

References 61 publications

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“…Results corroborating this view have been seen more recently in experiments on cells from humans (Morley et al 1982;Turner et al 1985;Ramsey et al 1995;Tucker et al 1999) and also in computed models of aging (Kirkwood and Proctor 2003). As originally suggested by Burnet (1973), the somatic mutation theory of aging implies that impaired fidelity of the DNA replication and repair system would result in premature aging, a hypothesis supported by a wealth of recent data showing associations of genetic defects in these systems with accelerated aging in both mice and men (Garinis et al 2008).…”

Section: Szilard's Assumptionssupporting

confidence: 60%

“…Major arguments in support of a causal relation between DNA damage and aging are the role of DNA as the primary informational biomolecule (Vijg 2000) and the fact that all other macromolecules that are subject to age-related damage (mostly proteins and lipids) are renewable, whereas any acquired error in DNA may have irreversible consequences (Garinis et al 2008). Some of the first experimental evidence for a causal relationship between somatic mutations and aging came from studies on mouse liver cells showing an inverse correlation of induced and spontaneous chromosome aberrations with life expectancy.…”

Section: Szilard's Assumptionsmentioning

confidence: 99%

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The Szilard Hypothesis on the Nature of Aging Revisited

et al. 2009

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This year marks the 50th anniversary of a nearly forgotten hypothesis on aging by Leo Szilard, best known for his pioneering work in nuclear physics, his participation in the Manhattan Project during World War II, his opposition to the nuclear arms race in the postwar era, and his pioneering ideas in biology. Given a specific set of assumptions, Szilard hypothesized that the major reason for the phenomenon of aging was aging hits, e.g., by ionizing radiation, to the gene-bearing chromosomes and presented a mathematical target-hit model enabling the calculation of the average and maximum life span of a species, as well as the influence of increased exposure to DNA-damaging factors on life expectancy. While many new findings have cast doubt on the specific features of the model, this was the first serious effort to posit accumulated genetic damage as a cause of senescence. Here, we review Szilard's assumptions in the light of current knowledge on aging and reassess his mathematical model in an attempt to reach a conclusion on the relevance of Szilard's aging hypothesis today.

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Section: Szilard's Assumptionssupporting

confidence: 60%

Section: Szilard's Assumptionsmentioning

confidence: 99%

The Szilard Hypothesis on the Nature of Aging Revisited

et al. 2009

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“…Steady state levels of oxidative lesions in the genome are known to be affected by age, metabolic activity, and organismal lifespan, as well as by exposure to exogenous oxidative stress [Adelman et al, 1988;Fraga et al, 1990;Cadet et al, 2002;Proteggente et al, 2002;Loft et al, 2012;De Luca et al, 2013]. In particular, an increase in spontaneous DNA damage in the aging animal has led to the hypothesis that accumulation of DNA damage and alterations in cellular response to genomic damage may be primary causes for aging [Hasty et al, 2003;Garinis et al, 2008;Maslov et al, 2013]. If left unrepaired, DNA damage can result in mutations generated during replication, cell death or senescence, or altered transcription of genes important to cellular function.…”

Section: Introductionmentioning

confidence: 99%

Oxidative DNA damage in disease—Insights gained from base excision repair glycosylase‐deficient mouse models

Sampath

2014

Environ and Mol Mutagen

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Cellular components, including nucleic acids, are subject to oxidative damage. If left unrepaired, this damage can lead to multiple adverse cellular outcomes, including increased mutagenesis and cell death. The major pathway for repair of oxidative base lesions is the base excision repair pathway, catalyzed by DNA glycosylases with overlapping but distinct substrate specificities. To understand the role of these glycosylases in the initiation and progression of disease, several transgenic mouse models have been generated to carry a targeted deletion or overexpression of one or more glycosylases. This review summarizes some of the major findings from transgenic animal models of altered DNA glycosylase expression, especially as they relate to pathologies ranging from metabolic disease and cancer to inflammation and neuronal health. Environ. Mol. Mutagen. 55:689-703, 2014. V C 2014 Wiley Periodicals, Inc.

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“…They show a characteristic gene expression pattern with suppression of the insulin-like signaling (ILS) and activation of oxidative stress response pathways. [43][44][45][46] The transcriptomic modulation in segmental progeroid NER mutants is believed to reflect a "survival response" 47,48 since suppression of ILS through caloric restriction is associated with lifespan extension. 49,50 Similarly, characterizing the transcriptomic signatures of C. elegans xpa-1 mutants has proved to be highly informative toward understanding how normal-or near-normal-phenotypes are maintained in the absence of effective DNA repair.…”

Section: Hormesis Maintains Wildtype Phenotypes In Dna Repair Mutantsmentioning

confidence: 99%

Active transcriptomic and proteomic reprogramming in theC. elegansnucleotide excision repair mutant xpa-1

Kassahun

Nilsen

2013

Worm

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O xidative stress promotes human aging and contributes to common neurodegenerative diseases. Endogenous DNA damage induced by oxidative stress is believed to be an important promoter of neurodegenerative diseases. Although a large amount of evidence correlates a reduced DNA repair capacity with aging and neurodegenerative disease, there is little direct evidence of causality. Moreover, the contribution of oxidative DNA damage to the aging process is poorly understood. We have used the nematode Caenorhabditis elegans to study the contribution of oxidative DNA damage and repair to aging. C. elegans is particularly well suited to tackle this problem because it has a minimum complexity DNA repair system, which enables us to circumvent the important limitation presented by the extensive redundancy of DNA repair enzymes in mammals. Oxidative DNA Damage and Aging in C. elegansThe free radical theory of aging is an example of a hypothesis that, because it intuitively makes sense, is attractive both to scientists and to the general public. The theory has been enormously influential and has inspired scientists to test its implications ever since its first formulation by Denham Harman. 1 As such it is a good theory because it suggests many testable hypotheses. However, few experiments have provided direct support of the original theory. This has led to the formulation of many offshoots like the mitochondrial theory of aging and the stochastic damage accumulation theory of aging.One prediction that can be made from all of these theories is that oxidative damage to cellular macromolecules contributes to the progressive loss of function associated with aging. As DNA, unlike other cellular macromolecules, cannot be replaced in its entirety, it seems logical that maintenance of genomic stability would promote longevity and limit functional loss during aging.A role for passive and stochastic accumulation of oxidative DNA damage in aging is often dismissed by scientists outside the DNA repair field for three principal reasons; first, even though levels of reactive oxygen species (ROS) increase with age 2,3 and DNA repair capacity diminishes with age, 4 it has been difficult to unequivocally show that oxidative DNA damage accumulates with age. Also, since a plethora of different types of DNA lesions are induced by ROS, it is not entirely clear which types of lesions are more relevant to the aging phenotype. Second, there is no good correlation between mutation accumulation and aging. [5][6][7] Third, mutants that fail to repair oxidative DNA damage show normal lifespan. However, there are technical and biological factors that would explain these observations and further research is needed to determine whether and how oxidative DNA damage contributes to aging. Segmental Progeroid NER SyndromesIt is often overlooked that DNA damage may not only be mutagenic, but also

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DNA damage and ageing: new-age ideas for an age-old problem

Cited by 334 publications

References 61 publications

The Szilard Hypothesis on the Nature of Aging Revisited

The Szilard Hypothesis on the Nature of Aging Revisited

Oxidative DNA damage in disease—Insights gained from base excision repair glycosylase‐deficient mouse models

Active transcriptomic and proteomic reprogramming in theC. elegansnucleotide excision repair mutant xpa-1

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