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Background and Current State of the Art

To maintaining the health of our population and the European economy amid a growing proportion of elderly people it is imperative to identify strategies to prevent or delay age-associated decline in organ function and disease. Aged individuals have an increased risk of developing numerous debilitating diseases, including osteoporosis, cardiovascular disease, cognitive impairment, diabetes and cancer. However, in order to develop therapeutic strategies for delaying age-related pathology, a better understanding of the underlying causes of ageing is required.

DNA damage and ageing

Within the complex chemical machinery of each cell, all biomolecules are subject to damage caused by spontaneous reactions and by endogenous and exogenous reactive agents. It is thus widely believed that accumulation of damage underlies aging. The almost exclusive link between syndromes with phenotypes resembling accelerated ageing in many organs and tissues (segmental progeria), and inborn defects in DNA metabolism points to genomic damage as a major culprit in the ageing process. In principle, all other macromolecules are renewable, whereas nuclear DNA, the blueprint of virtually all cellular RNA and proteins, is irreplaceable; any acquired error if not repaired becomes permanent and may have irreversible consequences. In spite of its enormous length and explicit physicochemical vulnerability, cellular function relies on the integrity of the somatic genome, which must be preserved during the entire lifetime of an organism. Cells have evolved an intricate genome maintenance apparatus, consisting of several sophisticated DNA repair and DNA damage checkpoint systems that trigger cell cycle, or induce senescence or cell death. This elaborate network also includes machineries to maintain telomeres that protect the ends of chromosomes, systems to repair mitochondrial DNA and processes that maintain the epigenetic code. These mechanisms ensure that genetic information remains functionally intact for extended periods and is faithfully transmitted. It is estimated that thousands of DNA lesions occur daily in the nuclear genome of every cell as consequence of exogenous (e.g. UV, ionizing radiation) and endogenous (e.g. ROS) sources of DNA damage.

The consequences of DNA damage

Some DNA lesions are primarily mutagenic thus promoting cancer. Others are mainly cytotoxic or cytostatic, triggering cell death or senescence, causing age-related degenerative changes. A major source of genome instability is the erosion of protective telomeres with each cell division resulting in cellular senescence when they become critically shorten. The chemical nature, frequency and location of lesions in the genome as well as the fidelity of repair systems determine the outcome. Despite their high efficiency, genome maintenance systems cannot cope with all of the insults inflicted over a lifetime, leading to a gradual accumulation of DNA damage. Certain DNA lesions are poorly recognized by the repair machinery, while telomere attrition results in highly cytotoxic double strand break formation. Consequently, accumulation of DNA lesions and telomere attrition lead to cellular senescence or cell death and eventually to loss of organismal homeostasis over time. These critical outcomes of DNA damage, cancer and age-related diseases represent dominant health care problems in modern societies stressing the enormous medical impact of genome (in)stability.

Until recently, the daunting complexity of the ageing process, the conspicuous lack of tools to study it, and a dearth of experimentally tractable model systems have greatly hindered any hypothesis-driven reductionist approaches to understand the molecular basis of ageing. In addressing the impact of chronic DNA damage in ageing, we have put forward a multidisciplinary approach to study this central thematic area at the molecular, cellular and systems level by assembling a group of scientists with cross-disciplinary expertise and capabilities.

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Figure 1. Chronic DNA damage and its impact on ageing.
DNA is continuously damaged by chemical alterations (such as spontaneous hydrolysis, deamination, telomere attrition), by environmental agents as well as endogenous products (i.e. ROS). Cells respond through a battery of DNA repair and genome surveillance systems that counteract DNA damage, thereby ensuring that their vital genetic information is preserved and faithfully transmitted to progeny. Nevertheless, a fraction of the DNA damage escapes repair and accumulates, resulting in mutations, senescence or cell death and cellular dysfunction with advancing age.

The CodeAge ITN will include several genetic model systems (S. cerevisiae, C. elegans, Mus musculus, human cells) employing cutting edge technologies. This integrated approach is likely to provide a pioneering groundwork into the basic mechanisms of age-related pathology driven by chronic DNA damage. In combination with the expected identification of accessible biomarkers, allowing monitoring of intervention studies, this program will contribute to a better knowledge-driven drug development to prevent or counteract age-associated pathologies in order to improve quality of life to the elderly.

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