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      A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis.

      Nature

      Syndrome, metabolism, Somatotrophs, physiopathology, genetics, Progeria, Mice, Liver, antagonists & inhibitors, Insulin-Like Growth Factor I, Humans, Growth Hormone, Gene Expression Regulation, deficiency, Endonucleases, DNA-Binding Proteins, DNA Repair, DNA Damage, Cell Line, Animals, physiology, Aging

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          Abstract

          XPF-ERCC1 endonuclease is required for repair of helix-distorting DNA lesions and cytotoxic DNA interstrand crosslinks. Mild mutations in XPF cause the cancer-prone syndrome xeroderma pigmentosum. A patient presented with a severe XPF mutation leading to profound crosslink sensitivity and dramatic progeroid symptoms. It is not known how unrepaired DNA damage accelerates ageing or its relevance to natural ageing. Here we show a highly significant correlation between the liver transcriptome of old mice and a mouse model of this progeroid syndrome. Expression data from XPF-ERCC1-deficient mice indicate increased cell death and anti-oxidant defences, a shift towards anabolism and reduced growth hormone/insulin-like growth factor 1 (IGF1) signalling, a known regulator of lifespan. Similar changes are seen in wild-type mice in response to chronic genotoxic stress, caloric restriction, or with ageing. We conclude that unrepaired cytotoxic DNA damage induces a highly conserved metabolic response mediated by the IGF1/insulin pathway, which re-allocates resources from growth to somatic preservation and life extension. This highlights a causal contribution of DNA damage to ageing and demonstrates that ageing and end-of-life fitness are determined both by stochastic damage, which is the cause of functional decline, and genetics, which determines the rates of damage accumulation and decline.

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          Most cited references 39

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          The plasticity of aging: insights from long-lived mutants.

          Mutations in genes affecting endocrine signaling, stress responses, metabolism, and telomeres can all increase the life spans of model organisms. These mutations have revealed evolutionarily conserved pathways for aging, some of which appear to extend life span in response to sensory cues, caloric restriction, or stress. Many mutations affecting longevity pathways delay age-related disease, and the molecular analysis of these pathways is leading to a mechanistic understanding of how these two processes--aging and disease susceptibility--are linked.
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            Gene expression profile of aging and its retardation by caloric restriction.

            The gene expression profile of the aging process was analyzed in skeletal muscle of mice. Use of high-density oligonucleotide arrays representing 6347 genes revealed that aging resulted in a differential gene expression pattern indicative of a marked stress response and lower expression of metabolic and biosynthetic genes. Most alterations were either completely or partially prevented by caloric restriction, the only intervention known to retard aging in mammals. Transcriptional patterns of calorie-restricted animals suggest that caloric restriction retards the aging process by causing a metabolic shift toward increased protein turnover and decreased macromolecular damage.
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              Modulation of mammalian life span by the short isoform of p53.

              Overexpression of the short isoform of p53 (p44) has unexpectedly uncovered a role for p53 in the regulation of size and life span in the mouse. Hyperactivation of the insulin-like growth factor (IGF) signaling axis by p44 sets in motion a kinase cascade that clamps potentially unimpeded growth through p21Cip1. This suggests that pathways of gene activity known to regulate longevity in lower organisms are linked in mammals via p53 to mechanisms for controlling cell proliferation. Thus, appropriate expression of the short and long p53 isoforms might maintain a balance between tumor suppression and tissue regeneration, a major requisite for long mammalian life span.
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                Author and article information

                Journal
                10.1038/nature05456
                17183314

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