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Amelioration of premature aging in mtDNA mutator mouse by exercise: the interplay of oxidative stress, PGC-1?, p53, and DNA damage. A hypothesis.

ABSTRACT: The mtDNA mutator mouse lacks the proofreading capacity of the sole mtDNA polymerase, leading to accumulation of somatic mtDNA mutations, and a profound premature aging phenotype including elevated oxidative stress and apoptosis, and reduced mitochondrial function. We have previously reported that endurance exercise alleviates the aging phenotype in the mutator mice, reduces oxidative stress, and enhances mitochondrial biogenesis. Here we summarize our findings, with the emphasis on the central role of p53 in these adaptations. We demonstrate that mtDNA in sedentary and exercised PolG mice carry similar amounts of mutations in muscle, but in addition to that sedentary mice have more non-mutational damage, which is mitigated by exercise. It follows therefore that the profound alleviation of the mtDNA mutator phenotype in muscle by exercise may not require a reduction in mtDNA mutational load, but rather a decrease of mtDNA damage and/or oxidative stress. We further hypothesize that the observed 'alleviation without a reduction of mutational load' implies that the oxidative stress in PolG muscle is maintained, at least in part, by the 'malicious cycle', a hypothetical positive feedback potentially driven by the 'transcriptional mutagenesis', that is the conversion of chemically modified nucleotides into mutant RNA bases by the mitochondrial RNA polymerase.

SUBMITTER: Safdar A

PROVIDER: S-EPMC5592087 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Amelioration of premature aging in mtDNA mutator mouse by exercise: the interplay of oxidative stress, PGC-1α, p53, and DNA damage. A hypothesis.

Safdar Adeel A Annis Sofia S Kraytsberg Yevgenya Y Laverack Chloe C Saleem Ayesha A Popadin Konstantin K Woods Dori C DC Tilly Jonathan L JL Khrapko Konstantin K

Current opinion in genetics & development 20160601

The mtDNA mutator mouse lacks the proofreading capacity of the sole mtDNA polymerase, leading to accumulation of somatic mtDNA mutations, and a profound premature aging phenotype including elevated oxidative stress and apoptosis, and reduced mitochondrial function. We have previously reported that endurance exercise alleviates the aging phenotype in the mutator mice, reduces oxidative stress, and enhances mitochondrial biogenesis. Here we summarize our findings, with the emphasis on the central ...[more]

PMID: 27497229

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Project description:BackgroundAge-related hyperkyphosis is multifactorial and involves alterations of vertebral bone, intervertebral discs (IVD) and paraspinal muscles. The relative contribution of these tissues remains unclear. Here, we compared differences in vertebral bone microarchitecture and IVD thickness between prematurely aging mice with spinal hyperkyphosis and wild type littermates.MethodsThoracolumbar vertebral columns were dissected from homozygous Polg D257A and age-matched wild type littermates. Micro-computed tomography was performed to quantify cortical and trabecular bone parameters at anterior and posterior portions of T8-L4 vertebrae. In addition, vertebral shape, transaxial facet joint orientation and IVD thickness were quantified. Differences in anterior/posterior ratios between genotypes were compared by Student's t-test and association between vertebral bone and IVD parameters was investigated using Pearson correlation analysis.ResultsHyperkyphotic homozygous mice displayed generalized osteopenia that was more pronounced at the posterior compared with anterior portion of thoracolumbar vertebrae. An increase in the anterior/posterior ratio of trabecular bone parameters was revealed at the thoracolumbar junction (T13-L1). Polg D257A displayed diffuse loss of cortical bone thickness, yet anterior/posterior ratios were unchanged. Despite generalized and regional bone loss, vertebral shape was unaffected. PolG D257A mice showed a 10-20 % reduction of IVD thickness at both thoracic and lumbar levels, with only minimal histopathological changes. IVD thickness was negatively correlated with anterior/posterior ratios of trabecular bone parameters, as well as with more coronally oriented facet joints, but negatively correlated with the anterior/posterior ratio of cortical bone thickness.ConclusionsAging-induced regional changes of vertebral trabecular and cortical bone did not lead to altered vertebral shape in Polg D257A mice but may indirectly cause hyperkyphosis through reduction of IVD thickness. These findings suggest a limited role for aging-induced bone loss in spinal hyperkyphosis and warrants further research on the involvement of paraspinal muscle degeneration.

Project description:Cellular senescence is a hallmark of normal aging and aging-related syndromes, including the premature aging disorder Hutchinson-Gilford Progeria Syndrome (HGPS), a rare genetic disorder caused by a single mutation in the LMNA gene that results in the constitutive expression of a truncated splicing mutant of lamin A known as progerin. Progerin accumulation leads to increased cellular stresses including unrepaired DNA damage, activation of the p53 signaling pathway and accelerated senescence. We previously established that the p53 isoforms ?133p53 and p53? regulate senescence in normal human cells. However, their role in premature aging is unknown. Here we report that p53 isoforms are expressed in primary fibroblasts derived from HGPS patients, are associated with their accelerated senescence and that their manipulation can restore the replication capacity of HGPS fibroblasts. We found that in near-senescent HGPS fibroblasts, which exhibit low levels of ?133p53 and high levels of p53?, restoration of ?133p53 expression was sufficient to extend replicative lifespan and delay senescence, despite progerin levels and abnormal nuclear morphology remaining unchanged. Conversely, ?133p53 depletion or p53? overexpression accelerated the onset of senescence in otherwise proliferative HGPS fibroblasts. Our data indicate that ?133p53 exerts its role by modulating full-length p53 (FLp53) signaling to extend the replicative lifespan and promotes the repair of spontaneous progerin-induced DNA double-strand breaks (DSBs). We showed that ?133p53 dominant-negative inhibition of FLp53 occurs directly at the p21/CDKN1A and miR-34a promoters, two p53 senescence-associated genes. In addition, ?133p53 expression increased the expression of DNA repair RAD51, likely through upregulation of E2F1, a transcription factor that activates RAD51, to promote repair of DSBs. In summary, our data indicate that ?133p53 modulates p53 signaling to repress progerin-induced early onset of senescence in HGPS cells. Therefore, restoration of ?133p53 expression may be a novel therapeutic strategy to treat aging-associated phenotypes of HGPS in vivo.

Dataset Information

Amelioration of premature aging in mtDNA mutator mouse by exercise: the interplay of oxidative stress, PGC-1?, p53, and DNA damage. A hypothesis.

Publications

Amelioration of premature aging in mtDNA mutator mouse by exercise: the interplay of oxidative stress, PGC-1α, p53, and DNA damage. A hypothesis.

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