The Continuum of Aging and Age-Related Diseases: Common Mechanisms but Different Rates

Frontiers in Medicine, Год журнала: 2018, Номер 5

Опубликована: Март 12, 2018

Geroscience, the new interdisciplinary field that aims to understand relationship between aging and chronic age-related diseases (ARDs) geriatric syndromes (GSs), is based on epidemiological evidence experimental data major risk factor for such pathologies assumes ARDs/GSs share a common set of basic biological mechanisms. A consequence primary target medicine combat instead any single ARD/GSs one by one, as favored fragmentation into hundreds specialties sub-specialties. If same molecular cellular mechanisms underpin both ARDs/GSs, question emerges: which difference, if any, ARDs/GSs? The hypothesis ARDs GSs frailty can be conceptualized accelerated will discussed analyzing in particular frailty, sarcopenia, obstructive pulmonary disease, cancer, neurodegenerative Alzheimer Parkinson well Down syndrome an example progeroid syndrome. According this integrated view, become part continuum where precise boundaries do not exist two extremes are represented centenarians, who largely avoided or postponed most characterized decelerated aging, patients suffered more severe their 60s, 70s, 80s show signs respectively. In these extremes, there intermediate trajectories representing sort gray area. Thus, clinically different, classical are, indeed, result peculiar combinations alterations regarding same, limited shared with process. Whether individual follow trajectory depend his/her genetic background interacting lifelong environmental lifestyle factors. manifestations it urgent identify markers capable distinguishing chronological age subjects at higher developing GSs. To aim, we propose use DNA methylation, N-glycans profiling, gut microbiota composition complement available disease-specific markers.

Язык: Английский

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Ataxia telangiectasia: a review

Orphanet Journal of Rare Diseases, Год журнала: 2016, Номер 11(1)

Опубликована: Ноя. 25, 2016

Ataxia telangiectasia (A-T) is an autosomal recessive disorder primarily characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility and radiation sensitivity. A-T often referred to as a genome instability or DNA damage response syndrome. The world-wide prevalence of estimated be between 1 in 40,000 100,000 live births. complex with substantial variability the severity features affected individuals, at different ages. Neurological symptoms most first appear early childhood when children begin sit walk. They have immunological abnormalities including immunoglobulin antibody deficiencies lymphopenia. People increased predisposition for cancers, particularly lymphoid origin. Pulmonary disease problems feeding, swallowing nutrition are common, there also may dermatological endocrine manifestations. caused mutations ATM (Ataxia Telangiectasia, Mutated) gene which encodes protein same name. primary role coordination cellular signaling pathways double strand breaks, oxidative stress other genotoxic stress. diagnosis usually suspected combination neurologic clinical (ataxia, abnormal control eye movement, postural instability) one more following vary their appearance: frequent sinopulmonary infections specific laboratory (e.g. IgA deficiency, lymphopenia especially affecting T lymphocytes alpha-fetoprotein levels). Because certain neurological arise later, should carefully considered any ataxic child otherwise elusive diagnosis. A can confirmed finding absence deficiency its kinase activity cultured cell lines, and/or identification pathological gene. There several rare disorders that physicians must consider diagnosing confused A-T. Differentiation these various possible selected tests, sequencing. Antenatal performed if family been identified child. In identifying mutations, antenatal made haplotype analysis unambiguous has through findings analysis. Genetic counseling help members patient understand genetic testing feasible, how test results interpreted. Treatment associated symptomatic supportive, no treatments known slow stop neurodegeneration. However, manifestations A-T, e.g. pulmonary disease, failure thrive diabetes treated effectively.

Язык: Английский

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SIRT6 Is Responsible for More Efficient DNA Double-Strand Break Repair in Long-Lived Species

Cell, Год журнала: 2019, Номер 177(3), С. 622 - 638.e22

Опубликована: Апрель 1, 2019

Язык: Английский

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Iron mediated toxicity and programmed cell death: A review and a re-examination of existing paradigms

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Год журнала: 2016, Номер 1864(2), С. 399 - 430

Опубликована: Дек. 6, 2016

Язык: Английский

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DNA Damage and Associated DNA Repair Defects in Disease and Premature Aging

The American Journal of Human Genetics, Год журнала: 2019, Номер 105(2), С. 237 - 257

Опубликована: Авг. 1, 2019

Язык: Английский

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DNA damage and repair in age-related inflammation

Nature reviews. Immunology, Год журнала: 2022, Номер 23(2), С. 75 - 89

Опубликована: Июль 13, 2022

Язык: Английский

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Cellular functions of the protein kinase ATM and their relevance to human disease

Nature Reviews Molecular Cell Biology, Год журнала: 2021, Номер 22(12), С. 796 - 814

Опубликована: Авг. 24, 2021

Язык: Английский

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Chemical screening identifies ATM as a target for alleviating senescence

Nature Chemical Biology, Год журнала: 2017, Номер 13(6), С. 616 - 623

Опубликована: Март 27, 2017

Язык: Английский

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ATM-Deficient Colorectal Cancer Cells Are Sensitive to the PARP Inhibitor Olaparib

Translational Oncology, Год журнала: 2017, Номер 10(2), С. 190 - 196

Опубликована: Фев. 6, 2017

The ataxia telangiectasia mutated (ATM) protein kinase plays a central role in the cellular response to DNA damage. Loss or inactivation of both copies ATM gene leads telangiectasia, devastating childhood condition characterized by neurodegeneration, immune deficiencies, and cancer predisposition. is also absent approximately 40% mantle cell lymphomas (MCLs), we previously showed that MCL lines with loss are sensitive poly-ADP ribose polymerase (PARP) inhibitors. Next-generation sequencing patient tumors has revealed altered many human cancers including colorectal, lung, prostate, breast. Here, show colorectal line SK-CO-1 lacks detectable expression PARP inhibitor olaparib. Similarly, HCT116 cells shRNA depletion olaparib, p53 enhances this sensitivity. Moreover, olaparib combination KU55933, sensitivity enhanced deletion p53. Together our studies suggest inhibitors may have potential for treating dysfunction and/or mutation when combined an inhibitor.

Язык: Английский

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Oxidative stress, mitochondrial abnormalities and antioxidant defense in Ataxia-telangiectasia, Bloom syndrome and Nijmegen breakage syndrome

Redox Biology, Год журнала: 2016, Номер 11, С. 375 - 383

Опубликована: Дек. 28, 2016

Rare pleiotropic genetic disorders, Ataxia-telangiectasia (A-T), Bloom syndrome (BS) and Nijmegen breakage (NBS) are characterised by immunodeficiency, extreme radiosensitivity, higher cancer susceptibility, premature aging, neurodegeneration insulin resistance. Some of these functional abnormalities can be explained aberrant DNA damage response chromosomal instability. It has been suggested that one possible common denominator conditions could chronic oxidative stress caused endogenous ROS overproduction impairment mitochondrial homeostasis. Recent studies indicate new, alternative sources in A-T, BS NBS cells, including NADPH oxidase 4 (NOX4), oxidised low-density lipoprotein (ox-LDL) or Poly (ADP-ribose) polymerases (PARP). Mitochondrial such as changes the ultrastructure function mitochondria, excess mROS production well have also reported cells. cells inextricably linked to high levels reactive oxygen species (ROS), thereby, may a major phenotypic hallmark diseases. Due presence disturbances, considered Excess activity antioxidant enzymes an insufficient amount low molecular weight antioxidants new pharmacological strategies for patients suffering from aforementioned However, at current stage research we unable ascertain if free radical scavengers improve condition prolong survival time patients. Therefore, it is necessary conduct experimental human model.

Язык: Английский

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