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      Childhood adverse life events and skeletal muscle mitochondrial function

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          Abstract

          Social stress experienced in childhood is associated with adverse health later in life. Mitochondrial function has been implicated as a mechanism for how stressful life events “get under the skin” to influence physical well-being. Using data from the Study of Muscle, Mobility, and Aging ( n = 879, 59% women), linear models examined whether adverse childhood events (i.e., physical abuse) were associated with two measures of skeletal muscle mitochondrial energetics in older adults: (i) maximal adenosine triphosphate production (ATP max) and (ii) maximal state 3 respiration (Max OXPHOS). Forty-five percent of the sample reported experiencing one or more adverse childhood events. After adjustment, each additional event was associated with −0.08 SD (95% confidence interval = −0.13, −0.02) lower ATP max. No association was observed with Max OXPHOS. Adverse childhood events are associated with lower ATP production in later life. Findings indicate that mitochondrial function may be a mechanism for understanding how early social stress influences health in later life.

          Abstract

          Adverse life events experienced in early life may influence skeletal muscle mitochondrial energy production among older adults.

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          Most cited references60

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          The Hallmarks of Aging

          Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects. Copyright © 2013 Elsevier Inc. All rights reserved.
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            Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences (ACE) Study.

            The relationship of health risk behavior and disease in adulthood to the breadth of exposure to childhood emotional, physical, or sexual abuse, and household dysfunction during childhood has not previously been described. A questionnaire about adverse childhood experiences was mailed to 13,494 adults who had completed a standardized medical evaluation at a large HMO; 9,508 (70.5%) responded. Seven categories of adverse childhood experiences were studied: psychological, physical, or sexual abuse; violence against mother; or living with household members who were substance abusers, mentally ill or suicidal, or ever imprisoned. The number of categories of these adverse childhood experiences was then compared to measures of adult risk behavior, health status, and disease. Logistic regression was used to adjust for effects of demographic factors on the association between the cumulative number of categories of childhood exposures (range: 0-7) and risk factors for the leading causes of death in adult life. More than half of respondents reported at least one, and one-fourth reported > or = 2 categories of childhood exposures. We found a graded relationship between the number of categories of childhood exposure and each of the adult health risk behaviors and diseases that were studied (P or = 50 sexual intercourse partners, and sexually transmitted disease; and 1.4- to 1.6-fold increase in physical inactivity and severe obesity. The number of categories of adverse childhood exposures showed a graded relationship to the presence of adult diseases including ischemic heart disease, cancer, chronic lung disease, skeletal fractures, and liver disease. The seven categories of adverse childhood experiences were strongly interrelated and persons with multiple categories of childhood exposure were likely to have multiple health risk factors later in life. We found a strong graded relationship between the breadth of exposure to abuse or household dysfunction during childhood and multiple risk factors for several of the leading causes of death in adults.
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              Decline in skeletal muscle mitochondrial function with aging in humans.

              Cumulative mtDNA damage occurs in aging animals, and mtDNA mutations are reported to accelerate aging in mice. We determined whether aging results in increased DNA oxidative damage and reduced mtDNA abundance and mitochondrial function in skeletal muscle of human subjects. Studies performed in 146 healthy men and women aged 18-89 yr demonstrated that mtDNA and mRNA abundance and mitochondrial ATP production all declined with advancing age. Abundance of mtDNA was positively related to mitochondrial ATP production rate, which in turn, was closely associated with aerobic capacity and glucose tolerance. The content of several mitochondrial proteins was reduced in older muscles, whereas the level of the oxidative DNA lesion, 8-oxo-deoxyguanosine, was increased, supporting the oxidative damage theory of aging. These results demonstrate that age-related muscle mitochondrial dysfunction is related to reduced mtDNA and muscle functional changes that are common in the elderly.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: InvestigationRole: ResourcesRole: ValidationRole: Writing - review & editing
                Role: ConceptualizationRole: Writing - review & editing
                Role: Data curationRole: Formal analysisRole: SoftwareRole: ValidationRole: VisualizationRole: Writing - review & editing
                Role: Formal analysisRole: SoftwareRole: ValidationRole: Writing - review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing - review & editing
                Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing - review & editing
                Role: Funding acquisitionRole: Methodology
                Role: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: Writing - review & editing
                Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: ResourcesRole: Supervision
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing - review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing - original draft
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: Validation
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: ResourcesRole: SupervisionRole: Writing - review & editing
                Journal
                Sci Adv
                Sci Adv
                sciadv
                advances
                Science Advances
                American Association for the Advancement of Science
                2375-2548
                08 March 2024
                06 March 2024
                : 10
                : 10
                : eadj6411
                Affiliations
                [ 1 ]Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
                [ 2 ]Department of Radiology, University of Washington, Seattle, WA, USA.
                [ 3 ]California Pacific Medical Center Research Institute, San Francisco, CA, USA.
                [ 4 ]Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
                [ 5 ]Division of Geriatrics, Department of Medicine, UCSF School of Medicine, San Francisco, CA, USA.
                [ 6 ]Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA, USA.
                [ 7 ]Department of Physical Therapy, University of Florida, Gainesville, FL, USA.
                [ 8 ]Department of Internal Medicine-Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
                [ 9 ]Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA.
                [ 10 ]AdventHealth, Translational Research Institute, Orlando, FL, USA.
                [ 11 ]Department of Medicine-Division of Geriatrics, Gerontology, and Palliative Care, University of California San Diego School of Medicine, La Jolla, CA, USA.
                Author notes
                [* ]Corresponding author. Email: duchowny@ 123456umich.edu
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0001-9771-8454
                https://orcid.org/0000-0001-5187-2149
                https://orcid.org/0000-0003-4278-6438
                https://orcid.org/0000-0003-1621-9309
                https://orcid.org/0000-0003-4938-9478
                https://orcid.org/0000-0003-3640-486X
                https://orcid.org/0000-0001-6554-631X
                https://orcid.org/0000-0002-0106-1150
                https://orcid.org/0000-0001-8808-260X
                https://orcid.org/0000-0002-2805-2115
                https://orcid.org/0000-0002-5786-4622
                Article
                adj6411
                10.1126/sciadv.adj6411
                10917337
                38446898
                76524c82-a5f6-439e-ae63-355b3f38ad11
                Copyright © 2024 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

                History
                : 07 July 2023
                : 01 February 2024
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100007154, Wake Forest University;
                Award ID: P30AG021332
                Funded by: FundRef http://dx.doi.org/10.13039/100012736, Institute on Aging, College of Medicine, University of Florida;
                Award ID: AG059416
                Funded by: FundRef http://dx.doi.org/10.13039/501100023864, NHS Innovation Accelerator;
                Award ID: P30AG024827
                Funded by: FundRef http://dx.doi.org/10.13039/501100023864, NHS Innovation Accelerator;
                Award ID: R00AG066846
                Funded by: National Center for Advancing Translational Science at Wake Forest University;
                Award ID: UL1 0TR001420
                Categories
                Research Article
                Social and Interdisciplinary Sciences and Public Health
                SciAdv r-articles
                Cell Biology
                Social Sciences
                Health and Medicine
                Custom metadata
                Mjoy Toledo

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