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      Adipose Tissue Quality in Aging: How Structural and Functional Aspects of Adipose Tissue Impact Skeletal Muscle Quality

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          Abstract

          The interplay between adipose tissue and skeletal muscle and the impact on mobility and aging remain enigmatic. The progressive decline in mobility promoted by aging has been previously attributed to the loss of skeletal mass and function and more recently linked to changes in body fat composition and quantity. Regardless of body size, visceral and intermuscular adipose depots increase with aging and are associated with adverse health outcomes. However, the quality of adipose tissue, in particular abdominal subcutaneous as it is the largest depot, likely plays a significant role in aging outcomes, such as mobility decline, though its communication with other tissues such as skeletal muscle. In this review, we discuss the age-associated development of a pro-inflammatory profile, cellular senescence, and metabolic inflexibility in abdominal subcutaneous adipose tissue. Collectively, these facets of adipose tissue quality influence its secretory profile and crosstalk with skeletal muscle and likely contribute to the development of muscle atrophy and disability. Therefore, the identification of the key structural and functional components of adipose tissue quality—including necrosis, senescence, inflammation, self-renewal, metabolic flexibility—and adipose tissue-secreted proteins that influence mobility via direct effects on skeletal muscle are necessary to prevent morbidity/mortality in the aging population.

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          Most cited references48

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          Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study

          Background Cellular senescence is a key mechanism that drives age-related diseases, but has yet to be targeted therapeutically in humans. Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal cellular senescence-associated disease. Selectively ablating senescent cells using dasatinib plus quercetin (DQ) alleviates IPF-related dysfunction in bleomycin-administered mice. Methods A two-center, open-label study of intermittent DQ (D:100 mg/day, Q:1250 mg/day, three-days/week over three-weeks) was conducted in participants with IPF (n = 14) to evaluate feasibility of implementing a senolytic intervention. The primary endpoints were retention rates and completion rates for planned clinical assessments. Secondary endpoints were safety and change in functional and reported health measures. Associations with the senescence-associated secretory phenotype (SASP) were explored. Findings Fourteen patients with stable IPF were recruited. The retention rate was 100% with no DQ discontinuation; planned clinical assessments were complete in 13/14 participants. One serious adverse event was reported. Non-serious events were primarily mild-moderate, with respiratory symptoms (n = 16 total events), skin irritation/bruising (n = 14), and gastrointestinal discomfort (n = 12) being most frequent. Physical function evaluated as 6-min walk distance, 4-m gait speed, and chair-stands time was significantly and clinically-meaningfully improved (p < .05). Pulmonary function, clinical chemistries, frailty index (FI-LAB), and reported health were unchanged. DQ effects on circulat.ing SASP factors were inconclusive, but correlations were observed between change in function and change in SASP-related matrix-remodeling proteins, microRNAs, and pro-inflammatory cytokines (23/48 markers r ≥ 0.50). Interpretation Our first-in-humans open-label pilot supports study feasibility and provides initial evidence that senolytics may alleviate physical dysfunction in IPF, warranting evaluation of DQ in larger randomized controlled trials for senescence-related diseases. ClinicalTrials.gov identifier: NCT02874989 (posted 2016–2018).
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            A senescent cell bystander effect: senescence-induced senescence

            Summary Senescent cells produce and secrete various bioactive molecules including interleukins, growth factors, matrix-degrading enzymes and reactive oxygen species (ROS). Thus, it has been proposed that senescent cells can damage their local environment, and a stimulatory effect on tumour cell growth and invasiveness has been documented. However, it was unknown what effect, if any, senescent cells have on their normal, proliferation-competent counterparts. We show here that senescent cells induce a DNA damage response, characteristic for senescence, in neighbouring cells via gap junction-mediated cell–cell contact and processes involving ROS. Continuous exposure to senescent cells induced cell senescence in intact bystander fibroblasts. Hepatocytes bearing senescence markers clustered together in mice livers. Thus, senescent cells can induce a bystander effect, spreading senescence towards their neighbours in vitro and, possibly, in vivo.
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              JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age

              Chronic, low grade, sterile inflammation frequently accompanies aging and age-related diseases. Cellular senescence is associated with the production of proinflammatory chemokines, cytokines, and extracellular matrix (ECM) remodeling proteases, which comprise the senescence-associated secretory phenotype (SASP). We found a higher burden of senescent cells in adipose tissue with aging. Senescent human primary preadipocytes as well as human umbilical vein endothelial cells (HUVECs) developed a SASP that could be suppressed by targeting the JAK pathway using RNAi or JAK inhibitors. Conditioned medium (CM) from senescent human preadipocytes induced macrophage migration in vitro and inflammation in healthy adipose tissue and preadipocytes. When the senescent cells from which CM was derived had been treated with JAK inhibitors, the resulting CM was much less proinflammatory. The administration of JAK inhibitor to aged mice for 10 wk alleviated both adipose tissue and systemic inflammation and enhanced physical function. Our findings are consistent with a possible contribution of senescent cells and the SASP to age-related inflammation and frailty. We speculate that SASP inhibition by JAK inhibitors may contribute to alleviating frailty. Targeting the JAK pathway holds promise for treating age-related dysfunction.
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                Author and article information

                Journal
                Nutrients
                Nutrients
                nutrients
                Nutrients
                MDPI
                2072-6643
                23 October 2019
                November 2019
                : 11
                : 11
                : 2553
                Affiliations
                [1 ]Translational Research Institute, Advent Health, 301 East Princeton Street, Orlando, FL 32804, USA; flaviagiolo@ 123456gmail.com
                [2 ]School of Physical Education and Sport of Ribeirao Preto, University of Sao Paulo, Avenida Bandeirantes 3900, Ribeirao Preto, SP, 14040-907, Brazil; ellenfreitas@ 123456usp.br
                [3 ]Internal Medicine Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, 1 Medical Center Blvd, Winston-Salem, NC 27157, USA; jnjustic@ 123456wakehealth.edu
                [4 ]Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA; kershawe@ 123456pitt.edu
                Author notes
                [* ]Correspondence: Lauren.Sparks@ 123456adventhealth.com ; Tel.: +1-407-303-7352
                Author information
                https://orcid.org/0000-0002-3887-4868
                Article
                nutrients-11-02553
                10.3390/nu11112553
                6893709
                31652734
                696d9d00-acc4-41a2-8c3f-77d8c0942542
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 10 October 2019
                : 21 October 2019
                Categories
                Review

                Nutrition & Dietetics
                adipose tissue,skeletal muscle,aging,mobility,senescence,inflammation,secretory
                Nutrition & Dietetics
                adipose tissue, skeletal muscle, aging, mobility, senescence, inflammation, secretory

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