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      Circulating levels of monocyte chemoattractant protein‐1 as a potential measure of biological age in mice and frailty in humans

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          A serum biomarker of biological versus chronological age would have significant impact on clinical care. It could be used to identify individuals at risk of early‐onset frailty or the multimorbidities associated with old age. It may also serve as a surrogate endpoint in clinical trials targeting mechanisms of aging. Here, we identified MCP‐1/ CCL2, a chemokine responsible for recruiting monocytes, as a potential biomarker of biological age. Circulating monocyte chemoattractant protein‐1 ( MCP‐1) levels increased in an age‐dependent manner in wild‐type ( WT) mice. That age‐dependent increase was accelerated in Ercc1 −/Δ and Bubr1 H/H mouse models of progeria. Genetic and pharmacologic interventions that slow aging of Ercc1 −/Δ and WT mice lowered serum MCP‐1 levels significantly. Finally, in elderly humans with aortic stenosis, MCP‐1 levels were significantly higher in frail individuals compared to nonfrail. These data support the conclusion that MCP‐1 can be used as a measure of mammalian biological age that is responsive to interventions that extend healthy aging.

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          Most cited references 36

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          The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs

          The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and the burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen-activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these same factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1 −/Δ mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1 −/Δ mice, delaying age-related symptoms and pathology, osteoporosis, and loss of intervertebral disk proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.
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            A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis.

            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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              NF-κB inhibition delays DNA damage-induced senescence and aging in mice.

              The accumulation of cellular damage, including DNA damage, is thought to contribute to aging-related degenerative changes, but how damage drives aging is unknown. XFE progeroid syndrome is a disease of accelerated aging caused by a defect in DNA repair. NF-κB, a transcription factor activated by cellular damage and stress, has increased activity with aging and aging-related chronic diseases. To determine whether NF-κB drives aging in response to the accumulation of spontaneous, endogenous DNA damage, we measured the activation of NF-κB in WT and progeroid model mice. As both WT and progeroid mice aged, NF-κB was activated stochastically in a variety of cell types. Genetic depletion of one allele of the p65 subunit of NF-κB or treatment with a pharmacological inhibitor of the NF-κB-activating kinase, IKK, delayed the age-related symptoms and pathologies of progeroid mice. Additionally, inhibition of NF-κB reduced oxidative DNA damage and stress and delayed cellular senescence. These results indicate that the mechanism by which DNA damage drives aging is due in part to NF-κB activation. IKK/NF-κB inhibitors are sufficient to attenuate this damage and could provide clinical benefit for degenerative changes associated with accelerated aging disorders and normal aging.

                Author and article information

                Aging Cell
                Aging Cell
                Aging Cell
                John Wiley and Sons Inc. (Hoboken )
                31 December 2017
                April 2018
                : 17
                : 2 ( doiID: 10.1111/acel.2018.17.issue-2 )
                [ 1 ] Department of Molecular Medicine Center on Aging The Scripps Research Institute Jupiter FL USA
                [ 2 ] Robert and Arlene Kogod Center on Aging Mayo Clinic College of Medicine Rochester MN USA
                [ 3 ] Department of Physical Medicine and Rehabilitation Mayo Clinic College of Medicine Rochester MN USA
                [ 4 ] Laboratory of Epidemiology and Population Science National Institute on Aging National Institutes of Health Baltimore MD USA
                [ 5 ] Division of Biomedical Statistics and Informatics Department of Health Sciences Research Mayo Clinic College of Medicine Rochester MN USA
                [ 6 ] Department of Pediatric and Adolescent Medicine Mayo Clinic College of Medicine Rochester MN USA
                [ 7 ] Department of Pathology University of Washington Seattle WA USA
                [ 8 ] Department of Comparative Medicine University of Washington Seattle WA USA
                Author notes
                [* ] Correspondence

                Laura Niedernhofer, The Scripps Research Institute, Department of Molecular Medicine, Center on Aging, Jupiter, FL, USA.

                Email: lniedern@

                © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 2, Tables: 0, Pages: 7, Words: 5160
                Funded by: NIH/NIA
                Award ID: P01 AG043376
                Award ID: R24 AG047115
                Award ID: R01 AG038550
                Award ID: T32 AG000057
                Award ID: AG052958
                Award ID: AG053832
                Funded by: National Institute of Aging Intramural Research Program,National Institutes of Health
                Award ID: AG000519
                Original Article
                Original Articles
                Custom metadata
                April 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version= mode:remove_FC converted:13.03.2018


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