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      Strategies and Challenges in Clinical Trials Targeting Human Aging

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          Abstract

          Interventions that target fundamental aging processes have the potential to transform human health and health care. A variety of candidate drugs have emerged from basic and translational research that may target aging processes. Some of these drugs are already in clinical use for other purposes, such as metformin and rapamycin. However, designing clinical trials to test interventions that target the aging process poses a unique set of challenges. This paper summarizes the outcomes of an international meeting co-ordinated by the NIH-funded Geroscience Network to further the goal of developing a translational pipeline to move candidate compounds through clinical trials and ultimately into use. We review the evidence that some drugs already in clinical use may target fundamental aging processes. We discuss the design principles of clinical trials to test such interventions in humans, including study populations, interventions, and outcomes. As examples, we offer several scenarios for potential clinical trials centered on the concepts of health span (delayed multimorbidity and functional decline) and resilience (response to or recovery from an acute health stress). Finally, we describe how this discussion helped inform the design of the proposed Targeting Aging with Metformin study.

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          Most cited references59

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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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            Rapamycin: one drug, many effects.

            The mammalian target of rapamycin (mTOR) signaling pathway is a master regulator of cell growth and metabolism. Deregulation of the mTOR pathway has been implicated in a number of human diseases such as cancer, diabetes, obesity, neurological diseases, and genetic disorders. Rapamycin, a specific inhibitor of mTOR, has been shown to be useful in the treatment of certain diseases. Here we discuss its mechanism of action and highlight recent findings regarding the effects and limitations of rapamycin monotherapy and the potential utility of combination therapy with rapamycin. Copyright © 2014 Elsevier Inc. All rights reserved.
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              Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial.

              The worldwide increase in type 2 diabetes mellitus is becoming a major health concern. We aimed to assess the effect of acarbose in preventing or delaying conversion of impaired glucose tolerance to type 2 diabetes. In a multicentre, placebo-controlled randomised trial, we randomly allocated patients with impaired glucose tolerance to 100 mg acarbose or placebo three times daily. The primary endpoint was development of diabetes on the basis of a yearly oral glucose tolerance test (OGTT). Analyses were by intention to treat. We randomly allocated 714 patients with impaired glucose tolerance to acarbose and 715 to placebo. We excluded 61 (4%) patients because they did not have impaired glucose tolerance or had no postrandomisation data. 211 (31%) of 682 patients in the acarbose group and 130 (19%) of 686 on placebo discontinued treatment early. 221 (32%) patients randomised to acarbose and 285 (42%) randomised to placebo developed diabetes (relative hazard 0.75 [95% CI 0.63-0.90]; p=0.0015). Furthermore, acarbose significantly increased reversion of impaired glucose tolerance to normal glucose tolerance (p<0.0001). At the end of the study, treatment with placebo for 3 months was associated with an increase in conversion of impaired glucose tolerance to diabetes. The most frequent side-effects to acarbose treatment were flatulence and diarrhoea. Acarbose could be used, either as an alternative or in addition to changes in lifestyle, to delay development of type 2 diabetes in patients with impaired glucose tolerance.
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                Author and article information

                Journal
                J Gerontol A Biol Sci Med Sci
                J. Gerontol. A Biol. Sci. Med. Sci
                gerona
                gerona
                The Journals of Gerontology Series A: Biological Sciences and Medical Sciences
                Oxford University Press (US )
                1079-5006
                1758-535X
                November 2016
                16 August 2016
                16 August 2016
                : 71
                : 11
                : 1424-1434
                Affiliations
                1Division of Geriatrics, University of California San Francisco .
                2Department of Medicine, Division of Endocrinology and
                3Institute for Aging Research, Albert Einstein College of Medicine , Bronx, New York.
                4Department of Hematology and Transplant Center, Mayo Clinic , Rochester, Minnesota.
                5Department of Biology, University of Alabama at Birmingham .
                6Robert and Arlene Kogod Center on Aging, Mayo Clinic , Rochester, Minnesota.
                7Geriatrics Center and Institute of Gerontology, University of Michigan , Ann Arbor.
                Author notes
                *These authors contributed equally to this work.
                Address correspondence to Nir Barzilai, MD, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Belfer 701, Bronx, NY 10461. E-mail: nir.barzilai@ 123456einstein.yu.edu

                Decision Editor: Rafael de Cabo, PhD

                Article
                10.1093/gerona/glw149
                5055653
                27535968
                01bcf1f2-9527-4b20-afa4-af283a589120
                © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 22 March 2016
                : 12 July 2016
                Page count
                Pages: 11
                Funding
                Funded by: National Institutes of Health, http://dx.doi.org/10.13039/100000002;
                Award ID: R24AG044396
                Categories
                Special Issue: Moving Geroscience Into Uncharted Waters: Perspective
                Editor's choice

                Geriatric medicine
                aging,clinical trials,metformin,rapamycin,acarbose
                Geriatric medicine
                aging, clinical trials, metformin, rapamycin, acarbose

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