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      Late-life targeting of the IGF-1 receptor improves healthspan and lifespan in female mice

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          Abstract

          Diminished growth factor signaling improves longevity in laboratory models, while a reduction in the somatotropic axis is favorably linked to human aging and longevity. Given the conserved role of this pathway on lifespan, therapeutic strategies, such as insulin-like growth factor-1 receptor (IGF-1R) monoclonal antibodies (mAb), represent a promising translational tool to target human aging. To this end, we performed a preclinical study in 18-mo-old male and female mice treated with vehicle or an IGF-1R mAb (L2-Cmu, Amgen Inc), and determined effects on aging outcomes. Here we show that L2-Cmu preferentially improves female healthspan and increases median lifespan by 9% ( P = 0.03) in females, along with a reduction in neoplasms and inflammation ( P ≤ 0.05). Thus, consistent with other models, targeting IGF-1R signaling appears to be most beneficial to females. Importantly, these effects could be achieved at advanced ages, suggesting that IGF-1R mAbs could represent a promising therapeutic candidate to delay aging.

          Abstract

          Reduced IGF-1 signaling increases longevity in many organisms. Here, Mao et al. show that administration of an anti-IGF-1R antibody is well tolerated and delays aging in female mice; importantly, late-life targeting is sufficient to achieve the beneficial effects.

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          Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein.

          The Drosophila melanogaster gene chico encodes an insulin receptor substrate that functions in an insulin/insulin-like growth factor (IGF) signaling pathway. In the nematode Caenorhabditis elegans, insulin/IGF signaling regulates adult longevity. We found that mutation of chico extends fruit fly median life-span by up to 48% in homozygotes and 36% in heterozygotes. Extension of life-span was not a result of impaired oogenesis in chico females, nor was it consistently correlated with increased stress resistance. The dwarf phenotype of chico homozygotes was also unnecessary for extension of life-span. The role of insulin/IGF signaling in regulating animal aging is therefore evolutionarily conserved.
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            Interventions to Slow Aging in Humans: Are We Ready?

            The workshop entitled ‘Interventions to Slow Aging in Humans: Are We Ready?’ was held in Erice, Italy, on October 8–13, 2013, to bring together leading experts in the biology and genetics of aging and obtain a consensus related to the discovery and development of safe interventions to slow aging and increase healthy lifespan in humans. There was consensus that there is sufficient evidence that aging interventions will delay and prevent disease onset for many chronic conditions of adult and old age. Essential pathways have been identified, and behavioral, dietary, and pharmacologic approaches have emerged. Although many gene targets and drugs were discussed and there was not complete consensus about all interventions, the participants selected a subset of the most promising strategies that could be tested in humans for their effects on healthspan. These were: (i) dietary interventions mimicking chronic dietary restriction (periodic fasting mimicking diets, protein restriction, etc.); (ii) drugs that inhibit the growth hormone/IGF-I axis; (iii) drugs that inhibit the mTOR–S6K pathway; or (iv) drugs that activate AMPK or specific sirtuins. These choices were based in part on consistent evidence for the pro-longevity effects and ability of these interventions to prevent or delay multiple age-related diseases and improve healthspan in simple model organisms and rodents and their potential to be safe and effective in extending human healthspan. The authors of this manuscript were speakers and discussants invited to the workshop. The following summary highlights the major points addressed and the conclusions of the meeting.
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              Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer

              Summary The National Institute on Aging Interventions Testing Program (ITP) evaluates agents hypothesized to increase healthy lifespan in genetically heterogeneous mice. Each compound is tested in parallel at three sites, and all results are published. We report the effects of lifelong treatment of mice with four agents not previously tested: Protandim, fish oil, ursodeoxycholic acid (UDCA) and metformin – the latter with and without rapamycin, and two drugs previously examined: 17‐α‐estradiol and nordihydroguaiaretic acid (NDGA), at doses greater and less than used previously. 17‐α‐estradiol at a threefold higher dose robustly extended both median and maximal lifespan, but still only in males. The male‐specific extension of median lifespan by NDGA was replicated at the original dose, and using doses threefold lower and higher. The effects of NDGA were dose dependent and male specific but without an effect on maximal lifespan. Protandim, a mixture of botanical extracts that activate Nrf2, extended median lifespan in males only. Metformin alone, at a dose of 0.1% in the diet, did not significantly extend lifespan. Metformin (0.1%) combined with rapamycin (14 ppm) robustly extended lifespan, suggestive of an added benefit, based on historical comparison with earlier studies of rapamycin given alone. The α‐glucosidase inhibitor, acarbose, at a concentration previously tested (1000 ppm), significantly increased median longevity in males and 90th percentile lifespan in both sexes, even when treatment was started at 16 months. Neither fish oil nor UDCA extended lifespan. These results underscore the reproducibility of ITP longevity studies and illustrate the importance of identifying optimal doses in lifespan studies.
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                Author and article information

                Contributors
                +718-430-4278 , derek.huffman@einstein.yu.edu
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                19 June 2018
                19 June 2018
                2018
                : 9
                : 2394
                Affiliations
                [1 ]ISNI 0000000121791997, GRID grid.251993.5, Department of Molecular Pharmacology, , Albert Einstein College of Medicine, ; Bronx, NY 10461 USA
                [2 ]ISNI 0000000121791997, GRID grid.251993.5, Department of Medicine, , Albert Einstein College of Medicine, ; Bronx, NY 10461 USA
                [3 ]ISNI 0000000121791997, GRID grid.251993.5, Institute for Aging Research, , Albert Einstein College of Medicine, ; Bronx, NY 10461 USA
                [4 ]ISNI 0000000121791997, GRID grid.251993.5, Department of Genetics, , Albert Einstein College of Medicine, ; Bronx, NY 10461 USA
                [5 ]ISNI 0000000121791997, GRID grid.251993.5, Obstetrics and Gynecology and Women’s Health, , Albert Einstein College of Medicine, ; Bronx, 10461 NY USA
                [6 ]ISNI 0000 0001 0629 5880, GRID grid.267309.9, Barshop Institute for Longevity and Aging Studies and Department of Pathology, , University of Texas Health Science Center at San Antonio, ; San Antonio, TX 78245 USA
                [7 ]ISNI 0000 0004 0617 9080, GRID grid.414059.d, Geriatric Research, Education & Clinical Center (GRECC), , Audie L. Murphy Memorial VA Hospital, ; San Antonio, TX 78229 USA
                [8 ]ISNI 0000000106344187, GRID grid.265892.2, School of Health Professions, , The University of Alabama at Birmingham, ; Birmingham, AL 35294 USA
                [9 ]ISNI 0000 0001 0790 959X, GRID grid.411377.7, School of Public Health, , Indiana University, ; Bloomington, IN 47405 USA
                [10 ]ISNI 0000000106344187, GRID grid.265892.2, School of Public Health, , The University of Alabama at Birmingham, ; Birmingham, AL 35294 USA
                [11 ]ISNI 0000 0001 0657 5612, GRID grid.417886.4, Department of Pharmacokinetics and Drug Metabolism, , Amgen Inc., ; Thousand Oaks, CA 91320 USA
                [12 ]ISNI 0000 0001 0657 5612, GRID grid.417886.4, Oncology Research, Amgen Inc., ; Thousand Oaks, CA 91320 USA
                [13 ]ISNI 0000 0001 2156 6853, GRID grid.42505.36, Davis School of Gerontology, , University of Southern California, ; Los Angeles, CA 90089 USA
                Author information
                http://orcid.org/0000-0003-4448-8565
                http://orcid.org/0000-0002-1185-3987
                http://orcid.org/0000-0002-9026-9999
                Article
                4805
                10.1038/s41467-018-04805-5
                6008442
                29921922
                b0fa9678-fbbe-49bc-8e5c-8ee172f3c743
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 31 August 2017
                : 16 May 2018
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