19
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          The FDA approved drug rapamycin increases lifespan in rodents and delays age-related dysfunction in rodents and humans. Nevertheless, important questions remain regarding the optimal dose, duration, and mechanisms of action in the context of healthy aging. Here we show that 3 months of rapamycin treatment is sufficient to increase life expectancy by up to 60% and improve measures of healthspan in middle-aged mice. This transient treatment is also associated with a remodeling of the microbiome, including dramatically increased prevalence of segmented filamentous bacteria in the small intestine. We also define a dose in female mice that does not extend lifespan, but is associated with a striking shift in cancer prevalence toward aggressive hematopoietic cancers and away from non-hematopoietic malignancies. These data suggest that a short-term rapamycin treatment late in life has persistent effects that can robustly delay aging, influence cancer prevalence, and modulate the microbiome.

          DOI: http://dx.doi.org/10.7554/eLife.16351.001

          eLife digest

          Old age is the single greatest risk factor for many diseases including heart disease, arthritis, cancer and dementia. By delaying the biological aging process, it may be possible to reduce the impact of age-related diseases, which could have great benefits for society and the quality of life of individuals. A drug called rapamycin, which is currently used to prevent organ rejection in transplant recipients, is a leading candidate for targeting aging. Rapamycin increases lifespan in several types of animals and delays the onset of many age-related conditions in mice.

          Nearly all of the aging-related studies in mice have used the same dose of rapamycin given throughout the lives of the animals. Lifelong treatment with rapamycin wouldn’t be practical in humans and is likely to result in undesirable side effects. For example, the high doses of rapamycin used in transplant patients cause side effects including poor wound healing, elevated blood cholesterol levels, and mouth ulcers. Before rapamycin can be used to promote healthy aging in humans, researchers must better understand at what point in life the drug is most effective, and what dose to use to provide the biggest benefit while limiting the side effects.

          Now, Bitto et al. show that treating mice with rapamycin for a short period during middle age increases the life expectancy of the mice by up to 60%. In the experiments, mice were given two different doses of rapamycin for only three months starting at 20 months old (equivalent to about 60-65 years old in humans). After receiving the lower dose, both male and female mice lived about 50% longer than untreated mice, and showed improvements in their muscle strength and motor coordination. When given the higher dose, male mice showed an even greater increase in life expectancy, but the female mice did not. These female mice had an increased risk of developing rare and aggressive forms of blood cancer, but were protected from other types of cancer.

          Both drug treatments also caused substantial changes in the gut bacteria of the male and female mice, which could be related to effects of rapamycin on metabolism, immunity and health. More studies are needed to uncover precisely how such short-term treatments can yield long-term changes in the body, and how such changes are related to lifespan and healthy aging.

          DOI: http://dx.doi.org/10.7554/eLife.16351.002

          Related collections

          Most cited references23

          • Record: found
          • Abstract: found
          • Article: not found

          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.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Rapamycin slows aging in mice.

            Rapamycin increases lifespan in mice, but whether this represents merely inhibition of lethal neoplastic diseases, or an overall slowing in multiple aspects of aging is currently unclear. We report here that many forms of age-dependent change, including alterations in heart, liver, adrenal glands, endometrium, and tendon, as well as age-dependent decline in spontaneous activity, occur more slowly in rapamycin-treated mice, suggesting strongly that rapamycin retards multiple aspects of aging in mice, in addition to any beneficial effects it may have on neoplastic disease. We also note, however, that mice treated with rapamycin starting at 9 months of age have significantly higher incidence of testicular degeneration and cataracts; harmful effects of this kind will guide further studies on timing, dosage, and tissue-specific actions of rapamycin relevant to the development of clinically useful inhibitors of TOR action. © 2012 The Authors. Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells.

              Age-related declines in hematopoietic stem cell (HSC) function may contribute to anemia, poor response to vaccination, and tumorigenesis. Here, we show that mammalian target of rapamycin (mTOR) activity is increased in HSCs from old mice compared to those from young mice. mTOR activation through conditional deletion of Tsc1 in the HSCs of young mice mimicked the phenotype of HSCs from aged mice in various ways. These included increased abundance of the messenger RNA encoding the CDK inhibitors p16(Ink4a), p19(Arf), and p21(Cip1); a relative decrease in lymphopoiesis; and impaired capacity to reconstitute the hematopoietic system. In old mice, rapamycin increased life span, restored the self-renewal and hematopoiesis of HSCs, and enabled effective vaccination against a lethal challenge with influenza virus. Together, our data implicate mTOR signaling in HSC aging and show the potential of mTOR inhibitors for restoring hematopoiesis in the elderly.
                Bookmark

                Author and article information

                Contributors
                Role: Reviewing editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                23 August 2016
                2016
                : 5
                : e16351
                Affiliations
                [1 ]deptDepartment of Pathology , University of Washington , Seattle, United States
                [2 ]deptVaccine and Infectious Disease Division , Fred Hutchinson Cancer Research Center , Seattle, United States
                [3 ]deptDepartment of Environmental and Occupational Health Sciences , University of Washington , Seattle, United States
                [4 ]deptDepartment of Biostatistics , University of Washington , Seattle, United States
                [5 ]deptDepartment of Veterinary Pathobiology , University of Missouri , Columbia, United States
                [6 ]deptDepartment of Comparative Medicine , University of Washington , Seattle, United States
                [7]Harvard University , United States
                [8]Harvard University , United States
                Author notes
                [†]

                These authors contributed equally to this work.

                Author information
                http://orcid.org/0000-0002-1311-3421
                Article
                16351
                10.7554/eLife.16351
                4996648
                27549339
                27fd0411-354a-4d32-a35c-06ba63faa7e1
                © 2016, Bitto et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 24 March 2016
                : 03 August 2016
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000049, National Institute on Aging;
                Award ID: T32AG000057
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001691, Japan Society for the Promotion of Science;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100008732, Uehara Memorial Foundation;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100004358, Samsung;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000049, National Institute on Aging;
                Award ID: P30AG013280
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100007812, University of Washington;
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Cancer Biology
                Developmental Biology and Stem Cells
                Research Article
                Custom metadata
                2.5
                Three months treatment with the drug rapamycin increases lifespan, alters cancer prevalence, remodels the microbiome, and improves functional measures of health in middle aged mice in a dose- and sex-dependent manner.

                Life sciences
                aging,longevity,mtor,microbiome,cancer,healthspan,mouse
                Life sciences
                aging, longevity, mtor, microbiome, cancer, healthspan, mouse

                Comments

                Comment on this article