CoChat
Sign Up
Cited by 62

The DOI matches its Crossref record; 20 of the 20 references it cites were found in a registry or an index.

Hypothalamic mTORC2 is essential for metabolic health and longevity

Chellappa, Karthikeyani, Brinkman, Jacqueline A., Mukherjee, Sarmistha, Morrison, Mark, Alotaibi, Mohammed I., Carbajal, Kathryn A., Alhadeff, Amber L., Perron, Isaac J., Yao, Rebecca, Purdy, Cole S., DeFelice, Denise M., Wakai, Matthew H., Tomasiewicz, Jay, Lin, Amy, Meyer, Emma, Peng, Yajing, Arriola Apelo, Sebastian I., Puglielli, Luigi, Betley, J. Nicholas, Paschos, Georgios K., Baur, Joseph A., Lamming, Dudley W.·2019·Aging Cell
DOI 10.1111/acel.13014PMC PMC6718533
Open this paper in CoChat — free account

Abstract

The mechanistic target of rapamycin (mTOR) is an evolutionarily conserved protein kinase that regulates growth and metabolism. mTOR is found in two protein complexes, mTORC1 and mTORC2, that have distinct components and substrates and are both inhibited by rapamycin, a macrolide drug that robustly extends lifespan in multiple species including worms and mice. Although the beneficial effect of rapamycin on longevity is generally attributed to reduced mTORC1 signaling, disruption of mTORC2 signaling can also influence the longevity of worms, either positively or negatively depending on the temperature and food source. Here, we show that loss of hypothalamic mTORC2 signaling in mice decreases activity level, increases the set point for adiposity, and renders the animals susceptible to diet‐induced obesity. Hypothalamic mTORC2 signaling normally increases with age, and mice lacking this pathway display higher fat mass and impaired glucose homeostasis throughout life, become more frail with age, and have decreased overall survival. We conclude that hypothalamic mTORC2 is essential for the normal metabolic health, fitness, and lifespan of mice. Our results have implications for the use of mTORC2‐inhibiting pharmaceuticals in the treatment of brain cancer and diseases of aging.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1111/acel.13014

Cites

20 of 20 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Genetic inhibition of mTORC2 in one or more tissues of a mouse can result in frailty, hyperphagia, insulin resistance, hyperlipidemia, hypercholesterolemia, hyperglycemia, kyphosis, and/or obesity depending upon the specific tissues in which mTORC2 is inhibited.

    “Genetic inhibition of mTORC2 in one or more tissues of a mouse can result in frailty, hyperphagia, insulin resistance, hyperlipidemia, hypercholesterolemia, hyperglycemia, kyphosis, and/or obesity depending upon the specific tissues in which mTORC2 is inhibited 114–117, 68.”

    From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [115]

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Whole body deficiency of mTORC2 signaling, or tissue-specific inhibition of mTORC2 signaling in the brain, liver, or adipose tissue, reduces lifespan in C57BL/6J mice.

    “Whole body deficiency of mTORC2 signaling, or tissue-specific inhibition of mTORC2 signaling in the brain, liver, or adipose tissue, reduces lifespan in C57BL/6J mice 114–117.”

    From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [115]

    The Results section ('mTORC2 signaling is essential for healthspan and lifespan'; page unavailable) reports that hypothalamic Rictor deletion shortened lifespan in both female and male mice. The Introduction also reports reduced male lifespan after whole-body RICTOR depletion or hepatic Rictor deletion. The paper does not establish reduced lifespan from adipose-specific inhibition, and its Materials and Methods say the experimental mice were backcrossed to C57BL/6N, not C57BL/6J. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 106

  1. 10.1016/j.molmet.2015.03.001 · DOI
  2. 10.1093/gerona/glw064 · DOI
  3. 10.1093/gerona/glw090 · DOI
  4. 10.1111/acel.12425 · DOI · Paper page
  5. 10.1210/jc.76.2.309 · DOI
  6. 10.1038/nrendo.2013.64 · DOI
  7. 10.7554/eLife.16351 · DOI · Paper page
  8. 10.1016/j.cmet.2009.11.010 · DOI · Paper page
  9. 10.1093/ije/dyt160 · DOI
  10. 10.1152/physiolgenomics.00082.2002 · DOI
  11. 10.1126/science.289.5487.2122 · DOI · Paper page
  12. 10.3389/fphys.2018.00898 · DOI
  13. 10.1523/JNEUROSCI.2781-15.2015 · DOI
  14. 10.1038/nn.4495 · DOI · Paper page
  15. 10.1159/000455865 · DOI
  16. 10.2337/db14-0567 · DOI
  17. 10.1016/j.molmet.2014.12.001 · DOI
  18. 10.1126/science.271.5251.994 · DOI
  19. 10.1158/0008-5472.CAN-08-3014 · DOI
  20. 10.1126/science.1124147 · DOI · Paper page
  21. 10.1113/expphysiol.1987.sp003096 · DOI
  22. 10.1093/gerona/glz056 · DOI
  23. 10.1001/jama.2012.113905 · DOI · Paper page
  24. 10.2337/db15-0982 · DOI
  25. 10.1016/j.celrep.2016.05.092 · DOI · Paper page
  26. 10.1074/jbc.M114.579565 · DOI
  27. 10.1159/000357338 · DOI
  28. 10.1016/j.neuro.2010.10.006 · DOI
  29. 10.1016/j.ccr.2008.12.017 · DOI · Paper page
  30. 10.1126/science.7624777 · DOI · Paper page
  31. 10.1016/j.neuroscience.2012.06.054 · DOI
  32. 10.1111/j.1474-9726.2006.00267.x · DOI · Paper page
  33. 10.2337/db13-0651 · DOI
  34. 10.1093/geronj/48.3.B97 · DOI
  35. 10.1152/jappl.1985.59.3.826 · DOI
  36. 10.1093/gerona/glr027 · DOI
  37. 10.1016/j.exger.2016.05.012 · DOI
  38. 10.1016/S0014-5793(99)00336-1 · DOI
  39. 10.1097/MED.0b013e32830b10bb · DOI
  40. 10.1038/nrendo.2013.67 · DOI · Paper page
  41. 10.1093/gerona/glu315 · DOI
  42. 10.1016/j.cub.2004.09.057 · DOI
  43. 10.1371/journal.pbio.0060254 · DOI
  44. 10.1016/j.cmet.2016.05.009 · DOI · Paper page
  45. 10.2337/db14-0568 · DOI · Paper page
  46. 10.1016/j.molmet.2014.01.014 · DOI
  47. 10.1523/JNEUROSCI.3202-10.2010 · DOI
  48. 10.1186/s12899-018-0036-0 · DOI
  49. 10.1128/MCB.01405-07 · DOI
  50. 10.2337/db09-1061 · DOI
  51. 10.1016/j.amjmed.2014.02.026 · DOI
  52. 10.1186/2193-1801-3-735 · DOI · Paper page
  53. 10.1096/fj.13-237743 · DOI
  54. 10.1111/acel.12256 · DOI · Paper page
  55. 10.1126/science.1215135 · DOI · Paper page
  56. 10.2337/db09-1303 · DOI
  57. 10.1017/thg.2016.56 · DOI
  58. 10.1016/j.brainres.2009.09.050 · DOI
  59. 10.1038/srep39472 · DOI
  60. 10.1111/j.1474-9726.2011.00791.x · DOI
  61. 10.1038/s41467-018-04805-5 · DOI · Paper page
  62. 10.3389/fnins.2017.00055 · DOI
  63. 10.1093/gerona/glq178 · DOI · Paper page
  64. 10.1016/0149-7634(94)90023-X · DOI
  65. 10.1111/acel.12248 · DOI · Paper page
  66. 10.1016/0047-6374(96)01734-4 · DOI
  67. 10.1016/j.cmet.2009.03.005 · DOI
  68. 10.1007/BF00223799 · DOI
  69. 10.1056/NEJMoa1014296 · DOI · Paper page
  70. 10.18632/aging.101346 · DOI
  71. 10.1016/j.cub.2016.12.009 · DOI
  72. 10.1038/427411b · DOI
  73. 10.1016/j.celrep.2018.06.082 · DOI
  74. 10.1159/000100982 · DOI
  75. 10.1126/science.7624776 · DOI · Paper page
  76. 10.1016/j.cub.2015.12.046 · DOI · Paper page
  77. 10.1101/gad.1381406 · DOI · Paper page
  78. 10.1098/rspb.2006.3544 · DOI
  79. 10.1172/JCI41985 · DOI
  80. 10.1038/srep43068 · DOI
  81. 10.1046/j.1525-142x.2002.01053.x · DOI
  82. 10.1016/j.cub.2004.06.054 · DOI · Paper page
  83. 10.1093/ageing/27.5.579 · DOI
  84. 10.1111/acel.12313 · DOI
  85. 10.1016/j.devcel.2006.08.013 · DOI
  86. 10.1101/gad.1775409 · DOI · Paper page
  87. 10.1038/ncomms11365 · DOI
  88. 10.1016/j.neuron.2011.12.010 · DOI
  89. Therneau T. M., 2015, A package for survival analysis in S
  90. 10.1038/nmeth.1806 · DOI · Paper page
  91. 10.1093/gerona/54.11.B492 · DOI
  92. 10.1016/j.cmet.2012.10.008 · DOI
  93. 10.1111/j.1742-1241.2008.01957.x · DOI
  94. 10.1038/nutd.2013.4 · DOI
  95. 10.1503/cmaj.051351 · DOI · Paper page
  96. 10.1093/gerona/glt136 · DOI
  97. 10.1016/j.cmet.2017.07.001 · DOI
  98. 10.1002/cne.21529 · DOI
  99. 10.1016/S0896-6273(03)00331-3 · DOI
  100. 10.1126/scitranslmed.aad3305 · DOI
  101. 10.1016/j.neuron.2012.03.043 · DOI · Paper page
  102. 10.1073/pnas.1417838112 · DOI
  103. 10.1096/fj.201701211R · DOI
  104. 10.1073/pnas.1616255114 · DOI
  105. 10.2174/138920311795659407 · DOI
  106. 10.1007/s10519-010-9425-2 · DOI

Cited by

Sorted by citations

Metadata

Authors
Chellappa, K., Brinkman, J. A., Mukherjee, S., Morrison, M., Alotaibi, M. I., Carbajal, K. A., Alhadeff, A. L., Perron, I. J., Yao, R., Purdy, C. S., DeFelice, D. M., Wakai, M. H., Tomasiewicz, J., Lin, A., Meyer, E., Peng, Y., Arriola Apelo, S. I., Puglielli, L., Betley, J. N., Paschos, G. K., Baur, J. A., & Lamming, D. W.
Affiliations
  • Department of Physiology and Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine University of Pennsylvania Philadelphia PA USA
  • Department of Medicine University of Wisconsin‐Madison Madison WI USA
  • Department of Biology, School of Arts and Sciences University of Pennsylvania Philadelphia PA USA
  • Center for Sleep and Circadian Neurobiology, Perelman School of Medicine University of Pennsylvania Philadelphia PA USA
ORCID
Lamming, Dudley W.
Venue
Aging Cell
Publisher
Wiley
Published
2019-08
Volume
18
Issue
5
ISSN
  • 1474-9718
  • 1474-9726
DOI
10.1111/acel.13014
PMC
PMC6718533
Cited by
62
References
20
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • National Institute on Aging (AG041765, AG050135, AG051974, AG056771, AG062328, AG043483)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK098656)
  • National Institutes of Health
  • American Federation for Aging Research
  • Crohn's and Colitis Foundation
  • Saudi Arabian Cultural Mission
  • American Diabetes Association (1-16-PMF-001)
  • U.S. Department of Veterans Affairs (I01-BX004031)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review