CoChat
Sign Up
Cited by 34

The DOI matches its Crossref record; 7 of the 7 references it cites were found in a registry or an index.

Ovariectomy uncouples lifespan from metabolic health and reveals a sex-hormone-dependent role of hepatic mTORC2 in aging

Arriola Apelo, Sebastian I, Lin, Amy, Brinkman, Jacqueline A, Meyer, Emma, Morrison, Mark, Tomasiewicz, Jay L, Pumper, Cassidy P, Baar, Emma L, Richardson, Nicole E, Alotaibi, Mohammed, Lamming, Dudley W·2020·eLife
DOI 10.7554/elife.56177PMC PMC7386906
Open this paper in CoChat — free account

Abstract

Inhibition of mTOR (mechanistic Target Of Rapamycin) signaling by rapamycin promotes healthspan and longevity more strongly in females than males, perhaps because inhibition of hepatic mTORC2 (mTOR Complex 2) specifically reduces the lifespan of males. Here, we demonstrate using gonadectomy that the sex-specific impact of reduced hepatic mTORC2 is not reversed by depletion of sex hormones. Intriguingly, we find that ovariectomy uncouples lifespan from metabolic health, with ovariectomized females having improved survival despite paradoxically having increased adiposity and decreased control of blood glucose levels. Further, ovariectomy unexpectedly promotes midlife survival of female mice lacking hepatic mTORC2, significantly increasing the survival of those mice that do not develop cancer. In addition to identifying a sex hormone-dependent role for hepatic mTORC2 in female longevity, our results demonstrate that metabolic health is not inextricably linked to lifespan in mammals, and highlight the importance of evaluating healthspan in mammalian longevity studies.

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 · 10.7554/elife.56177

Cites

7 of 7 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?

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: 45

  1. Arantes-Oliveira, 2002, Regulation of life-span by germ-line stem cells in Caenorhabditis elegans, Science, 295, 502, 10.1126/science.1065768 · DOI
  2. Arriola Apelo, 2016, Intermittent administration of rapamycin extends the life span of female C57BL/6J mice, The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 71, 876, 10.1093/gerona/glw064 · DOI
  3. Asdell, 1967, The effects of sex steroid hormones upon longevity in rats, Reproduction, 14, 113, 10.1530/jrf.0.0140113 · DOI
  4. Bailey, 1980, Role of ovarian hormones in the long-term control of glucose homeostasis effects of insulin secretion, Diabetologia, 19, 475, 10.1007/BF00281829 · DOI
  5. Bansal, 2015, Uncoupling lifespan and healthspan in Caenorhabditis elegans longevity mutants, PNAS, 112, E277, 10.1073/pnas.1412192112 · DOI · Paper page
  6. Bellantuono, 2020, A toolbox for the longitudinal assessment of healthspan in aging mice, Nature Protocols, 15, 540, 10.1038/s41596-019-0256-1 · DOI · Paper page
  7. Benedusi, 2015, Ovariectomy shortens the life span of female mice, Oncotarget, 6, 10801, 10.18632/oncotarget.2984 · DOI
  8. Berman, 2006, Germ-cell loss extends C. elegans life span through regulation of DAF-16 by kri-1 and lipophilic-hormone signaling, Cell, 124, 1055, 10.1016/j.cell.2006.01.039 · DOI
  9. Bitto, 2016, Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice, eLife, 5, 10.7554/eLife.16351 · DOI · Paper page
  10. Brayton, 2012, Pathobiology of aging mice and GEM: background strains and experimental design, Veterinary Pathology, 49, 85, 10.1177/0300985811430696 · DOI
  11. Chang, 2019, TGFB-INHB/activin signaling regulates age-dependent autophagy and cardiac health through inhibition of MTORC2, Autophagy, 6, 1, 10.1080/15548627.2019.1704117 · DOI · Paper page
  12. Chellappa, 2019, Hypothalamic mTORC2 is essential for metabolic health and longevity, Aging Cell, 18, 10.1111/acel.13014 · DOI · Paper page
  13. Comhaire, 2016, Hormone replacement therapy and longevity, Andrologia, 48, 65, 10.1111/and.12419 · DOI
  14. Drori, 1976, Environmental effects on longevity in the male rat: exercise, mating, castration and restricted feeding, Experimental Gerontology, 11, 25, 10.1016/0531-5565(76)90007-3 · DOI
  15. Dumas, 2020, Next generation strategies for geroprotection via mTORC1 inhibition, The Journals of Gerontology: Series A, 75, 14, 10.1093/gerona/glz056 · DOI
  16. Garratt, 2017, Sex differences in lifespan extension with acarbose and 17-α estradiol: gonadal hormones underlie male-specific improvements in glucose tolerance and mTORC2 signaling, Aging Cell, 16, 1256, 10.1111/acel.12656 · DOI · Paper page
  17. Garratt, 2018, Male lifespan extension with 17-α estradiol is linked to a sex-specific metabolomic response modulated by gonadal hormones in mice, Aging Cell, 17, 10.1111/acel.12786 · DOI · Paper page
  18. Hatle, 2013, Life-extending ovariectomy in grasshoppers increases somatic storage, but dietary restriction with an equivalent feeding rate does not, Experimental Gerontology, 48, 966, 10.1016/j.exger.2013.06.006 · DOI
  19. Inoue, 2010, Effects of castration on insulin levels and glucose tolerance in the mouse differ from those in man, The Prostate, 70, 1628, 10.1002/pros.21198 · DOI
  20. Iwasa, 2018, The effects of ovariectomy and lifelong high-fat diet consumption on body weight, appetite, and lifespan in female rats, Hormones and Behavior, 97, 25, 10.1016/j.yhbeh.2017.10.005 · DOI
  21. Kaeberlein, 2005, Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients, Science, 310, 1193, 10.1126/science.1115535 · DOI · Paper page
  22. Kaeberlein, 2018, How healthy is the healthspan concept?, GeroScience, 40, 361, 10.1007/s11357-018-0036-9 · DOI · Paper page
  23. Kapahi, 2004, Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway, Current Biology, 14, 885, 10.1016/j.cub.2004.03.059 · DOI · Paper page
  24. Kennedy, 2016, The mechanistic target of rapamycin: the grand ConducTOR of metabolism and aging, Cell Metabolism, 23, 990, 10.1016/j.cmet.2016.05.009 · DOI · Paper page
  25. Kleinert, 2014, Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo, Molecular Metabolism, 3, 630, 10.1016/j.molmet.2014.06.004 · DOI
  26. Lamming, 2012, Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity, Science, 335, 1638, 10.1126/science.1215135 · DOI · Paper page
  27. Lamming, 2014, Diminished mTOR signaling: a common mode of action for endocrine longevity factors, SpringerPlus, 3, 10.1186/2193-1801-3-735 · DOI · Paper page
  28. Lamming, 2014, Hepatic signaling by the mechanistic target of rapamycin complex 2 (mTORC2), The FASEB Journal, 28, 300, 10.1096/fj.13-237743 · DOI
  29. Lamming, 2014, Depletion of rictor, an essential protein component of mTORC2, decreases male lifespan, Aging Cell, 13, 911, 10.1111/acel.12256 · DOI · Paper page
  30. Levy, 1998, Correct homeostasis model assessment (HOMA) evaluation uses the computer program, Diabetes Care, 21, 2191, 10.2337/diacare.21.12.2191 · DOI
  31. Medvedik, 2007, MSN2 and MSN4 link calorie restriction and TOR to sirtuin-mediated lifespan extension in Saccharomyces cerevisiae, PLOS Biology, 5, 10.1371/journal.pbio.0050261 · DOI · Paper page
  32. Miller, 2014, Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction, Aging Cell, 13, 468, 10.1111/acel.12194 · DOI
  33. Min, 2012, The lifespan of korean eunuchs, Current Biology, 22, R792, 10.1016/j.cub.2012.06.036 · DOI
  34. Mizunuma, 2014, mTORC2-SGK-1 acts in two environmentally responsive pathways with opposing effects on longevity, Aging Cell, 13, 869, 10.1111/acel.12248 · DOI · Paper page
  35. Nadon, 2008, Design of aging intervention studies: the NIA interventions testing program, Age, 30, 187, 10.1007/s11357-008-9048-1 · DOI · Paper page
  36. Pirimoglu, 2011, Glucose tolerance of premenopausal women after menopause due to surgical removal of ovaries, Climacteric, 14, 453, 10.3109/13697137.2010.539723 · DOI
  37. Postic, 1999, Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using cre recombinase, Journal of Biological Chemistry, 274, 305, 10.1074/jbc.274.1.305 · DOI · Paper page
  38. Powers, 2006, Extension of chronological life span in yeast by decreased TOR pathway signaling, Genes & Development, 20, 174, 10.1101/gad.1381406 · DOI · Paper page
  39. Sarbassov, 2006, Prolonged rapamycin treatment inhibits mTORC2 assembly and akt/PKB, Molecular Cell, 22, 159, 10.1016/j.molcel.2006.03.029 · DOI · Paper page
  40. Schreiber, 2015, Rapamycin-mediated mTORC2 inhibition is determined by the relative expression of FK506-binding proteins, Aging Cell, 14, 265, 10.1111/acel.12313 · DOI
  41. Schreiber, 2019, A novel rapamycin analog is highly selective for mTORC1 in vivo, Nature Communications, 10, 10.1038/s41467-019-11174-0 · DOI · Paper page
  42. Soukas, 2009, Rictor/TORC2 regulates fat metabolism, feeding, growth, and life span in Caenorhabditis elegans, Genes & Development, 23, 496, 10.1101/gad.1775409 · DOI · Paper page
  43. Stubbins, 2012, Estrogen modulates abdominal adiposity and protects female mice from obesity and impaired glucose tolerance, European Journal of Nutrition, 51, 861, 10.1007/s00394-011-0266-4 · DOI
  44. Yu, 2019, Calorie-Restriction-Induced insulin sensitivity is mediated by adipose mTORC2 and not required for lifespan extension, Cell Reports, 29, 236, 10.1016/j.celrep.2019.08.084 · DOI · Paper page
  45. Yuan, 2015, Effects of estrogen on insulin sensitivity and adipokines in mice, Zhongguo Yi Xue Ke Xue Yuan Xue Bao. Acta Academiae Medicinae Sinicae, 37, 269, 10.3881/j.issn.1000-503X.2015.03.004 · DOI

Cited by

Sorted by citations

See all 34

Metadata

Authors
Arriola Apelo, S. I., Lin, A., Brinkman, J. A., Meyer, E., Morrison, M., Tomasiewicz, J. L., Pumper, C. P., Baar, E. L., Richardson, N. E., Alotaibi, M., & Lamming, D. W.
Affiliations
  • Department of Dairy Science, University of Wisconsin-Madison, Madison, United States
  • William S. Middleton Memorial Veterans Hospital, Madison, United States
ORCID
Lamming, Dudley W
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2020-07-28
Volume
9
ISSN
2050-084X
DOI
10.7554/elife.56177
PMC
PMC7386906
Cited by
34
References
7
Language
en
Licence
Funders
  • American Federation for Aging Research
  • National Institute on Aging (AG041765, AG050135, AG051974, AG056771, AG062328, AG000213)
  • American Diabetes Association (1-16-PMF-001)
  • National Center for Advancing Translational Sciences (UL1TR002373)
  • Glenn Foundation for Medical Research
  • U.S. Department of Veterans Affairs (I01-BX004031)
  • School of Medicine and Public Health, University of Wisconsin-Madison

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