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Depletion of Rictor, an essential protein component of m TORC 2, decreases male lifespan

Lamming, Dudley W., Mihaylova, Maria M., Katajisto, Pekka, Baar, Emma L., Yilmaz, Omer H., Hutchins, Amanda, Gultekin, Yetis, Gaither, Rachel, Sabatini, David M.·2014·Aging Cell
DOI 10.1111/acel.12256PMC PMC4172536
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Abstract

Summary: Rapamycin, an inhibitor of the mechanistic target of rapamycin (m TOR), robustly extends the lifespan of model organisms including mice. We recently found that chronic treatment with rapamycin not only inhibits m TOR complex 1 (m TORC 1), the canonical target of rapamycin, but also inhibits m TOR complex 2 (m TORC 2) in vivo. While genetic evidence strongly suggests that inhibition of m TORC 1 is sufficient to promote longevity, the impact of m TORC 2 inhibition on mammalian longevity has not been assessed. RICTOR is a protein component of m TORC 2 that is essential for its activity. We examined three different mouse models of Rictor loss: mice heterozygous for Rictor, mice lacking hepatic Rictor, and mice in which Rictor was inducibly deleted throughout the body in adult animals. Surprisingly, we find that depletion of RICTOR significantly decreases male, but not female, lifespan. While the mechanism by which RICTOR loss impairs male survival remains obscure, we find that the effect of RICTOR depletion on lifespan is independent of the role of hepatic m TORC 2 in promoting glucose tolerance. Our results suggest that inhibition of m TORC 2 signaling is detrimental to males, which may explain in part why interventions that decrease m TOR signaling show greater efficacy in females.

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Figure 1 Depletion of RICTOR impairs male, but not female, lifespan. (A,B) Kaplan–Meier plots showing lifespans of (A) male and (B) female mice heterozygous for Rictor. (C,D) Kaplan–Meier plots showing lifespans of (C) male and (D) female mice in which Rictor was deleted specifically in the liver (L-RKO). Littermate control mice (wt) of rictor+/− and L-RKO mice were pooled for analysis, and control lifespan curves are duplicated in A/C and B/D. The survival of 155 mice was analyzed as follows: Females (39 wild-type, 21 rictor+/−, 33 L-RKO), Males (30 wild-type, 14 rictor+/−, 18 L-RKO). Raw data and statistical information can be found in Tables S1 and S2.
Figure 1 Depletion of RICTOR impairs male, but not female, lifespan. (A,B) Kaplan–Meier plots showing lifespans of (A) male and (B) female mice heterozygous for Rictor. (C,D) Kaplan–Meier plots showing lifespans of (C) male and (D) female mice in which Rictor was deleted specifically in the liver (L-RKO). Littermate control mice (wt) of rictor+/− and L-RKO mice were pooled for analysis, and control lifespan curves are duplicated in A/C and B/D. The survival of 155 mice was analyzed as follows: Females (39 wild-type, 21 rictor+/−, 33 L-RKO), Males (30 wild-type, 14 rictor+/−, 18 L-RKO). Raw data and statistical information can be found in Tables S1 and S2.CC BY · PubMed Central
Figure 2 Inducible depletion of RICTOR impairs male lifespan. (A) Kaplan–Meier plot showing survival of male wild-type and UbC-RKO mice treated with tamoxifen at 10 weeks of age. The survival of 26 mice was analyzed as follows: Males (11 wild-type, 15 UbC-RKO). (B) Kaplan–Meier plot showing survival of male wild-type and UbC-RKO mice treated with tamoxifen at 9 months of age. The survival of 25 mice was analyzed as follows: Males (10 wild-type, 15 UbC-RKO). Raw data and statistical information can be found in Tables S1 and S2. (C) Depletion of RICTOR results in gray hair and kyphosis. Pictured: 15-month-old wild-type (left) and UbC-RKO mice (right) from which Rictor was excised at 10 weeks of age. (D) Weight change of wild-type and UbC-RKO mice over 30 weeks, starting at 10 weeks of age.
Figure 2 Inducible depletion of RICTOR impairs male lifespan. (A) Kaplan–Meier plot showing survival of male wild-type and UbC-RKO mice treated with tamoxifen at 10 weeks of age. The survival of 26 mice was analyzed as follows: Males (11 wild-type, 15 UbC-RKO). (B) Kaplan–Meier plot showing survival of male wild-type and UbC-RKO mice treated with tamoxifen at 9 months of age. The survival of 25 mice was analyzed as follows: Males (10 wild-type, 15 UbC-RKO). Raw data and statistical information can be found in Tables S1 and S2. (C) Depletion of RICTOR results in gray hair and kyphosis. Pictured: 15-month-old wild-type (left) and UbC-RKO mice (right) from which Rictor was excised at 10 weeks of age. (D) Weight change of wild-type and UbC-RKO mice over 30 weeks, starting at 10 weeks of age.CC BY · PubMed Central
Figure 3 Analysis of mTOR signaling in the livers of L-RKO and rictor+/− mice. (A,B) Analysis of protein expression and phosphorylation in the livers of wild-type and (A) rictor+/− and (B) L-RKO mice fasted overnight and then refed for 3 h. (C) Quantification of the expression of RICTOR and AKT relative to β-tubulin, and the phosphorylation of AKT S473, T450, and T308 relative to AKT. Analysis was of 10-week-old mice (n = 14 wild-type, 8 rictor+/− and 7 L-RKO males; 12 wild-type, 6 rictor+/− and 6 L-RKO females, * = P < 0.05). (D) Analysis of the phosphorylation of mTORC1 substrates in the livers of wild-type and L-RKO mice fasted overnight and then refed for 3 h. (E) Quantification of the phosphorylation of the mTORC1 substrates S6K1 T389, 4E-BP1 T37/S46, and 4E-BP1 S65, and the S6K1 substrate S6 S240/244 relative to each total protein in 10-week-old mice (n = 6 wild-type, 7 L-RKO males; 6 wild-type, 6 L-RKO females, * = P < 0.05).
Figure 3 Analysis of mTOR signaling in the livers of L-RKO and rictor+/− mice. (A,B) Analysis of protein expression and phosphorylation in the livers of wild-type and (A) rictor+/− and (B) L-RKO mice fasted overnight and then refed for 3 h. (C) Quantification of the expression of RICTOR and AKT relative to β-tubulin, and the phosphorylation of AKT S473, T450, and T308 relative to AKT. Analysis was of 10-week-old mice (n = 14 wild-type, 8 rictor+/− and 7 L-RKO males; 12 wild-type, 6 rictor+/− and 6 L-RKO females, * = P < 0.05). (D) Analysis of the phosphorylation of mTORC1 substrates in the livers of wild-type and L-RKO mice fasted overnight and then refed for 3 h. (E) Quantification of the phosphorylation of the mTORC1 substrates S6K1 T389, 4E-BP1 T37/S46, and 4E-BP1 S65, and the S6K1 substrate S6 S240/244 relative to each total protein in 10-week-old mice (n = 6 wild-type, 7 L-RKO males; 6 wild-type, 6 L-RKO females, * = P < 0.05).CC BY · PubMed Central
Figure 4 L-RKO mice, but not rictor+/− mice, have impaired glucose tolerance. (A) Glucose tolerance is impaired in 10-week-old male L-RKO mice, but not in male rictor+/− mice (n = 7 wt, 7 rictor+/−, 7 L-RKO). (B) Glucose tolerance test performed on 10-week-old female wt, rictor+/− and L-RKO mice (n = 9 wt, 8 rictor+/−, 6 L-RKO). (C) Glucose tolerance is impaired in 9-month-old male L-RKO mice, but not rictor+/− mice (n = 10 wt, 6 rictor+/−, 8 L-RKO). (D) Glucose tolerance is impaired in 15-month-old female L-RKO, but not rictor+/− mice (n = 7 wt, 10 rictor+/−, 6 L-RKO). (E) Impaired glucose tolerance in female L-RKO mice at 4 months of age (n = 5 wt, 8 L-RKO). In all panels, *= P < 0.05, # = P < 0.06 L-RKO vs. wild-type, two-tailed t-test; error bars indicate standard error. (F) Model for the regulation of lifespan by mTORC1 and mTORC2.
Figure 4 L-RKO mice, but not rictor+/− mice, have impaired glucose tolerance. (A) Glucose tolerance is impaired in 10-week-old male L-RKO mice, but not in male rictor+/− mice (n = 7 wt, 7 rictor+/−, 7 L-RKO). (B) Glucose tolerance test performed on 10-week-old female wt, rictor+/− and L-RKO mice (n = 9 wt, 8 rictor+/−, 6 L-RKO). (C) Glucose tolerance is impaired in 9-month-old male L-RKO mice, but not rictor+/− mice (n = 10 wt, 6 rictor+/−, 8 L-RKO). (D) Glucose tolerance is impaired in 15-month-old female L-RKO, but not rictor+/− mice (n = 7 wt, 10 rictor+/−, 6 L-RKO). (E) Impaired glucose tolerance in female L-RKO mice at 4 months of age (n = 5 wt, 8 L-RKO). In all panels, *= P < 0.05, # = P < 0.06 L-RKO vs. wild-type, two-tailed t-test; error bars indicate standard error. (F) Model for the regulation of lifespan by mTORC1 and mTORC2.CC BY · PubMed Central

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Metadata

Authors
Lamming, D. W., Mihaylova, M. M., Katajisto, P., Baar, E. L., Yilmaz, O. H., Hutchins, A., Gultekin, Y., Gaither, R., & Sabatini, D. M.
Affiliations
  • Department of Medicine University of Wisconsin Madison WI 53705 USA
  • Whitehead Institute for Biomedical Research Cambridge MA 02142 USA
Venue
Aging Cell
Publisher
Wiley
Published
2014-07-25
Volume
13
Issue
5
Pages
911-917
ISSN
  • 1474-9718
  • 1474-9726
DOI
10.1111/acel.12256
PMC
PMC4172536
Cited by
111
References
8
Language
en
Licence
creativecommons.org/licenses/by/3.0/ (vor)
Funders
  • National Institute on Aging (AG041765)
  • American Federation for Aging Research
  • Ellison Medical Foundation
  • Howard Hughes Medical Institute
  • Damon Runyon Cancer Research Foundation (DRG-2146-13)
  • American Diabetes Association

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