Regulation of mTOR complexes in long-lived growth hormone receptor knockout and Snell dwarf mice

被引:0
作者
Shi, Xiaofang [1 ]
Endicott, S. Joseph [1 ]
Miller, Richard A. [1 ,2 ,3 ]
机构
[1] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Geriatr Ctr, Ann Arbor, MI 48109 USA
[3] Univ Michigan, Sch Med, Paul F Glenn Ctr Biol Aging Res, Ann Arbor, MI 48109 USA
来源
AGING-US | 2022年 / 14卷 / 06期
关键词
aging; lifespan extension; mTOR; TSC; growth hormone receptor; LIFE-SPAN; MAMMALIAN TARGET; TSC1-TSC2; COMPLEX; PRODUCT TUBERIN; RAPAMYCIN MTOR; CELL-GROWTH; PHOSPHORYLATION; KINASE; MUTANT; RAPTOR;
D O I
暂无
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Downregulation of mTOR (mechanistic target of rapamycin) can extend lifespan in multiple species, including mice. Growth hormone receptor knockout mice (GHRKO) and Snell dwarf mice have 40% or greater lifespan increase, and have lower mTORC1 function, which might reflect alteration in mTORC1 components or alteration of upstream proteins that modulate mTOR activity. Here we report reduction of mTORC components DEPTOR and PRAS40 in liver of these long-lived mice; these changes are opposite in direction to those that would be expected to lead to lower mTORC1 function. In contrast, levels of the upstream regulators TSC1 and TSC2 are elevated in GHRKO and Snell liver, kidney and skeletal muscle, and the ratio of phosphorylated TSC2 to total TSC2 is lower in the tissues of the long-lived mutant mice. In addition, knocking down TSC2 in GHRKO fibroblasts reversed the effects of the GHRKO mutation on mTORC1 function. Thus increased amounts of unphosphorylated, active, inhibitory TSC may contribute to lower mTORC1 function in these mice.
引用
收藏
页码:2442 / 2461
页数:20
相关论文
共 36 条
[11]   Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism [J].
Gingras, AC ;
Gygi, SP ;
Raught, B ;
Polakiewicz, RD ;
Abraham, RT ;
Hoekstra, MF ;
Aebersold, R ;
Sonenberg, N .
GENES & DEVELOPMENT, 1999, 13 (11) :1422-1437
[12]   AMPK phosphorylation of raptor mediates a metabolic checkpoint [J].
Gwinn, Dana M. ;
Shackelford, David B. ;
Egan, Daniel F. ;
Mihaylova, Maria M. ;
Mery, Annabelle ;
Vasquez, Debbie S. ;
Turk, Benjamin E. ;
Shaw, Reuben J. .
MOLECULAR CELL, 2008, 30 (02) :214-226
[13]   The TSC1-TSC2 complex: a molecular switchboard controlling cell growth [J].
Huang, Jingxiang ;
Manning, Brendan D. .
BIOCHEMICAL JOURNAL, 2008, 412 :179-190
[14]   TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling [J].
Inoki, K ;
Li, Y ;
Zhu, TQ ;
Wu, J ;
Guan, KL .
NATURE CELL BIOLOGY, 2002, 4 (09) :648-657
[15]   Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling [J].
Inoki, K ;
Li, Y ;
Xu, T ;
Guan, KL .
GENES & DEVELOPMENT, 2003, 17 (15) :1829-1834
[16]   Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients [J].
Kaeberlein, M ;
Powers, RW ;
Steffen, KK ;
Westman, EA ;
Hu, D ;
Dang, N ;
Kerr, EO ;
Kirkland, KT ;
Fields, S ;
Kennedy, BK .
SCIENCE, 2005, 310 (5751) :1193-1196
[17]   Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway [J].
Kapahi, P ;
Zid, BM ;
Harper, T ;
Koslover, D ;
Sapin, V ;
Benzer, S .
CURRENT BIOLOGY, 2004, 14 (10) :885-890
[18]   A C-ELEGANS MUTANT THAT LIVES TWICE AS LONG AS WILD-TYPE [J].
KENYON, C ;
CHANG, J ;
GENSCH, E ;
RUDNER, A ;
TABTIANG, R .
NATURE, 1993, 366 (6454) :461-464
[19]   MTOR interacts with Raptor to form a nutrient-sensitive complex that signals to the cell growth machinery [J].
Kim, DH ;
Sarbassov, DD ;
Ali, SM ;
King, JE ;
Latek, RR ;
Erdjument-Bromage, H ;
Tempst, P ;
Sabatini, DM .
CELL, 2002, 110 (02) :163-175
[20]   mTOR at the nexus of nutrition, growth, ageing and disease (vol 29, pg 145, 2020) [J].
Liu, Grace Y. ;
Sabatini, David M. .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2020, 21 (04) :246-246