PMID- 34453483
OWN - NLM
STAT- MEDLINE
DCOM- 20220124
LR  - 20221005
IS  - 1474-9726 (Electronic)
IS  - 1474-9718 (Print)
IS  - 1474-9718 (Linking)
VI  - 20
IP  - 9
DP  - 2021 Sep
TI  - Genetic reduction of mTOR extends lifespan in a mouse model of Hutchinson-Gilford 
      Progeria syndrome.
PG  - e13457
LID - 10.1111/acel.13457 [doi]
LID - e13457
AB  - Hutchinson-Gilford progeria syndrome (HGPS) is a rare accelerated aging disorder 
      most notably characterized by cardiovascular disease and premature death from 
      myocardial infarction or stroke. The majority of cases are caused by a de novo 
      single nucleotide mutation in the LMNA gene that activates a cryptic splice donor 
      site, resulting in production of a toxic form of lamin A with a 50 amino acid 
      internal deletion, termed progerin. We previously reported the generation of a 
      transgenic murine model of progeria carrying a human BAC harboring the common 
      mutation, G608G, which in the single-copy state develops features of HGPS that 
      are limited to the vascular system. Here, we report the phenotype of mice bred to 
      carry two copies of the BAC, which more completely recapitulate the phenotypic 
      features of HGPS in skin, adipose, skeletal, and vascular tissues. We further 
      show that genetic reduction of the mechanistic target of rapamycin (mTOR) 
      significantly extends lifespan in these mice, providing a rationale for 
      pharmacologic inhibition of the mTOR pathway in the treatment of HGPS.
CI  - (c) 2021 The Authors. Aging Cell published by the Anatomical Society and John Wiley 
      & Sons Ltd.
FAU - Cabral, Wayne A
AU  - Cabral WA
AD  - Molecular Genetics Section, Center for Precision Health Research, National Human 
      Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
FAU - Tavarez, Urraca L
AU  - Tavarez UL
AD  - Molecular Genetics Section, Center for Precision Health Research, National Human 
      Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
FAU - Beeram, Indeevar
AU  - Beeram I
AD  - Translational Musculoskeletal Innovation Initiative, Carl J. Shapiro Department 
      of Orthopedic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical 
      School, Boston, MA, USA.
FAU - Yeritsyan, Diana
AU  - Yeritsyan D
AD  - Translational Musculoskeletal Innovation Initiative, Carl J. Shapiro Department 
      of Orthopedic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical 
      School, Boston, MA, USA.
FAU - Boku, Yoseph D
AU  - Boku YD
AD  - Molecular Genetics Section, Center for Precision Health Research, National Human 
      Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
FAU - Eckhaus, Michael A
AU  - Eckhaus MA
AD  - Diagnostic and Research Services Branch, Division of Veterinary Resources, Office 
      of the Director, National Institutes of Health, Bethesda, MD, USA.
FAU - Nazarian, Ara
AU  - Nazarian A
AD  - Translational Musculoskeletal Innovation Initiative, Carl J. Shapiro Department 
      of Orthopedic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical 
      School, Boston, MA, USA.
FAU - Erdos, Michael R
AU  - Erdos MR
AD  - Molecular Genetics Section, Center for Precision Health Research, National Human 
      Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
FAU - Collins, Francis S
AU  - Collins FS
AD  - Molecular Genetics Section, Center for Precision Health Research, National Human 
      Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
LA  - eng
GR  - Z01 HG200305/ImNIH/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
DEP - 20210828
PL  - England
TA  - Aging Cell
JT  - Aging cell
JID - 101130839
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - *Disease Models, Animal
MH  - Humans
MH  - *Longevity
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Progeria/*metabolism
MH  - TOR Serine-Threonine Kinases/genetics/*metabolism
PMC - PMC8441492
OTO - NOTNLM
OT  - S6 Kinase
OT  - lamin A/C
OT  - laminopathies
OT  - mTOR
OT  - progeria
COIS- The authors declare no competing interests.
EDAT- 2021/08/29 06:00
MHDA- 2022/01/27 06:00
PMCR- 2021/09/01
CRDT- 2021/08/28 08:38
PHST- 2021/08/29 06:00 [pubmed]
PHST- 2022/01/27 06:00 [medline]
PHST- 2021/08/28 08:38 [entrez]
PHST- 2021/09/01 00:00 [pmc-release]
AID - ACEL13457 [pii]
AID - 10.1111/acel.13457 [doi]
PST - ppublish
SO  - Aging Cell. 2021 Sep;20(9):e13457. doi: 10.1111/acel.13457. Epub 2021 Aug 28.