PMID- 29997249
OWN - NLM
STAT- MEDLINE
DCOM- 20191004
LR  - 20191007
IS  - 1946-6242 (Electronic)
IS  - 1946-6234 (Linking)
VI  - 10
IP  - 449
DP  - 2018 Jul 11
TI  - TORC1 inhibition enhances immune function and reduces infections in the elderly.
LID - eaaq1564 [pii]
LID - 10.1126/scitranslmed.aaq1564 [doi]
AB  - Inhibition of the mechanistic target of rapamycin (mTOR) protein kinase extends 
      life span and ameliorates aging-related pathologies including declining immune 
      function in model organisms. The objective of this phase 2a randomized, 
      placebo-controlled clinical trial was to determine whether low-dose mTOR 
      inhibitor therapy enhanced immune function and decreased infection rates in 264 
      elderly subjects given the study drugs for 6 weeks. A low-dose combination of a 
      catalytic (BEZ235) plus an allosteric (RAD001) mTOR inhibitor that selectively 
      inhibits target of rapamycin complex 1 (TORC1) downstream of mTOR was safe and 
      was associated with a significant (P = 0.001) decrease in the rate of infections 
      reported by elderly subjects for a year after study drug initiation. In addition, 
      we observed an up-regulation of antiviral gene expression and an improvement in 
      the response to influenza vaccination in this treatment group. Thus, selective 
      TORC1 inhibition has the potential to improve immune function and reduce 
      infections in the elderly.
CI  - Copyright (c) 2018 The Authors, some rights reserved; exclusive licensee American 
      Association for the Advancement of Science. No claim to original U.S. Government 
      Works.
FAU - Mannick, Joan B
AU  - Mannick JB
AUID- ORCID: 0000-0002-9681-4126
AD  - Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA. 
      jmannick@restorbio.com lloyd.klickstein@novartis.com.
FAU - Morris, Melody
AU  - Morris M
AD  - Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
FAU - Hockey, Hans-Ulrich P
AU  - Hockey HP
AUID- ORCID: 0000-0002-7051-3640
AD  - Biometrics Matters Limited, Hamilton 3216, New Zealand.
FAU - Roma, Guglielmo
AU  - Roma G
AUID- ORCID: 0000-0002-8020-4219
AD  - Novartis Institutes for Biomedical Research, Novartis Campus, 4056 Basel, 
      Switzerland.
FAU - Beibel, Martin
AU  - Beibel M
AD  - Novartis Institutes for Biomedical Research, Novartis Campus, 4056 Basel, 
      Switzerland.
FAU - Kulmatycki, Kenneth
AU  - Kulmatycki K
AD  - Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
FAU - Watkins, Mollie
AU  - Watkins M
AD  - Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
FAU - Shavlakadze, Tea
AU  - Shavlakadze T
AD  - Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
FAU - Zhou, Weihua
AU  - Zhou W
AD  - Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
FAU - Quinn, Dean
AU  - Quinn D
AD  - P3 Research, Newtown, Wellington 6242, New Zealand.
FAU - Glass, David J
AU  - Glass DJ
AUID- ORCID: 0000-0001-6187-4164
AD  - Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
FAU - Klickstein, Lloyd B
AU  - Klickstein LB
AUID- ORCID: 0000-0002-4108-9123
AD  - Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA. 
      jmannick@restorbio.com lloyd.klickstein@novartis.com.
LA  - eng
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Sci Transl Med
JT  - Science translational medicine
JID - 101505086
RN  - 0 (Antibodies, Viral)
RN  - 0 (Imidazoles)
RN  - 0 (Quinolines)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - RUJ6Z9Y0DT (dactolisib)
SB  - IM
CIN - Sci Immunol. 2018 Aug 3;3(26):. PMID: 30076283
CIN - Nat Rev Immunol. 2018 Sep;18(9):543. PMID: 30082757
MH  - Aged
MH  - Antibodies, Viral/immunology
MH  - Communicable Diseases/blood/drug therapy/genetics/*immunology
MH  - Dose-Response Relationship, Drug
MH  - Everolimus/adverse effects/pharmacology/*therapeutic use
MH  - Humans
MH  - Imidazoles/adverse effects/pharmacology/*therapeutic use
MH  - *Immunity
MH  - Influenza, Human/blood/immunology/prevention & control
MH  - Mechanistic Target of Rapamycin Complex 1/*antagonists & inhibitors/metabolism
MH  - Quinolines/adverse effects/pharmacology/*therapeutic use
MH  - Up-Regulation/drug effects
MH  - Vaccination
EDAT- 2018/07/13 06:00
MHDA- 2019/10/08 06:00
CRDT- 2018/07/13 06:00
PHST- 2017/10/07 00:00 [received]
PHST- 2017/11/01 00:00 [revised]
PHST- 2018/03/23 00:00 [accepted]
PHST- 2018/07/13 06:00 [entrez]
PHST- 2018/07/13 06:00 [pubmed]
PHST- 2019/10/08 06:00 [medline]
AID - 10/449/eaaq1564 [pii]
AID - 10.1126/scitranslmed.aaq1564 [doi]
PST - ppublish
SO  - Sci Transl Med. 2018 Jul 11;10(449):eaaq1564. doi: 10.1126/scitranslmed.aaq1564.