PMID- 26676933
OWN - NLM
STAT- MEDLINE
DCOM- 20170111
LR  - 20181113
IS  - 1474-9726 (Electronic)
IS  - 1474-9718 (Print)
IS  - 1474-9718 (Linking)
VI  - 15
IP  - 2
DP  - 2016 Apr
TI  - A network pharmacology approach reveals new candidate caloric restriction 
      mimetics in C. elegans.
PG  - 256-66
LID - 10.1111/acel.12432 [doi]
AB  - Caloric restriction (CR), a reduction in calorie intake without malnutrition, 
      retards aging in several animal models from worms to mammals. Developing CR 
      mimetics, compounds that reproduce the longevity benefits of CR without its side 
      effects, is of widespread interest. Here, we employed the Connectivity Map to 
      identify drugs with overlapping gene expression profiles with CR. Eleven 
      statistically significant compounds were predicted as CR mimetics using this 
      bioinformatics approach. We then tested rapamycin, allantoin, trichostatin A, 
      LY-294002 and geldanamycin in Caenorhabditis elegans. An increase in lifespan and 
      healthspan was observed for all drugs except geldanamycin when fed to wild-type 
      worms, but no lifespan effects were observed in eat-2 mutant worms, a genetic 
      model of CR, suggesting that life-extending effects may be acting via CR-related 
      mechanisms. We also treated daf-16 worms with rapamycin, allantoin or 
      trichostatin A, and a lifespan extension was observed, suggesting that these 
      drugs act via DAF-16-independent mechanisms, as would be expected from CR 
      mimetics. Supporting this idea, an analysis of predictive targets of the drugs 
      extending lifespan indicates various genes within CR and longevity networks. We 
      also assessed the transcriptional profile of worms treated with either rapamycin 
      or allantoin and found that both drugs use several specific pathways that do not 
      overlap, indicating different modes of action for each compound. The current work 
      validates the capabilities of this bioinformatic drug repositioning method in the 
      context of longevity and reveals new putative CR mimetics that warrant further 
      studies.
CI  - (c) 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley 
      & Sons Ltd.
FAU - Calvert, Shaun
AU  - Calvert S
AD  - Integrative Genomics of Ageing Group, Institute of Integrative Biology, 
      University of Liverpool, Liverpool, UK.
FAU - Tacutu, Robi
AU  - Tacutu R
AD  - Integrative Genomics of Ageing Group, Institute of Integrative Biology, 
      University of Liverpool, Liverpool, UK.
FAU - Sharifi, Samim
AU  - Sharifi S
AD  - Integrative Genomics of Ageing Group, Institute of Integrative Biology, 
      University of Liverpool, Liverpool, UK.
FAU - Teixeira, Rute
AU  - Teixeira R
AD  - Integrative Genomics of Ageing Group, Institute of Integrative Biology, 
      University of Liverpool, Liverpool, UK.
FAU - Ghosh, Pratul
AU  - Ghosh P
AD  - Integrative Genomics of Ageing Group, Institute of Integrative Biology, 
      University of Liverpool, Liverpool, UK.
FAU - de Magalhaes, Joao Pedro
AU  - de Magalhaes JP
AD  - Integrative Genomics of Ageing Group, Institute of Integrative Biology, 
      University of Liverpool, Liverpool, UK.
LA  - eng
GR  - P40 OD010440/OD/NIH HHS/United States
GR  - BB/J014516/1/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20151216
PL  - England
TA  - Aging Cell
JT  - Aging cell
JID - 101130839
RN  - 0 (Anti-Obesity Agents)
RN  - 0 (Chromones)
RN  - 0 (Hydroxamic Acids)
RN  - 0 (Morpholines)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - 344S277G0Z (Allantoin)
RN  - 3X2S926L3Z (trichostatin A)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Allantoin/pharmacology
MH  - Animals
MH  - Anti-Obesity Agents/*pharmacology
MH  - Biomimetic Materials/*pharmacology
MH  - Caenorhabditis elegans/*drug effects/physiology
MH  - Caloric Restriction/*methods
MH  - Cell Line
MH  - Chromones/pharmacology
MH  - Connectome
MH  - Hydroxamic Acids/pharmacology
MH  - Longevity/drug effects/physiology
MH  - Models, Animal
MH  - Morpholines/pharmacology
MH  - Rats
MH  - Sirolimus/pharmacology
PMC - PMC4783339
OTO - NOTNLM
OT  - Caenorhabditis elegans
OT  - aging
OT  - drug repositioning
OT  - lifespan
OT  - longevity
OT  - pharmacogenomics
EDAT- 2015/12/18 06:00
MHDA- 2017/01/12 06:00
PMCR- 2016/04/01
CRDT- 2015/12/18 06:00
PHST- 2015/11/08 00:00 [accepted]
PHST- 2015/12/18 06:00 [entrez]
PHST- 2015/12/18 06:00 [pubmed]
PHST- 2017/01/12 06:00 [medline]
PHST- 2016/04/01 00:00 [pmc-release]
AID - ACEL12432 [pii]
AID - 10.1111/acel.12432 [doi]
PST - ppublish
SO  - Aging Cell. 2016 Apr;15(2):256-66. doi: 10.1111/acel.12432. Epub 2015 Dec 16.