PMID- 26729005
OWN - NLM
STAT- MEDLINE
DCOM- 20170111
LR  - 20230816
IS  - 1474-9726 (Electronic)
IS  - 1474-9718 (Print)
IS  - 1474-9718 (Linking)
VI  - 15
IP  - 2
DP  - 2016 Apr
TI  - Mitochondrial metabolites extend lifespan.
PG  - 336-48
LID - 10.1111/acel.12439 [doi]
AB  - Disruption of mitochondrial respiration in the nematode Caenorhabditis elegans 
      can extend lifespan. We previously showed that long-lived respiratory mutants 
      generate elevated amounts of alpha-ketoacids. These compounds are structurally 
      related to alpha-ketoglutarate, suggesting they may be biologically relevant. Here, 
      we show that provision of several such metabolites to wild-type worms is 
      sufficient to extend their life. At least one mode of action is through 
      stabilization of hypoxia-inducible factor-1 (HIF-1). We also find that an 
      alpha-ketoglutarate mimetic, 2,4-pyridinedicarboxylic acid (2,4-PDA), is alone 
      sufficient to increase the lifespan of wild-type worms and this effect is blocked 
      by removal of HIF-1. HIF-1 is constitutively active in isp-1(qm150) Mit mutants, 
      and accordingly, 2,4-PDA does not further increase their lifespan. Incubation of 
      mouse 3T3-L1 fibroblasts with life-prolonging alpha-ketoacids also results in HIF-1alpha 
      stabilization. We propose that metabolites that build up following mitochondrial 
      respiratory dysfunction form a novel mode of cell signaling that acts to regulate 
      lifespan.
CI  - (c) 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley 
      & Sons Ltd.
FAU - Mishur, Robert J
AU  - Mishur RJ
AD  - The Barshop Institute for Longevity and Aging Studies, University of Texas Health 
      Science Center at San Antonio, San Antonio, TX, 78229, USA.
AD  - Department of Physiology, University of Texas Health Science Center at San 
      Antonio, San Antonio, TX, 78229, USA.
FAU - Khan, Maruf
AU  - Khan M
AD  - The Barshop Institute for Longevity and Aging Studies, University of Texas Health 
      Science Center at San Antonio, San Antonio, TX, 78229, USA.
AD  - Department of Physiology, University of Texas Health Science Center at San 
      Antonio, San Antonio, TX, 78229, USA.
FAU - Munkacsy, Erin
AU  - Munkacsy E
AD  - The Barshop Institute for Longevity and Aging Studies, University of Texas Health 
      Science Center at San Antonio, San Antonio, TX, 78229, USA.
AD  - Department of Cellular & Structural Biology, University of Texas Health Science 
      Center at San Antonio, San Antonio, TX, 78229, USA.
FAU - Sharma, Lokendra
AU  - Sharma L
AD  - Department of Cellular & Structural Biology, University of Texas Health Science 
      Center at San Antonio, San Antonio, TX, 78229, USA.
FAU - Bokov, Alex
AU  - Bokov A
AD  - Department of Epidemiology and Biostatistics, University of Texas Health Science 
      Center at San Antonio, San Antonio, TX, 78229, USA.
FAU - Beam, Haley
AU  - Beam H
AD  - The Barshop Institute for Longevity and Aging Studies, University of Texas Health 
      Science Center at San Antonio, San Antonio, TX, 78229, USA.
FAU - Radetskaya, Oxana
AU  - Radetskaya O
AD  - The Barshop Institute for Longevity and Aging Studies, University of Texas Health 
      Science Center at San Antonio, San Antonio, TX, 78229, USA.
FAU - Borror, Megan
AU  - Borror M
AD  - The Barshop Institute for Longevity and Aging Studies, University of Texas Health 
      Science Center at San Antonio, San Antonio, TX, 78229, USA.
FAU - Lane, Rebecca
AU  - Lane R
AD  - The Barshop Institute for Longevity and Aging Studies, University of Texas Health 
      Science Center at San Antonio, San Antonio, TX, 78229, USA.
FAU - Bai, Yidong
AU  - Bai Y
AD  - Department of Cellular & Structural Biology, University of Texas Health Science 
      Center at San Antonio, San Antonio, TX, 78229, USA.
FAU - Rea, Shane L
AU  - Rea SL
AD  - The Barshop Institute for Longevity and Aging Studies, University of Texas Health 
      Science Center at San Antonio, San Antonio, TX, 78229, USA.
AD  - Department of Physiology, University of Texas Health Science Center at San 
      Antonio, San Antonio, TX, 78229, USA.
LA  - eng
GR  - T32 AG021890/AG/NIA NIH HHS/United States
GR  - GM-109434/GM/NIGMS NIH HHS/United States
GR  - I01 BX002211/BX/BLRD VA/United States
GR  - P40 OD010440/OD/NIH HHS/United States
GR  - R21 AG047561/AG/NIA NIH HHS/United States
GR  - RF1 AG068283/AG/NIA NIH HHS/United States
GR  - K12 GM111726/GM/NIGMS NIH HHS/United States
GR  - R01 GM109434/GM/NIGMS NIH HHS/United States
GR  - AG-047561/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20160105
PL  - England
TA  - Aging Cell
JT  - Aging cell
JID - 101130839
RN  - 0 (Caenorhabditis elegans Proteins)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Ketoglutaric Acids)
SB  - IM
MH  - 3T3-L1 Cells
MH  - Animals
MH  - Caenorhabditis elegans/*metabolism
MH  - Caenorhabditis elegans Proteins/*metabolism
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism
MH  - Ketoglutaric Acids/*metabolism
MH  - Longevity/*physiology
MH  - Mice
MH  - Mitochondria/*metabolism
PMC - PMC4783347
OTO - NOTNLM
OT  - Caenorhabditis elegans
OT  - EGL-9/PHD
OT  - Mit mutants
OT  - aging
OT  - glutaric acidemia
OT  - hypoxia-inducible factor isp-1
OT  - hypoxia-inducible factor-1
OT  - jumonji domain-containing
OT  - metabolism
OT  - mitochondria
OT  - alpha-ketoglutarate-dependent hydroxylases
EDAT- 2016/01/06 06:00
MHDA- 2017/01/12 06:00
PMCR- 2016/04/01
CRDT- 2016/01/06 06:00
PHST- 2015/11/24 00:00 [accepted]
PHST- 2016/01/06 06:00 [entrez]
PHST- 2016/01/06 06:00 [pubmed]
PHST- 2017/01/12 06:00 [medline]
PHST- 2016/04/01 00:00 [pmc-release]
AID - ACEL12439 [pii]
AID - 10.1111/acel.12439 [doi]
PST - ppublish
SO  - Aging Cell. 2016 Apr;15(2):336-48. doi: 10.1111/acel.12439. Epub 2016 Jan 5.