Mitochondrial ROS production correlates with, but does not directly regulate lifespan in Drosophila.
The Mitochondrial Free Radical Theory of Aging (MFRTA) is currently one of the most widely accepted theories used to explain aging. From MFRTA three basic predictions can be made: long-lived individuals or species should produce fewer mitochondrial Reactive Oxygen Species (mtROS) than short-lived individuals or species; a decrease in mtROS production will increase lifespan; and an increase in mtROS production will decrease lifespan. It is possible to add a further fourth prediction: if ROS is controlling longevity separating these parameters through selection would be impossible. These predictions have been tested in Drosophila melanogaster. Firstly, we studied levels of mtROS production and lifespan of three wild-type strains of Drosophila, Oregon R, Canton S and Dahomey. Oregon R flies live the longest and produce significantly fewer mtROS than both Canton S and Dahomey. These results are therefore in accordance with the first prediction. A new transgenic Drosophila model expressing the Ciona intestinalis Alternative Oxidase (AOX) was used to test the second prediction. In fungi and plants, AOX expression regulates both free radical production and lifespan. In Drosophila, AOX expression decreases mtROS production, but does not increase lifespan. This result contradicts the second prediction of MFRTA. The third prediction was tested in flies mutant for the gene dj-1beta. These flies are characterized by an age-associated decline in locomotor function and increased levels of mtROS production. Nevertheless, dj-1beta mutant flies do not display decreased lifespan, which again is in contradiction with MFRTA. In our final experiment we utilized flies with DAH mitochondrial DNA in an OR nuclear background, and OR mitochondrial DNA in DAH nuclear background. From this, Mitochondrial DNA does not control free radical production, but it does determine longevity of females independently of mtROS production. In summary, these results do not systematically support the predictions of the MFRTA. Accordingly, MFRTA should be revised to accommodate these findings.
Sanz
Alberto
A
Institute of Medical Technology and Tampere University Hospital, FI-33014 University of Tampere, Finland. Alberto.Sanz@uta.fi
Fernández-Ayala
Daniel J M
DJ
Stefanatos
Rhoda Ka
RK
Jacobs
Howard T
HT
D000375:Aging / Q000378:metabolism*; D000818:Animals; D004331:Drosophila melanogaster / Q000378:metabolism*; D005260:Female; D008136:Longevity; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D010101:Oxygen Consumption; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013045:Species Specificity
D017382:Reactive Oxygen Species
Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4138-43
10759557
EMBO Rep. 2006 Mar;7(3):341-5
16322757
Plant Physiol. 1998 Oct;118(2):599-607
9765546
Endocrinology. 2005 Sep;146(9):3713-7
15919745
Cell Metab. 2009 May;9(5):449-60
19416715
Exp Gerontol. 2007 Jul;42(7):601-9
17446027
Free Radic Biol Med. 2003 Oct 15;35(8):938-48
14556858
J Neurochem. 2006 Nov;99(4):1062-72
16836655
Mitochondrion. 2007 Jun;7 Suppl:S51-61
17482887
Aging Cell. 2006 Dec;5(6):463-71
17054663
Free Radic Biol Med. 2007 Aug 15;43(4):477-503
17640558
Mech Ageing Dev. 2005 Nov;126(11):1206-12
16087218
Aging Cell. 2007 Oct;6(5):607-18
17596208
J Intern Med. 2008 Feb;263(2):167-78
18226094
Am J Physiol Regul Integr Comp Physiol. 2004 Jan;286(1):R71-9
12969875
N Engl J Med. 1997 Oct 2;337(14):986-94
9309105
Exp Gerontol. 2000 Mar;35(2):167-85
10767577
Aging Cell. 2006 Jun;5(3):225-33
16842495
Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14807-12
17766438
J Biol Chem. 2003 Jul 18;278(29):26418-22
12743125
Rejuvenation Res. 2007 Sep;10(3):281-92
17665967
Cell Metab. 2005 Feb;1(2):145-52
16054055
J Gerontol A Biol Sci Med Sci. 2005 Nov;60(11):1378-85
16339322
Antioxid Redox Signal. 2006 Mar-Apr;8(3-4):582-99
16677102
Aging Cell. 2010 Apr;9(2):191-202
20089120
Mech Ageing Dev. 1993 Nov;72(1):67-76
8114521
Biochim Biophys Acta. 2009 Oct;1790(10):1005-14
19524016
Proc Natl Acad Sci U S A. 2004 May 18;101(20):7663-8
15136717
Genome Biol. 2007;8(12):R262
18067683
J Insect Physiol. 2000 Nov 1;46(11):1477-1480
10891576
Biogerontology. 2008 Feb;9(1):57-66
17972157
Proc Natl Acad Sci U S A. 2010 May 18;107(20):9105-10
20435911
Free Radic Biol Med. 2008 Nov 1;45(9):1217-9
18789385
Am J Physiol Heart Circ Physiol. 2008 Nov;295(5):H1882-94
18757483
Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16382-7
17056719
Genes Dev. 2008 Dec 1;22(23):3236-41
19056880
Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3486-9
14993600
Exp Gerontol. 2006 Oct;41(10):952-6
16962276
Nat Genet. 1998 Jun;19(2):171-4
9620775
J Gerontol A Biol Sci Med Sci. 2005 Feb;60(2):175-80
15814858
EMBO Mol Med. 2009 Apr;1(1):30-6
20049701
Free Radic Biol Med. 1995 Oct;19(4):499-504
7590400
Curr Aging Sci. 2008 Mar;1(1):10-21
20021368
Science. 2003 Sep 19;301(5640):1731-3
14500985
Exp Gerontol. 2006 Apr;41(4):439-47
16530367
Exp Gerontol. 2006 Jan;41(1):1-10
16226003
J Biol Chem. 2005 Nov 11;280(45):37331-8
16148000
Aging Cell. 2010 Feb;9(1):78-91
19968628
Ann N Y Acad Sci. 2004 Jun;1019:388-91
15247051