title: AMP-activated protein kinase and FoxO transcription factors in dietary restriction-induced longevity.
abstract: Aging is regulated by modifications in single genes and by simple changes in the environment. The signaling pathway connecting insulin to FoxO transcription factors integrates environmental stimuli to regulate lifespan. FoxO transcription factors are directly phosphorylated in response to insulin/growth factor signaling by the protein kinase Akt, thereby causing their sequestration in the cytoplasm. In the absence of insulin/growth factors, FoxO factors translocate to the nucleus where they trigger a range of cellular responses, including resistance to oxidative stress--a phenotype highly coupled with lifespan extension. Our recent results indicate that FoxO transcription factors are also regulated in response to nutrient deprivation by the AMP-activated protein kinase (AMPK) pathway. The energy-sensing AMPK directly phosphorylates FoxO transcription factors at six regulatory sites. AMPK phosphorylation enhances FoxO transcriptional activity, leading to the expression of specific target genes involved in stress resistance and changes in energy metabolism. The AMPK-FoxO pathway plays a crucial role in the ability of a dietary restriction regimen to extend lifespan in Caenorhabditis elegans. Understanding the intricate signaling networks that translate environmental conditions like dietary restriction into changes in gene expression that extend lifespan will be of critical importance to identify ways to delay the onset of aging and age-dependent diseases.
authors.affiliation: Department of Genetics, Stanford University, Stanford, California 94305, USA.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Greer
authors.forename: Max R
authors.initials: MR
authors.lastname: Banko
authors.forename: Anne
authors.initials: A
authors.lastname: Brunet
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D017173:Caenorhabditis elegans / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D005786:Gene Expression Regulation; D008136:Longevity; D010766:Phosphorylation; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D014157:Transcription Factors; D055372:AMP-Activated Protein Kinases
references.citation: Aging Cell. 2006 Apr;5(2):119-26
references.pmid: 16626391
references.citation: Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):15998-6003
references.pmid: 15520384
references.citation: JAMA. 2004 Mar 10;291(10):1226-30
references.pmid: 15010444
references.citation: Aging Cell. 2006 Dec;5(6):487-94
references.pmid: 17081160
references.citation: Ann N Y Acad Sci. 2004 Jun;1019:412-23
references.pmid: 15247056
references.citation: Exp Gerontol. 2003 Sep;38(9):947-54
references.pmid: 12954481
references.citation: Cell Metab. 2005 Jan;1(1):15-25
references.pmid: 16054041
references.citation: Mech Ageing Dev. 2004 Sep;125(9):633-9
references.pmid: 15491682
references.citation: Science. 2005 Nov 18;310(5751):1193-6
references.pmid: 16293764
references.citation: Curr Biol. 2004 May 25;14(10):885-90
references.pmid: 15186745
references.citation: Med Hypotheses. 2004;63(2):334-9
references.pmid: 15236799
references.citation: Neurobiol Aging. 1989 Nov-Dec;10(6):669-75
references.pmid: 2628778
references.citation: Curr Biol. 2007 Oct 9;17(19):1646-56
references.pmid: 17900900
references.citation: Diabetes. 2002 Aug;51(8):2420-5
references.pmid: 12145153
references.citation: Nature. 2004 Apr 1;428(6982):569-74
references.pmid: 15058305
references.citation: Science. 2000 Sep 22;289(5487):2126-8
references.pmid: 11000115
references.citation: Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13091-6
references.pmid: 9789046
references.citation: Mech Ageing Dev. 2006 Jan;127(1):48-56
references.pmid: 16280150
references.citation: PLoS Genet. 2005 Jul;1(1):119-28
references.pmid: 16103914
references.citation: J Gerontol. 1987 Jan;42(1):78-81
references.pmid: 3794202
references.citation: Annu Rev Biochem. 2008;77:727-54
references.pmid: 18373439
references.citation: Am J Physiol Endocrinol Metab. 2005 Jan;288(1):E228-35
references.pmid: 15328073
references.citation: J Biol Chem. 2007 Oct 12;282(41):30107-19
references.pmid: 17711846
references.citation: Gerontology. 2005 Jan-Feb;51(1):19-28
references.pmid: 15591752
references.citation: Am J Physiol Endocrinol Metab. 2004 Nov;287(5):E1032-7
references.pmid: 15251868
references.citation: Curr Biol. 2005 Nov 22;15(22):2063-8
references.pmid: 16303568
references.citation: Cancer Res. 2005 Aug 1;65(15):7023-30
references.pmid: 16061689
references.citation: Exp Gerontol. 2005 Aug-Sep;40(8-9):685-93
references.pmid: 16125352
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6659-63
references.pmid: 15096581
references.citation: Nature. 2007 May 31;447(7144):550-5
references.pmid: 17476212
references.citation: Aging Cell. 2006 Dec;5(6):515-24
references.pmid: 17096674
references.citation: Nature. 2007 May 31;447(7144):545-9
references.pmid: 17538612
references.citation: Aging Cell. 2008 Jun;7(3):394-404
references.pmid: 18331616
references.citation: Aging Cell. 2009 Apr;8(2):113-27
references.pmid: 19239417