title: The temporal scaling of Caenorhabditis elegans ageing.
abstract: The process of ageing makes death increasingly likely, involving a random aspect that produces a wide distribution of lifespan even in homogeneous populations. The study of this stochastic behaviour may link molecular mechanisms to the ageing process that determines lifespan. Here, by collecting high-precision mortality statistics from large populations, we observe that interventions as diverse as changes in diet, temperature, exposure to oxidative stress, and disruption of genes including the heat shock factor hsf-1, the hypoxia-inducible factor hif-1, and the insulin/IGF-1 pathway components daf-2, age-1, and daf-16 all alter lifespan distributions by an apparent stretching or shrinking of time. To produce such temporal scaling, each intervention must alter to the same extent throughout adult life all physiological determinants of the risk of death. Organismic ageing in Caenorhabditis elegans therefore appears to involve aspects of physiology that respond in concert to a diverse set of interventions. In this way, temporal scaling identifies a novel state variable, r(t), that governs the risk of death and whose average decay dynamics involves a single effective rate constant of ageing, kr. Interventions that produce temporal scaling influence lifespan exclusively by altering kr. Such interventions, when applied transiently even in early adulthood, temporarily alter kr with an attendant transient increase or decrease in the rate of change in r and a permanent effect on remaining lifespan. The existence of an organismal ageing dynamics that is invariant across genetic and environmental contexts provides the basis for a new, quantitative framework for evaluating the manner and extent to which specific molecular processes contribute to the aspect of ageing that determines lifespan.
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Stroustrup
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Winston E
authors.initials: WE
authors.lastname: Anthony
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Zachary M
authors.initials: ZM
authors.lastname: Nash
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Gowda
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Gomez
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Isaac F
authors.initials: IF
authors.lastname: López-Moyado
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Javier
authors.initials: J
authors.lastname: Apfeld
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Walter
authors.initials: W
authors.lastname: Fontana
mesh_terms: D000375:Aging / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics; D003643:Death; D004032:Diet; D051858:Forkhead Transcription Factors / Q000235:genetics; D007700:Kinetics; D008136:Longevity / Q000235:genetics / Q000502:physiology*; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011972:Receptor, Insulin / Q000235:genetics; D012306:Risk; D013696:Temperature; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics
chemical_list: D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; C541178:HIF-1 protein, C elegans; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; C474710:heat shock factor-1, C elegans; D019869:Phosphatidylinositol 3-Kinases; C100662:AGE-1 protein, C elegans; C107483:DAF-2 protein, C elegans; D011972:Receptor, Insulin
references.citation: Aging Cell. 2009 Sep;8(5):524-41
references.pmid: 19575768
references.citation: Mech Ageing Dev. 2005 Sep;126(9):1011-6
references.pmid: 15893805
references.citation: Dev Dyn. 2010 May;239(5):1405-12
references.pmid: 20140911
references.citation: Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13091-6
references.pmid: 9789046
references.citation: Genetics. 2002 Jul;161(3):1101-12
references.pmid: 12136014
references.citation: J Gerontol A Biol Sci Med Sci. 2001 Aug;56(8):B331-9
references.pmid: 11487591
references.citation: Cell Metab. 2010 Sep 8;12(3):260-72
references.pmid: 20816092
references.citation: Science. 2003 Sep 19;301(5640):1731-3
references.pmid: 14500985
references.citation: Biogerontology. 2010 Feb;11(1):53-65
references.pmid: 19444640
references.citation: Nature. 2003 Jul 17;424(6946):277-83
references.pmid: 12845331
references.citation: Nat Genet. 1996 May;13(1):25-34
references.pmid: 8673100
references.citation: Aging Cell. 2009 Dec;8(6):666-75
references.pmid: 19747231
references.citation: Genes Dev. 2007 Nov 15;21(22):2976-94
references.pmid: 18006689
references.citation: Trends Genet. 2013 Sep;29(9):506-12
references.pmid: 23769208
references.citation: Mech Ageing Dev. 2005 Sep;126(9):929-37
references.pmid: 15896824
references.citation: Mech Ageing Dev. 1976 Sep-Oct;5(5):371-87
references.pmid: 823385
references.citation: Mech Ageing Dev. 2012 Sep-Oct;133(9-10):600-10
references.pmid: 22898738
references.citation: Exp Gerontol. 2009 Mar;44(3):190-200
references.pmid: 19007875
references.citation: Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7540-4
references.pmid: 7638227
references.citation: Science. 2006 Nov 3;314(5800):825-8
references.pmid: 17082459
references.citation: Aging Cell. 2011 Apr;10(2):318-26
references.pmid: 21241450
references.citation: Demography. 1979 Aug;16(3):439-54
references.pmid: 510638
references.citation: Methods Cell Biol. 2012;107:353-81
references.pmid: 22226530
references.citation: Science. 2003 May 16;300(5622):1142-5
references.pmid: 12750521
references.citation: Nature. 1962 Nov 3;196:454-7
references.pmid: 13976970
references.citation: Nature. 2002 Oct 24;419(6909):808-14
references.pmid: 12397350
references.citation: Cell. 2008 Mar 21;132(6):1025-38
references.pmid: 18358814
references.citation: Cell. 2003 Nov 14;115(4):489-502
references.pmid: 14622602
references.citation: Nat Methods. 2013 Jul;10(7):665-70
references.pmid: 23666410
references.citation: PLoS Genet. 2011 Sep;7(9):e1002306
references.pmid: 21980307