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Accelerated protein evolution analysis reveals genes and pathways associated with the evolution of mammalian longevity

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Abstract

The genetic basis of the large species differences in longevity and aging remains a mystery. Thanks to recent large-scale genome sequencing efforts, the genomes of multiple species have been sequenced and can be used for cross-species comparisons to study species divergence in longevity. By analyzing proteins under accelerated evolution in several mammalian lineages where maximum lifespan increased, we identified genes and processes that are candidate targets of selection when longevity evolves. We identified several proteins with longevity-specific selection patterns, including COL3A1 that has previously been related to aging and proteins related to DNA damage repair and response such as DDB1 and CAPNS1. Moreover, we found that processes such as lipid metabolism and cholesterol catabolism show such patterns of selection and suggest a link between the evolution of lipid metabolism, cholesterol catabolism, and the evolution of longevity. Lastly, we found evidence that the proteasome–ubiquitin system is under selection specific to lineages where longevity increased and suggest that its selection had a role in the evolution of longevity. These results provide evidence that natural selection acts on species when longevity evolves, give insights into adaptive genetic changes associated with the evolution of longevity in mammals, and provide evidence that at least some repair systems are selected for when longevity increases.

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References

  • Aledo JC, Li Y, de Magalhães JP, Ruíz-Camacho M, Pérez-Claros JA (2011) Mitochondrially encoded methionine is inversely related to longevity in mammals. Aging Cell 10:198–207

    Article  PubMed  CAS  Google Scholar 

  • Alekseev S, Kool H, Rebel H, Fousteri M, Moser J, Backendorf C, de Gruijl FR, Vrieling H, Mullenders LH (2005) Enhanced DDB2 expression protects mice from carcinogenic effects of chronic UV-B irradiation. Cancer Res 65:10298–10306

    Article  PubMed  CAS  Google Scholar 

  • Arcaro A, Zvelebil MJ, Wallasch C, Ullrich A, Waterfield MD, Domin J (2000) Class II phosphoinositide 3-kinases are downstream targets of activated polypeptide growth factor receptors. Mol Cel Bio 20:3817–3830

    Article  CAS  Google Scholar 

  • Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G (2000) Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25:25–29

    Article  PubMed  CAS  Google Scholar 

  • Austad SN (2005) Diverse aging rates in metazoans: targets for functional genomics. Mech Ageing Dev 126:43–49

    Article  PubMed  CAS  Google Scholar 

  • Austad SN (2009) Comparative biology of aging. J Gerontol A Biol Sci Med Sci 64:199–201

    Article  PubMed  Google Scholar 

  • Brégégère F, Milner Y, Friguet B (2006) The ubiquitin–proteasome system at the crossroads of stress-response and ageing pathways: a handle for skin care? Ageing Res Rev 5:60–90

    Article  PubMed  Google Scholar 

  • Cutler RG (1979) Evolution of human longevity: a critical overview. Mech Ageing Dev 9:337–354

    Article  PubMed  CAS  Google Scholar 

  • de Magalhães JP, Church GM (2007) Analyses of human–chimpanzee orthologous gene pairs to explore evolutionary hypotheses of aging. Mech Ageing Dev 128:355–364

    Article  PubMed  Google Scholar 

  • de Magalhães JP, Costa J (2009) A database of vertebrate longevity records and their relation to other life-history traits. J Evol Biol 22:1770–1774

    Article  PubMed  Google Scholar 

  • de Magalhães JP, Toussaint O (2002) The evolution of mammalian aging. Exp Gerontol 37:769–775

    Article  PubMed  Google Scholar 

  • de Magalhães JP, Costa J, Church GM (2007) An analysis of the relationship between metabolism, developmental schedules and longevity using phylogenetic independent contrasts. J Gerontol A Biol Sci Med Sci 62:149–160

    Article  PubMed  Google Scholar 

  • de Magalhães JP, Budovsky A, Lehmann G, Costa J, Li Y, Fraifeld V, Chuch GM (2009a) The Human Ageing Genomic Resources: online databases and tools for biogerontologists. Aging Cell 8:65–72

    Article  PubMed  Google Scholar 

  • de Magalhães JP, Curado J, Chuch GM (2009b) Meta-analysis of age-related gene expression profiles identifies common signatures of aging. Bioinformatics 25:875–881

    Article  PubMed  Google Scholar 

  • Demarchi F, Schneider C (2007) The calpain system as a modulator of stress/damage response. Cell Cycle 6:136–138

    Article  PubMed  CAS  Google Scholar 

  • Didichenko SA, Fragoso CM, Thelen M (2003) Mitotic and stress-induced phosphorylation of HsPI3K-C2alpha targets the protein for degradation. J Biol Chem 278:26055–26064

    Article  PubMed  CAS  Google Scholar 

  • Edwards RJ, Shields DC (2004) GASP: Gapped Ancestral Sequence Prediction for proteins. BMC Bioinformatics 5:123

    Google Scholar 

  • Finch CE (1990) Longevity, senescence, and the genome. University of Chicago Press, Chicago

    Google Scholar 

  • Finch CE, Stanford CB (2004) Meat-adaptive genes and the evolution of slower aging in humans. Q Rev Biol 79:3–50

    Article  PubMed  CAS  Google Scholar 

  • Freitas AA, de Magalhães JP (2011) A review and appraisal of the DNA damage theory of ageing. Mutat Res 728:12–22

    Article  PubMed  CAS  Google Scholar 

  • Gourlay CW, Ayscough KR (2005) The actin cytoskeleton: a key regulator of apoptosis and ageing? Nat Rev Mol Cell Biol 6:583–589

    Article  PubMed  CAS  Google Scholar 

  • Grantham R (1974) Amino acid difference formula to help explain protein evolution. Science 185:862–864

    Article  PubMed  CAS  Google Scholar 

  • Groisman R, Polanowska J, Kuraoka I, Sawada J, Saijo M, Drapkin R, Kisselev AF, Tanaka K, Nakatani Y (2003) The ubiquitin ligase activity in the DDB2 and CSA complexes is differentially regulated by the COP9 signalosome in response to DNA damage. Cell 113:357–367

    Article  PubMed  CAS  Google Scholar 

  • Harper JM, Salmon AB, Leiser SF, Galecki AT, Miller RA (2007) Skin-derived fibroblasts from long-lived species are resistant to some, but not all, lethal stresses and to the mitochondrial inhibitor rotenone. Aging Cell 6:1–13

    Article  PubMed  CAS  Google Scholar 

  • Hart RW, Setlow RB (1974) Correlation between deoxyribonucleic acid excision-repair and life-span in a number of mammalian species. Proc Natl Acad Sci USA 71:2169–2173

    Article  PubMed  CAS  Google Scholar 

  • Hulbert AJ (2008) Explaining longevity of different animals: is membrane fatty acid composition the missing link? Age (Dordr) 30:89–97

    Article  CAS  Google Scholar 

  • Jobson RW, Nabholz B, Galtier N (2010) An evolutionary genome scan for longevity-related natural selection in mammals. Mol Biol Evol 27:840–847

    Article  PubMed  CAS  Google Scholar 

  • Kapetanaki MG, Guerrero-Santoro J, Bisi DC, Hsieh CL, Rapic-Otrin V, Levine AS (2006) The DDB1-CUL4ADDB2 ubiquitin ligase is deficient in xeroderma pigmentosum group E and targets histone H2A at UV-damaged DNA sites. Proc Natl Acad Sci USA 103:2588–2593

    Article  PubMed  CAS  Google Scholar 

  • Kim EB, Fang X, Fushan AA, Huang Z, Lobanov AV, Han L, Marino SM, Sun X, Turanov AA, Yang P, Yim SH, Zhao X, Kasaikina MV, Stoletzki N, Peng C, Polak P, Xiong Z, Kiezun A, Zhu Y, Chen Y, Kryukov GV, Zhang Q, Peshkin L, Yang L, Bronson RT, Buffenstein R, Wang B, Han C, Li Q, Chen L, Zhao W, Sunyaev SR, Park TJ, Zhang G, Wang J, Gladyshev VN (2011) Genome sequencing reveals insights into physiology and longevity of the naked mole rat. Nature 479:223–227

    Article  PubMed  CAS  Google Scholar 

  • Kirkwood TB, Austad SN (2000) Why do we age? Nature 408:233–238

    Article  PubMed  CAS  Google Scholar 

  • Kua C-H (2006) Uncoupling the relationship between fatty acids and longevity. IUBMB Life 58:153–155

    Article  PubMed  CAS  Google Scholar 

  • Li J, Wang Q-E, Zhu Q, El-Mahdy MA, Wani G, Praetorius-Ibba M, Wani AA (2006) DNA damage binding protein component DDB1 participates in nucleotide excision repair through DDB2 DNA-binding and cullin 4A ubiquitin ligase activity. Cancer Res 66:8590–8597

    Article  PubMed  CAS  Google Scholar 

  • Li L, Ye H, Guo H, Yin Y (2010) Arabidopsis IWS1 interacts with transcription factor BES1 and is involved in plant steroid hormone brassinosteroid regulated gene expression. Proc Natl Acad Sci USA 107:3918–3923

    Article  PubMed  CAS  Google Scholar 

  • Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER, Hurov KE, Luo J, Bakalarski CE, Zhao Z, Solimini N, Lerenthal Y, Shiloh Y, Gygi SP, Elledge SJ (2007) ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316:1160–1166

    Article  PubMed  CAS  Google Scholar 

  • Miller RA (2001) A position paper on longevity genes. Sci Aging Knowledge Environ 2001:vp6

  • Nishitani H, Sugimoto N, Roukos V, Nakanishi Y, Saijo M, Obuse C, Tsurimoto T, Nakayama KI, Nakayama K, Fujita M, Lygerou Z, Nishimoto T (2006) Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4 target human Cdt1 for proteolysis. EMBO J 25:1126–1136

    Article  PubMed  CAS  Google Scholar 

  • Pérez VI, Buffenstein R, Masamsetti V, Leonard S, Salmon AB, Mele J, Andziak B, Yang T, Edrey Y, Friguet B, Ward W, Richardson A, Chaudhuri A (2009) Protein stability and resistance to oxidative stress are determinants of longevity in the longest-living rodent the naked mole-rat. Proc Natl Acad Sci USA 106:3059–3064

    Article  PubMed  Google Scholar 

  • Ricklefs RE (2010) Life-history connections to rates of aging in terrestrial vertebrates. Proc Natl Acad Sci USA 107:10314–10319

    Article  PubMed  CAS  Google Scholar 

  • Salmon AB, Leonard S, Masamsetti V, Pierce A, Podlutsky AJ, Podlutskaya N, Richardson A, Austad SN, Chaudhuri AR (2009) The long lifespan of two bat species is correlated with resistance to protein oxidation and enhanced protein homeostasis. FASEB J 23:2317–2326

    Article  PubMed  CAS  Google Scholar 

  • Samuelson AV, Carr CE, Ruvkun G (2007) Gene activities that mediate increased life span of C. elegans insulin-like signaling mutants. Genes Dev 21:2976–2994

    Article  PubMed  CAS  Google Scholar 

  • Sjögren C, Nasmyth K (2001) Sister chromatid cohesion is required for postreplicative double-strand break repair in Saccharomyces cerevisiae. Curr Biol 11:991–995

    Article  PubMed  Google Scholar 

  • Terashima Y, Onai N, Murai M, Enomoto M, Poonpiriya V, Hamada T, Motomura K, Suwa M, Ezaki T, Haga T, Kanegasaki S, Matsushima K (2005) Pivotal function for cytoplasmic protein FROUNT in CCR2-mediated monocyte chemotaxis. Nat Immunol 6:827–835

    Article  PubMed  CAS  Google Scholar 

  • Weidenheim KM, Dickson DW, Rapin I (2009) Neuropathology of Cockayne syndrome: evidence for impaired development, premature aging and neurodegeneration. Mech Ageing Dev 130:619–636

    Article  PubMed  CAS  Google Scholar 

  • Wu CH, Apweiler R, Bairoch A, Natale DA, Barker WC, Boeckmann B, Ferro S, Gasteiger E, Huang H, Lopez R, Magrane M, Martin MJ, Mazumder R, O’Donovan C, Redaschi N, Suzek B (2006) The Universal Protein Resource (UniProt): an expanding universe of protein information. Nucleic Acids Res 34:D187–D191

    Article  PubMed  CAS  Google Scholar 

  • Wyse CA, Coogan AN, Selman C, Hazlerigg DG, Speakman JR (2010) Association between mammalian lifespan and circadian free-running period: the circadian resonance hypothesis revisited. Biol Lett 6:696–698

    Article  PubMed  CAS  Google Scholar 

  • Zhang W, Chen T, Wan T, He L, Li N, Yuan Z, Cao X (2000) Cloning of DPK a novel dendritic cell-derived protein kinase activating the ERK1/ERK2 and JNK/SAPK pathways. Biochem Biophys Res Commun 274:872–879

    Article  PubMed  CAS  Google Scholar 

  • Zhang J, Webb DM, Podlaha O (2002) Accelerated protein evolution and origins of human-specific features: Foxp2 as an example. Genetics 162:1825–1835

    PubMed  CAS  Google Scholar 

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Acknowledgments

YL was supported by a Postgraduate Scholarship from the Natural Sciences and Engineering Research Council of Canada. JPM thanks the BBSRC (BB/G024774/1 & BB/H008497/1), the Ellison Medical Foundation, and a Marie Curie International Reintegration Grant within EC-FP7 for supporting work in his lab.

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  1. Yang Li

    Present address: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

Authors and Affiliations

  1. Integrative Genomics of Ageing Group, Institute of Integrative Biology, University of Liverpool, Biosciences Building, Room 245, Crown Street, Liverpool, L69 7ZB, UK

    Yang Li & João Pedro de Magalhães

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  1. Yang Li
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  2. João Pedro de Magalhães
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Correspondence to João Pedro de Magalhães.

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Li, Y., de Magalhães, J.P. Accelerated protein evolution analysis reveals genes and pathways associated with the evolution of mammalian longevity. AGE 35, 301–314 (2013). https://doi.org/10.1007/s11357-011-9361-y

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  • DOI: https://doi.org/10.1007/s11357-011-9361-y

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