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Age (Dordr). 2006 June; 28(2): 201–208.
Published online 2006 June 3. doi:  10.1007/s11357-006-9006-8
PMCID: PMC2464728

The age of heterozygosity


Two mutant mouse models of longevity in which the loss of only one copy of the gene leads to a significantly increased lifespan have recently been described: Igf1r+/- and mclk1+/-. Igf1r encodes a transmembrane receptor kinase for the insulin-like growth factor-1, and mclk1 encodes a hydroxylase that is necessary for the biosynthesis of ubiquinone. Interestingly, the motivation for testing the longevity of both of these mutants came from observations in the nematode Caenorhabditis elegans. IGF-1R protein is homologous to DAF-2 and mCLK1 is the mouse orthologue of the C. elegans enzyme CLK-1. In worms, the homozygous inactivation of both of these longevity genes is viable and no dominant mutations are known. In addition to aging slowly, old mclk1+/- mice were found to undergo loss-of-heterozygosity at the mclk1 locus, which results in clones of mclk1-/- cells in the liver, presumably because mclk1-/- cells can outcompete mclk1+/- cells under certain conditions. We will discuss how these observations suggest novel directions of research, but also call for some caution in the interpretation of past and future results.

Key words: aging, evolutionary conservation, loss-of-heterozygosity, mclk1, mouse models of longevity, ubiquinone


insulin-like growth factor-1
embryonic stem


  • Accili D, Drago J, Lee EJ, Johnson MD, Cool MH, Salvatore P, Asico LD, Jose PA, Taylor SI, Westphal H (1996) Early neonatal death in mice homozygous for a null allele of the insulin receptor gene. Nat Genet 12:106–109 [PubMed]

  • Barsyte D, Lovejoy DA, Lithgow GJ (2001) Longevity and heavy metal resistance in daf-2 and age-1 long-lived mutants of Caenorhabditis elegans. Faseb J 15: 627–634 [PubMed]

  • Bartke A, Brown-Borg H, Mattison J, Kinney B, Hauck S, Wright C (2001) Prolonged longevity of hypopituitary dwarf mice. Exp Gerontol 36:21–28 [PubMed]

  • Bluher M, Kahn BB, Kahn CR (2003) Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299:572–574 [PubMed]

  • Branicky R, Benard C, Hekimi S (2000) clk-1, mitochondria, and physiological rates. Bioessays 22:48–56 [PubMed]

  • Brown-Borg HM, Borg KE, Meliska CJ, Bartke A (1996) Dwarf mice and the ageing process. Nature 384:33 [PubMed]

  • Delafontaine P (1995) Insulin-like growth factor I and its binding proteins in the cardiovascular system. Cardiovasc Res 30:825–834 [PubMed]

  • De Martinis M, Franceschi C, Monti D, Ginaldi L (2005) Inflamm-ageing and lifelong antigenic load as major determinants of ageing rate and longevity. FEBS Lett 579:2035–2039 [PubMed]

  • Devilee P, Cleton-Jansen AM, Cornelisse CJ (2001) Ever since Knudson. Trends Genet 17:569–573 [PubMed]

  • Dorman JB, Albinder B, Shroyer T, Kenyon C (1995) The age-1 and daf-2 genes function in a common pathway to control the lifespan of Caenorhabditis elegans. Genetics 141:1399–1406 [PubMed]

  • Franceschi C, Olivieri F, Marchegiani F, Cardelli M, Cavallone L, Capri M, Salvioli S, Valensin S, De Benedictis G, Di Iorio A, Caruso C, Paolisso G, Monti D (2005) Genes involved in immune response/inflammation, IGF1/insulin pathway and response to oxidative stress play a major role in the genetics of human longevity: the lesson of centenarians. Mech Ageing Dev 126:351–361 [PubMed]

  • Frith CH, Highman B, Burger G, Sheldon WD (1983) Spontaneous lesions in virgin and retired breeder BALB/c and C57BL/6 mice. Lab Anim Sci 33:273–286 [PubMed]

  • Gems D, Sutton AJ, Sundermeyer ML, Albert PS, King KV, Edgley ML, Larsen PL, Riddle DL (1998) Two pleiotropic classes of daf-2 mutation affect larval arrest, adult behavior, reproduction and longevity in Caenorhabditis elegans. Genetics 150:129–155 [PubMed]

  • Hekimi S, Burgess J, Bussiere F, Meng Y, Benard C (2001) Genetics of lifespan in C. elegans: molecular diversity, physiological complexity, mechanistic simplicity. Trends Genet 17:712–718 [PubMed]

  • Hihi AK, Kebir H, Hekimi S (2003) Sensitivity of Caenorhabditis elegans clk-1 mutants to ubiquinone side-chain length reveals multiple ubiquinone-dependent processes. J Biol Chem 278:41013–41018 [PubMed]

  • Holzenberger M, Dupont J, Ducos B, Leneuve P, Geloen A, Even PC, Cervera P, Le Bouc Y (2003) IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421:182–187 [PubMed]

  • Honda Y, Honda S (1999) The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans. Faseb J 13:1385–1393 [PubMed]

  • Jazwinski SM (1998) Genetics of longevity. Exp Gerontol 33:773–783 [PubMed]

  • Johnson TE, Henderson S, Murakami S, de Castro E, de Castro SH, Cypser J, Rikke B, Tedesco P, Link C (2002) Longevity genes in the nematode Caenorhabditis elegans also mediate increased resistance to stress and prevent disease. J Inherit Metab Dis 25:197–206 [PubMed]

  • Jonassen T, Larsen PL, Clarke CF (2001) A dietary source of coenzyme Q is essential for growth of long-lived Caenorhabditis elegans clk-1 mutants. Proc Natl Acad Sci USA 98:421–426 [PubMed]

  • Joshi RL, Lamothe B, Cordonnier N, Mesbah K, Monthioux E, Jami J, Bucchini D (1996) Targeted disruption of the insulin receptor gene in the mouse results in neonatal lethality. EMBO J 15:1542–1547 [PubMed]

  • Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R (1993) A C. elegans mutant that lives twice as long as wild type. Nature 366:461–464 [PubMed]

  • Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G (1997) daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277:942–946 [PubMed]

  • Levavasseur F, Miyadera H, Sirois J, Tremblay ML, Kita K, Shoubridge E, Hekimi S (2001) Ubiquinone is necessary for mouse embryonic development but is not essential for mitochondrial respiration. J Biol Chem 276:46160–46164 [PubMed]

  • Liang H, Masoro EJ, Nelson JF, Strong R, McMahan CA, Richardson A (2003) Genetic mouse models of extended lifespan. Exp Gerontol 38:1353–1364 [PubMed]

  • Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A (1993) Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75:59–72 [PubMed]

  • Liu X, Jiang N, Hughes B, Bigras E, Shoubridge E, Hekimi S (2005) Evolutionary conservation of the clk-1-dependent mechanism of longevity: loss of mclk1 increases cellular fitness and lifespan in mice. Genes Dev 19:2424–2434 [PubMed]

  • Magalhaes JP de, Cabral JA, Magalhaes D (2005) The influence of genes on the aging process of mice: a statistical assessment of the genetics of aging. Genetics 169:265–274 [PubMed]

  • Masoro EJ (2000) Hormesis is the beneficial action resulting from the response of an organism to a low-intensity stressor. Hum Exp Toxicol 19:340–341 [PubMed]

  • Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi PP, Lanfrancone L, Pelicci PG (1999) The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402:309–313 [PubMed]

  • Miyadera H, Amino H, Hiraishi A, Taka H, Murayama K, Miyoshi H, Sakamoto K, Ishii N, Hekimi S, Kita K (2001) Altered quinone biosynthesis in the long-lived clk-1 mutants of Caenorhabditis elegans. J Biol Chem 276:7713–7716 [PubMed]

  • Morris JZ, Tissenbaum HA, Ruvkun G (1996) A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature 382:536–539 [PubMed]

  • Murakami S, Johnson TE (1996) A genetic pathway conferring life extension and resistance to UV stress in Caenorhabditis elegans. Genetics 143:1207–1218 [PubMed]

  • Nakau M, Miyoshi H, Seldin MF, Imamura M, Oshima M, Taketo MM (2002) Hepatocellular carcinoma caused by loss of heterozygosity in Lkb1 gene knockout mice. Cancer Res 62:4549–4553 [PubMed]

  • Sherr CJ (2004) Principles of tumor suppression. Cell 116:235–246 [PubMed]

  • Smith GS, Walford RL, Mickey MR (1973) Lifespan and incidence of cancer and other diseases in selected long-lived inbred mice and their F 1 hybrids. J Natl Cancer Inst 50:1195–1213 [PubMed]

  • Stenmark P, Grunler J, Mattsson J, Sindelar PJ, Nordlund P, Berthold DA (2001) A new member of the family of di-iron carboxylate proteins. Coq7 (clk-1), a membrane-bound hydroxylase involved in ubiquinone biosynthesis. J Biol Chem 276:33297–33300 [PubMed]

  • Suzuki A, de la Pompa JL, Stambolic V, Elia AJ, Sasaki T, del Barco Barrantes I, Ho A, Wakeham A, Itie A, Khoo W, Fukumoto M, Mak TW (1998) High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr Biol 8:1169–1178 [PubMed]

  • Wong A, Boutis P, Hekimi S (1995) Mutations in the clk-1 gene of Caenorhabditis elegans affect developmental and behavioral timing. Genetics 139:1247–1259 [PubMed]

Articles from Age are provided here courtesy of American Aging Association