, Volume 29, Issue 1, pp 15–28 | Cite as

Effects of calorie restriction on chromosomal stability in rhesus monkeys (Macaca mulatta)

  • Charleen M. MooreEmail author
  • Betty G. Dunn
  • C. Alex McMahan
  • Mark A. Lane
  • George S. Roth
  • Donald K. Ingram
  • Julie A. Mattison


The basic tenet of several theories on aging is increasing genomic instability resulting from interactions with the environment. Chromosomal aberrations have been used as classic examples of increasing genomic instability since they demonstrate an increase in numerical and structural abnormalities with age in many species including humans. This accumulating damage may augment many aging processes and initiate age-related diseases, such as neoplasias. Calorie restriction (CR) is one of the most robust interventions for reducing the frequency of age-related diseases and for extending life span in many short-lived organisms. However, the mechanisms for the anti-aging effects of CR are not yet well understood. A study of rhesus monkeys was begun in 1987 to determine if CR is also effective in reducing the frequency of age-related diseases and retarding aging in a long-lived mammal. Male monkeys were begun on the diet in 1987, and females were added in 1992 to examine a possible difference in response to CR by sex. The CR monkeys have been maintained for over 10 years on a low-fat nutritional diet that provides a 30% calorie reduction compared to a control (CON) group. Because of the greater similarity of nonhuman primates to humans in life span and environmental responses to diet compared with those of rodents, the rhesus monkey provides an excellent model for the effects of CR in humans. This study examined the effects of CR on chromosomal instability with aging. Significant age effects were found in both CR and CON groups for the number of cells with aneuploidy: old animals had a higher loss and a higher gain than young animals. However, there was no effect of age on chromosomal breakage or structural aberrations in either diet group. Diet had only one significant effect: the CR group had a higher frequency of chromatid gaps than did the CON group. CR, implemented in adult rhesus monkeys, does not have a major effect on the reduction of numerical or structural aberrations related to aging.

Key words

aging calorie restriction chromosomal stability diet rhesus monkeys 



This study was supported in part by a grant from the National Institute on Aging. We acknowledge the excellent technical assistance of Catherine D. Weaver, B.S., and the staff at NIH, Poolesville, in particular April Hobbs and Edward Tilmont and veterinarians Drs. Doug Powell and Rick Herbert.


  1. Ames BN, Gold L, Willett WC (1995) The causes and prevention of cancer. Proc Natl Acad Sci USA 92:5258–5265PubMedCrossRefGoogle Scholar
  2. Bender MA, Preston RJ, Leonard RC, Pyatt BE, Gooch PC, Shelby MD (1988) Chromosomal aberration and sister-chromatid exchange frequencies in peripheral blood lymphocytes of a large human population sample. Mutat Res 204:421–433PubMedCrossRefGoogle Scholar
  3. Bender MA, Preston RJ, Leonard RC, Gooch PC, (1989) Chromosomal aberration and sister-chromatid exchange frequencies in peripheral blood lymphocytes of a large human population sample. II. Extension of age range. Mutat Res 212:149–154PubMedGoogle Scholar
  4. Black A, Tilmont EM, Handy AM, Ingram DK, Roth GS, Lane MA (2000) Calorie restriction reduces the incidence of proliferative disease: preliminary data from the NIA CR in nonhuman primate study. Gerontologist 40, Special Issue II, p 5Google Scholar
  5. Bochkov NP (1972) Spontaneous chromosome aberrations in human somatic cells. Humangenetik 16:159–164PubMedCrossRefGoogle Scholar
  6. Bodkin NL, Alexander TM, Ortmeyer HK, Johnson E, Hansen BD (2003) Morbidity and mortality in laboratory-maintained rhesus monkeys and effects of long-term dietary restriction. J Gerontol Biol Sci 58A:212–219Google Scholar
  7. Bolognesi C, Abbondandolo A, Barale R, Casalone R, Dalpra L, De Ferrari M, Degrassi F, Forni A, Lamberti L, Lando C, Migliore L, Padovani P, Pasquini R, Puntoni R, Sbrana I, Stella M, Bonassi S (1997) Age-related increase of base-line frequencies of sister chromatid exchanges, chromosomal aberrations and micronuclei in human lymphocytes. Cancer Epidemiol Biomark Prev 6:249–256Google Scholar
  8. Bonassi S, Abbondandolo A, Camurri L, Dalpra L, De Ferrari M, Degrassi F, Forni A, Lamberti L, Lando C, Padovani P, Sbrana I, Vecchio D, Puntoni R (1995) Are chromosome aberrations in circulating lymphocytes predictive of future cancer onset in humans? Cancer Genet Cytogenet 79:133–135PubMedCrossRefGoogle Scholar
  9. Bonassi S, Ugolini D, Kirsch-Volders, Strömberg U, Vermeulen R, Tucker JD (2005) Human population studies with cytogenetic biomarkers: review of the literature and future prospectives. Environ Mol Mutagen 45:258–270PubMedCrossRefGoogle Scholar
  10. Catalan J, Surralles J, Falck GCM, Autio K, Norppa H (2000) Segregation of sex chromosomes in human lymphocytes. Mutagenesis 15:251–255PubMedCrossRefGoogle Scholar
  11. Chessen A, Collins A (1997) Assessment of the role of diet in cancer prevention. Cancer Lett 114:237–245CrossRefGoogle Scholar
  12. Cohen MM, Levy HP (1989) Chromosome instability syndromes. Adv Hum Genet 18:42–149Google Scholar
  13. Crott JW, Fenech M (1999) Effect of vitamin C supplementation on chromosome damage, apoptosis and necrosis ex vivo. Carcinogenesis 20:1035–1041PubMedCrossRefGoogle Scholar
  14. Curtis H, Crowley C (1963) Chromosome aberrations in liver cells in relation to the somatic mutation theory of aging. Radiat Res 19:337–344PubMedCrossRefGoogle Scholar
  15. DePinho RA (2000) The age of cancer. Nature 408:248–254PubMedCrossRefGoogle Scholar
  16. Evans HJ (1979) The induction of aberrations in human chromosomes following exposure to mutagens/carcinogens. In: Emmelot P, Kriek E (eds) Environmental carcinogens. Elsevier, Amsterdam, pp 57–74Google Scholar
  17. Fenech M (1998) Chromosomal damage rate, aging and diet. Ann NY Acad Sci 854:23–36PubMedCrossRefGoogle Scholar
  18. Fenech M (2002) Micronutrients and genomic stability: a new paradigm for recommended dietary allowances (RDAs). Food Chem Toxicol 40:1113–1117PubMedCrossRefGoogle Scholar
  19. Fenech M, Rinaldi J (1994) The relationship between micronuclei in human lymphocytes and plasma levels of vitamin C, vitamin E, vitamin B12 and folic acid. Carcinogenesis 15:1405–1411PubMedCrossRefGoogle Scholar
  20. Fenech M, Stockley C, Aitken C (1997) Moderate wine consumption protects against hydrogen peroxide-induced DNA damage. Mutagenesis 12:289–296PubMedCrossRefGoogle Scholar
  21. Fitzgerald PH, McEwan CM (1977) Total aneuploidy and age-related sex chromosome aneuploidy in cultured lymphocytes of normal men and women. Hum Genet 39:329–337PubMedCrossRefGoogle Scholar
  22. Ford JH, Russell JA (1985) Differences in the error mechanisms affecting sex and autosomal chromosomes in women of different ages within the reproductive age group. Am J Hum Genet 37:973–983PubMedGoogle Scholar
  23. Galloway S, Buckton K (1978) Aneuploidy and aging: chromosome studies on a random sample of the population using G-banding. Cytogenet Cell Genet 20:78–95PubMedCrossRefGoogle Scholar
  24. Galloway SM, Berry PK, Nichols WW, Wolman SR, Soper KA, Stolley PD, Archer P (1986) Chromosome aberrations in individuals occupationally exposed to ethylene oxide, and in a large control population. Mutat Res 170:55–74PubMedCrossRefGoogle Scholar
  25. Guttenbach M, Schakowski R, Schmid M (1994) Aneuploidy and ageing: sex chromosome exclusion into micronuclei. Hum Genet 94:295–298PubMedCrossRefGoogle Scholar
  26. Guttenbach M, Koschorz B, Bernthaler U, Grimm T, Schmid M (1995) Sex chromosome loss and aging: in situ hybridization studies on human interphase nuclei. Am J Hum Genet 57:1143–1150PubMedGoogle Scholar
  27. Hagmar L, Brogger A, Hansteen I, Heim S, Hogstedt B, Knudsen L, Lambert B, Linnainmaa K, Mitelman F, Nordenson I, Reuterwall C, Salomaa S, Skerfving S, Sorsa M (1994) Cancer risk in humans predicted by increased levels of chromosomal aberrations in lymphocytes: Nordic Study Group on the health risk of chromosome damage. Cancer Res 54:2919–2922PubMedGoogle Scholar
  28. Hando JC, Nath J, Tucker JD (1994) Sex chromosomes, micronuclei and aging in women. Chromosoma 103:186–192PubMedCrossRefGoogle Scholar
  29. Hirsch-Kauffmann M, Schweiger M (1999) Aging and chromosomal instability. Rev Physiol Biochem Pharmacol 139:141–174PubMedCrossRefGoogle Scholar
  30. Ingram DK, Cutler RG, Weindruch R, Renquist DM, Knapka JJ, April M, Belcher CT, Clark MA, Hatcherson CD, Marriott BM, Roth GS (1990) Dietary restriction and aging: the initiation of a primate study. J Gerontol 45:B148–B163PubMedGoogle Scholar
  31. Jacobs PA, Court-Brown WM, Doll R (1961) Distribution of human chromosome counts in relation to age. Nature 191:1178–1180PubMedCrossRefGoogle Scholar
  32. Jacobs PA, Brunton M, Court-Brown WM, Doll R, Goldstein H (1963) Change in human chromosome count distributions with age: evidence for a sex difference. Nature 197:1080–1081PubMedCrossRefGoogle Scholar
  33. Jacobs PA, Brunton M, Court-Brown WM (1964) Cytogenetic studies in leucocytes on the general population: subjects 65 years or more. Ann Hum Genet 27:353–365PubMedCrossRefGoogle Scholar
  34. Lane MA, Ingram DK, Roth GS (1997) Beyond the rodent model: calorie restriction in rhesus monkeys. AGE 20:45–56CrossRefGoogle Scholar
  35. Lane MA, Mattison J, Ingram DK, Roth GS (2002) Caloric restriction and aging in primates: relevance to humans and possible CR mimetics. Microsc Res Tech 59:335–338PubMedCrossRefGoogle Scholar
  36. Lucas JN, Deng W, Moore D, Hill F, Wade M, Lewis A, Sailes F, Kramer C, Hsieh A, Galvan N (1999) Background ionizing radiation plays a minor role in the production of chromosome translocations in a control population. Int J Radiat Biol 75:819–827PubMedCrossRefGoogle Scholar
  37. Ly DH, Lockhart DJ, Lerner RA, Schultz PG (2000) Mitotic misregulation and human aging. Science 287:2486–2492PubMedCrossRefGoogle Scholar
  38. Marlhens F, Al Achkar W, Aurias A, Couturier J, Dutrillaux AM, Gerbault-Seureau M, Hoffschir F, Lamoliatte E, Lefrancois D, Lombard M, Muleris M, Prieur M, Prod’homme M, Sabatier L, Viegas-Péquignot E, Volobouev V, Dutrillaux B (1986) The rate of chromosome breakage is age dependent in lymphocytes of adult controls. Hum Genet 73:290–297PubMedCrossRefGoogle Scholar
  39. Martin GM, Ohshima J (2000) Lessons from human progeroid syndromes. Nature 408:263–266PubMedCrossRefGoogle Scholar
  40. Martin GM, Smith AC, Ketterer DJ, Ogburn CE, Disteche CM (1985) Increased chromosomal aberrations in first metaphases of cells isolated form the kidneys of aged mice. Isr J Med 21:296–301Google Scholar
  41. Mattevi MS, Salzano FM (1975) Senescence and human chromosome changes. Humangenetik 27:1–8PubMedGoogle Scholar
  42. Mattison JA, Lane MA, Roth GS, Ingram DK (2003) Calorie restriction in rhesus monkeys. Exp Gerontol 38:35–46PubMedCrossRefGoogle Scholar
  43. Maurer B, Guttenbach M, Schmid M (2003) Chromosomal instability in normative aging. In: Hisama FM, Weissman SM, Martin GM (eds) Chromosomal instability and aging. basic science and clinical implications. pp 125–147Google Scholar
  44. McCay CM, Crowell MF, Maynard LA (1935) The effect of retarded growth upon the length of the lifespan and upon ultimate body size. J Nutr 10:63–79Google Scholar
  45. McCullagh P, Nelder JA (1989) Generalized linear models. Chapman and Hall, New YorkGoogle Scholar
  46. Moore CM, Janish C, Eddy CA, Hubbard GB, Leland MM, Rogers J (1999) Cytogenetic and fertility studies of a rheboon, rhesus macaque (Macaca mulatta) x baboon (Papio hamadryas) cross: further support for a single karyotype nomenclature. Am J Phys Anthropol 110:119–127PubMedCrossRefGoogle Scholar
  47. Nath J, Tucker JD, Hando JC (1995) Y chromosome aneuploidy, micronuclei, kinetochores and aging in men. Chromosoma 103:725–731PubMedCrossRefGoogle Scholar
  48. Nowinski GP, Van Dyke DL, Tilley BC, Jacobsen G, Babu VR, Worsham MJ, Wilson GN, Weiss L (1990) The frequency of aneuploidy in cultured lymphocytes is correlated with age and gender but not with reproductive history. Am J Hum Genet 46:1101–1111PubMedGoogle Scholar
  49. Obe G, Herha J (1978) Chromosomal aberrations in heavy smokers. Hum Genet 41:259–263PubMedCrossRefGoogle Scholar
  50. Ortiz R, Campos C, Gómez JL, Espinoza M, Ramos-Motilla M, Betancourt M (1994) Sister-chromatid exchange (SCE) and cell proliferation in lymphocytes from infected and non-infected children with severe protein calorie malnutrition (PCM). Mutat Res 312:33–37PubMedGoogle Scholar
  51. Pierre R, Hoagland H (1972) Age-associated aneuploidy: loss of the Y chromosome from human bone marrow cells with aging. Cancer 30:889–894PubMedCrossRefGoogle Scholar
  52. Prieur M, Achkar A, Aurias A, Couturier J, Dutrillaux A, Dutrillaux B, Flury-Herard A, Gerbault-Seureau M, Hoffschir F, Lamoliatte E, Lefrancois D, Lombard M, Muleris M, Ricoul M, Sabatier L, Viegas-Pequinot E (1988) Acquired chromosome rearrangements in human lymphocytes: effects of aging. Hum Genet 79:147–150PubMedCrossRefGoogle Scholar
  53. Ramsey MJ, Moore DH, Briner JF, Lee DA, Olsen L, Senft JR, Tucker JD (1995) The effects of age and life-style factors on the accumulation of cytogenetic damage as measured by chromosomal painting. Mutat Res 338:95–106PubMedGoogle Scholar
  54. Richard F, Aurias A, Couturier J, Dutrillaux AM, Flüry-Hérard A, Gerbault-Seureau M, Hoffschir F, Lamoliatte E, Lefrancois D, Lombard M, Muleris M, Prieur M, Richoul M, Sabatier L, Viegas-Péquignot E, Volobouev V, Dutrillaux B (1993) Aneuploidy in human lymphocytes: an extensive study of eight individuals of various ages. Mutat Res 295:71–80PubMedGoogle Scholar
  55. Roth GS, Ingram DK, Lane MA (1999) Calorie restriction in primates: will it work and how will we know? J Am Geriatr Soc 47:896–903PubMedGoogle Scholar
  56. Schneider EL (1978) Cytogenetics of aging. In: Schneider EL (ed) The genetics of aging. Plenum, New York, pp 27–52Google Scholar
  57. Semsei I (2000) On the nature of aging. Mech Ageing Devel 117:93–108PubMedCrossRefGoogle Scholar
  58. Solomon E, Borrow J, Goddard AD (1991) Chromosomal aberrations and cancer. Science 254:1153–1160PubMedCrossRefGoogle Scholar
  59. Stevenson KG, Curtis HJ (1961) Chromosomal aberrations in irradiated and nitrogen mustard-treated mice. Radiat Res 15:774–785PubMedCrossRefGoogle Scholar
  60. Stone JF, Sandberg AA (1995) Sex chromosome aneuploidy and aging. Mutat Res 338:107–113PubMedGoogle Scholar
  61. Tucker JD, Lee DA, Ramsey MJ, Briner J, Olsen L, Moore II DH (1994) On the frequency of chromosome exchanges in a control population measured by chromosome painting. Mutat Res 313:193–202PubMedGoogle Scholar
  62. Tucker JD, Spruill MD, Ramsey MJ, Director AD, Nath J (1999) Frequency of spontaneous chromosome aberrations in mice: effects of age. Mutat Res 425:135–141PubMedGoogle Scholar
  63. Vijg J, Gossen JA (1993) Somatic mutations and cellular aging. Comp Biochem Physiol 104B:429–437Google Scholar
  64. Weinberg J, Stanyon R, Jauch A, Cremer T (1992) Homologies in human and Macaca fuscata chromosomes revealed by in situ suppression hybridization with human chromosome specific libraries. Chromosoma 101:265–270CrossRefGoogle Scholar
  65. Weindruch R, Walford R (1988) The retardation of aging and disease by dietary restriction. Thomas, Springfield, ILGoogle Scholar
  66. Weirich-Schwaiger H, Weirich HG, Gruber B, Schweiger M, Hirsch-Kauffmann M (1994) Correlation between senescence and DNA repair in cells from young and old individuals and in premature aging syndromes. Mutat Res 316:37–48PubMedGoogle Scholar
  67. Wojda A, Witt M (2003) Manifestations of ageing at the cytogenetic level. J Appl Genet 44:383–399PubMedGoogle Scholar
  68. Xue K, Wang S, Zhou P, Wu P, Zhang R, Xu Z, Chen W, Wang Y (1992) Micronucleus formation in peripheral blood lymphocytes from smokers and the influence of alcohol- and tea-drinking habits. Int J Cancer 50:702–705PubMedCrossRefGoogle Scholar
  69. Yu BP (1994) Modulation of aging processes by dietary restriction. CRC, Boca RatonGoogle Scholar

Copyright information

© American Aging Association, Media, PA, USA 2006

Authors and Affiliations

  • Charleen M. Moore
    • 1
    Email author
  • Betty G. Dunn
    • 2
  • C. Alex McMahan
    • 3
  • Mark A. Lane
    • 4
  • George S. Roth
    • 5
  • Donald K. Ingram
    • 4
    • 6
  • Julie A. Mattison
    • 4
  1. 1.Department of Cellular and Structural BiologyUniversity of Texas Health Science Center at San AntonioSan AntonioUSA
  2. 2.Department of Clinical Laboratory SciencesUniversity of Texas Health Science Center at San AntonioSan AntonioUSA
  3. 3.Department of PathologyUniversity of Texas Health Science Center at San AntonioSan AntonioUSA
  4. 4.Laboratory of Experimental Gerontology, Gerontology Research CenterNational Institute on AgingBaltimoreUSA
  5. 5.GeroSciencePylesvilleUSA
  6. 6.Nutritional Neuroscience and Aging Laboratory, Pennington Biomedical Research CenterLouisiana State University SystemBaton RougeUSA

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