Skip to main content

Advertisement

SpringerLink
Log in

Gender-specific association of ADA genetic polymorphism with human longevity

  • Research Article
  • Published:
Biogerontology Aims and scope Submit manuscript

Abstract

Aim of this study was to investigate whether the polymorphic ADA (Adenosine Deaminase, EC 3.5.4.4) gene, which determines the cellular level of adenosine and plays a crucial role in the regulation of the immune system and in the control of metabolic rates, is involved in longevity. 884 unrelated healthy individuals (age range 10–106 years, 400 males and 484 females) from central Italy were studied. ADA genotyping was performed by RFLP-PCR. Frequency distributions were compared using the chi-square test and a three-way contingency table analysis by a log linear model was applied to test independence between the variables. We found that ADA influences human life-span in a sex and age specific way. An increased frequency of ADA*2 carriers was found in males aged 80–85, and a decreased frequency in males over 85 (χ2 = 13.93; df = 3; P = 0.003); significant differences among the age groups was not found in females. A strong interaction among age groups, ADA genotype and sex (G = 15.086; df = 3; P = 0.0017) was found. Males aged 80–85 could be protected from ischemic stroke by higher levels of adenosine (determined by the ADA*2 allele). The decrease of ADA*2 carriers in males over 85 may depend essentially on immunological factors; reduced levels of adenosine protect from asthma and other pulmonary diseases and lead to a reduced activation of inflammatory cells and pro-inflammatory cytokines production. Moreover, the low level of adenosine may potentiate the activity of NK and other cellular effectors against tumor cells. The negligible effect of ADA genetic polymorphism in females suggest a marginal influence of genetic factors in determining longevity in this sex, confirming previous reports.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Battistuzzi G, Scozzari R, Santolamazza P, Terrenato L, Modiano G (1974) Comparative activity of red cell adenosine deaminase allelic forms. Nature 251:711–713

    Article  PubMed  CAS  Google Scholar 

  • Bellizzi D, Rose G, Cavalcante P, Covello G, Dato S, De Rango F, Greco V, Maggiolini M, Feraco E, Mari V, Franceschi C, Passarino G, De Benedictis G (2005) A novel VNTR enhancer within the SIRT3 gene, a human homologue of SIR2, is associated with survival at oldest ages. Genomics 85:258–263

    Article  PubMed  CAS  Google Scholar 

  • Blackburn MR (2003) Too much of a good thing: adenosine overload in adenosine-deaminase-deficient mice. Trends Pharmacol Sci 24:66–70

    Article  PubMed  CAS  Google Scholar 

  • Chunn JL, Mohsenin A, Young HW, Lee CG, Elias JA, Kellems RE, Blackburn MR (2006) Partially adenosine deaminase-deficient mice develop pulmonary fibrosis in association with adenosine elevations. Am J Physiol Lung Cell Mol Physiol 290:579–587

    Article  CAS  Google Scholar 

  • De Luca M, Rose G, Bonafè M, Garasto S, Greco V, Weir BS, Franceschi C, De Benedictis G (2001) Sex-specific longevity associations defined by Tyrosine Hydroxylase-Insulin-Insulin Growth Factor 2 haplotypes on the 11p15.5 chromosomal region. Exp Gerontol 36:1663–1671

    Article  PubMed  Google Scholar 

  • Dong RP, Kameoka J, Hegen M, Tanaka T, Xu Y, Schlossman SF et al (1996) Characterization of adenosin deaminase binding to human CD26 on T cells and its biologic role in immune response. J Immunol 156:1349–1355

    PubMed  CAS  Google Scholar 

  • Feoktistov I, Garland EM, Goldstein AE, Zeng D, Belardinelli L, Wells JN, Biaggioni I (2001) Inhibition of human mast cell activation with the novel selective adenosine A(2B) receptor antagonist 3-isobutyl-8-pyrrolidinoxanthine (IPDX)(2). Biochem Pharmacol 62:1163–1173

    Google Scholar 

  • Franco R, Pacheco R, Gatell JM, Gallart T, Lluis C (2007) Enzymatic and extraenzymatic role of adenosine deaminase 1 in T-cell-dendritic cell contacts and in alterations of the immune function. Crit Rev Immunol 27:495–509

    PubMed  CAS  Google Scholar 

  • Guralnik JM, Balfour JL, Volpato S (2000) The ratio of older women to men: historical perspectives and cross-national comparisons. Aging (Milano) 12:65–76

    CAS  Google Scholar 

  • Heistad DD, Marcus ML, Gourley JK, Busija DW (1981) Effect of adenosine and dipyridamole on cerebral blood flow. Am J Physiol 240:775–780

    Google Scholar 

  • Hirschhorn R, Yang DR, Israni A (1994) An Asp8Asn substitution results in the adenosine deaminase (ADA) genetic polymorphism (ADA 2 allozyme): occurrence on different chromosomal backgrounds and apparent intragenic crossover. Ann Hum Genet 58:1–9

    Article  PubMed  CAS  Google Scholar 

  • Horváth I, Hunt J, Barnes PJ, Alving K, Antczak A, Baraldi E, Becher G, van Beurden WJ, Corradi M, Dekhuijzen R, Dweik RA, Dwyer T, Effros R, Erzurum S, Gaston B, Gessner C, Greening A, Ho LP, Hohlfeld J, Jöbsis Q, Laskowski D, Loukides S, Marlin D, Montuschi P, Olin AC, Redington AE, Reinhold P, van Rensen EL, Rubinstein I, Silkoff P, Toren K, Vass G, Vogelberg C, Wirtz H (2005) ATS/ERS task force on exhaled breath condensate: exhaled breath condensate: methodological recommendations and unresolved questions. Eur Respir J 26:523–548

    Article  PubMed  CAS  Google Scholar 

  • Huszár E, Horváth I, Barát E, Herjavecz I, Böszörményi-Nagy G, Kollai M (1998) Elevated circulating adenosine level potentiates antigen-induced immediate bronchospasm and bronchoconstrictor mediator release in sensitized guinea pigs. J Allergy Clin Immunol 102:687–691

    Article  PubMed  Google Scholar 

  • Ivanova R, Hénon N, Lepage V, Charron D, Vicaut E, Schächter F (1998) HLA-DR alleles display sex-dependent effects on survival and discriminate between individual and familial longevity. Hum Mol Genet 7:187–194

    Article  PubMed  CAS  Google Scholar 

  • Kameoka J, Tanaka T, Nojima Y, Schlossman SF, Morimoto C (1993) Direct association of adenosine deaminase with T cell activation antigen, CD26. Science 261:466–469

    Article  PubMed  CAS  Google Scholar 

  • Laghi Pasini F, Guideri F, Picano E, Parenti G, Petersen C, Varga A, Di Perri T (2000) Increase in plasma adenosine during brain ischemia in man: a study during transient ischemic attacks, and stroke. Brain Res Bull 51:327–330

    Article  PubMed  CAS  Google Scholar 

  • Mendelsohn ME, Karas RH (1999) The protective effects of estrogen on the cardiovascular system. N Engl J Med 340:1801–1811

    Article  PubMed  CAS  Google Scholar 

  • Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215

    Article  PubMed  CAS  Google Scholar 

  • Montesanto A, Passarino G, Senatore A, Carotenuto L, De Benedictis G (2008) Spatial analysis and surname analysis: complementary tools for shedding light on human longevity patterns. Ann Hum Genet 72:253–260

    Article  PubMed  CAS  Google Scholar 

  • Passarino G, Montesanto A, Dato S, Giordano S, Domma F, Mari V, Feraco E, De Benedictis G (2006) Sex and age specificity of susceptibility genes modulating survival at old age. Hum Hered 62:213–220

    Article  PubMed  Google Scholar 

  • Pido-Lopez J, Imami N, Aspinall R (2001) Both age and gender affect thymic output: more recent thymic migrants in females than males as they age. Clin Exp Immunol 125:409–413

    Article  PubMed  CAS  Google Scholar 

  • Raskovalova T, Lokshin A, Huang X, Jackson EK, Gorelik E (2006) Adenosine-mediated inhibition of cytotoxic activity and cytokine production by IL-2/NKp46-activated NK cells: involvement of protein kinase A isozyme I (PKA I). Immunol Res 36:91–99

    Article  PubMed  CAS  Google Scholar 

  • Salvioli S, Olivieri F, Marchegiani F, Cardelli M, Santoro A, Bellavista E, Mishto M, Invidia L, Capri M, Valensin S, Sevini F, Cevenini E, Celani L, Lescai F, Gonos E, Caruso C, Paolisso G, De Benedictis G, Monti D, Franceschi C (2006) Genes, ageing and longevity in humans: problems, advantages and perspectives. Free Radic Res 40:1303–1323

    Article  PubMed  CAS  Google Scholar 

  • Schächter F (1998) Causes, effects, and constraints in the genetics of human longevity. Am J Hum Genet 62:1008–1014

    Article  PubMed  Google Scholar 

  • Sokal RR, Rohlf JF (1981) Biometry. WH Freeman, New York

    Google Scholar 

  • Sun CX, Zhong H, Mohsenin A, Morschl E, Chunn JL, Molina JG, Belardinelli L, Zeng D, Blackburn MR (2006) Role of A2B adenosine receptor signaling in adenosine-dependent pulmonary inflammation and injury. J Clin Invest 116:2173–2182

    Article  PubMed  CAS  Google Scholar 

  • Sun Y, Wu F, Sun F, Huang P (2008) Adenosine promotes IL-6 release in airway epithelia. J Immunol 180:4173–4181

    PubMed  CAS  Google Scholar 

  • Tan Q, De Benedictis G, Yashi AI, Bonafe M, DeLuca M, Valensin S, Vaupel JW, Franceschi C (2001) Measuring the genetic influence in modulating the human life span: gene-environment interaction and the sex-specific genetic effect. Biogerontology 2:141–153

    Article  PubMed  CAS  Google Scholar 

  • Tavilani H, Sheikh N, Vaisi-raygani A, Setarehbadi R (2008) Sex differences in adenosine deaminase activity of stroke patients. Clin Chem Lab Med 46:506–509

    Article  PubMed  CAS  Google Scholar 

  • Viña J, Borrás C, Gambini J, Sastre J, Pallardó FV (2005) Why females live longer than males: control of longevity by sex hormones. Sci Aging Knowledge Environ 2005(23):pe17

  • Weidemann W, Hanke H (2002) Cardiovascular effects of androgens. Cardiovasc Drug Rev 20:175–198

    Article  PubMed  CAS  Google Scholar 

  • Yasuda N, Inoue T, Horizoe T, Nagata K, Minami H, Kawata T et al (2003) Functional characterization of the adenosine receptor contributing to glycogenolysis and gluconeogenesis in rat hepatocytes. Eur J Pharmacol 459:159–166

    Article  PubMed  CAS  Google Scholar 

  • Zhong H, Wu Y, Belardinelli L, Zeng D (2006) A2B adenosine receptors induce IL-19 from bronchial epithelial cells, resulting in TNF-alpha increase. Am J Respir Cell Mol Biol 35:587–592

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Cynthia L. Pon and Claudio O. Gualerzi for checking the English.

Conflict of interest

None declared.

Author information

Authors and Affiliations

  1. Laboratory of Human Genetics, Department of Molecular, Cellular and Animal Biology, University of Camerino, Via Gentile III da Varano, 62032, Camerino, Italy

    Valerio Napolioni & Nazzareno Lucarini

Authors
  1. Valerio Napolioni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nazzareno Lucarini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nazzareno Lucarini.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Napolioni, V., Lucarini, N. Gender-specific association of ADA genetic polymorphism with human longevity. Biogerontology 11, 457–462 (2010). https://doi.org/10.1007/s10522-010-9266-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10522-010-9266-7

Keywords

Search

Navigation