Three-way contingency table by a Log-linear model

G d.f. P xyz interaction 15.086 3 0.00177 xy independence 19.806 6 0.00299 xz independence 16.874 4 0.00204 yz independence 27.964 6 9.544 9 10-5

x age, y ADA genotype (ADA 1*/1* vs. ADA*2 carriers), z sex

Discussion

The significant increase of ADA 2-1 subjects detected in males aged 80–85 is likely due to the protective effect of the elevated cellular concentrations of adenosine during ischemic attack, whose occurrence drastically increases in this period of life. Indeed, adenosine accumulates during brain ischemia and has vasodilation and neuroprotective effects (Heistad et al. 1981). Furthermore, the report that the level of plasma adenosine increases following an ischemic stroke (Laghi Pasini et al. 2000), can be correlated with the finding that, compared to women, men undergoing an ischemic stroke experience a reduction in plasma ADA activity (Tavilani et al. 2008). It is possible that such a reduction is an adaptive mech- anism to protect the male brain from ischemic injury through an increase in adenosine availability.

type on female longevity beyond age 85, we suggest that this might be due to the action of estrogens throughout their entire life, in light of the beneficial effects of estrogens on the vascular system (Mendel- sohn and Karas 1999; Vin˜a et al. 2005; Weidemann and Hanke 2002) brought about by the reduction of the low-density lipoprotein (LDL) cholesterol and increase in the high-density lipoprotein (HDL) cho- lesterol that they cause. So, unlike men, women are less subject to vascular damage and therefore are less sensitive to the consequences of the ADA 2-1 genotype and to the cellular concentration of aden- osine. On the other hand, it is possible that women over age 85 might respond to the sex-specific differences in thymic output (Pido-Lopez et al. 2001). It has been shown that thymic involution occur more rapidly in males than in females. Thus, if one assumes that thymus involution plays a central role in the development of an immunological risk profile and that ADA deficiency increases thymic

As regards the reduction of ADA 2-1 genotype in [85 males, we suggest that it is probably due to the higher level of cellular adenosine determined by above-mentioned genotype. In fact, adenosine trig- gers the release of IL-6, a disability and mortality predictor among the elderly, as well as IL-1b, a pro- inflammatory molecule associated with poor physical performance and diminished muscle strength in older persons (Sun et al. 2008). Higher levels of adenosine were also found to be positively correlated with the

Chunn JL, Mohsenin A, Young HW, Lee CG, Elias JA, Kellems RE, Blackburn MR (

) Partially adenosine deaminase-deficient mice develop pulmonary fibrosis in association with adenosine elevations. Am J Physiol Lung Cell Mol Physiol

:

–

De Luca M, Rose G, Bonafe` M, Garasto S, Greco V, Weir BS, Franceschi C, De Benedictis G (

) Sex-specific lon- gevity associations defined by Tyrosine Hydroxylase- Insulin-Insulin Growth Factor

haplotypes on the

p

chromosomal region. Exp Gerontol

:

–

Dong RP, Kameoka J, Hegen M, Tanaka T, Xu Y, Schlossman SF et al (

) Characterization of adenosin deaminase binding to human CD

on T cells and its biologic role in immune response. J Immunol

:

–

Feoktisto

,Garlan

M,Goldstei

E,Zen

,Belardinell

, Wells JN, Biaggioni I (

) Inhibition of human mast cell activation with the novel selective adenosine A(

B) recep- tor antagonist

-isobutyl-

-pyrrolidinoxanthine (IPDX)(

). Biochem Pharmacol

:

–

Franco R, Pacheco R, Gatell JM, Gallart T, Lluis C (

) Enzymatic and extraenzymatic role of adenosine deami- nase

in T-cell-dendritic cell contacts and in alterations of the immune function. Crit Rev Immunol

:

–

Guralnik JM, Balfour JL, Volpato S (

) The ratio of older women to men: historical perspectives and cross-national comparisons. Aging (Milano)

:

–

Heistad DD, Marcus ML, Gourley JK, Busija DW (

) Effect of adenosine and dipyridamole on cerebral blood flow. Am J Physiol

:

–

Hirschhorn R, Yang DR, Israni A (

) An Asp

Asn sub- stitution results in the adenosine deaminase (ADA) genetic polymorphism (ADA

allozyme): occurrence on different chromosomal backgrounds and apparent intra- genic crossover. Ann Hum Genet

:

–

Horva´th 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, Jo¨bsis Q, Laskowski D, Loukides S, Marlin D, Montuschi P, Olin AC, Redington AE, Reinhold P, van Rensen EL, Rubin- stein I, Silkoff P, Toren K, Vass G, Vogelberg C, Wirtz H (

) ATS/ERS task force on exhaled breath condensate: exhaled breath condensate: methodological recommen- dations and unresolved questions. Eur Respir J

:

–

Husza´r E, Horva´th I, Bara´t E, Herjavecz I, Bo¨szo¨rme´nyi-Nagy G, Kollai M (

) Elevated circulating adenosine level potentiates antigen-induced immediate bronchospasm and bronchoconstrictor mediator release in sensitized guinea pigs. J Allergy Clin Immunol

:

–

Ivanova R, He´non N, Lepage V, Charron D, Vicaut E, Scha¨chter F (

) HLA-DR alleles display sex-dependent effects on survival and discriminate between individual and familial longevity. Hum Mol Genet

:

–

Kameoka J, Tanaka T, Nojima Y, Schlossman SF, Morimoto C (

) Direct association of adenosine deaminase with T cell activation antigen, CD

Science

:

–

Laghi Pasini F, Guideri F, Picano E, Parenti G, Petersen C, Varga A, Di Perri T (

) Increase in plasma adenosine during brain ischemia in man: a study during transient ischemic attacks, and stroke. Brain Res Bull

:

–