Heterozygosity plays a positive role in the attainment of longevity. Abstract: Genes involved in cardiovascular diseases (CVD) play an opposite role in human longevity. The alpha-1 antitrypsin (AAT) is a serine-protease inhibitor required for the prevention of proteolytic tissue damage by neutrophil elastase. The role of AAT in CVD has not been definitively assessed, and its effect on longevity has not yet been fully studied. To clarify these points, we have studied the distribution of AAT allele variants in three cohorts: 127 young patients affected by acute myocardial infarction (AMI), 255 young controls, and 143 centenarians from Sicily. The Z allele frequency was most frequent in centenarians (13.3%), intermediate in healthy young controls (3.1%), and less frequent in AMI patients (1.2%) (P = 0.0000001). The heterozygous MZ genotype was significantly overrepresented in centenarians (38/143) and underrepresented in AMI patients (3/127), with intermediate values in young controls (16/255) (P = 0.0000001). After adjustment for well-recognized AMI risk factors, the MZ genotype still predicted a significant negative risk factor for developing AMI in the Sicilian population. Thus, our data show a positive role of MZ heterozygosity in the attainment of successful aging linked to the positive effects of this genotype versus cardiovascular ischemic diseases.

F. List` G. Candore (&) M. P. Grimaldi D. Lio G. Colonna-Romano V. Orlando C. Caruso Dipartimento di Biopatologia e Metodologie Biomediche, Gruppo di Studio sullImmunosenescenza, Corso Tukory, Palermo, Italy e-mail: gcandore@unipa.it G. Paolisso Dipartimento di Medicina Geriatria e Malattie Metaboliche, II Universita` di Napoli, Napoli, Italy Centenarian offspring, who have an increased likelihood of surviving up to 100 years, show a reduced prevalence of cardiovascular diseases (CVD) and less frequency of cardiovascular risk. Istituto Nazionale di Riposo e Cura per Anziani, Ancona, Italy.

Alpha-1 antitrypsin (AAT), also referred to as an alpha-proteinase inhibitor (Pi), is a 52 kD glycoprotein secreted by hepatocytes and, to a lesser extent, by lung epithelial cells and phagocytes into the plasma at a concentration of 1.93.5 mg/ml. It is proposed to play an important role in protecting vulnerable elastic tissue in the lungs, gut, and vasculature from degradation by neutrophil elastase. Its severe deficiency is involved in chronic obstructive pulmonary disease (COPD) (De Meo and Silverman 2004; Lomas and Parfrey 2004; Luisetti and Seersholm 2004). The Pi gene, located on chromosome 14q32.1 (OMIM: 107400), is 12.2 Kb in length with seven exons and six introns. The encoded protein includes 394 amino acids with the active site of the enzyme inhibitor at methionine 358. It inhibits a variety of serine proteinases but its preferred target is neutrophil elastase that is bound to the active site and permanently inactivated (De Meo and Silverman).

A Danish study (Dahl et al.) found that ZZ AAT deficiency and MZ deficiency patients affected by coronary artery disease (CAD) have lower blood than MM/MS patients. Furthermore, heterozygosity was associated with reduced ischemic cerebrovascular disease (ICVD) CAD. The authors supposed that neutrophil can play a favorable role in CVD destroying elastic tissue of the arterial it alters the distensibility of the vessel wall, thus blood pressure and cardiac load. Since blood pressure is protective against ICVD CAD, AAT deficiency might be associated reduced risk of development of these diseases through this mechanism (Ooyama and 1995; Zureik et al. 2002; Dahl et al.). However, in that year, another report seemingly contrasting results (Talmud et al. 2003). In fact, the other authors demonstrated that the progression of atherosclerosis was with low AAT levels. They suggested elastase activity attributable to AAT deficiency accelerates hardening of arterial walls and (Talmud et al. 2003). However, analysis was very limited in scope and number (several dozens of patients), and mostly dealt.