Haplotype Frequency in controls Frequency in centenarians AA 2.1+1.4% 1.3+1.4% AG 51.9+3.9% 56.6+5.0% GA 10.6+2.5% 4.7+2.3% GG 35.7+3.6% 37.3+4.9% P=0.456

between centenarians and controls (P=0.298) as well as haplotype distribution (P=0.326) (Table 6A and B). The only difference is the absence of the haplotype with G in position IVS2nt-124 and delT in IVSnt169 in young controls. As a consequence, the linkage disequilibrium analysis of such a haplotype becomes significant (w2=8.579, with P=0.003).

polymorphisms of FasL gene in the same groups of and studied DNA from 76 young controls and centenarians. As reported in Table 4A and B, distribution of genotypes and allele frequency of 124 polymorphism does not show any significant between the groups of centenarians and young either considering the whole groups (w2=1.254, P=0.263), or considering the female subgroups (w2=1.029, with P=0.310). The same analysis was out for the IVS3nt169 polymorphism, and the results reported in Table 5A and B. We have not found difference between the whole groups (w2=0.668, P=0.315) as well as between the female (w2=0.491, with P=0.782).



centenarians, i.e. those individuals who have been able to reach the extreme limit of human life avoiding the major age- related diseases, and who are considered the best model of physiological successful aging.28–34 The immune system of these exceptional individuals undergoes a complex and profound remodelling,27,28 that includes a paradoxical,

Finally, we have analyzed FasL genotypes in combina- tion, as in the case of Fas polymorphisms, and we have estimated the haplotype frequencies in both populations.

Table 4A Genotype and allele frequency of the IVS2nt-124 FasL polymorphism in young controls and centenarian subjects

Genotype Allele frequency A/A A/G G/G A G Controls (n=77) 48 (62.3%) 29 (37.7%) 0 (0%) 81.2% 18.8% Centenarians (n=46) 34 (73.9%) 12 (26.1%) 0 (0%) 86.9% 13.1% w2=1.254 z=1.005 P=0.263 P=0.315

Genotype Allele frequency A/A A/G G/G A G Controls (n=77) 48 (62.3%) 29 (37.7%) 0 (0%) 81.2% 18.8% Centenarians (n=46) 34 (73.9%) 12 (26.1%) 0 (0%) 86.9% 13.1% w2=1.254 z=1.005 P=0.263 P=0.315 B Genotype and allele frequency of the IVS2nt-124 FasL polymorphism in young controls and centenarian females Genotype Allele frequency A/A A/G G/G A G Controls (n=33) 19 (57.6%) 14 (42.4%) 0 (0%) 78.8% 21.2% Centenarians (n=39) 28 (71.8%) 11 (28.2%) 0 (0%) 85.9% 14.1% w2=1.029 z=0.900 P=0.310 P=0.368

B Genotype and allele frequency of the IVS2nt-124 FasL polymorphism in young controls and centenarian females

Genotype Allele frequency A/A A/G G/G A G Controls (n=33) 19 (57.6%) 14 (42.4%) 0 (0%) 78.8% 21.2% Centenarians (n=39) 28 (71.8%) 11 (28.2%) 0 (0%) 85.9% 14.1% w2=1.029 z=0.900 P=0.310 P=0.368

Table 5A Genotype and allele frequency of the IVS3nt-169 FasL polymorphism in young controls and centenarian subjects

Genotype Allele frequency T/T T/delT delT/delT T delT Controls (n=76) 55 (72.4%) 15 (19.7%) 6 (7.9%) 82.2% 17.8% Centenarians (n=42) 33 (78.6%) 7 (16.7%) 2 (4.8%) 86.9% 13.1% w2=0.668 z=0.736 P=0.315 P=0.462 B Genotype and allele frequency of the IVS3nt-169 FasL polymorphism in young controls and centenarian females Genotype Allele frequency T/T T/delT delT/delT T delT Controls (n=33) 25 (75.7%) 5 (15.2%) 3 (9.1%) 83.3% 16.7% Centenarians (n=39) 30 (76.9%) 7 (17.9%) 2 (5.2%) 85.9% 14.1% w2=0.491 z=0.200 P=0.782 P=0.842

Genotype Allele frequency T/T T/delT delT/delT T delT Controls (n=76) 55 (72.4%) 15 (19.7%) 6 (7.9%) 82.2% 17.8% Centenarians (n=42) 33 (78.6%) 7 (16.7%) 2 (4.8%) 86.9% 13.1% w2=0.668 z=0.736 P=0.315 P=0.462

B Genotype and allele frequency of the IVS3nt-169 FasL polymorphism in young controls and centenarian females

Genotype Allele frequency T/T T/delT delT/delT T delT Controls (n=33) 25 (75.7%) 5 (15.2%) 3 (9.1%) 83.3% 16.7% Centenarians (n=39) 30 (76.9%) 7 (17.9%) 2 (5.2%) 85.9% 14.1% w2=0.491 z=0.200 P=0.782 P=0.842

Table 6A FasL combined genotype frequency in centenarian and control

Genotype Group IVS2nt-124 IVS3nt169 Controls Centenarians A/A T/T 29 (38.2%) 23 (54.7%) A/A T/delT 12 (15.8%) 6 (14.3%) A/A delT/delT 6 (7.9%) 1 (2.4%) A/G T/T 26 (34.2%) 10 (23.8%) A/G T/delT 3 (3.9%) 1 (2.4%) A/G delT/delT 0 1 (2.4%) G/G T/T 0 0 G/G T/delT 0 0 G/G delT/delT 0 0 w2=6.083 P=0.298

B Haplotype frequency estimation for FasL polymorphisms in control and centenarian subjects. For each frequency, the calculated mean+standard deviation is reported

Haplotype Frequency in controls Frequency in centenarians A T 63.1+2.9% 74.4+7.5% A delT 17.7+2.7% 11.3%+5.7% G T 19.1+2.9% 12.5%+4.4% G delT 0 1.7+1.7% P=0.326

unexpected increase in parameters linked to inflammation, such as the capacity to produce proinflammatory cytokines,35 including TNF, which is involved in the induction of apoptosis in a variety of cell types.