DISCUSSION

and in the balancing of the pro-inflammatory/anti-in- flammatory pathways (26). Elevated IL-6 levels are asso- ciated with the development and severity of CHD, as well as with the transition to plaque instability (25, 27). Carriers of the –174G SNP appear to be prone to develop lipid abnormalities and have poorer glucose handling capaci- ty, higher glycosylated blood hemoglobin, higher fasting insulin levels, and higher insulin sensitivity (28). Accord- ingly, C+ men have been suggested to be protected from CHD (29, 30). Thus, in an aging population, those people who have the tendency to produce elevated IL-6 quantities are less likely to reach the goal of longevity, probably due to their increased proneness to cardiovas- cular events. The discrepancies observed in some studies on the association between IL-6 –174 SNP and CHD (25) may be due to the fact that the influence of individual genotype on plasma IL-6 levels is rather variable and may depend on the genetic background of the population under study (31).

Aging is associated with chronic, low-grade inflam- matory activity leading to long-term tissue damage, and systemic chronic inflammation has been found to be re- lated to all-cause mortality risk in older persons. The genetic constitution of the organism interacting with sys- temic inflammation may also cause defined organ-specific illnesses, indicating the critical importance of unregulated systemic inflammation in the shortening of survival in hu- mans (2, 3, 22). Thus, inflammatory cytokines are be- lieved to play a pathogenetic role in age-related diseases, and genetic variations located within their promoter re- gions have been shown to influence susceptibility to age- related diseases by modifying gene transcription and therefore cytokine production. Conversely, controlling inflammatory status may avoid or delay the main leading cause of death, i.e., coronary heart disease (CHD), lead- ing to successful aging and longevity (2, 3, 22-25).

IL-6 plays a pivotal role in acute phase responses

Table 2 - Frequencies for –174G→C IL-6 gene SNP, for –1082G→A IL-10 gene SNP, and for +874T→A IFN-γ-10 gene SNP in tenarians and controls from Sardinia (absolute number of genes analyzed per group in brackets).

Alleles IL-6 IL-6 IL-10 IL-10 IFN-γ IFN-γ –174G –174C –1082G –1082A +874T +874A Centenarians 0.719 (161) 0.281 (63) 0.575 (100) 0.425 (74) 0.490 (94) 0.510 (98) Men 0.750 (54) 0.250 (18) 0.578 (37) 0.422 (27) 0.531 (34) 0.469 (30) Women 0.704 (107) 0.296 (45) 0.573 (63) 0.427 (47) 0.469 (60) 0.531 (68) Controls 0.704 (193) 0.296 (81) 0.576 (98) 0.424 (72) 0.495 (93) 0.515 (95) Men 0.706 (96) 0.294 (40) 0.548 (34) 0.452 (28) 0.458 (33) 0.542 (39) Women 0.703 (97) 0.297 (41) 0.592 (64) 0.408 (44) 0.517 (60) 0.483 (56)

χ2 test with Yate’s correction was performed to calculate significant different SNP distribution between centenarians and controls. No significant differences were observed. Note that cytokine SNPs were respectively typed in 112 centenarians and 137 controls (IL-6), 87 centenarians and 85 controls (IL-10), and 96 centenarians and 94 controls (IFN-γ).

ward the same change in Irish nonagenarians (15). In- terestingly, a decrease in IFN-γ +874T SNP was observed among female Sardinian centenarians, although the dif- ferences did not reach statistical significance (Table 2). This last datum may be due to the relatively small number of Sardinian female centenarians, which may have limited the statistical power of the study. Thus, in our opinion, the Italian findings are not due to chance.

considered to mediate potent downregulation of inflam- matory responses (32). Serum levels of IL-10 are de- creased in patients with unstable angina, in keeping with data from animal studies which indicate that IL-10 plays a protective role in atherosclerosis (33). Some case-con- trol studies do not support the role of IL-10 polymor- phisms in CHD (34, 35). However, a recent study sug- gests that –1082A allele, associated with low production of cytokine IL-10 and elevated markers of systemic in- flammation such as C-reactive protein, is predictive of higher cardiovascular morbidity in dialysis patients com- pared with the –1082G genotype. Moreover, a prelimi- nary report in two Italian samples of patients affected by myocardial infarction suggests the protective role of IL-10 –1082G SNP (36, 37).

However, it must be remembered that, in Sardinia, male and female centenarians are apparently almost equal in number (2/1), unlike other areas in Europe. This suggests the relevance of peculiar genetic or envi- ronmental characteristics responsible for the attain- ment of longevity by men (12, 17, 18), which may make the possession of these IL-6 and IL-10 SNPs not relevant for men. It is noteworthy that the epidemio- logical data available on CHD in Sardinia indicate the low mortality of this population, compared with main- land Italy. Interestingly, the frequency of the well-known risk factor APOEε 4 is unusually low and, most inter- estingly, does not change in the different age groups, i.e., does not decrease in old subjects, and does not in- fluence lipid metabolism (41).

IFN-γ is one of the pivotal cytokines in the induction of immune-mediated inflammatory responses (38). No data have yet been presented on the association between CHD and IFN-γ polymorphisms. However, in both ex- perimental animals and human beings, IFN-γ is involved

It is therefore seemingly puzzling that these polymor- phisms, which probably avoid or delay death linked to CHD, are associated with longevity in Italians but not in Sar- dinians. Several possibilities may explain this discrepancy.

On the whole, these findings suggest that cytokine/ longevity associations have a population-specific com- ponent, being affected by the population-specific gene pool as well as by gene-environment interactions and behaving as survival rather than longevity assurance genes (2).