Association between longevity and cytokine gene polymorphisms: A study in Sardinian centenarians. 

Giovanni Mario Pes, Domenico Lio, Ciriaco Carru, Luca Deiana, Giovannella Claudio Franceschi, Luigi Ferrucci, Fabiola Oliveri, Letizia Scola, Antonio Crivello, Giuseppina Candore, Giuseppina Colonna-Romano, and Calogero Caruso analyzed the data according to gender. The study aimed to determine if gene polymorphisms of cytokines that regulate immune-inflammatory responses affect life expectancy in the Sardinian population. The study analyzed cytokine/longevity associations in a population-specific component affected by the population-specific gene pool and gene-environment interactions that behave as survival rather than longevity genes. 

The background and aims of the study were to determine if genetic determinants of longevity reside in polymorphisms for immune system genes that regulate immune-inflammatory responses. Human longevity is directly correlated with optimal functioning of the immune system. The immune system's role in longevity must be studied to understand better the role of the immune system in longevity. Cytokine dysregulation plays a key role in proposed remodeling of the immune-inflammatory responses accompanying old age. By regulating the type and magnitude of the immune response in the elderly, it may play a pivotal role in aging and survival.

The study analyzed IL-6, IL-10 and IFN- gene polymorphisms in 112 centenarians from Sardinia and 137 sixty-year-old controls from the same geographic area. The results showed no significant differences between centenarians and controls on analyzing IL-6, IL-10 and IFN- genotype and allele frequencies among centenarians and controls, either together or when data were analyzed by gender.

In conclusion, gene polymorphisms of cytokines playing a major regulatory role in the inflammatory response do not affect life expectancy in the Sardinian population. Cytokine/longevity associations have a population-specific component, being affected by the population-specific gene pool as well as by gene-environment interactions, behaving as survival rather than longevity genes.The following text has been proofread and improved:

Cytokine polymorphisms are associated 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 developing lipid abnormalities and have poorer glucose handling capacity, higher glycosylated blood hemoglobin, higher fasting insulin levels, and higher insulin sensitivity (28). Accordingly, C+ men have been suggested to be protected from CHD (29, 30). Thus, in an aging population, those people who tend to produce elevated IL-6 quantities are less likely to reach the goal of longevity, probably due to their increased proneness to cardiovascular 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 inflammatory activity leading to long-term tissue damage, and systemic chronic inflammation has been found to be related to all-cause mortality risk in older persons. The genetic constitution of the organism interacting with systemic inflammation may also cause defined organ-specific illnesses, indicating the critical importance of unregulated systemic inflammation in shortening survival in humans (2, 3, 22). Thus, inflammatory cytokines are believed to play a pathogenetic role in age-related diseases, and genetic variations located within their promoter regions 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: coronary heart disease (CHD), leading to successful aging and longevity (2, 3, 22-25). IL-6 plays a pivotal role in acute phase responses.

Table 2 - Frequencies for 174GC IL-6 gene SNP, for 1082GA IL-10 gene SNP, and for +874TA IFN--10 gene SNP in centenarians and controls from Sardinia (absolute number of genes analyzed per group in brackets).

Alleles          IL-6              IL-6              IL-10            IL-10               IFN-             IFN-
                     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)

A chi-squared test with Yates 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-).