Long-term tissue damage can result from chronic inflammation, which has been linked to increased mortality risk in older individuals. Additionally, systemic chronic inflammation can cause organ-specific illnesses when interacting with an organism's genetic makeup. For instance, inflammatory processes play a pathogenetic role in age-related diseases like Alzheimer's disease, Parkinson's disease, atherosclerosis, type 2 diabetes, sarcopenia, and osteoporosis. These diseases are initiated or worsened by systemic inflammation, indicating the critical importance of unregulated systemic inflammation in shortening human survival. Proinflammatory cytokines are believed to contribute to age-related diseases, and genetic variations within their promoter regions have been shown to influence susceptibility to these diseases by increasing gene transcription and cytokine production.

In this study, we evaluated the association between longevity and alleles of IL-10 and TNF-a, which have opposite functions in inflammatory reactions. IL-10 primarily acts as an anti-inflammatory factor while TNF-a acts predominantly as a proinflammatory factor. We found that the number of male centenarians homozygous for the G genotype associated with high IL-10 production was significantly higher than that of younger controls. There were no significant differences between women and control subjects. The genotypic frequencies of TNF-a promoter SNPs G and A associated with low and high TNF-a production were not significantly different between centenarians and controls. However, there was a significant increase of the anti-inflammatory genotype (IL-10 GG/TNF-a GG) in centenarian men compared to controls.

Inflammatory markers predict disability and mortality in elderly cohorts, and a persistent inflammatory state has been proposed to be involved in the causal pathway of certain age-related chronic conditions. Thus, it is intriguing that the possession of an anti-inflammatory genotype is significantly increased in male centenarians. Conversely, genetic variations determining increased production of anti-inflammatory cytokines or decreased production of proinflammatory cytokines have been shown to be associated with successful ageing, suggesting a role for the control of the inflammatory state in the attainment of longevity.

Recently, the distribution of several single nucleotide polymorphisms (SNPs) has been shown to be different in centenarians than in younger people. For instance, the +874T allele involved in high production of the proinflammatory cytokine IFN-g was found less frequently in centenarian women than in control women. Also, the proportion of subjects homozygous for the G allele at the 174 IL-6 locus characterized by high serum levels of the proinflammatory cytokine IL-6 was significantly decreased in centenarian men. Conversely, the presence of the -1082 GG genotype associated with high production of the anti-inflammatory cytokine IL-10 was significantly increased in centenarian men compared to younger male subjects.

In this study, we investigated the frequency of the -1082G fi A IL-10 promoter SNP in a larger cohort of 72 centenarian men and its interaction with -308A fi G TNF-a SNP. We found that the IL-10 gene SNP -1082G fi A had a significant influence on longevity in men, both separately and in association with TNF-a gene SNP 3082Afi G. This result is remarkable considering that centenarian men are relatively rare compared to centenarian women. 

IL-10 and TNF-a are cytokines with complex and predominantly opposing roles in inflammatory responses. The principal routine function of IL-10 is to limit and ultimately terminate inflammatory responses, whereas TNF-a determines strength, effectiveness, and duration of local and systemic inflammatory reactions. The stimulation of human blood samples with bacterial lipopolysaccharide showed large interperson variations of IL-10 and TNF-a.

Overall, our findings suggest that genetic variations affecting cytokine production play a crucial role in the attainment of longevity. The control of the inflammatory state may be critical in aging successfully.corrections and improvements: