obtained from each participant or their legal representative. 

The study investigated the influence of IGF-1R rs2229765, IL-6 rs1800795, circulating IGF-1 and IL-6 on male longevity in a population-based prospective study (Treviso Longeva TRELONG). Genetics and the environment were found to impact human longevity, and previous studies have explored the role of genetics in exceptional longevity. Inflammation plays a dual role in aging physiology, as both an acute inflammatory response that benefits survival and as a chronic inflammatory state that often parallels neurodegenerative disorders, autoimmunity, and cancer. 

The insulin/IGF-1 pathway and the pro-inflammatory cytokine network appear to play an important role in modulating longevity. The IIS triggers intracellular downstream transcription factors as a result of a cascade starting from the membrane receptors of insulin and IGF-1. Biochemical or genetic attenuation of IIS has been linked to increased lifespan, likely due to slower cell growth rate and metabolism. In humans, circulating IGF-1 decreases with age and is also modified by sex hormones. 

A synonymous polymorphism (rs2229765) on the IGF-1 receptor gene (IGF-1R) consisting of a G to A transition at nucleotide 3174 leading to the amino acid change Glu->Glu at position 1043 (E1043E) has been positively associated with longevity in the Italian population. Interleukin-6 (IL-6) is a key pro-inflammatory molecule whose circulating level in humans tends to rise over time. The role of rs1800795 in longevity has been explored in the Italian population with controversial results; however, a higher IL-6 circulating level is almost invariably a negative predictor of survival.

Plasma IGF-1 was assayed by sandwich-type enzyme-linked immunosorbent assay (ELISA), and plasma IL-6 was measured by another sandwich-type ELISA. The influence of IGF-1R rs2229765, IL-6 rs1800795, circulating IGF-1, and IL-6 on survival curves was assessed in a sample of elderly people from Treviso (Italy) who were followed for seven years from baseline (TRELONG Study), with particular attention to sex-specific patterns. 

The age and sex of the TRELONG study population are summarized in Table I. The sample included individuals aged 70 years and older, with a male-to-female ratio of 0.87. The survival curves were plotted by sex and stratifying for IGF1R rs2229765 genotype. Multivariate regression analysis including several confounders indicated that the rs2229765 G/G genotype significantly increased the hazard ratio in comparison to the A/A genotype, suggesting a positive role of the latter on male survival. 

The study protocol was approved by the Ethics Committee of the National Institute on Research and Care of the Elderly (INRCA, Italy), and written informed consent was obtained from each participant or their legal representative. Blood samples were collected by venipuncture and genotyped for rs2229765 and rs1800795 using genomic DNA extracted from leukocytes. Consent for blood collection was obtained from each participant or their legal representative.participants was observed in the IL-6 rs1800795 genotype analysis, with no effect on survival found. The odds ratios for men and women with the C/G and G/G genotypes, corrected for age and using the C/C genotype as reference, did not show any significant influence on survival. Multivariate regression confirmed the lack of influence on survival. The genotypes were assessed as previously described.

Circulating levels of IL-6 were found to rise with age and correlate with disability and mortality. This observation was extended to consider a possible sex-specific pattern, which showed a more pronounced effect on survival in men than in women. In fact, in men, IL-6 levels in the second quartile were already marginally significant in increasing mortality risk and became a clearly deleterious predictor of survival from the third quartile onwards. The association was attenuated in women. Multivariate analysis confirmed that IL-6 levels in the fourth quartile were associated with a significant increase in mortality, although the association was attenuated in women.

An age-related decrease in IGF-1 levels was observed, which was more significant in males. However, survival curves of participants were similar when plotted according to IGF-1 level and sex. A possible combined effect of IL-6 and IGF-1 on survival was also checked. The group with reduced performance in survival was the opposite of the reference (high IL-6 and low IGF-1).