FNDC5 (irisin) gene and exceptional longevity: a functional replication study with rs16835198 and rs726344 SNPs

Area of Science:

• Genetics and Aging Research
• Metabolic Health and Longevity

Background:

• Irisin, a hormone precursor, is linked to reduced obesity and insulin resistance, potentially contributing to healthy aging.
• The FNDC5 gene, encoding irisin, is a candidate for influencing exceptional longevity (EL) due to its role in metabolic health.
• Specific FNDC5 gene single-nucleotide polymorphisms (SNPs), rs16835198 and rs726344, have been associated with insulin sensitivity.

Purpose of the Study:

• To investigate the association between two FNDC5 gene SNPs (rs16835198 and rs726344) and exceptional longevity (EL).
• To determine the functional significance of these SNPs on gene activity using luciferase reporter assays.
• To analyze genotype and allele frequencies of these SNPs in centenarian and control cohorts across different ethnicities.

Main Methods:

• Luciferase gene reporter assays were performed to assess the functional impact of rs16835198 and rs726344 SNPs.
• Genotype and allele distributions of the SNPs were compared between centenarians and healthy controls in Spanish, Italian, and Japanese cohorts.
• Logistic regression analysis, adjusted for sex, was used to evaluate the association between SNPs and EL.

Main Results:

• The rs726344 SNP demonstrated functional significance, with the A-allele showing higher luciferase activity than the G-allele (P=0.04).
• The rs16835198 SNP showed a trend towards higher luciferase activity with the T-allele compared to the G-allele (P=0.07).
• No significant differences in genotype or allele frequencies for either SNP were found between centenarians and controls in any of the studied cohorts. No significant association between these SNPs and EL was identified.

Conclusions:

• While the rs726344 SNP in the FNDC5 gene exhibits functional effects on gene activity, it is not associated with exceptional longevity in the studied populations.
• The investigated FNDC5 gene variants do not appear to play a significant role in determining centenarian status.
• Further research involving larger, diverse cohorts and additional genetic variants within the irisin signaling pathway is warranted to fully understand its contribution to longevity.