👤 Aleksandra Nekrasova

Most genomic studies compare the genomes of long-living adults to those of the general population to identify potential genetic markers of longevity. We propose a refined approach: focusing on the genetic makeup of healthy, long-living adults to detect mechanisms promoting both longer lifespan and improved quality of life. To this end, we analyzed medical and genomic data from 3,703 long-living adults aged ≥90 years and 22,354 individuals aged 18-75 years (total N = 26,057). Using whole-genome sequencing (WGS) and a genome-wide association study (GWAS), we found that variants with significant and negative associations with longevity in the GWAS were located in genes such as APOE, APOC1, and CFAP46, which are implicated in an increased risk of age-related diseases. However, the presence or absence of these variants should not be considered a definitive determinant of longevity or sustained health after the age of 90. We found that healthy longevity was positively associated with variants within the MYO18B, TBC1D28, and LOC105376454 genes. To demonstrate the multifactorial nature of the examined phenotypes, we constructed polygenic score models that accounted for nonlinear interactions among the predictors. Trial registration: Clinical Trials NCT06268132 (for long-living adults). Registered 22 February 2024 (retrospectively registered). Show less

Apolipoprotein A-I (ApoA-I) is the main structural and functional protein component of high-density lipoprotein. ApoA-I has been shown to regulate lipid metabolism and inflammation in macrophages. Recently, we found the moderate expression of endogenous apoA-I in human monocytes and macrophages and showed that pro-inflammatory cytokine tumor necrosis factor α (TNFα) increases apoA-I mRNA and stimulates ApoA-I protein secretion by human monocytes and macrophages. Here, we present data about molecular mechanisms responsible for the TNFα-mediated activation of apoA-I gene in human monocytes and macrophages. This activation depends on JNK and MEK1/2 signaling pathways in human monocytes, whereas inhibition of NFκB, JNK, or p38 blocks an increase of apoA-I gene expression in the macrophages treated with TNFα. Nuclear receptor PPARα is a ligand-dependent regulator of apoA-I gene, whereas LXRs stimulate apoA-I mRNA transcription and ApoA-I protein synthesis and secretion by macrophages. Treatment of human macrophages with PPARα or LXR synthetic ligands as well as knock-down of LXRα, and LXRβ by siRNAs interfered with the TNFα-mediated activation of apoA-I gene in human monocytes and macrophages. At the same time, TNFα differently regulated the levels of PPARα, LXRα, and LXRβ binding to the apoA-I gene promoter in THP-1 cells. Obtained results suggest a novel tissue-specific mechanism of the TNFα-mediated regulation of apoA-I gene in monocytes and macrophages and show that endogenous ApoA-I might be positively regulated in macrophage during inflammation. Show less