Association of the methylation of age-related epigenetic marker ELOVL2 with neurophysiological alterations and immunosenescence during aging and its modulation by the APOE genotype.
DNA methylation of the ELOVL2 (Elongation of Very Long Chain Fatty Acids Protein 2) promoter is one of the most robust molecular biomarkers for chronological age; however, whether ELOVL2 plays a functional role in brain aging and immunosenescence, and whether the APOE genotype modulates these effects, has not been fully explored. This study investigated the associations among ELOVL2 methylation, APOE genotype, and neurophysiological changes in the brain, as well as indicators of immunosenescence of peripheral blood T cells during aging.
We examined 72 non-demented volunteers aged 20-88 years, stratified by APOE genotype (41 APOE-, 31 APOE+). ELOVL2 methylation levels were measured via bisulfite conversion and pyrosequencing. Participants underwent cognitive screening, auditory P3 event-related potential (ERP) recordings, and resting-state MRI functional connectivity (rsFC) assessments. In a subgroup of 18 healthy subjects, we examined peripheral blood T-cell subsets and analyzed the association of CD3+HLA-DR+ T cells with ELOVL2 methylation and neurophysiological characteristics.
ELOVL2 CpG promoter methylation (chr 6:11044880. GRCh37) was associated with P3 ERP latency in both the overall sample and APOE4+ carriers, remaining significant even after adjusting for age; however, this association was not significant in APOE4- individuals. DNA methylation of ELOVL2 was inversely correlated with fMRI rsFC in the salience-, and memory-related, and central autonomic networks, indicating disrupted connectivity within these networks. An increased proportion of CD3+ cells expressing the immune activation marker HLA-DR was correlated with elevated ELOVL2 methylation level and with decreased fMRI rsFC in brain networks, including circuits related to the DMN medial prefrontal cortex, amygdala, and cerebellum.
The results imply a close link between ELOVL2 methylation, inflammaging and brain dysfunction, which is modulated by APOE4+ genotype.
We examined 72 non-demented volunteers aged 20-88 years, stratified by APOE genotype (41 APOE-, 31 APOE+). ELOVL2 methylation levels were measured via bisulfite conversion and pyrosequencing. Participants underwent cognitive screening, auditory P3 event-related potential (ERP) recordings, and resting-state MRI functional connectivity (rsFC) assessments. In a subgroup of 18 healthy subjects, we examined peripheral blood T-cell subsets and analyzed the association of CD3+HLA-DR+ T cells with ELOVL2 methylation and neurophysiological characteristics.
ELOVL2 CpG promoter methylation (chr 6:11044880. GRCh37) was associated with P3 ERP latency in both the overall sample and APOE4+ carriers, remaining significant even after adjusting for age; however, this association was not significant in APOE4- individuals. DNA methylation of ELOVL2 was inversely correlated with fMRI rsFC in the salience-, and memory-related, and central autonomic networks, indicating disrupted connectivity within these networks. An increased proportion of CD3+ cells expressing the immune activation marker HLA-DR was correlated with elevated ELOVL2 methylation level and with decreased fMRI rsFC in brain networks, including circuits related to the DMN medial prefrontal cortex, amygdala, and cerebellum.
The results imply a close link between ELOVL2 methylation, inflammaging and brain dysfunction, which is modulated by APOE4+ genotype.
Authors
Ponomareva Ponomareva, Kuznetsova Kuznetsova, Petrova Petrova, Andreeva Andreeva, Protasova Protasova, Konovalov Konovalov, Krotenkova Krotenkova, Malina Malina, Kolesnikova Kolesnikova, Kanavets Kanavets, Kuprianova Kuprianova, Mitrofanov Mitrofanov, Vavilova Vavilova, Boyko Boyko, Kovalenko Kovalenko, Sapozhnikov Sapozhnikov, Fokin Fokin, Illarioshkin Illarioshkin, Rogaev Rogaev
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