ELOVL2
Elongation of very long chain fatty acids protein 2 (EC 2.3.1.199) (3-keto acyl-CoA synthase ELOVL2) (ELOVL fatty acid elongase 2) (ELOVL FA elongase 2) (Very long chain 3-ketoacyl-CoA synthase 2) (Very long chain 3-oxoacyl-CoA synthase 2) [ELG3] [SSC2]
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DNA methylation of the ELOVL2 (Elongation Of Very Long Chain Fatty Acids-Like 2) promoter is one of the most robust molecular biomarkers for chronological age, but whether ELOVL2 plays a functional role in aging has not been explored. ELOVL2 encodes a transmembrane protein involved in the synthesis of very long polyunsaturated fatty acids (VLC-PUFAs). These fatty acids play important roles in retinal biology and photoreceptor renewal, key processes implicated in age-related eye diseases such as age-related macular degeneration (AMD). Here, we summarize our work deciphering the role of ELOVL2 in the eye emphasizing the potential functional role of age-related DNA methylation in the pathophysiology of AMD.
Keywords
- Aging
- Macular degeneration
- Membrane structure
- Polyunsaturated fatty acids
DNA methylation analysis in a variety of genes has brought promising results in age estimation. The main aim of this study was to evaluate DNA methylation levels from four age-correlated genes, ELOVL2, FHL2, EDARADD and PDE4C, in blood samples of healthy Portuguese individuals. Fifty-three samples were analyzed through the bisulfite polymerase chain reaction (PCR) sequencing method for CpG dinucleotide methylation status. Linear regression models were used to analyze relationships between methylation levels and chronological age. The highest age-associated CpG in each locus was chosen to build a multi-locus age prediction model (APM), allowing to obtain a Mean Absolute Deviation (MAD) between chronological and predicted ages of 5.35 years, explaining 94.1% of age variation. Validation approaches demonstrated the accuracy and reproducibility of the proposed multi-locus APM. Testing the APM in 51 blood samples from deceased individuals a MAD of 9.72 years was obtained. Potential differences in methylation status between samples from living and deceased individuals could exist since the highest age-correlated CpGs were different in some genes between both groups. In conclusion, our study using the bisulfite PCR sequencing method is in accordance with the high age prediction accuracy of DNA methylation levels in four previously reported age-associated genes. DNA methylation pattern differences between blood samples from living and deceased individuals should be taken into account in forensic contexts.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aging
- Child
- Child, Preschool
- CpG Islands
- Cyclic Nucleotide Phosphodiesterases, Type 4
- DNA Methylation
- Edar-Associated Death Domain Protein
- Fatty Acid Elongases
- Female
- Forensic Genetics
- Humans
- Infant
- LIM-Homeodomain Proteins
- Male
- Middle Aged
- Muscle Proteins
- Polymerase Chain Reaction
- Transcription Factors
- Young Adult
Keywords
- Age the living
- CpGs
- DNA methylation age
- Forensic epigenetics
- Forensic sciences
Methylation of the regulatory region of the elongation of very-long-chain fatty acids-like 2 (ELOVL2) gene, an enzyme involved in elongation of long-chain polyunsaturated fatty acids, is one of the most robust biomarkers of human age, but the critical question of whether ELOVL2 plays a functional role in molecular aging has not been resolved. Here, we report that Elovl2 regulates age-associated functional and anatomical aging in vivo, focusing on mouse retina, with direct relevance to age-related eye diseases. We show that an age-related decrease in Elovl2 expression is associated with increased DNA methylation of its promoter. Reversal of Elovl2 promoter hypermethylation in vivo through intravitreal injection of 5-Aza-2'-deoxycytidine (5-Aza-dc) leads to increased Elovl2 expression and rescue of age-related decline in visual function. Mice carrying a point mutation C234W that disrupts Elovl2-specific enzymatic activity show electrophysiological characteristics of premature visual decline, as well as early appearance of autofluorescent deposits, well-established markers of aging in the mouse retina. Finally, we find deposits underneath the retinal pigment epithelium in Elovl2 mutant mice, containing components found in human drusen, a pathologic hallmark of age related macular degeneration. These findings indicate that ELOVL2 activity regulates aging in mouse retina, provide a molecular link between polyunsaturated fatty acids elongation and visual function, and suggest novel therapeutic strategies for the treatment of age-related eye diseases.
MeSH Terms
- Aging
- Animals
- Cell Line
- DNA Methylation
- Decitabine
- Down-Regulation
- Fatty Acid Elongases
- Fatty Acids, Unsaturated
- Female
- Humans
- Macular Degeneration
- Male
- Mice
- Mice, Transgenic
- Point Mutation
- Promoter Regions, Genetic
- Retina
- Retinal Pigment Epithelium
Keywords
- DNA methylation
- ELOVL2
- PUFA
- age-related macular degeneration
- aging
- retina
Age estimation using DNA methylation levels has been widely investigated in recent years because of its potential application in forensic genetics. The main aim of this study was to develop an age predictor model (APM) for blood samples of deceased individuals based in five age-correlated genes. Fifty-one samples were analyzed through the bisulfite polymerase chain reaction (PCR) sequencing method for DNA methylation evaluation in genes ELOVL2, FHL2, EDARADD, PDE4C, and C1orf132. Linear regression was used to analyze relationships between methylation levels and age. The model using the highest age-correlated CpG from each locus revealed a correlation coefficient of 0.888, explaining 76.3% of age variation, with a mean absolute deviation from the chronological age (MAD) of 6.08 years. The model was validated in an independent test set of 19 samples producing a MAD of 8.84 years. The developed APM seems to be informative and could have potential application in forensic analysis.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- CpG Islands
- Cyclic Nucleotide Phosphodiesterases, Type 4
- DNA Methylation
- Edar-Associated Death Domain Protein
- Fatty Acid Elongases
- Female
- Forensic Genetics
- Genetic Markers
- Humans
- LIM-Homeodomain Proteins
- Linear Models
- Male
- Middle Aged
- Muscle Proteins
- Polymerase Chain Reaction
- Sequence Analysis, DNA
- Sulfites
- Transcription Factors
- Young Adult
Keywords
- DNA methylation age
- bisulfite PCR sequencing
- deceased individuals
- forensic epigenetics
- forensic science
{{medline-entry |title=Human aging DNA methylation signatures are conserved but accelerated in cultured fibroblasts. |pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31156022 |abstract=Aging is associated with progressive and site-specific changes in DNA methylation (DNAm). These global changes are captured by DNAm clocks that accurately predict chronological age in humans but relatively little is known about how clocks perform [i]in vitro[/i]. Here we culture primary human fibroblasts across the cellular lifespan (~6 months) and use four different DNAm clocks to show that age-related DNAm signatures are conserved and accelerated [i]in vitro[/i]. The Skin