RETRACTED: Impaired lipid metabolism by age-dependent DNA methylation alterations accelerates aging

Abstract

Epigenetic alterations and metabolic dysfunction are two hallmarks of aging. However, the mechanism of how their interaction regulates aging, particularly in mammals, remains largely unknown. Here we show ELOVL fatty acid elongase 2 (Elovl2), a gene whose epigenetic alterations are most highly correlated with age prediction, contributes to aging by regulating lipid metabolism. Impaired Elovl2 function disturbs lipid synthesis with increased endoplasmic reticulum stress and mitochondrial dysfunction, leading to key accelerated aging phenotypes. Restoration of mitochondrial activity can rescue age-related macular degeneration (AMD) phenotypes induced by Elovl2 deficiency in human retinal pigmental epithelial (RPE) cells. We revealed an epigenetic–metabolism axis contributing to aging and potentially to antiaging therapy.

Role of Long Chain Fatty Acids in Developmental Programming in Ruminants

“…For the first and second points, previous to the mating, the role of the FA in the sperm quality has been the most described [ 34 ]. Little information is available with regard to the effect of dietary FA and epigenetic changes in offspring using ruminants such as animal models [ 35 ]. Nevertheless, for mammals, a few pieces of evidence have described the role of PUFA in the spermatozoa epigenome, in particular, DNA oxidation, DNA methylation, and gene expression associated with lipid metabolism [ 30 ].…”

Epigenetic Clock: DNA Methylation in Aging

“…Increasing methylation of Elovl2 has recently been reported to be a crucial driver of aging by inducing a stress response in the endoplasmic reticulum and promoting mitochondrial dysfunction [ 6 ]. In some degenerative diseases, mitochondrial DNA and genes encoding the enzymes responsible for mitochondrial biogenesis, such as Mfn2 in diabetes, are hypermethylated and compromise the electron transport chain [ 72 ].…”

“…These modifications alter the extent to which DNA is wrapped around histones and the availability of genes within the DNA to be activated. Recently, numerous studies have emphasized the unique role of DNA methylation in aging [ 6 , 7 ]. In addition to its effects on the aging process, a function shared by other epigenomic regulators, DNA methylation can also predict aging status.…”

The use of DNA methylation clock in aging research

“…56 Other studies have identified several genes that are highly correlated with DNA methylation age including ELOVL fatty acid elongase 2 ( ELOVL2 ) and H3K36 methyltransferase ( NSD1 ). 127,128 ELOVL2 is the master controller of poly-unsaturated fatty acid synthesis and was most significantly related to DNA methylation age. Although the relationship of ELOVL2 to DNA methylation clocks has been well documented, the mechanism underlying how age-related ELOVL2 methylation contributes to aging is unknown.…”

“…A recent report documented a dramatic increase in ELOVL2 methylation that was accompanied by downregulation of ELOVL2 expression levels in aged human fibroblasts. 128 Moreover, dysfunction of the Elovl2 protein interferes with lipid metabolism and synthesis, increasing endoplasmic reticulum stress and mitochondrial dysfunction, which are associated with accelerated aging. A recent gene screening study found that DNA methylation clocks tick more quickly in the blood of patients with Sotos syndrome, a familial developmental disorder caused by inactivation mutations of NSD1.…”