Caloric restriction mitigates age-associated hippocampal differential CG and non-CG methylation
| Autor: | Arlan Richardson, Dustin R. Masser, Laura Otalora, Willard M. Freeman, Archana Unnikrishnan, Niran Hadad, Jordan Jackson, David R. Stanford |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
DNA (Cytosine-5-)-Methyltransferase 1
Male 0301 basic medicine Aging medicine.medical_specialty Neurogenesis Bisulfite sequencing Calorie restriction Gene Expression Biology Hippocampus Neuroprotection DNA methyltransferase Article Dioxygenases Epigenesis Genetic 03 medical and health sciences 0302 clinical medicine Memory Internal medicine Gene expression medicine Animals Epigenetics Cognitive decline Caloric Restriction 030304 developmental biology 0303 health sciences General Neuroscience Neurodegeneration Methylation DNA Methylation medicine.disease Mice Inbred C57BL 030104 developmental biology Endocrinology Cognitive Aging DNA methylation DNMT1 Neurology (clinical) Nervous System Diseases Geriatrics and Gerontology 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | Neurobiology of Aging. 67:53-66 |
| ISSN: | 0197-4580 |
| Popis: | Brain aging is marked by cognitive decline and increased susceptibility to neurodegeneration. Epigenetic mechanisms, including DNA methylation, are vital to CNS cellular function and memory formation, and are dysregulated with aging and age-related neurodegenerative disease. Caloric-restriction (CR), an established pro-longevity intervention, increases neurogenesis, improves memory function, and protects from age-associated pathologies. However, the molecular mechanisms promoting the neuroprotective effect of CR remain largely unknown. We tested the role of DNA methylation as a mechanism for CR-induced neuroprotection in the old hippocampus. Hippocampal DNA from young (3M) and old (24M) male mice fed ad libitum and 24M old mice fed 40% calorie-restricted diet from 3M of age were examined by genome-wide bisulfite sequencing to measure methylation levels at base-specific resolution. Over 22 million CG and CH (non-CG) sites were examined. Of the ~40,000 differentially methylated CGs (dmCGs) and ~80,000 CHs (dmCHs) observed with aging, 35% and 38%, respectively, were prevented by CR. Unique to dmCHs, CR preferentially prevented age-related hypermethylation. A diet-specific methylation response was observed in both CG and CH contexts. Diet-induced dmCHs were enriched in unexpected genomic locations including promoters and CG islands including hypermethylation of DNMT1 and Tet3 promoters corresponding to reduced gene expression. These findings demonstrate for the first time that caloric-restriction prevents age-induced cytosine methylation changes in the old brain in combination with diet-specific methylation changes that may function to maintain epigenetic homeostasis through epigenetic auto-regulation. The prevention of age-dmCGs/CHs by CR emphasizes the prominent role of DNA methylation as a driver of the aging process. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect