Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism

Oliver Hahn,Simon Andrews,Linda Partridge,Oliver Hendrich,Wolf Reik,Gabriella Ficz,Sebastian Grönke,Andreas Beyer,Thomas M Stubbs,Felix Krueger,Michael J Wakelam,Qifeng Zhang

doi:10.1186/s13059-017-1187-1

Abstract

BackgroundDietary restriction (DR), a reduction in food intake without malnutrition, increases most aspects of health during aging and extends lifespan in diverse species, including rodents. However, the mechanisms by which DR interacts with the aging process to improve health in old age are poorly understood. DNA methylation could play an important role in mediating the effects of DR because it is sensitive to the effects of nutrition and can affect gene expression memory over time.ResultsHere, we profile genome-wide changes in DNA methylation, gene expression and lipidomics in response to DR and aging in female mouse liver. DR is generally strongly protective against age-related changes in DNA methylation. During aging with DR, DNA methylation becomes targeted to gene bodies and is associated with reduced gene expression, particularly of genes involved in lipid metabolism. The lipid profile of the livers of DR mice is correspondingly shifted towards lowered triglyceride content and shorter chain length of triglyceride-associated fatty acids, and these effects become more pronounced with age.ConclusionsOur results indicate that DR remodels genome-wide patterns of DNA methylation so that age-related changes are profoundly delayed, while changes at loci involved in lipid metabolism affect gene expression and the resulting lipid profile.

Highlights

Dietary restriction (DR), a reduction in food intake without malnutrition, increases most aspects of health during aging and extends lifespan in diverse species, including rodents
Dietary restriction transcriptionally regulates enzymes involved in DNA methylation To investigate the effects of age and DR on gene expression and DNA methylation, we used females of the long-lived F1 hybrid mouse strain (C3B6F1), which responds to DR with a robust increase in lifespan [3]
We identified 4232 and 4418 differentially expressed genes (DEGs) between ad libitum (AL) and DR in young and old animals, respectively, with 3005 DEGs in common (Fig. 1a, b), a highly significant overlap between young and old animals

Summary

Introduction

Dietary restriction (DR), a reduction in food intake without malnutrition, increases most aspects of health during aging and extends lifespan in diverse species, including rodents. DNA methylation could play an important role in mediating the effects of DR because it is sensitive to the effects of nutrition and can affect gene expression memory over time. Increasing frailty as result of declining organismal function characterizes aging, which is the major risk factor for prevalent diseases of older people such as diabetes, cancer and neurodegenerative disorders [1, 2]. Environmental and genetic interventions can ameliorate the effects of aging, with nutrition, nutrient-sensing signaling networks and metabolism playing evolutionarily conserved roles [1, 3,4,5]. Dietary restriction (DR), in which food intake is reduced

Methods

Results

Discussion

Conclusion