Epigenetic Aging Signatures in Mice Livers Are Slowed by Dwarfism, Calorie Restriction and Rapamycin Treatment

Overview

Journal Genome Biol

Specialties Biology
Genetics

Date 2017 Mar 30

PMID 28351423

Citations 159

Authors

Tina Wang

Brian Tsui

Jason F Kreisberg

Neil A Robertson

Andrew M Gross

Michael Ku Yu

Hannah Carter

Holly M Brown-Borg

Peter D Adams

Trey Ideker

Affiliations

Soon will be listed here.

Abstract

Background: Global but predictable changes impact the DNA methylome as we age, acting as a type of molecular clock. This clock can be hastened by conditions that decrease lifespan, raising the question of whether it can also be slowed, for example, by conditions that increase lifespan. Mice are particularly appealing organisms for studies of mammalian aging; however, epigenetic clocks have thus far been formulated only in humans.

Results: We first examined whether mice and humans experience similar patterns of change in the methylome with age. We found moderate conservation of CpG sites for which methylation is altered with age, with both species showing an increase in methylome disorder during aging. Based on this analysis, we formulated an epigenetic-aging model in mice using the liver methylomes of 107 mice from 0.2 to 26.0 months old. To examine whether epigenetic aging signatures are slowed by longevity-promoting interventions, we analyzed 28 additional methylomes from mice subjected to lifespan-extending conditions, including Prop1 dwarfism, calorie restriction or dietary rapamycin. We found that mice treated with these lifespan-extending interventions were significantly younger in epigenetic age than their untreated, wild-type age-matched controls.

Conclusions: This study shows that lifespan-extending conditions can slow molecular changes associated with an epigenetic clock in mice livers.

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References

MEDVEDEV Z . An attempt at a rational classification of theories of ageing. Biol Rev Camb Philos Soc. 1990; 65(3):375-98. DOI: 10.1111/j.1469-185x.1990.tb01428.x. View

Horvath S, Garagnani P, Bacalini M, Pirazzini C, Salvioli S, Gentilini D . Accelerated epigenetic aging in Down syndrome. Aging Cell. 2015; 14(3):491-5. PMC: 4406678. DOI: 10.1111/acel.12325. View

Orozco L, Morselli M, Rubbi L, Guo W, Go J, Shi H . Epigenome-wide association of liver methylation patterns and complex metabolic traits in mice. Cell Metab. 2015; 21(6):905-17. PMC: 4454894. DOI: 10.1016/j.cmet.2015.04.025. View

Maegawa S, Gough S, Watanabe-Okochi N, Lu Y, Zhang N, Castoro R . Age-related epigenetic drift in the pathogenesis of MDS and AML. Genome Res. 2014; 24(4):580-91. PMC: 3975058. DOI: 10.1101/gr.157529.113. View

Langmead B, Salzberg S . Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012; 9(4):357-9. PMC: 3322381. DOI: 10.1038/nmeth.1923. View

Avrahami D, Li C, Zhang J, Schug J, Avrahami R, Rao S . Aging-Dependent Demethylation of Regulatory Elements Correlates with Chromatin State and Improved β Cell Function. Cell Metab. 2015; 22(4):619-32. PMC: 4598285. DOI: 10.1016/j.cmet.2015.07.025. View

Wilkinson J, Burmeister L, Brooks S, Chan C, Friedline S, Harrison D . Rapamycin slows aging in mice. Aging Cell. 2012; 11(4):675-82. PMC: 3434687. DOI: 10.1111/j.1474-9726.2012.00832.x. View

Yates A, Akanni W, Amode M, Barrell D, Billis K, Carvalho-Silva D . Ensembl 2016. Nucleic Acids Res. 2015; 44(D1):D710-6. PMC: 4702834. DOI: 10.1093/nar/gkv1157. View

Sun D, Luo M, Jeong M, Rodriguez B, Xia Z, Hannah R . Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. Cell Stem Cell. 2014; 14(5):673-88. PMC: 4070311. DOI: 10.1016/j.stem.2014.03.002. View

10.

Horvath S . DNA methylation age of human tissues and cell types. Genome Biol. 2013; 14(10):R115. PMC: 4015143. DOI: 10.1186/gb-2013-14-10-r115. View

11.

Bartke A, Westbrook R . Metabolic characteristics of long-lived mice. Front Genet. 2012; 3:288. PMC: 3521393. DOI: 10.3389/fgene.2012.00288. View

12.

Krueger F, Andrews S . Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications. Bioinformatics. 2011; 27(11):1571-2. PMC: 3102221. DOI: 10.1093/bioinformatics/btr167. View

13.

Reizel Y, Spiro A, Sabag O, Skversky Y, Hecht M, Keshet I . Gender-specific postnatal demethylation and establishment of epigenetic memory. Genes Dev. 2015; 29(9):923-33. PMC: 4421981. DOI: 10.1101/gad.259309.115. View

14.

Zampieri M, Ciccarone F, Calabrese R, Franceschi C, Burkle A, Caiafa P . Reconfiguration of DNA methylation in aging. Mech Ageing Dev. 2015; 151:60-70. DOI: 10.1016/j.mad.2015.02.002. View

15.

Miller R, Harrison D, Astle C, Fernandez E, Flurkey K, Han M . Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell. 2013; 13(3):468-77. PMC: 4032600. DOI: 10.1111/acel.12194. View

16.

Laird P . Principles and challenges of genomewide DNA methylation analysis. Nat Rev Genet. 2010; 11(3):191-203. DOI: 10.1038/nrg2732. View

17.

Gross A, Jaeger P, Kreisberg J, Licon K, Jepsen K, Khosroheidari M . Methylome-wide Analysis of Chronic HIV Infection Reveals Five-Year Increase in Biological Age and Epigenetic Targeting of HLA. Mol Cell. 2016; 62(2):157-168. PMC: 4995115. DOI: 10.1016/j.molcel.2016.03.019. View

18.

Cannon M, Buchner D, Hester J, Miller H, Sehayek E, Nadeau J . Maternal nutrition induces pervasive gene expression changes but no detectable DNA methylation differences in the liver of adult offspring. PLoS One. 2014; 9(3):e90335. PMC: 3940881. DOI: 10.1371/journal.pone.0090335. View

19.

Gravina S, Dong X, Yu B, Vijg J . Single-cell genome-wide bisulfite sequencing uncovers extensive heterogeneity in the mouse liver methylome. Genome Biol. 2016; 17(1):150. PMC: 4934005. DOI: 10.1186/s13059-016-1011-3. View

20.

Leek J, Johnson W, Parker H, Jaffe A, Storey J . The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics. 2012; 28(6):882-3. PMC: 3307112. DOI: 10.1093/bioinformatics/bts034. View