Stochastic epigenetic mutations (DNA methylation) increase exponentially in human aging and correlate with X chromosome inactivation skewing in females.
In this study we applied a new analytical strategy to investigate the relations between stochastic epigenetic mutations (SEMs) and aging. We analysed methylation levels through the Infinium HumanMethylation27 and HumanMethylation450 BeadChips in a population of 178 subjects ranging from 3 to 106 years. For each CpG probe, epimutated subjects were identified as the extreme outliers with methylation level exceeding three times interquartile ranges the first quartile (Q1-(3 x IQR)) or the third quartile (Q3+(3 x IQR)). We demonstrated that the number of SEMs was low in childhood and increased exponentially during aging. Using the HUMARA method, skewing of X chromosome inactivation (XCI) was evaluated in heterozygotes women. Multivariate analysis indicated a significant correlation between log(SEMs) and degree of XCI skewing after adjustment for age (β = 0.41; confidence interval: 0.14, 0.68; p-value = 0.0053). The PATH analysis tested the complete model containing the variables: skewing of XCI, age, log(SEMs) and overall CpG methylation. After adjusting for the number of epimutations we failed to confirm the well reported correlation between skewing of XCI and aging. This evidence might suggest that the known correlation between XCI skewing and aging could not be a direct association but mediated by the number of SEMs.
Istituto Auxologico Italiano IRCCS, Cusano Milanino, 20095 Milan, Italy.
Davide
D
Gentilini
Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum- University of Bologna, Bologna 40138, Italy.|Interdepartmental Center "L. Galvani", University of Bologna, Bologna 40126, Italy.
Paolo
P
Garagnani
Istituto Auxologico Italiano IRCCS, Cusano Milanino, 20095 Milan, Italy.
Serena
S
Pisoni
Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum- University of Bologna, Bologna 40138, Italy.|Interdepartmental Center "L. Galvani", University of Bologna, Bologna 40126, Italy.
Maria Giulia
MG
Bacalini
Istituto Auxologico Italiano IRCCS, Cusano Milanino, 20095 Milan, Italy.
Luciano
L
Calzari
Geriatric Unit, IRCCS Ca' Granda Foundation Maggiore Policlinico Hospital, Milan, Italy.
Daniela
D
Mari
Istituto Auxologico Italiano IRCCS, Cusano Milanino, 20095 Milan, Italy.|Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
Giovanni
G
Vitale
Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum- University of Bologna, Bologna 40138, Italy.|Interdepartmental Center "L. Galvani", University of Bologna, Bologna 40126, Italy.
Claudio
C
Franceschi
Istituto Auxologico Italiano IRCCS, Cusano Milanino, 20095 Milan, Italy.
Anna Maria
AM
Di Blasio
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000502:physiology*; D015992:Body Mass Index; D002648:Child; D002675:Child, Preschool; D041321:Chromosomes, Human, X / Q000502:physiology*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D049951:X Chromosome Inactivation; D055815:Young Adult
DNA methylation; X chromosome inactivation skewing; aging; epigenetics; epimutations