Age dependent Skewing of X Chromosome Inactivation appears delayed in Centenarians' offspring. Is there a role for allelic imbalance in Healthy Aging and Longevity?

Recently, it has been proposed that age-related X Chromosome Inactivation (XCI) skewing can clinically result in late-onset X-linked disorders. This observation lead to hypothesize that age-related skewed XCI might also influence life span in women. To investigate this issue we employed a new experimental model of longevity and healthy aging including 55 female centenarians, 40 of their offspring, 33 age-matched offspring of both non long-lived parents and 41 young women. Peripheral blood DNA from 169 females was screened for heterozygosity at the HUMARA locus. We confirmed that skewing of XCI is an age dependent phenomenon. However, skewed XCI was significantly less severe and frequent in centenarians' offspring (degree of skewing (DS) = 0.16 + 0.02) compared to age-matched offspring of both non-long lived parents (DS = 0.24 + 0.02) (p<0.05). A second goal was to assess if changes in XCI pattern could be a consequence of loss of methylation on X chromosome. Using a methylation array evaluating 1085 CpG sites across X chromosome and eleven CpG sites located at HUMARA locus, no differences in methylation levels and profiles emerged between all groups analysed thus suggesting that age-associated epigenetic changes could not influence HUMARA results. In conclusion, the results presented herein highlight for the first time an interesting link between skewing of XCI and healthy aging and longevity. We speculate that the allelic imbalance produced by XCI skewing may compromise the cooperative and compensatory organisation occurring between the two cell populations that make up the female mosaic. © 2011 The Authors Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.