Aggregate expression of genes lacking CpG islands increases with age and is positively associated with human mortality

In both mice and humans the misexpression of many genes lacking CpG islands (CGI- genes) increases with age, promoting inflammation and degenerative changes (Lee et al. 2021, ref. 1). In light of this recent discovery, we have revisited and expanded upon our previous work on gene expressions vs. aging and mortality in the three-generation CEPH (Centre d’Etudes du Polymorphisme Humain) Utah (CEU) families (Kerber et al. 2009, ref. 2). That study examined gene expressions in lymphoblastoid cell lines (LCLs) established in the early 1980s from all three CEU generations, in relation to age at blood draw, and in relation to the long-term survival of the grandparent generation. The 2009 study did not, however, consider the CGI status of genes, and it excluded from analysis genes not expressed in all of the subjects; therefore, the contribution to variation in age-at-death of inter-individual variation in the misexpression of genes with increasing age was not investigated. For the current study, after categorizing genes by their CGI status (- or +), we now find that most CGI- gene expressions in the LCLs increased with donor age, and after adjustment for donor age and sex, were positively associated with mortality risks. In contrast, most CGI+ gene expressions decreased with donor age, with higher expressions associated with decreased mortality risks. Of 7025 genes with known CGI status with expression detected in sufficient numbers of subjects from the grandparent generation to allow testing of association with mortality, 1834 genes were expressed in all subjects’ LCLs across all three generations, and 5191 were expressed in some, but not all subjects. We found the set of “not always expressed” genes to be highly enriched for CGI- genes. Furthermore, 49.4% of the CGI- genes were never expressed from ages 0-14, but expressed sometimes or always at older ages; in contrast, only 22.3% of the CGI+ genes were never expressed from ages 0-14, but expressed at older ages. These data support the model proposed by Lee et al. 2021, whereby tissue-restricted CGI- gene expressions become increasingly misexpressed during aging, contributing to loss of cellular identity, multiple aging-related pathologies, and ultimately death. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by NIH grants R01-AG022095 and R21-AG030034 and the Huntsman Cancer Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Institutional Review Board of the University of Utah gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.