Atavistic Genetic Expression Dissociation (AGED) during aging: meta-phylostratigraphic evidence of cellular- and tissue-levels phylogenetic dissociation

Aging is commonly attributed to accumulated damage, or evolved antagonistic genetic trade-offs, which lead to an accumulation of genetic damage, noise, or DNA methylation causing the misexpression of key genes necessary for longevity. We propose an atavistic dysregulation of gene expression at cellular and tissue-levels during aging, which frames aging as a gradual regression toward ancestral cellular states. Similar to the atavistic model of cancer, in which cells revert to unicellular-like behavior, aging may result from a progressive breakdown of coordinated morphogenetic control, leading organs and tissues to revert towards less integrated, ancient unicellular states. This view suggests that aging may involve a progressive reversal of the well-known ontogenetic tracing of prior phylogenetic embryonic characteristics. Moreover, as in cancer, aging could involve a loss of large-scale coordination, with different tissues reverting to ancient gene expression to different degrees. We tested this hypothesis using a meta-phylostratigraphic analysis to ask: do older human tissues express more ancient genes, and does the variance of transcriptional phylogenetic age across tissues increase with organismal age? We found: (1) An atavistic over-representation of differential expression in the most ancient genes for two multi-tissue aging databases covering skin, ovarian, immune, senescent and mesenchymal-senescent cells; (2) No atavistic over-representation of the differential genet expression during aging of brain cells and mesenchymal stem cells; and (3) overall age-dependent increase of heterogeneity in the direction of the phylogenetic position of tissues’ transcriptional profiles. Our analyses suggest that aging involves uncoordinated and tissue-specific phylogenetic changes in gene expression. Understanding aging as a structured, heterogenous atavistic process opens new avenues for rejuvenation, focusing on restoring multicellular coherence with respect to evolutionarily-youthful gene expression.