Postmitotic cell longevity–associated genes: a transcriptional signature of postmitotic maintenance in neural tissues

Abstract Different cell types have different postmitotic maintenance requirements. Nerve cells, however, are unique in this respect as they need to survive and preserve their functional complexity for the entire lifetime of the organism, and failure at any level of their supporting mechanisms leads to a wide range of neurodegenerative conditions. Whether these differences across tissues arise from the activation of distinct cell type–specific maintenance mechanisms or the differential activation of a common molecular repertoire is not known. To identify the transcriptional signature of postmitotic cellular longevity (PMCL), we compared whole-genome transcriptome data from human tissues ranging in longevity from 120 days to over 70 years and found a set of 81 genes whose expression levels are closely associated with increased cell longevity. Using expression data from 10 independent sources, we found that these genes are more highly coexpressed in longer-living tissues and are enriched in specific biological processes and transcription factor targets compared with randomly selected gene samples. Crucially, we found that PMCL-associated genes are downregulated in the cerebral cortex and substantia nigra of patients with Alzheimer's and Parkinson's disease, respectively, as well as Hutchinson-Gilford progeria-derived fibroblasts, and that this downregulation is specifically linked to their underlying association with cellular longevity. Moreover, we found that sexually dimorphic brain expression of PMCL-associated genes reflects sexual differences in lifespan in humans and macaques. Taken together, our results suggest that PMCL-associated genes are part of a generalized machinery of postmitotic maintenance and functional stability in both neural and non-neural cells and support the notion of a common molecular repertoire differentially engaged in different cell types with different survival requirements.