Gene expression signatures of human cell and tissue longevity

Abstract

Different cell types within the body exhibit substantial variation in the average time they live, ranging from days to the lifetime of the organism. The underlying mechanisms governing the diverse lifespan of different cell types are not well understood. To examine gene expression strategies that support the lifespan of different cell types within the human body, we obtained publicly available RNA-seq data sets and interrogated transcriptomes of 21 somatic cell types and tissues with reported cellular turnover, a bona fide estimate of lifespan, ranging from 2 days (monocytes) to a lifetime (neurons). Exceptionally long-lived neurons presented a gene expression profile of reduced protein metabolism, consistent with neuronal survival and similar to expression patterns induced by longevity interventions such as dietary restriction. Across different cell lineages, we identified a gene expression signature of human cell and tissue turnover. In particular, turnover showed a negative correlation with the energetically costly cell cycle and factors supporting genome stability, concomitant risk factors for aging-associated pathologies. In addition, the expression of p53 was negatively correlated with cellular turnover, suggesting that low p53 activity supports the longevity of post-mitotic cells with inherently low risk of developing cancer. Our results demonstrate the utility of comparative approaches in unveiling gene expression differences among cell lineages with diverse cell turnover within the same organism, providing insights into mechanisms that could regulate cell longevity. Human tissue and cell types exhibit different gene signatures based on their cellular lifespans. Vadim Gladyshev and colleagues from Brigham and Women’s Hospital, Harvard Medical School, analyzed the gene expression patterns of 21 different cell types with cellular turnover times ranging from 2 days (white blood cells) to a lifetime (neurons). This turnover–defined as the balance between cell proliferation and death–has been shown to be a good estimate of cellular lifespan. The authors found that long-lived cell lineages, including those of the muscle and the brain, showed lower expression of genes involved in promoting cell division and maintaining genomic fidelity, consistent with a molecular path toward longevity. The finding that cells use lineage-specific strategies to alter their lifespans lays the groundwork for future therapies that promote human longevity by modifying gene expression profiles.