A new analysis has revealed a core set of genes involved in aging in both humans and mice. Together with a broader set of age-related genes assembled by the study , this resource will serve as a launching point for further investigations of the mechanisms behind aging and age-related diseases.
The heart of the matter
Numerous studies have tracked age-related molecular changes, with changes showing up in cellular metabolism and the transcriptome, proteome, and epigenome. While the accumulation of this data has improved our understanding of aging, no unifying picture has emerged. Some of the age-related changes seem to be specific to particular tissues, and it’s also not clear how many of these pathways are shared between different organisms.
An international team of researchers set out to answer these questions. They carried out a multi-layer and multi-tissue analysis of aging in male mice and then built on that by comparing their findings with gene expression data from human studies.
The first step was to characterize age-related genetic and epigenetic changes in different tissues of the same species. The researchers harvested livers, hearts, and quadriceps muscles from male mice of different ages. They then analyzed gene expression, DNA methylation, and three types of histone modification in these tissues.
Their analysis revealed differences in how these “omics” layers changed with age in these three tissues. Gene expression changes were most significant in the liver, while changes in the heart and muscle tissue were predominantly related to methylation and histones. Despite these differences, analysis showed that many of the genes affected by aging in the three tissues are involved in the same processes. While conclusions from one tissue type might not be applicable in another because different molecular factors are involved, the aging footprint is reflected in common biological processes in all three tissues.
Core age-related genes shared with humans
To figure out the core players in these shared processes, the team checked to see if the genes they had found shared binding sites for any transcription factors, genes that regulate the expression of other genes. They found a few binding motifs that were more common than would be expected, which pointed them towards a handful of transcription factors that may act as common regulators of the molecular changes associated with aging.
Having found these core age-related transcription factors, the next step was to check whether the same relationship exists in humans. The researchers used human gene expression data from other studies to investigate whether these transcription factors are affected by age. They found that many of them also had age-dependent expression in humans. Further analysis showed that variation in some of these genes was associated with differences in longevity, reinforcing the notion that they act as drivers of age-related processes in humans, though the authors note that these results are based on small samples and so “must be treated with caution and may not necessarily imply causality”.
Many genes and pathways have been linked to aging, yet our understanding of underlying molecular mechanisms is still lacking. Here, we measure changes in the transcriptome, histone modifications, and DNA methylome in three metabolic tissues of adult and aged mice. Transcriptome and methylome changes dominate the liver aging footprint, whereas heart and muscle globally increase chromatin accessibility, especially in aging pathways. In mouse and human data from multiple tissues and regulatory layers, age-related transcription factor expression changes and binding site enrichment converge on putative aging modulators, including ZIC1, CXXC1, HMGA1, MECP2, SREBF1, SREBF2, ETS2, ZBTB7A, and ZNF518B. Using Mendelian randomization, we establish possible epidemiological links between expression of some of these transcription factors or their targets, including CXXC1, ZNF518B, and BBC3, and longevity. We conclude that conserved modulators are at the core of the molecular footprint of aging, and variation in tissue-specific expression of some may affect human longevity.
This research has not found genes “for” aging or longevity. Rather, it has identified a core set of genetic regulators that are involved in aging in different tissues and species, although precisely how is a mystery awaiting further investigation. The study also serves as a rich source of data, a multi-omics, multi-tissue, multi-species analysis of genes involved in processes related to aging. The authors close by calling their work “a hypothesis-generating resource of candidate aging regulators” – an apt summary of their contribution, and we hope that future research will build upon it.
Bou Sleiman, M., Jha, P., Houtkooper, R., Williams, R.W., Wang, X., and Auwerx, J. The Gener-Regulatory Footprint of Aging Highlights Conserved Central Regulators. Cell Reports, doi: 10.1016/j.celrep.2020.108203