Are there common regulators of aging to be found among transcription factors? Sweeping, complex, tissue-specific and species-specific changes in gene expression take place over the course of aging. If these are reactions to comparatively straightforward processes of molecular damage at the root of aging, processes that are similar between species, then it is possible that there also exist at least a few regulators that are also comparatively straightforward and similar between species. Where is the leap from simplicity to complexity? Is it that the immediate reaction to damage is complicated, with a hundred different sensors and systems reacting in their own ways? Or is the reaction to damage marshaled by a few controlling systems at the top level, leading to a sea of complexity downstream of those controlling systems? Which of these is the case makes a big difference as to the type of potential rejuvenation therapies that might be useful to attempt – though in either case repairing the damage sounds like a better idea to me.

Here, we measure changes in the transcriptome, histone modifications, and DNA methylome in three metabolic tissues of adult and aged mice. Our main question was whether common regulatory players underlie the seemingly tissue- and species-specific molecular footprint of aging. We show that although the molecular footprint of aging evolves differently across tissues, striking similarities emerge in terms of affected pathways and underlying regulators. For instance, the liver’s aging footprint is dominated by changes in transcriptome and DNA methylome. In contrast, transcriptomes of heart and quadriceps are relatively stable but have marked changes in histone modification profiles around genes. Despite all these differences, similar pathways are affected in these distinct layers.

The striking similarity in transcription factor (TF) enrichment between different mouse and human tissues implies that there may be a common and perhaps restricted set of TFs underlying the aging footprint across tissues and species. The ZIC1 motif is highly enriched across multiple tissues and gene-regulatory layers. ZIC1 increases with age in many peripheral human tissues. Although its relationship or possible implication in aging has not been studied extensively, it has been shown that its brown adipose tissue (BAT) expression increases with age and body mass index, concurrently with a decrease in BAT activity. In addition, ZIC1 and ZIC2 transactivate apolipoprotein E (APOE) expression, one of the strongest human longevity determinants. The facts that APOE increases with age and that higher APOE levels correlate with negative outcomes in age-related diseases such as Alzheimer’s disease render ZIC1 a prime candidate driver of gene regulatory changes associated with aging.

We also identify other TFs, such as HMGA1, TBP, and CXXC1, as candidate regulators of the aging process. HMGA1 has been linked to mitochondrial function, repair, and maintenance and is implicated in promoting senescence-associated heterochromatic foci, which are associated with transcriptional repression. In addition, it has recently been shown to promote the senescence-associated secretory phenotype (SASP) through its effect on NAD+ metabolism. The TATA box binding protein (TBP) motif is enriched in genes that decrease with age. Although this TF has not been directly linked to aging, it can harbor variations in polyglutamine repeats, which may be relevant in age-related processes such as neuro-muscular degenerative disease. CXXC1, or Cfp1, is a member of the Setd1 H3K4 methyltransferase complex and binds non-methylated DNA of transcriptionally permissive promoters. Given the trend for hypermethylation with age, CXXC1 binding to many promoters may be affected, which may lead to differences in H3K4 methylation. CXXC1 may therefore be an important link between the different molecular layers, which merits further mechanistic investigation, especially given that its motif’s enrichment varies in direction in different tissues, suggesting a complex context-dependent relationship with aging.