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The Gene-Regulatory Footprint of Aging Highlights Conserved Central Regulators.

ABSTRACT: 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.

SUBMITTER: Bou Sleiman M

PROVIDER: S-EPMC7527782 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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The Gene-Regulatory Footprint of Aging Highlights Conserved Central Regulators.

Bou Sleiman Maroun M Jha Pooja P Houtkooper Riekelt R Williams Robert W RW Wang Xu X Auwerx Johan J

Cell reports 20200901 13

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 laye ...[more]

PMID: 32997995

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Project description:Background: Calorie restriction (CR) is the only intervention known to extend lifespan in a wide range of organisms, including mammals. However, the mechanisms by which it regulates mammalian aging remain largely unknown and the involvement of the TOR and Sirtuin pathways (which regulate aging in lower organisms) remain controversial. Femaleness is a second phenotype generally associated with longevity but the relationship between sex-biased and CR-induced gene expression remains undetermined. Methodology/Principal Findings: We generated microarray gene expression data from livers of male mice fed high calorie or CR diets, and we find that CR significantly changes the expression of over 3,000 genes, many between 10- and 50-fold. We compare our data to the GenAge database of known aging-related genes and to prior microarray expression data of genes expressed differently between male and female mice. CR generally feminizes gene expression and many of the most significantly changed individual genes are involved in aging, hormone signaling, and p53-associated regulation of the cell cycle and apoptosis. Among the genes showing the largest and most statistically significant CR-induced expression differences are Ddit4, a key regulator of the TOR pathway, and Nnmt, a regulator of lifespan linked to the Sirtuin pathway. Using Western analyses, we confirmed post-translational inhibition of the TOR pathway. Conclusions: Our data show that CR induces widespread gene expression changes and acts through highly evolutionarily conserved pathways, from microorganisms to mammals, and that its life-extension effects might arise partly from a shift toward a gene expression profile more typical of the longer-lived female sex. Keywords: Two-class gene expression comparison. Calorie restriction (CR) versus HIGH CALORIE feeding. Design of the experiment is a two-class paired design in which the two classes are HIGH CALORIE and CALORIE RESTRICTION (CR) dietary regimens fed to mice, resulting in 15 HIGH CALORIE microarrays and 8 CR microarrays; 23 total microarrays. Four HIGH CALORIE and 2 CR microarrays were produced using pools of 3 RNA samples for each microarray (6 pools of 3, plus 17 individual samples = 35 individual mouse liver samples, 23 microarrays). Total liver RNA was labeled directly. Reference RNA: Stratagene Universal Mouse Reference RNA.

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The Gene-Regulatory Footprint of Aging Highlights Conserved Central Regulators.

Publications

The Gene-Regulatory Footprint of Aging Highlights Conserved Central Regulators.

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