Kwok, A. J. | Search bioRxiv

bioRxiv2024

Functional and multi-omic aging rejuvenation with GLP-1R agonism

Identifying readily implementable methods that can effectively counteract aging is urgently needed for tackling age-related degenerative disorders. Here, we conducted functional assessments and deep molecular phenotyping in the aging mouse to demonstrate that glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment attenuates body-wide age-related changes. Apart from improvements in physical and cognitive performance, the age-counteracting effects are prominently evident at multiple omic levels. These span the transcriptomes and DNA methylomes of various tissues, organs and circulating white blood cells, as well as the plasma metabolome. Importantly, the beneficial effects are specific to aged mice, not young adults, and are achieved with a low dosage of GLP-1RA which has a negligible impact on food consumption and body weight. The molecular rejuvenation effects exhibit organ-specific characteristics, which are generally heavily dependent on hypothalamic GLP-1R. We benchmarked the GLP-1RA age-counteracting effects against those of mTOR inhibition, a well-established anti-aging intervention, observing a strong resemblance across the two strategies. Our findings have broad implications for understanding the mechanistic basis of the clinically observed pleiotropic effects of GLP-1RAs, the design of intervention trials for age-related diseases, and the development of anti-aging-based therapeutics.

systems biology↗

bioRxiv2023

eQTLs identify regulatory networks and drivers of variation in the individual response to sepsis

Sepsis is a clinical syndrome of life-threatening organ dysfunction caused by a dysregulated response to infection, for which disease heterogeneity is a major obstacle to developing targeted treatments. We have previously identified gene expression-based patient subgroups (Sepsis Response Signatures: SRS) informative for outcome and underlying pathophysiology. Here we aimed to investigate the role of genetic variation in determining the host transcriptomic response and to delineate regulatory networks underlying SRS. Using genotyping and RNA-seq data on 638 adult sepsis patients, we report 16,049 independent expression (eQTLs) and 32 co-expression module (modQTLs) quantitative trait loci in this disease context. We identified significant interactions between SRS and genotype for 1,578 SNP-gene pairs, and combined transcription factor (TF) binding site information (SNP2TFBS) and predicted regulon activity (DoRothEA) to identify candidate upstream regulators. These included HIF1A and CEBPB, which were associated with progenitor and immature neutrophil subsets respectively, further implicating glycolysis and emergency granulopoiesis in SRS1. Overall, these approaches identified putative mechanistic links between host genetic variation, cell subtypes, and the individual transcriptomic response to infection. Understanding the regulatory networks underlying patient heterogeneity provides additional information for developing immunomodulatory treatments and a personalised medicine approach to treating sepsis.

genomics↗