Computer prediction and genetic analysis identifies retinoic acid modulation as a driver of conserved longevity pathways in genetically-diverse Caenorhabditis nematodes

Banse, S. A.; Sedore, C. A.; Coleman-Hulbert, A.; Johnson, E.; Onken, B.; Hall, D.; Segerdell, E.; Jackson, E. G.; Song, Y.; Osman, H. C.; Xue, J.; Basttistoni, E.; Guo, S.; Foulger, A.; Achanta, M.; Sheikh, M.; Fitzgibbon, T.; Willis, J. H.; Woodruff, G. C.; Driscoll, M.; Lithgow, G.; Phillips, P. C.

doi:10.1101/2024.10.23.619838

Home/Archive/bioRxiv

bioRxiv · 10.1101/2024.10.23.619838

Computer prediction and genetic analysis identifies retinoic acid modulation as a driver of conserved longevity pathways in genetically-diverse Caenorhabditis nematodes

View original source ↗Export metadata ↓

Abstract

Aging is a pan-metazoan process with significant consequences for human health and society--discovery of new compounds that ameliorate the negative health impacts of aging promise to be of tremendous benefit across a number of age-based comorbidities. One method to prioritize a testable subset of the nearly infinite universe of potential compounds is to use computational prediction of their likely anti-aging capacity. Here we present a survey of longevity effects for 16 compounds suggested by a previously published computational prediction set, capitalizing upon the comprehensive, multi-species approach utilized by the Caenorhabditis Intervention Testing Program (CITP). While eleven compounds (aldosterone, arecoline, bortezomib, dasatinib, decitabine, dexamethasone, erlotinib, everolimus, gefitinib, temsirolimus, and thalidomide) either had no effect on median lifespan or were toxic, five compounds (all-trans retinoic acid, berberine, fisetin, propranolol, and ritonavir) extended lifespan in Caenorhabditis elegans. These computer predictions yield a remarkable positive hit rate of 30%. Deeper genetic characterization of the longevity effects of one of the most efficacious compounds, the endogenous signaling ligand all-trans retinoic acid (atRA, designated tretinoin in medical products), which is widely prescribed for treatment of acne, skin photoaging and acute promyelocytic leukemia, demonstrated a requirement for the regulatory kinases AKT-1 and AKT-2. While the canonical Akt-target FOXO/DAF-16 was largely dispensable, other conserved Akt-targets (Nrf2/SKN-1 and HSF1/HSF-1), as well as the conserved catalytic subunit of AMPK AAK-2, were all necessary for longevity extension by atRA. Evolutionary conservation of retinoic acid as a signaling ligand and the structure of the downstream effector network of retinoic acid combine to suggest that the all-trans retinoic acid pathway is an ancient metabolic regulatory system that can modulate lifespan. Our results highlight the potential of combining computational prediction of longevity interventions with the power of nematode functional genetics and underscore that the manipulation of a conserved metabolic regulatory circuit by co-opting endogenous signaling molecules is a powerful approach for discovering aging interventions.

Source connections

Published article ↗

Explore related subjects

genetics Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Banse, S. A., Sedore, C. A., Coleman-Hulbert, A., Johnson, E., Onken, B., Hall, D., Segerdell, E., Jackson, E. G., Song, Y., Osman, H. C., Xue, J., Basttistoni, E., Guo, S., Foulger, A., Achanta, M., Sheikh, M., Fitzgibbon, T., Willis, J. H., Woodruff, G. C., Driscoll, M., Lithgow, G., Phillips, P. C.. 2024-10-26. Computer prediction and genetic analysis identifies retinoic acid modulation as a driver of conserved longevity pathways in genetically-diverse Caenorhabditis nematodes. https://doi.org/10.1101/2024.10.23.619838

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

A largely shared genetic architecture underlies Saccharomyces cerevisiae persistence across different mouse host genotypes

The extent to which interactions between microbial and host genotypes shape opportunistic pathogen persistence within hosts is an important open question. To assess the contribution of these interactions to persistence, we used Saccharomyces cerevisiae , a genetically tractable model for studying opportunistic fungal persistence in mammalian hosts. A pooled panel of barcoded haploid segregants from a cross between a laboratory strain and a clinical isolate, together with both parents, was introduced intravenously into seven genetically diverse mouse strains. We measured the relative persistence of segregants in mouse brains and livers using barcode sequencing. Persistence showed transgressive segregation in both organs. On average across the two organs, yeast genotype explained 45.2% of the variance in segregant persistence, whereas yeast genotype-by-host genotype interactions explained only 2.9%. Linkage mapping showed that loci detected in more host genotypes generally explained more phenotypic variance than those detected in fewer host genotypes. At some loci, genetic variation correlated with increased yeast persistence across multiple organs (general loci) while at others increased persistence in one organ came at the cost of decreased persistence in another (antagonistic loci). General loci contributed disproportionately to brain persistence, whereas liver persistence reflected contributions from both classes. The clinical parent showed greater persistence than the laboratory parent in every host-organ combination, and the additive effects of detected loci predicted the direction of this advantage. Overall, this work shows that in this system, relative microbial persistence is polygenic, with a strong additive component and only a very small contribution from microbial genotype-by-host genotype interactions.

genetics↗

bioRxiv2026

Host control and regulation of human anellovirus persistence

Anelloviruses are the most abundant and diverse eukaryotic viruses known to infect humans and can persist throughout our lifetimes. Despite their ubiquity, the host factors governing their physiologic distribution and abundance remain poorly understood. Here, we construct a viral pangenome of 2,023 strains to quantify anellovirus DNA in >1.1 million participants spanning three genetic biobanks. Genome-wide association studies identify 121 loci linked to viral persistence, predominantly via immune regulation by NF-kB signaling. Further, we associate variable anellovirus detection with conditions characterized by immune dysfunction, including lymphoid malignancies. By screening 3.2 petabases of human single-cell sequencing data, we identify myeloid progenitors in the bone marrow as a prominent site of anellovirus transcription in vivo. Finally, Perturb-seq of anellovirus proteins reveals that anellovirus ORF2, particularly from Alphatorquevirus, attenuates TNF-a-induced NF-kB signaling, connecting host genetic variation, cellular context, and viral immunomodulation to characterize the persistence of the eukaryotic human virome's most abundant component.

genetics↗

bioRxiv2026

Regulation of sociality and neuronal development by the translation initiation factor eIF4H1 in Drosophila

Most animal species exhibit some level of sociality. However, whether sociality-related traits evolved independently, or are instead derived from common core mechanisms, remains controversial. Nevertheless, an emerging theoretical framework stipulates that key aspects of how animals interact with their social environments may be regulated by a phylogenetically conserved genetic toolkit. Therefore, we hypothesized that mutations that lead to social deficits in specific human disorders may implicate genes that play conserved roles in the regulation of core social traits across Animalia. Specifically, here we focus on genes associated with Williams syndrome (WS), a rare human multi-system disorder characterized in part by hypersocial cognitive traits. WS is caused by a hemizygous chromosomal microdeletion of 25-28 protein-coding genes. Consequently, it has been hypothesized that haploinsufficiency in at least one of these genes plays an important role in the development and/or function of social neural circuits in humans. Because the Drosophila genome encodes orthologs of 17 of the 28 genes deleted in WS, we reasoned that at least some of them may serve a conserved role in the regulation of social traits across flies and humans, as predicted by the genetic toolkit framework. Using a neuron-specific RNAi knockdown screen, we identified eIF4H1, an ortholog of a highly conserved subunit of the eukaryotic translation initiation complex eIF4F, as a candidate gene for neuronal regulation of sociality in the fly. We show that eIF4H1 expression is predominantly neuronal in the adult fly brain, and that its action plays a differential role in the organization of specific dopaminergic neuron subtypes that are associated with sociality and cognitive functions. These results indicate that eIF4H1 may serve a conserved function in regulating the development of the neuronal circuits that regulate social behaviors, thus supporting the idea of a conserved sociality genetic toolkit.

genetics↗