Jason Miklas

All Publications

• Evolution of diapause in the African turquoise killifish by remodeling the ancient gene regulatory landscape. Cell Singh, P. P., Reeves, G. A., Contrepois, K., Papsdorf, K., Miklas, J. W., Ellenberger, M., Hu, C. K., Snyder, M. P., Brunet, A. 2024

  Abstract

  Suspended animation states allow organisms to survive extreme environments. The African turquoise killifish has evolved diapause as a form of suspended development to survive a complete drought. However, the mechanisms underlying the evolution of extreme survival states are unknown. To understand diapause evolution, we performed integrative multi-omics (gene expression, chromatin accessibility, and lipidomics) in the embryos of multiple killifish species. We find that diapause evolved by a recent remodeling of regulatory elements at very ancient gene duplicates (paralogs) present in all vertebrates. CRISPR-Cas9-based perturbations identify the transcription factors REST/NRSF and FOXOs as critical for the diapause gene expression program, including genes involved in lipid metabolism. Indeed, diapause shows a distinct lipid profile, with an increase in triglycerides with very-long-chain fatty acids. Our work suggests a mechanism for the evolution of complex adaptations and offers strategies to promote long-term survival by activating suspended animation programs in other species.

  View details for DOI 10.1016/j.cell.2024.04.048

  View details for PubMedID 38810644

• Author Correction: Lipid droplets and peroxisomes are co-regulated to drive lifespan extension in response to mono-unsaturated fatty acids. Nature cell biology Papsdorf, K., Miklas, J. W., Hosseini, A., Cabruja, M., Morrow, C. S., Savini, M., Yu, Y., Silva-García, C. G., Haseley, N. R., Murphy, L. M., Yao, P., de Launoit, E., Dixon, S. J., Snyder, M. P., Wang, M. C., Mair, W. B., Brunet, A. 2023

  View details for DOI 10.1038/s41556-023-01220-x

  View details for PubMedID 37567997

• Lipid droplets and peroxisomes are co-regulated to drive lifespan extension in response to mono-unsaturated fatty acids. Nature cell biology Papsdorf, K., Miklas, J. W., Hosseini, A., Cabruja, M., Morrow, C. S., Savini, M., Yu, Y., Silva-Garcia, C. G., Haseley, N. R., Murphy, L. M., Yao, P., de Launoit, E., Dixon, S. J., Snyder, M. P., Wang, M. C., Mair, W. B., Brunet, A. 2023

  Abstract

  Dietary mono-unsaturated fatty acids (MUFAs) are linked to longevity in several species. But the mechanisms by which MUFAs extend lifespan remain unclear. Here we show that an organelle network involving lipid droplets and peroxisomes is critical for MUFA-induced longevity in Caenorhabditis elegans. MUFAs upregulate the number of lipid droplets in fat storage tissues. Increased lipid droplet number is necessary for MUFA-induced longevity and predicts remaining lifespan. Lipidomics datasets reveal that MUFAs also modify the ratio of membrane lipids and ether lipids-a signature associated with decreased lipid oxidation. In agreement with this, MUFAs decrease lipid oxidation in middle-aged individuals. Intriguingly, MUFAs upregulate not only lipid droplet number but also peroxisome number. A targeted screen identifies genes involved in the co-regulation of lipid droplets and peroxisomes, and reveals that induction of both organelles is optimal for longevity. Our study uncovers an organelle network involved in lipid homeostasis and lifespan regulation, opening new avenues for interventions to delay aging.

  View details for DOI 10.1038/s41556-023-01136-6

  View details for PubMedID 37127715

• Males induce premature demise of the opposite sex by multifaceted strategies. Nature aging Booth, L. N., Shi, C., Tantilert, C., Yeo, R. W., Miklas, J. W., Hebestreit, K., Hollenhorst, C. N., Maures, T. J., Buckley, M. T., Murphy, C. T., Brunet, A. 2022; 2 (9): 809-823

  Abstract

  Interactions between the sexes negatively impact health in many species. In Caenorhabditis, males shorten the lifespan of the opposite sex-hermaphrodites or females. Here we use transcriptomic profiling and targeted screens to systematically uncover conserved genes involved in male-induced demise in C. elegans. Some genes (for example, delm-2, acbp-3), when knocked down, are specifically protective against male-induced demise. Others (for example, sri-40), when knocked down, extend lifespan with and without males, suggesting general mechanisms of protection. In contrast, many classical long-lived mutants are impacted more negatively than wild type by the presence of males, highlighting the importance of sexual environment for longevity. Interestingly, genes induced by males are triggered by specific male components (seminal fluid, sperm and pheromone), and manipulating these genes in combination in hermaphrodites induces stronger protection. One of these genes, the conserved ion channel delm-2, acts in the nervous system and intestine to regulate lipid metabolism. Our analysis reveals striking differences in longevity in single sex versus mixed sex environments and uncovers elaborate strategies elicited by sexual interactions that could extend to other species.

  View details for DOI 10.1038/s43587-022-00276-y

  View details for PubMedID 37118502

  View details for PubMedCentralID 4455605

• Long life depends on open communication. Nature cell biology Miklas, J. W., Brunet, A. 2022

  View details for DOI 10.1038/s41556-022-00908-w

  View details for PubMedID 35681007

• Support cells in the brain promote longevity. Science (New York, N.Y.) Miklas, J. W., Brunet, A. n. 2020; 367 (6476): 365–66

  View details for DOI 10.1126/science.aba4474

  View details for PubMedID 31974234

• Metabolism as an early predictor of DPSCs aging SCIENTIFIC REPORTS Macrin, D., Alghadeer, A., Zhao, Y., Miklas, J. W., Hussein, A. M., Detraux, D., Robitaille, A. M., Madan, A., Moon, R. T., Wang, Y., Devi, A., Mathieu, J., Ruohola-Baker, H. 2019; 9: 2195

  Abstract

  Tissue resident adult stem cells are known to participate in tissue regeneration and repair that follows cell turnover, or injury. It has been well established that aging impedes the regeneration capabilities at the cellular level, but it is not clear if the different onset of stem cell aging between individuals can be predicted or prevented at an earlier stage. Here we studied the dental pulp stem cells (DPSCs), a population of adult stem cells that is known to participate in the repair of an injured tooth, and its properties can be affected by aging. The dental pulp from third molars of a diverse patient group were surgically extracted, generating cells that had a high percentage of mesenchymal stem cell markers CD29, CD44, CD146 and Stro1 and had the ability to differentiate into osteo/odontogenic and adipogenic lineages. Through RNA seq and qPCR analysis we identified homeobox protein, Barx1, as a marker for DPSCs. Furthermore, using high throughput transcriptomic and proteomic analysis we identified markers for DPSC populations with accelerated replicative senescence. In particular, we show that the transforming growth factor-beta (TGF-β) pathway and the cytoskeletal proteins are upregulated in rapid aging DPSCs, indicating a loss of stem cell characteristics and spontaneous initiation of terminal differentiation. Importantly, using metabolic flux analysis, we identified a metabolic signature for the rapid aging DPSCs, prior to manifestation of senescence phenotypes. This metabolic signature therefore can be used to predict the onset of replicative senescence. Hence, the present study identifies Barx1 as a DPSCs marker and dissects the first predictive metabolic signature for DPSCs aging.

  View details for DOI 10.1038/s41598-018-37489-4

  View details for Web of Science ID 000458861700028

  View details for PubMedID 30778087

  View details for PubMedCentralID PMC6379364