All Publications

  • An in vivo resource of age-regulated C. elegans intestinal secretory-pathway proteins highlights secreted enzymes associated with lifespan regulation. Cell reports Miklas, J. W., Papsdorf, K., Sun, E. D., Tsenter, A., Haseley, N. R., Ameglio, B., Medoh, U. N., Richard, D., McCarthy, F., Artiles, K. L., Hims, A., Levina, A., Zhou, O. Y., Elias, J. E., Abu-Remaileh, M., Brunet, A. 2026; 45 (9): 117902

    Abstract

    Secreted proteins are essential to modulate homeostasis in the extracellular space and facilitate communication to distal cells or tissues. Yet, the identity and functional importance of extracellular proteins in aging have been understudied. Here we use proximity labeling followed by quantitative proteomics to systematically characterize proteins along the intestinal secretory pathway in C. elegans, focusing on secreted proteins. We identify intestine-secreted proteins that are modulated with age, and validate the secretion of these proteins in vivo. One of these secreted proteins, ACP7, is well conserved in humans, and its overexpression extends lifespan in a secretion-dependent manner. Interestingly, we find that ACP7 acts as a secreted phosphatase in the extracellular space. Finally, we identify additional proteins along the secretory pathway that regulate lifespan. Our systematic characterization of tissue-specific secreted proteins during aging uncovers conserved proteins that impact lifespan and highlights extracellular enzymes associated with lifespan regulation.

    View details for DOI 10.1016/j.celrep.2026.117902

    View details for PubMedID 42658673

  • 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

  • Metabolic Control over mTOR-Dependent Diapause-like State DEVELOPMENTAL CELL Hussein, A. M., Wang, Y., Mathieu, J., Margaretha, L., Song, C., Jones, D. C., Cavanaugh, C., Miklas, J. W., Mahen, E., Showalter, M. R., Ruzzo, W. L., Fiehn, O., Ware, C. B., Blau, C., Ruohola-Baker, H. 2020; 52 (2): 236-+

    Abstract

    Regulation of embryonic diapause, dormancy that interrupts the tight connection between developmental stage and time, is still poorly understood. Here, we characterize the transcriptional and metabolite profiles of mouse diapause embryos and identify unique gene expression and metabolic signatures with activated lipolysis, glycolysis, and metabolic pathways regulated by AMPK. Lipolysis is increased due to mTORC2 repression, increasing fatty acids to support cell survival. We further show that starvation in pre-implantation ICM-derived mouse ESCs induces a reversible dormant state, transcriptionally mimicking the in vivo diapause stage. During starvation, Lkb1, an upstream kinase of AMPK, represses mTOR, which induces a reversible glycolytic and epigenetically H4K16Ac-negative, diapause-like state. Diapause furthermore activates expression of glutamine transporters SLC38A1/2. We show by genetic and small molecule inhibitors that glutamine transporters are essential for the H4K16Ac-negative, diapause state. These data suggest that mTORC1/2 inhibition, regulated by amino acid levels, is causal for diapause metabolism and epigenetic state.

    View details for DOI 10.1016/j.devcel.2019.12.018

    View details for Web of Science ID 000509725500012

    View details for PubMedID 31991105

    View details for PubMedCentralID PMC7204393

  • 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

  • TFPa/HADHA is required for fatty acid beta-oxidation and cardiolipin re-modeling in human cardiomyocytes NATURE COMMUNICATIONS Miklas, J. W., Clark, E., Levy, S., Detraux, D., Leonard, A., Beussman, K., Showalter, M. R., Smith, A. T., Hofsteen, P., Yang, X., Macadangdang, J., Manninen, T., Raftery, D., Madan, A., Suomalainen, A., Kim, D., Murry, C. E., Fiehn, O., Sniadecki, N. J., Wang, Y., Ruohola-Baker, H. 2019; 10: 4671

    Abstract

    Mitochondrial trifunctional protein deficiency, due to mutations in hydratase subunit A (HADHA), results in sudden infant death syndrome with no cure. To reveal the disease etiology, we generated stem cell-derived cardiomyocytes from HADHA-deficient hiPSCs and accelerated their maturation via an engineered microRNA maturation cocktail that upregulated the epigenetic regulator, HOPX.  Here we report, matured HADHA mutant cardiomyocytes treated with an endogenous mixture of fatty acids manifest the disease phenotype: defective calcium dynamics and repolarization kinetics which results in a pro-arrhythmic state. Single cell RNA-seq reveals a cardiomyocyte developmental intermediate, based on metabolic gene expression. This intermediate gives rise to mature-like cardiomyocytes in control cells but, mutant cells transition to a pathological state with reduced fatty acid beta-oxidation, reduced mitochondrial proton gradient, disrupted cristae structure and defective cardiolipin remodeling. This study reveals that HADHA (tri-functional protein alpha), a monolysocardiolipin acyltransferase-like enzyme, is required for fatty acid beta-oxidation and cardiolipin remodeling, essential for functional mitochondria in human cardiomyocytes.

    View details for DOI 10.1038/s41467-019-12482-1

    View details for Web of Science ID 000489706400023

    View details for PubMedID 31604922

    View details for PubMedCentralID PMC6789043

  • High-Throughput Contractility Assay for Human Stem Cell-Derived Cardiomyocytes One Beat Closer to Tracking Heart Muscle Dynamics CIRCULATION RESEARCH Miklas, J. W., Salick, M. R., Kim, D. 2019; 124 (8): 1146-1148

    View details for DOI 10.1161/CIRCRESAHA.119.314844

    View details for Web of Science ID 000469343500007

    View details for PubMedID 30973811

    View details for PubMedCentralID PMC6461366

  • 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

  • Single-Cell Transcriptomic Analysis of Cardiac Differentiation from Human PSCs Reveals HOPX-Dependent Cardiomyocyte Maturation CELL STEM CELL Friedman, C. E., Quan Nguyen, Lukowski, S. W., Helfer, A., Chiu, H., Miklas, J., Levy, S., Suo, S., Han, J., Osteil, P., Peng, G., Jing, N., Baillie, G. J., Senabouth, A., Christ, A. N., Bruxner, T. J., Murry, C. E., Wong, E. S., Ding, J., Wang, Y., Hudson, J., Ruohola-Baker, H., Bar-Joseph, Z., Tam, P. P. L., Powell, J. E., Palpant, N. J. 2018; 23 (4): 586-+

    Abstract

    Cardiac differentiation of human pluripotent stem cells (hPSCs) requires orchestration of dynamic gene regulatory networks during stepwise fate transitions but often generates immature cell types that do not fully recapitulate properties of their adult counterparts, suggesting incomplete activation of key transcriptional networks. We performed extensive single-cell transcriptomic analyses to map fate choices and gene expression programs during cardiac differentiation of hPSCs and identified strategies to improve in vitro cardiomyocyte differentiation. Utilizing genetic gain- and loss-of-function approaches, we found that hypertrophic signaling is not effectively activated during monolayer-based cardiac differentiation, thereby preventing expression of HOPX and its activation of downstream genes that govern late stages of cardiomyocyte maturation. This study therefore provides a key transcriptional roadmap of in vitro cardiac differentiation at single-cell resolution, revealing fundamental mechanisms underlying heart development and differentiation of hPSC-derived cardiomyocytes.

    View details for DOI 10.1016/j.stem.2018.09.009

    View details for Web of Science ID 000446342800017

    View details for PubMedID 30290179

    View details for PubMedCentralID PMC6220122

  • Human Stem Cell-Derived Cardiac Model of Chronic Drug Exposure ACS BIOMATERIALS SCIENCE & ENGINEERING Nunes, S. S., Feric, N., Pahnke, A., Miklas, J. W., Li, M., Coles, J., Gagliardi, M., Keller, G., Radisic, M. 2017; 3 (9): 1911-1921

    Abstract

    Animal models have been instrumental in providing insight into the molecular basis of disease. While such information has been successfully applied to the study of human disease, this translation would be significantly strengthened by the availability of models based on human cells. This would be particularly important for cardiovascular disease, as the physiology of human cardiomyocytes (CMs) differs significantly from rodents. Here, we have generated a three-dimensional human engineered cardiac tissue, termed biowire, from human embryonic stem cell-derived CMs to investigate the effects of chronic (7 day) treatment with isoproterenol, endothelin-1, or angiotensin II. We show that biowires chronically treated with either isoproterenol, endothelin-1, or angiotensin II have disrupted myofibril alignment and significantly reduced force of contraction. Isoproterenol-treated biowires have upregulated brain natriuretic peptide and atrial natriuretic peptide gene expression. Endothelin-1 and angiotensin II-treated biowires demonstrated a significantly increased cell size. Endothelin-1-treated biowires exhibited increased cardiac troponin secretion into the culture media. This demonstrates that human biowires treated for 7 days with isoproterenol, angiotensin II, or endothelin-1 exhibit some changes compatible with hypertrophic cardiomyopathy.

    View details for DOI 10.1021/acsbiomaterials.5b00496

    View details for Web of Science ID 000410716100004

    View details for PubMedID 33440549

  • Metabolic remodeling in early development and cardiomyocyte maturation SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY Kreipke, R., Wang, Y., Miklas, J., Mathieu, J., Ruohola-Baker, H. 2016; 52: 84-92

    Abstract

    Aberrations in metabolism contribute to a large number of diseases, such as diabetes, obesity, cancer, and cardiovascular diseases, that have a substantial impact on the mortality rates and quality of life worldwide. However, the mechanisms leading to these changes in metabolic state--and whether they are conserved between diseases--is not well understood. Changes in metabolism similar to those seen in pathological conditions are observed during normal development in a number of different cell types. This provides hope that understanding the mechanism of these metabolic switches in normal development may provide useful insight in correcting them in pathological cases. Here, we focus on the metabolic remodeling observed both in early stage embryonic stem cells and during the maturation of cardiomyocytes.

    View details for DOI 10.1016/j.semcdb.2016.02.004

    View details for Web of Science ID 000372330300013

    View details for PubMedID 26912118

    View details for PubMedCentralID PMC4820352

https://orcid.org/0000-0002-9002-0667