About

Douglas Mashek is a Professor in Metabolic and Systems Biology and Medicine, specifically within the Endocrine and Diabetes Division at the University of Minnesota. He serves as the leader of the Biology of Aging Medical Discovery Team, which is part of the University of Minnesota’s Institute on the Biology of Aging and Metabolism. This interdisciplinary and trans-departmental institute within the Medical School focuses on advancing research on the fundamental biology of aging. The team embraces the Geroscience approach, which recognizes that old age is the greatest risk factor for most chronic diseases, including diabetes, osteoarthritis, cancer, and Alzheimer’s disease. Their research aims to discover fundamental mechanisms of aging that can be therapeutically targeted to reduce the risk of multiple age-related diseases with a single intervention. Mashek’s work is situated within this broader context of understanding cellular mechanisms of cancer and aging, contributing to the institute’s mission to improve health and well-being in alignment with the United Nations Sustainable Development Goal 3.

Research topics

• Biology
• Cell biology
• Medicine
• Internal medicine
• Computer Science
• Genetics
• Endocrinology
• Physical therapy
• Bioinformatics
• Animal science
• Theology
• Biochemistry
• Art
• Computational biology
• Philosophy
• Cancer research
• Gerontology

Selected publications

• ATGL-catalyzed lipid catabolism promotes DNA repair

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-04

  articleOpen accessSenior authorCorresponding

  An imbalance of DNA damage over DNA repair contributes to the genomic instability that drives aging and numerous age-related diseases. While numerous DNA repair mechanisms have been elucidated over decades of study, little is known about the contribution of metabolism to genomic stability. We report that adipose triglyceride lipase (ATGL), a primary lipolytic enzyme, promotes DNA repair. We show that lipid droplets (LDs) accumulate in response to DNA damage and that inhibition of LD biogenesis before genotoxic stress increases the persistence of DNA damage. Overexpression of ATGL (increasing lipolysis) enhances DNA repair in response to etoposide and ionizing radiation, thus reducing DNA damage burden. Mechanistically, ATGL promotes bulk acetylation of chromatin-bound proteins and blockade of the histone acetyltransferase p300 negates these effects. Further, ATGL-induced DNA repair attenuates the long-term consequences of DNA damage, and reducing senescence and enhancing viability. Overall, these studies reveal a novel role for LDs and LD proteins in DNA damage and repair, thus unveiling a mechanism through which lipid metabolism contributes to genomic stability.

  PublisherOA PDFDOI

• Relative Effects of Time-Restricted Eating, Energy-Restricted Eating, and Unrestricted Eating on Eating Patterns and Dietary Intake: Results From a Randomized Controlled Trial

  Journal of the Academy of Nutrition and Dietetics · 2026-03-01

  articleOpen access
  PublisherOA PDFDOI

• Heterozygous GAA knockout is nonconsequential on metabolism and the spatial liver transcriptome in high‐fat diet‐induced obese and prediabetic mice

  Physiological Reports · 2025-03-01 · 3 citations

  articleOpen access

  Glycophagy is the autophagic degradation of glycogen by the enzyme acid alpha-glucosidase (GAA). Although GAA inhibitors improve metabolic health by inhibiting GAA in the intestine, it is not clear if GAA inhibition in peripheral tissues such as the liver is metabolically beneficial. This study tested if the heterozygous knockout of GAA (HetKO-GAA) alters liver metabolism and metabolic health in mice fed a low-fat diet or a high-fat diet to induce obesity. HetKO-GAA mice fed either diet did not have altered body weight, glucose tolerance, insulin action, energy expenditure, substrate metabolism, liver glucose output, or liver triglycerides compared to control wildtype mice. A liver spatial transcriptomics analysis revealed that high-fat diet feeding reduced the gene abundance of predominantly metabolic pathways in both periportal and perivenous hepatocytes, and uniquely reduced ribosome gene abundance in perivenous hepatocytes. HetKO-GAA mice did not have significantly altered transcriptomes in periportal or perivenous hepatocytes compared to wildtype mice. In conclusion, heterozygous GAA knockout is nonconsequential on metabolism and metabolic health in high-fat diet induced obesity. Spatial transcriptomics revealed alterations in the transcriptome of periportal and perivenous hepatocytes from high-fat diet induced obese mice, highlighting novel targets that could be exploited to improve metabolic health in obesity.

  PublisherDOI

• Sorbate induces lysine sorbylation through noncanonical activities of class I HDACs to regulate the expression of inflammation genes

  Science Advances · 2025-05-30 · 4 citations

  articleOpen accessCorresponding

  Environmental factors may affect gene expression through epigenetic modifications of histones and transcription factors. Here, we report that cellular uptake of sorbate, a common food preservative, induces lysine sorbylation (Ksor) in mammalian cells and tissue mediated by the noncanonical activities of class I histone deacetylases (HDAC1-3). We demonstrated that HDAC1-3 catalyze sorbylation upon sorbate uptake and desorbylation in the absence of sorbate both in vitro and in cells. Sorbate uptake in mice livers significantly induced histone Ksor, correlating with decreased expressions of inflammation-response genes. Accordingly, sorbate treatment in macrophage RAW264.7 cells upon lipopolysaccharide (LPS) stimulation dose-dependently down-regulated proinflammatory gene expressions and nitric oxide production. Proteomic profiling identified RelA, a component of the NF-κB complex, and its interacting proteins as bona fide Ksor targets and sorbate treatment significantly decreased NF-κB transcriptional activities in response to LPS stimulation in RAW264.7 cells. Together, our study demonstrated a noncanonical mechanism of sorbate uptake in regulating epigenetic histone modifications and inflammatory gene expression.

  PublisherDOI

• Time‐restricted eating, caloric reduction, and unrestricted eating effects on weight and metabolism: a randomized trial

  Obesity · 2025-02-19 · 18 citations

  articleOpen access

  OBJECTIVE: Metabolic improvements may precede weight loss. We compared the effects of self-selected 8-h time-restricted eating (TRE), 15% caloric restriction (CR), and unrestricted eating (UE) on weight, body composition, caloric intake, glycemic measures, and metabolic flexibility. METHODS: In this 12-week randomized-controlled trial, we measured weight (primary outcome), body composition (dual-energy x-ray absorptiometry/magnetic resonance imaging), caloric intake (24-h recall), metabolic flexibility (indirect calorimetry during hyperinsulinemic-euglycemic clamp), and glycemic measures (hemoglobin A1c, hyperinsulinemic-euglycemic clamp, continuous glucose monitoring). RESULTS: ; 54.5% female, 84.1% White). Final eating windows were 9.8 h (95% CI: 9.0 to 10.6) for TRE, 12.9 h (95% CI: 11.9 to 13.9) for CR, and 11.8 h (95% CI: 11.0 to 12.7) for UE. Compared with UE (n = 29), weight changes were -1.4 kg (95% CI: -4.5 to 1.7; p = 0.53) with TRE (n = 30) and -2.5 kg (95% CI: -5.8 to 0.8; p = 0.18) with CR (n = 29). TRE showed lower metabolic flexibility than CR (-0.041 [95% CI: -0.080 to -0.002]). Weight, body composition, caloric intake, and glycemic measures were similar among groups. Eating window reduction correlated with decreased caloric intake and visceral fat. CONCLUSIONS: In a 12-week intervention, TRE did not lead to significant improvements in weight, average body composition, or glycemic or metabolic measures compared with CR or UE.

  PublisherOA PDFDOI

• The Sixth Annual Symposium of the Midwest Aging Consortium

  The Journals of Gerontology Series A · 2025-12-22

  articleOpen access

  Geroscience research benefits from interdisciplinary approaches, team science, and collaborations, which collectively facilitate the discovery of aging mechanisms and their translation into tangible, clinical interventions. Since its inception in 2019, the Midwest Aging Consortium (MAC) has provided an engaging platform for aging researchers in the United States' Midwest to connect, collaborate, and exchange ideas. The Sixth Annual Research Symposium of the MAC held at the Mayo Clinic in Rochester, Minnesota, in April 2025 highlighted the continued impact of the MAC in bringing together aging researchers, including many trainees and early career investigators, into a collaborative environment. This record-setting event featured interdisciplinary research on key aging mechanisms, including lipid metabolism, mitochondrial dysfunction, stress response, cellular senescence, and immune adaptations across organ systems. New therapeutic concepts and clinical trial approaches were presented. Cutting-edge methodologies including single-cell and spatial transcriptomics, metabolomics, and organoid cultures, to dissect aging process in tissue-specific and systemic contexts also were presented. Overall, the MAC symposium underscored the translational potential of geroscience and reinforced the MAC's mission to accelerate aging research through regional collaborations and innovation.

  PublisherOA PDFDOI

• Ketone body driven lipid remodeling supports thermogenic adaptation to fasting

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-17

  preprintOpen access

  Metabolic adaptation to fasting may have conferred survival advantage to early humans and predicts weight gain caused by overnutrition in modern societies. Fasting suppresses brown adipose tissue (BAT) thermogenesis; however, it is unclear how BAT rewires cellular metabolism to balance between energy conservation and heat generation. Here, we report that BAT in mice under fasting and cold challenge consumed ketone bodies, specifically acetoacetate (AcAc). Ablating liver ketogenesis decreased, while enhancing hepatic AcAc output defended, body temperature in mice facing the dual challenge. Using stable isotope tracing in brown adipocytes in vitro combined with quantitative analysis of metabolic fluxes and lipidomics in BAT from genetic mouse models, we disentangled the two metabolic fates of AcAc - terminal oxidation in the mitochondria and lipid biosynthesis in the cytosol. Notably, AcAc-sourced carbon preferentially supported polyunsaturated fatty acid synthesis in BAT, linking to the positive impact of intermittent fasting on lipid profiles in both mice and humans. Therefore, ketone body utilization by thermogenic adipocytes contributes to metabolic resilience of mammals and can be targeted to optimize benefits of dietary regimens.

  PublisherOA PDFDOI

• Sorbate Induces Lysine Sorbylation Through Non-Canonical Activities of Class I HDACs to Regulate the Expression of Inflammation Genes

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-12-12

  preprintOpen accessCorresponding

  Abstract Metabolic and environmental factors may impact gene expression through the production of active metabolites and epigenetic modifications of histones and transcription factors. In this study, we discovered that cellular uptake of sorbate, an FDA-approved and widely used food preservative, can induce lysine sorbylation (Ksor), a new posttranslational modification and epigenetic mark. We identified over 40 Ksor sites on core histones from mammalian cells and tissue upon sorbate uptake and further showed that the dynamics of histone Ksor could be regulated by the non-canonical activities of Class I histone deacetylases (HDAC1-3). We demonstrated that Class I HDACs catalyzed sorbylation upon sorbate uptake and desorbylation in the absence of sorbate both in vitro and in vivo. Sorbate uptake in mice livers led to a significant increase in histone Ksor without affecting overall histone acetylation, which correlated with the decreased expression of genes in inflammation signaling pathways. Accordingly, sorbate treatment in macrophage RAW264.7 cells upon LPS stimulation dose-dependently downregulated the expression of proinflammatory genes and production of nitric oxide. Global proteomic profiling revealed widespread lysine sorbylation substrates in diverse metabolic and signaling pathways and identified RelA (p65), a component of the NF-ĸB complex, and its interacting proteins as bona fide Ksor targets. Sorbate treatment significantly decreased NF-ĸB transcriptional activities in response to LPS stimulation in RAW264.7 cells. Taken together, our study demonstrated a non-canonical mechanism of sorbate uptake in regulating epigenetic histone modifications and inflammatory gene expression.

  PublisherOA PDFDOI

• Mechanisms coupling lipid droplets to MASLD pathophysiology

  Hepatology · 2024-10-30 · 21 citations

  articleSenior authorCorresponding

  Hepatic steatosis, the buildup of neutral lipids in lipid droplets (LDs), is commonly referred to as metabolic dysfunction-associated steatotic liver disease when alcohol or viral infections are not involved. Metabolic dysfunction-associated steatotic liver disease encompasses simple steatosis and the more severe metabolic dysfunction-associated steatohepatitis, characterized by inflammation, hepatocyte injury, and fibrosis. Previously viewed as inert markers of disease, LDs are now understood to play active roles in disease etiology and have significant nonpathological and pathological functions in cell signaling and function. These dynamic properties of LDs are tightly regulated by hundreds of proteins that coat the LD surface, controlling lipid metabolism, trafficking, and signaling. The following review highlights various facets of LD biology with the primary goal of discussing key mechanisms through which LDs promote the development of advanced liver diseases, including metabolic dysfunction-associated steatohepatitis.

  PublisherDOI

• TCuPGAN: A Novel Framework Developed for Optimizing Human-Machine Interactions in Citizen Science

  Communications in computer and information science · 2024-12-31

  book-chapter
  PublisherDOI

Recent grants

• Regulation and consequences of hepatic lipid droplet catabolism

  NIH · $1.7M · 2017–2022

• Functional Multi-omics of Aging

  NIH · $5.6M · 2008–2028

• NIH Grant R01DK090364

  NIH · $1.8M · 2016

• Role of ATGL and lipid metabolism in healthspan

  NIH · $1.6M · 2017–2023

• NIH Grant R56AG051599

  NIH · $198k · 2017

Frequent coauthors

• Mara T. Mashek

  University of Minnesota

  33 shared

• Lisa S. Chow

  University of Minnesota

  25 shared

• Katrina Dietsche

  University of Minnesota

  21 shared

• Rosalind Coleman

  University of North Carolina at Chapel Hill

  20 shared

• Gavin Fredrickson

  20 shared

• Xavier S. Revelo

  University of Minnesota

  20 shared

• Jesse W. Williams

  University of Minnesota

  18 shared

• Cyrus Jahansouz

  University of Minnesota

  18 shared

Labs

• Mashek LaboratoryPI

  Not provided

Awards & honors

• NIH/NIDDK National Research Service Award
• American Diabetes Association Junior Faculty Award
• Dannon Nutrition Leadership Institute
• Novo Nordisk Diabetes Innovation Award
• CFANS Distinguished Teaching Award