Anthony J. Covarrubias, PH.D.
650 Charles E Young Dr, CHS 26-200, Los Angeles, CA, 90095
MIMG, MBI, Metabolism Theme Space, Immunology Theme Space (I3T), and CTSI
- Investigate the role of NAD metabolism as a therapeutic target in metabolic disease, aging, and cancer: Nicotinamide adenine dinucleotide (NAD) is a redox coenzyme central to energy metabolism and an essential cofactor for non-redox NAD dependent enzymes including sirtuins and poly-ADP-ribose polymerases (PARPs). Recently, lower NAD levels have also been linked to multiple disease states including metabolic disease, cancer, and in aging tissues in both rodents and human patients. Thus, the Covarrubias will explore how NAD consuming and biosynthetic pathways are altered during these disease states, the biological mechanisms in which altered NAD levels impact metabolism, gene expression and cell biology, and explore NAD metabolism as a potential therapeutic target.
- Exploring the role of nutrient/metabolite levels and nutrient sensing pathways in the regulation of immune cell function: Dr. Covarrubias has made key discoveries showing how metabolite levels are sensed via nutrient sensing signaling pathways, such the Akt-mTOR pathway, to influence macrophage gene expression and inflammatory functions during obesity and lean condition. Conversely, Dr. Covarrubias has shown how macrophage-derived inflammation can influences tissue levels of the critical metabolites including NAD during aging. Thus, the Covarrubias Lab will continue to explore the crosstalk and integration between nutrient/metabolite levels, nutrient sensing signaling pathways, gene expression and immune cell function.
- Immune cell and senescent cell crosstalk in metabolic disease, aging, and cancer:The Covarrubias Lab hopes to build on the discovery that senescent cells directly influence the function of tissue-resident macrophages via the secretion of the SASP by senescent cells. For example, Dr. Covarrubias showed that exposure to SASP causes macrophages to proliferate, polarize to a pro-inflammatory M1-like state, and alter their metabolism. Thus, the Covarrubias Lab will continue to further characterize and explore how senescent cells influence macrophage biology and aging.
I am a first-generation college graduate and Latino scientist hailing from South Los Angeles. Due to lack of rigorous science programs and access to resources such as teachers, lab equipment, etc., advanced degrees in science are often unattainable goals for most young people in my community. In fact, few are able to attend college to obtain a bachelor’s degree. Fortunately, in high school I had the chance to attend UCLA Citylab. This one-day program encourages inner-city students to pursue the sciences by exposing them to research done at UCLA. This trip was the defining moment in my life where I decided that I was going to be a scientist. As a UCLA undergraduate student, I became the student director of UCLA Citylab and obtained my bachelor’s degree in Biochemistry, while also obtaining high-quality training in molecular biology and public health research to help better understand diseases such as metabolic disease and diabetes which are prevalent at high rates in my community.
During my PhD training, in the lab of Dr. Tiffany Horng at the Harvard T.H. Chan School of Public Health, my thesis focused on the role of nutrient sensing pathways in the regulation of macrophage polarization. Macrophages are essential immune cells that belong to the innate immune system and are key orchestrators in the initiation and resolution stages of inflammation and can polarize to distinct subsets such as the pro-inflammatory M1 state or the anti-inflammatory M2 state. Previous studies have shown that chronic inflammation during obesity is responsible for many of the metabolic diseases associated with nutrient excess such as type-II diabetes and atherosclerosis. Furthermore, it has been shown that macrophages are a key mediator of the inflammatory events involved in the pathogenesis of metabolic diseases. In my first publication based on my thesis work we were able to show that the nutrient-sensing Akt-mTORC1 pathway is a critical regulator of macrophagepolarization.
In a follow up study, we show that activation of the Akt target ACLY catalyzes the increase in cytosolic/nuclear pools of acetyl-CoA. This acetyl-CoA is then used by histone acetyltransferases to acetylate the promoters of canonical macrophage markers in murine macrophages that can be tuned to metabolic input/nutrient status via the Akt-ACLY pathway and thereby control M2 gene expression levels. These findings highlight a key role for the Akt pathway in regulating macrophage M2 polarization, and suggest how nutrient and metabolic status can fine-tune macrophage function via nutrient sensing pathways. As a result of my accomplishments, I was awarded multiple fellowships during my training including the Ford Foundation Pre-Doctoral Fellowship, a Ford Foundation Dissertation Fellowship, and a UC President’s Fellowship.
As a Postdoctoral fellow in the lab of Eric Verdin (UCSF, Gladstone Institute, and the Buck Institute) I have focused on how aging-related inflammation impacts metabolite levels such as NAD and other novel mechanisms contributing to aging-related inflammation and disease. In a recent manuscript published in Nature Metabolism we report that expression of the NAD hydrolase enzyme CD38 is elevated in resident pro-inflammatory macrophages from epididymal white adipose tissue (eWAT) and in the liver of old mice compared to young mice. Furthermore, we demonstrate using in vitro and in vivo experiments that accumulation of CD38+ macrophages in aged-tissues is a leading mechanism for the altered NAD metabolism observed during the aging process. Lastly, we show that enhanced CD38 expression by tissue resident macrophages during aging is driven by the senescence associated secretory phenotype (SASP), the secretion of inflammatory factors by senescent cells. As senescent cells progressively accumulate in adipose tissue and liver during aging, these results highlight a new causal link between visceral tissue senescence and tissue NAD decline during aging. Thus, suppressing CD38 expression and NADase activity by targeting macrophages and senescent cells may provide a therapeutic target to help restore NAD levels during aging.
Covarrubias, Anthony J., Rosalba Perrone, Alessia Grozio, and Eric Verdin. “NAD + Metabolism and Its Roles in Cellular Processes during Ageing.” Nature Reviews Molecular Cell Biology 22 (2): 119–41.
Covarrubias, A.J., Abhijit Kale, Rosalba Perrone, Jose Alberto Lopez-Dominguez, Angela Oliveira Pisco, Herbert G. Kasler, Mark S. Schmidt, et al. n.d. “Senescent Cells Promote Tissue NAD + Decline during Ageing via the Activation of CD38 + Macrophages.” Nature Metabolism.
Covarrubias, Anthony J., Abhijit Kale, Rosalba Perrone, Jose Alberto Lopez-Dominguez, Angela Oliveira Pisco, Herbert G. Kasler, Mark S. Schmidt, et al. “Aging-Related Inflammation Driven by Cellular Senescence Enhances NAD Consumption via Activation of CD38+ pro-Inflammatory Macrophages.” BioRxiv, 609438.
Newman, John C., Anthony J. Covarrubias, Minghao Zhao, Xinxing Yu, Philipp Gut, Che-Ping Ng, Yu Huang, Saptarsi Haldar, and Eric Verdin. “Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice.” Cell Metabolism 26 (3): 547-557.e8.
Covarrubias, Anthony J, Halil Ibrahim Aksoylar, Jiujiu Yu, Nathaniel W Snyder, Andrew J Worth, Shankar S Iyer, Jiawei Wang, et al. “Akt-MTORC1 Signaling Regulates Acly to Integrate Metabolic Input to Control of Macrophage Activation.” ELife 5: e11612.
Covarrubias, Anthony Joseph. The Role of Nutrient Sensing in Macrophage Polarization. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
Covarrubias, Anthony J., H. Ibrahim Aksoylar, and Tiffany Horng. “Control of Macrophage Metabolism and Activation by MTOR and Akt Signaling.” Seminars in Immunology, Macrophage activation and polarization, 27 (4): 286–96.
Covarrubias, Anthony J., and Tiffany Horng. “IL-6 Strikes a Balance in Metabolic Inflammation.” Cell Metabolism 19 (6): 898–99.
Byles, Vanessa, Anthony J. Covarrubias, Issam Ben-Sahra, Dudley W. Lamming, David M. Sabatini, Brendan D. Manning, and Tiffany Horng. “The TSC-MTOR Pathway Regulates Macrophage Polarization.” Nature Communications 4: 2834.
Covarrubias, Anthony, Vanessa Byles, and Tiffany Horng. “ROS Sets the Stage for Macrophage Differentiation.” Cell Research 23 (8): 984–85.
Chin, Arnold I., Andrea K. Miyahira, Anthony Covarrubias, Juli Teague, Beichu Guo, Paul W. Dempsey, and Genhong Cheng. “Toll-like Receptor 3–Mediated Suppression of TRAMP Prostate Cancer Shows the Critical Role of Type I Interferons in Tumor Immune Surveillance.” Cancer Research 70 (7): 2595–2603.