SYMPOSIUM 2021
2021 Symposium on Healthy Aging
To improve Human Health & Reduce the Burden of Age-Related Disease
Session 1: Healthspan-Extending Interventions
Sailendra (Nath) Nichenametla, OFAS
Discrete effects of methionine and cysteine on sulfur amino acid restriction-induced changes in adipose metabolism
Dr. Nichenametla received his PhD in Integrative Biosciences from Pennsylvania State University (Hershey, PA) and DVM from Sri Venkateswara Veterinary University (Tirupati, India). He has a longstanding interest in understanding how genetics and the environment—diet, in particular—shape health. During graduate and postdoctoral training, he investigated the effects of bioactive compounds in milk, berries, and dietary fiber on diseases such as colon cancer and metabolic syndrome. While training for his PhD, he investigated how genetic variation in humans alters an individual’s capacity to combat oxidative stress and risk for cancers.
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Discrete effects of methionine and cysteine on sulfur amino acid restriction-induced changes in adipose metabolism
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Sailendra Nichenametla1, Dwight Mattocks1, Diana Cooke1, Gene Ables1, Vishal Midya2, Virginia Malloy1, Wilfredo Mansilla3, Anna-Kate Shoveller3, John Pinto4
1Orentreich Foundation for the Advancement of Science, Cold Spring, N.Y., 2Icahn School of Medicine at Mount Sinai, New York, N.Y., 3University of Guelph, Guelph, Ontario, Canada, 4New York Medical College, Valhalla, N.Y.
Sulfur amino acid restriction (SAAR) is a dietary intervention that results in robust lifespan extension in multiple experimental models. A salient future of SAAR in laboratory animals is the remarkable improvement in adipose metabolism. Contrary to this, the effect of SAAR in humans is modest. Laboratory SAAR diet is chemically defined and formulated by decreasing the concentration of methionine (Met) and eliminating cysteine (Cys). However, due to the use of natural ingredients, the human SAAR diet cannot eliminate Cys. Although they can synthesize Cys from Met, rodents cannot meet metabolic demand as Met in the SAAR diet is low. Thus, they undergo both Met restriction (MR) and Cys restriction (CR), i.e., SAA restriction (SAAR = MR + CR). The Human SAAR diet results only in MR, as Cys level is typically unaltered. We present data that show MR and CR exert discrete effects on several SAAR phenotypes and that SAAR-induced changes in adipose metabolism are specifically due to CR.
Christian Sell
Metabolic regulation of the senescence program through methionine restriction and mTOR inhibition
Christian Sell obtained his undergraduate training at the State University of New York in Binghamton. He obtained his Ph.D. at the Albany Medical College and postdoctoral training at Temple University and Thomas Jefferson University. He joined the Faculty of the Medical College of Pennsylvania in 1994 as an Assistant Professor. He moved his research to the Lankenau Institute for Medical Research (Wynwood, PA) in 1998 and subsequently joined the faculty of the Drexel University College of Medicine (Philadelphia). His early research work focused on the role of IGF-1 signaling in cancer. He identified the IGF-1 receptor as critical for the transformed phenotype and as an anti-apoptotic factor. This work led to the use of anti-IGF strategies as anticancer therapy and set the stage for multiple clinical studies on the potential for anticancer therapies targeting the IGF-I signaling pathway. The basic biology of aging and cellular senescence has been a research focus in Dr. Sell’s laboratory for a number of years. He has performed studies on the influence of the growth hormone/IGF-1 axis on longevity, the comparative biology of aging, and the lifespan extending properties of rapamycin on human cells. His work has been featured on 60 Minutes and in multiple publications, including Philadelphia Magazine. He has published over 80 articles and book chapters and is the editor of the book, Exceptional Longevity, Single Cell Organisms to Man. Dr. Sell’s work has been cited over 9,000 times in the scientific literature.
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Metabolic regulation of the senescence program through methionine restriction and mTOR inhibition
Christian Sell, Manali Potnis, Eishi Noguchi
Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Penn.
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Longevity enhancing therapies such as methionine restriction, mTOR inhibition, and caloric restriction can have profound impact on lifespan and late life function, yet the mechanisms by which these interventions provide these benefits remain elusive. The laboratory is dedicated to the clinical development of these longevity enhancing therapies and to the understanding of the mechanisms involved in the benefits provided by these therapies. We have found that both methionine restriction and mTOR inhibition delay or prevent cellular senescence, a cell fate decision which produces an irreversible growth arrest, and phenotypic changes that increase inflammatory cytokine production. We have identified specific metabolic changes in the cell that link fatty acid oxidation to one carbon metabolism and histone modifications. These changes provide a mechanism allowing metabolic regulation of cell fate decisions such as entry into senescence and cell differentiation.
Manali Potnis
An evolving role for the long non-coding RNA H19 in aging and senescence
Manali Potnis is a Ph.D. candidate working with Dr. Christian Sell at the Drexel University in Philadelphia. Her research examines the role of long-non-coding RNA H19 in aging and senescence. She received her master’s in Molecular Biology from Drexel University. She is the recipient of The Aging Initiative fellowship, a college-wide initiative to support research in basic biology of aging. In addition to her research, she served as a student liaison for the Women in Medicine and Science Committee (WiMSC).
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Explore a captivating array of artworks, spanning
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An evolving role for the long non-coding RNA H19 in aging and senescence
Manali Potnis, Eishi Noguchi, Christian Sell
Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Penn.
The long non-coding RNA (lncRNA) H19 is a maternally imprinted gene transcript that, in conjunction with the neighboring Igf2 gene, is critical in controlling embryonic growth. Loss of H19 results in fetal overgrowth associated with Beckwith-Wiedemann syndrome, while elevated H19 occurs in human cancers. In the adult, H19 functions in cancer cells, where it promotes migration and is correlated with poor prognosis, and in adult stem cells where it is a key regulator of cell fate decisions during differentiation. While the function of H19 in primary somatic cells has not been defined, a reduction in the abundance of H19 has been reported during senescence in endothelial cells. Given the critical importance of H19 in cell fate decisions, it is likely that understanding the precise function of H19 in somatic cells in general and why reduced levels occur with cellular senescence will provide novel insights into both somatic cell maintenance and the senescence program. Towards this end, we examined the role of H19 in somatic cell growth using cardiac interstitial fibroblasts. Our results indicate that H19 is not only vital for somatic cell proliferation and survival, but that depletion of H19 leads to cell cycle arrest and the formation of abnormal nuclei, resulting in senescent cells. We are defining both the upstream regulators of H19 and the downstream mediators of senescence following H19 depletion. Overall, these results indicate an essential role for H19 in cell cycle progression, chromatin structure, and possibly proper mitotic division.
Panel Discussion
Sailendra Nichenametla, Christian Sell, Manali Potnis
Session 2: Trends in Aging Biology Research
Max Guo
Aging Biology Research Supported by the National Institute on Aging
Max Guo, Ph.D., is the Chief of the Genetics and Cell Biology Branch, Division of Aging Biology at the National Institute on Aging (NIA), NIH. Trained as a molecular biologist and biochemist, he obtained a Ph.D. in Biochemistry on the study of RNA splicing with Dr. Alan Lambowitz from the Ohio State University in 1992. He did his postdoctoral training on oncogenes with Dr. J. Michael Bishop at the University of California at San Francisco. Before joining NIH as a Program Officer in 2002, he was an Assistant Professor of Cancer Biology at the Sidney Kimmel Comprehensive Cancer Center of Johns Hopkins Medical School. He was a Program Officer of Genetics and Genomics at the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and National Heart, Lung and Blood Institute (NHLBI) from 2002 to 2007. From 2008-2011, he was the Deputy Director of the Division of Metabolism and Health Effects, NIAAA. He joined NIA in 2011, responsible for the genetics and chromatin portfolio.
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Aging biology research supported by the National Institute on Aging
Max Guo
Division of Aging Biology, National Institute on Aging, NIH,Bethesda, Md.
This presentation will highlight and discuss some research and research trends on aging biology supported by the National Institute on Aging (NIA). The Division of Aging Biology at NIA promotes and supports research and training on the molecular, cellular, and physiological mechanisms underlying normal aging and age-related pathologies. It supports basic, applied and translational research on the biology of aging, and its priorities include research on (1) mechanisms of aging, (2) hallmarks and biomarkers of aging, (3) rates of aging (including lifespan and healthspan), and (4) methods to alter those to improve health at older ages. The subjects of this aging biology research include model organisms (both invertebrates and vertebrates) and humans. In addition to research, some NIA funding-related topics will be also presented.
Session 3: Towards Translation of Sulfur Amino Acid Restriction
Zhen Dong
Cumulative consumption of sulfur amino acids intake and incidence of diabetes
Dr. Green is a recipient of the Dr. Norman Orentreich Award for Young Investigator on Aging, presented at the 2022 Annual Meeting of the American Aging Association (San Antonio, Tex.).
Cara Green completed her undergraduate degree in Molecular Biology and Biochemistry at the University of Durham (UK) in 2013, where she first became interested in aging, before travelling north to the University of Aberdeen in Scotland for her Ph.D. in Biological Sciences with Professor John Speakman. There, she specialized in calorie restriction and its impact on whole body metabolomics, focusing on the linear relationship in mice between calories and lifespan, and embarked on a tumultuous but rewarding journey with bioinformatics. In 2018, Ph.D. completed, she moved across the pond to the University of Wisconsin-Madison for a postdoctoral position with Dr. Dudley Lamming to further investigate the relationship between nutrition and age-associated diseases. She is particularly interested in the metabolic response to dietary protein and branched chain amino acids and the impact of sex and genetic background on such responses and what may govern them.
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Heterogeneity in the impact of dietary protein on metabolic health highlights the importance of precision dietetics
Cara Green1,2, Michaela Murphy1,2, Isaac Grunow1,2, Yang Liu1,2, Reji Babygirija1,2, Mariah Calubag1,2, Shelly Sonsalla1,2, Astrid Martin1,2, Yang Yeh1,2, Dudley Lamming1,2
1Department of Medicine, University of Wisconsin-Madison, Madison, Wis., USA
2William S. Middleton Memorial Veterans Hospital, Madison, Wis., USA
Low protein (LP) diets can improve metabolic health without caloric restriction and may be effective to promote healthy aging and combat diabetes and obesity. Many dietary recommendations exist at the population level, but individual information about the metabolic response to diet is lacking. In mice, an LP diet can promote weight loss, improve glycemic control, and increase lifespan; however, this is sex and strain dependent. It is unknown which key genes may be responsible for determining the individual response to dietary protein. To identify genetic markers that may determine how dietary protein impacts metabolism, we characterized 40 recombinant inbred strains of male and female BXD mice. We found huge variation across strains and sexes in the response to protein restriction (PR), including in weight loss, adiposity, and fasting blood glucose. PR promoted positive and negative responses depending on strain and sex; male mice could lose 4g or gain 6g after 8 weeks on PR depending on strain. One of the phenotypes almost universally improved by PR was fasting blood glucose; this was reflected in correlation analyses, in which 11 strains of mice showed a strong positive correlation (R > 0.4) between protein intake and fasting blood glucose, relative to only 5 strains with total calorie intake. Interestingly, there was very little correlation of protein with final lean mass, with 4 strains showing a positive (R > 0.4) correlation with protein intake. However, 21 BXD strains had a positive correlation between calorie intake and final lean mass, suggesting that calories, and not protein, in the diet is a modulator of fat-free mass in mice. Quantitative trait locus (QTL) analysis to discover links between these complex phenotypes and chromosome regions indicated there were no significant regions of interest conserved between males and females for any of the phenotypes we investigated. QTL analyses found genomic regions significantly associated with changes in lean mass and glucose tolerance with PR in males and females. In females, fasting blood glucose and fat mass were significantly associated with different genomic regions. These data show that the metabolic health effects of dietary protein are highly individualized based on sex and genetic background. This demonstrates the importance of precision dietetics to maximize metabolic health and the potential significance of personalized dietary strategies if a similar response exists in humans. In the future, this may help us to promote healthy aging and improve metabolic health on an individual basis.
Panel Discussion
Zhen Dong, Thomas Olsen, Kathrine Vinknes
Sulfur amino acids and metabolic outcomes – Preliminary data, challenges, and experiences from human clinical intervention studies
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Thomas Olsen1, Amany Elshorbaghy2, Emma Stolt1, Bente Øvrebø1, Kjetil Retterstøl1, Marleen van Greevenbroek3, Viktor Kožich4, Kjetil Retterstøl1, Helga Refsum1, Kathrine J. Vinknes1
1Department of Nutrition, University of Oslo, Oslo, Norway; 2Department of Pharmacology, University of Oxford, Oxford, U.K.; 3Department of Internal Medicine and CARIM School of Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands; 4Department of Pediatrics and Inherited Metabolic Disorders, Charles University, Praha, Czech Republic
Dietary sulfur amino acid (SAA) restriction is an established animal model for increasing lifespan and improving metabolic health. Data from human studies are limited.
From 2015-2019, we performed short-term randomized controlled pilot studies in normal-weight and overweight/obese participants to assess the feasibility of sulfur amino acid restriction (SAAR) and short-term metabolic effects. Main results from the pilot trials included changes in circulating biomarkers, including FGF21, and changes in plasma and urinary concentrations of several SAA and in adipose tissue mRNA expression in line with preclinical studies.
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In recent preliminary analyses on the pilot data, we assayed all sulfur metabolites (sulfurome), including less commonly assayed compounds such as inorganic sulfur compounds (sulfite, thiosulfate), organic sulfur metabolites (e.g. S-sulfocysteine), and H2S to explore the relation of specific sulfur metabolites with body composition, biomarkers, and adipocyte gene expression. Preliminary findings showed that intermediates in sulfur metabolism distal to methionine and cysteine differed between normal-weight and overweight individuals. In addition, short-term SAAR induced changes in several less commonly assayed sulfur analytes in plasma and urine.
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The findings from the pilot trials will be verified and explored further in an ongoing project (ClinicalTrials.gov: NCT04701346). The study is an 8-week randomized controlled dietary intervention in which we evaluate if dietary SAAR can reduce body weight and affect resting energy metabolism, substrate oxidation, and other parameters related to metabolic health. The participants are overweight and obese men and women (sample size = 40–50), aged 18–45 years, randomized to a diet with either low or high SAA. Outcomes include changes in body weight, body composition, and resting energy expenditure and in samples of blood, urine, feces, and adipose tissue. The objective of the trial is to establish effects of SAAR with an overarching aim to translate findings from previous animal experiments to humans.
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Finally, in a phase 1 dose-finding study, we are investigating the cysteine-lowering effects of the drug mesna (Uromitexan®), which increases urinary excretion of cysteine (ClinicalTrials.gov: NCT04449536). The ultimate goal of this project is to assess whether mesna can be beneficial for body weight reduction in individuals with obesity.
With these studies, we aim to establish the relevance of diet- or drug-induced SAAR in humans with regards to metabolic outcomes.
Session 4: Regulation of Metabolism & Senescence
Alessandro Bitto
Acarbose suppresses symptoms of mitochondrial disease in a mouse model of Leigh syndrome
Dr. Bitto is an Acting Instructor in the Department of Laboratory Medicine and Pathology, University of Washington Medical Center, Seattle, Wash. He received his Ph.D. from Drexel University College of Medicine in 2013. From 2013-2018, he was a postdoctoral fellow in the University of Washington Medical Center Department of Pathology.
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Acarbose suppresses symptoms of mitochondrial disease in a mouse model of Leigh syndrome
Alessandro Bitto, Matt Kaeberlein
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Wash.
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Mitochondrial diseases are pathologies characterized by impairment in mitochondrial function. Mitochondrial dysfunction is also a hallmark of the aging process. Rapamycin, a drug that increases lifespan and reduces the incidence of age-related pathologies in multiple models, increases survival and reduces the impact of neurological symptoms in a mouse model lacking the complex I subunit Ndufs4. Here we show that acarbose, another drug that extends lifespan in mice, suppresses symptoms of disease and improves survival of Ndufs4-/- mice. Unlike rapamycin, acarbose rescues disease phenotypes independently of mTOR inhibition. Furthermore, rapamycin and acarbose have additive effects on clasping and maximum lifespan in Ndufs4-/- mice. Acarbose rescues mitochondrial disease independently of glycolytic flux and Sirt3 activity by potentially remodeling the microbiome. This study provides the first evidence that the microbiome may rescue severe mitochondrial disease and proof of principle that biological aging and mitochondrial disorders are driven by common mechanisms.
Jay Johnson, Ph.D.
Dietary supplementation with compounds that produce methionine restriction-like benefits, including inhibition of insulin/IGF-1 signaling and improved healthspan
Jay Johnson received his doctorate in Molecular Biology from Case Western Reserve University (Cleveland, Ohio). His post-doctoral work at Fox Chase Cancer Center (Philadelphia, Pa.) used a liposarcoma model system to investigate the maintenance of telomeres, important nucleoprotein structures with roles in aging and cancer. Dr. Johnson then joined the University of Pennsylvania (Philadelphia), where his further post-doctoral studies explored cellular defects in patients with Werner and Bloom’s syndromes, genetic diseases characterized by accelerated aging and cancer predisposition. Dr. Johnson joined the Orentreich Foundation (Cold Spring, N.Y.) in 2015 and was promoted to the position of Associate Research Scientist (equivalent to a tenure-track Associate Professor) in 2020. His laboratory makes use of multiple model systems (i.e., yeast, cultured mouse and human cells, and mice) to explore the mechanistic basis of the benefits of methionine restriction and to identify novel interventions that improve healthspan.
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Dietary supplementation with compounds that produce methionine restriction-like benefits, including inhibition of insulin/IGF-1 signaling and improved healthspan
Jason D. Plummer, Jay E. Johnson
Orentreich Foundation for the Advancement of Science, Cold Spring, N.Y.
Methionine restriction (MR) dramatically extends the healthspan of several model organisms. For example, methionine-restricted rodents have less age-related pathology than control-fed littermates and are up to 45% longer-lived. Importantly, MR is feasible for humans and studies have suggested that methionine-restricted individuals may receive similar benefits to rodents. Unfortunately, long-term adherence to a methionine-restricted diet is likely to be challenging for many individuals. Prompted by this, our lab has sought to identify compounds that produce the benefits of MR, but in a normal, methionine-replete context. Here, we show that dietary supplementation with any one of four different amino acids is sufficient to produce the same beneficial metabolic effects typically observed for MR. Notably, supplemented animals are completely protected against diet-induced obesity, maintaining both normal glucose homeostasis and low levels of adiposity despite the challenge of a high-fat diet. Further, supplemented animals demonstrate the same beneficial plasma hormone changes as methionine-restricted mice, with altered circulating levels of IGF-1, FGF-21, leptin, and adiponectin. Finally, we find that similar interventions in budding yeast also mimic the ability of MR to extend the lifespan of this organism. Together, our findings reveal four novel dietary interventions that produce the same short-term healthspan benefits as MR, but in a methionine-replete context. Should future studies find that these interventions also produce MR-like benefits in humans, then supplementation with these compounds would represent an attractive alternative to maintaining a methionine-restricted diet.
Cristal Hill
Linking brain FGF21 signaling to improvements in health and lifespan during dietary protein restriction
Dr. Hill is the recipient of the Dr. Norman Orentreich Award for Young Investigator on Aging, presented at the 2021 Annual Meeting of the American Aging Association (July 20-23, 2021), Madison, WI.
Cristal M. Hill grew up in Birmingham, Al., with ambitions in veterinary medicine, but a strong interest in endocrine diseases developed while working at a local veterinary clinic during high school. Dr. Hill received her BS and MS degrees in animal sciences from Tuskegee University, with a thesis centered on inflammatory responses during cardiovascular disease. She then moved to Southern Illinois University School of Medicine, where, under the direction of Dr. Andrzej Bartke, she earned a Ph.D. in molecular biology, microbiology, and biochemistry, with a heavy focus on the mechanisms of biological aging. She is a postdoctoral fellow mentored by Jacqueline M. Stephens and Christopher D. Morrison at the Pennington Biomedical Research Center in Baton Rouge, La. Dr. Hill received a Maximizing Opportunities for Scientific and Academic Independent Careers – Pathway to Independence Award (MOSAIC NIH K99/R00) for her current research focusing on the effect of dietary protein content on adipose tissue function during aging. She also received a Ruth L. Kirschstein National Research Service Award (NRSA) Individual Postdoctoral Fellowship (Parent F32) for her earlier training and work focused on neuronal FGF21 signaling effects on metabolism during dietary protein restriction.
In the community, Dr. Hill is an advocate of connecting scientific data to the community through affiliations in both local and national organizations. She was a youth educator for the 4-H Club (University of Illinois at Urbana-Champaign), a mentor for Big Brothers Big Sisters, and served on the community leadership board of Central Illinois for the American Diabetes Association. While living in Baton Rouge, she has assisted with numerous STEM programs in both a church and public setting. She is also a member of Delta Sigma Theta Sorority, Inc., and Rotary International.
Dr. Hill’s commitment to fostering diversity includes teaching at all levels and mentoring undergraduates at various minority-serving institutions. She has held the position of Vice-Chair and Secretary of the American Aging Association Trainee Chapter (AGE-TC) and now holds the position of Chair for the AGE-TC Diversity, Equity, Inclusion, and Opportunities Committee. Dr. Hill continues to support diversity by endorsing an environment of institutional inclusion in the biomedical research workforce for individuals from underrepresented backgrounds.
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Linking brain FGF21 signaling to improvements in health and lifespan during dietary protein restriction
C.M. Hill1, D.C. Albarado1, L. Coco1, R. Spann1, M.S. Khan1, E. Qualls-Creekmore1, D. Burk1, S.J. Burke1, J.J. Collier1, S. Yu1, D. McDougal1, H.R. Berthoud1, H. Münzberg1, A. Bartke2, C.D. Morrison1
1Pennington Biomedical Research Center, Baton Rouge, La.; 2Depts of Internal Medicine & Physiology, Southern Illinois University School of Medicine, Springfield, Ill.
Dietary protein restriction (DPR), without reducing caloric intake, improves metabolic health and extends lifespan in various organisms. In addition, amino acid restriction, including methionine restriction (MR) and reducing branched chain amino acids (BCAA), also produces favorable outcomes on health and lifespan. Recent work demonstrates that DPR protects against obesity, increases energy expenditure, and improves glucose homeostasis, and this effect is largely mediated by the metabolic hormone FGF21. Other studies report that consistent high levels of FGF21 extend lifespan, as observed in transgenic mice overexpressing FGF21. DPR creates a unique physiological approach to define the underlying mechanisms that contribute to these beneficial effects. The goal of this work is to connect the effects of protein intake and FGF21 signaling on metabolism, feeding behavior, and longevity, and experiments in our lab have specifically focused on identifying the site of action and potential mechanisms through which DPR-induced FGF21 signaling improves metabolism and protects against aging. Our collective data demonstrate that FGF21 signaling in the brain is required for DPR-induced improvements in metabolism and that FGF21 is required for DPR to defend against age-related metabolic and physical impairment, and in turn, extend lifespan. This work is funded by the National Institutes of Health (NIH) F32DK115137, R01DK105032, R01DK121370, S10OD023703, R21AG062985.
Panel Discussion
Alessandro Bitto, Jay Johnson, Cristal Hill