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1
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Plummer JD, Johnson JE. Intermittent methionine restriction and selenium supplementation protect against inflammation and the development of dermatitis. J Inflamm (Lond) 2025; 22:24. [PMID: 40537808 DOI: 10.1186/s12950-025-00451-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Accepted: 06/11/2025] [Indexed: 06/22/2025] Open
Affiliation(s)
- Jason D Plummer
- Department of Biology, Orentreich Foundation for the Advancement of Science, Cold Spring, NY, USA
| | - Jay E Johnson
- Department of Biology, Orentreich Foundation for the Advancement of Science, Cold Spring, NY, USA.
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2
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McGilvrey MI, Fortier B, Cooke D, Mahdi MA, Tero B, Potts CM, Kaija A, Ryzhova L, Cora C, Richardson A, Guzior D, Pinz I, Vary C, Koza RA, Ables G, Liaw L. Short-term dietary methionine restriction with high fat diet counteracts metabolic dysfunction in male mice. Physiol Rep 2025; 13:e70405. [PMID: 40526038 DOI: 10.14814/phy2.70405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Revised: 04/30/2025] [Accepted: 05/19/2025] [Indexed: 06/19/2025] Open
Abstract
Dietary methionine restriction (MetR) promotes metabolic health, and we tested the impact of short durations of MetR on high fat diet (HFD)-induced metabolic dysfunction with the maintenance of HFD. Male C57BL/6J mice were fed HFD from 10 to 25 weeks of age, then maintained on HFD or fed HFD with 80% reduced methionine (HFD-MetR) for 3, 5, or 10 days. Blood, liver, adipose tissue, and aortae underwent phenotypic assessment, proteomics, and metabolomics. HFD-MetR induced rapid weight loss and robust metabolic improvement within 10 days. Significant reductions in body weight, circulating triglycerides, glucose, insulin, adipokines and hepatokines reflected metabolic health. Proteomics revealed enriched metabolic signatures in perivascular adipose tissue (PVAT) and structural remodeling signatures in aorta. Metabolomics identified a cardioprotective signature in blood plasma, and activated mitochondrial activity and energy production in liver and brown adipose tissue. HFD-MetR reversed metabolic dysfunction, and novel proteomic and metabolomic signatures were identified. Multi-organ molecular changes in lipid metabolism, mitochondrial function, and bioenergetics are predicted to impact adipose tissue and liver function and cardiovascular health. Our identification of rapid changes in protein and metabolite signatures with accelerated restoration of metabolic health can be leveraged to evaluate biomarkers of metabolic health and disease in a translational context.
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Affiliation(s)
- Marissa I McGilvrey
- Center for Molecular Medicine, MaineHealth Institute for Research, Scarborough, Maine, USA
- Graduate School of Biomedical Science and Engineering, University of Maine, Orono, Maine, USA
| | - Bethany Fortier
- Center for Molecular Medicine, MaineHealth Institute for Research, Scarborough, Maine, USA
| | - Diana Cooke
- Orentreich Foundation for the Advancement of Science, Inc., Cold Spring, New York, USA
| | - Maryam A Mahdi
- Center for Molecular Medicine, MaineHealth Institute for Research, Scarborough, Maine, USA
| | - Benjamin Tero
- Center for Molecular Medicine, MaineHealth Institute for Research, Scarborough, Maine, USA
| | - Christian M Potts
- Center for Molecular Medicine, MaineHealth Institute for Research, Scarborough, Maine, USA
| | - Abigail Kaija
- Center for Molecular Medicine, MaineHealth Institute for Research, Scarborough, Maine, USA
| | - Larisa Ryzhova
- Center for Molecular Medicine, MaineHealth Institute for Research, Scarborough, Maine, USA
| | - Carolina Cora
- Center for Molecular Medicine, MaineHealth Institute for Research, Scarborough, Maine, USA
- Graduate School of Biomedical Science and Engineering, University of Maine, Orono, Maine, USA
| | | | | | - Ilka Pinz
- Center for Molecular Medicine, MaineHealth Institute for Research, Scarborough, Maine, USA
| | - Calvin Vary
- Center for Molecular Medicine, MaineHealth Institute for Research, Scarborough, Maine, USA
- Graduate School of Biomedical Science and Engineering, University of Maine, Orono, Maine, USA
| | - Robert A Koza
- Center for Molecular Medicine, MaineHealth Institute for Research, Scarborough, Maine, USA
- Graduate School of Biomedical Science and Engineering, University of Maine, Orono, Maine, USA
| | - Gene Ables
- Orentreich Foundation for the Advancement of Science, Inc., Cold Spring, New York, USA
| | - Lucy Liaw
- Center for Molecular Medicine, MaineHealth Institute for Research, Scarborough, Maine, USA
- Graduate School of Biomedical Science and Engineering, University of Maine, Orono, Maine, USA
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3
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Hernández-Arciga U, Stamenkovic C, Yadav S, Nicoletti C, Albalawy WN, Al hammood F, Gonzalez TF, Naikwadi MU, Graham A, Smarz C, Little GJ, Williams SPG, McMahon B, Sipula IJ, Vandevender AM, Chuan B, Cooke D, Pinto AFM, Flores LC, Hartman HL, Diedrich JK, Brooke RT, Alder JK, Frahm KA, Pascal LE, Stolt E, Troensegaard H, Øvrebø B, Elshorbagy A, Molina E, Vinknes KJ, Tan RJ, Weisz OA, Bueno M, Eickelberg O, Steinhauser ML, Finkel T, Ables GP, Ikeno Y, Olsen T, Sacco A, Jurczak MJ, Sukoff Rizzo SJ, Parkhitko AA. Dietary methionine restriction started late in life promotes healthy aging in a sex-specific manner. SCIENCE ADVANCES 2025; 11:eads1532. [PMID: 40238871 PMCID: PMC12002124 DOI: 10.1126/sciadv.ads1532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Accepted: 03/11/2025] [Indexed: 04/18/2025]
Abstract
Aging is associated with dysregulated methionine metabolism and increased levels of enzymes in the tyrosine degradation pathway (TDP). To investigate the efficacy of targeting either methionine metabolism or the TDP for healthspan improvement in advanced age, we initiated dietary MetR or TDP inhibition in 18-month-old C57BL/6J mice. MetR significantly improved neuromuscular function, metabolic health, lung function, and frailty. In addition, we confirmed improved neuromuscular function from dietary MetR in 5XFAD mice, whose weight was not affected by MetR. We did not observe benefits with TDP inhibition. Single-nucleus RNA and ATAC sequencing of muscle revealed cell type-specific responses to MetR, although MetR did not significantly affect mouse aging epigenetic clock markers. Similarly, an 8-week MetR intervention in a human trial (NCT04701346) showed no significant impact on epigenetic clocks. The observed benefits from late-life MetR provide translational rationale to develop MetR mimetics as an antiaging intervention.
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Affiliation(s)
| | - Ceda Stamenkovic
- Development, Aging, and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
- Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Shweta Yadav
- Aging Institute of UPMC and the University of Pittsburgh, Pittsburgh, PA, USA
| | - Chiara Nicoletti
- Development, Aging, and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Wafaa N. Albalawy
- Renal Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Department of Human Genetics, School of Public Health, University of Pittsburgh, PA, USA
| | - Farazdaq Al hammood
- Aging Institute of UPMC and the University of Pittsburgh, Pittsburgh, PA, USA
| | | | | | - Aidan Graham
- Aging Institute of UPMC and the University of Pittsburgh, Pittsburgh, PA, USA
| | - Christian Smarz
- Aging Institute of UPMC and the University of Pittsburgh, Pittsburgh, PA, USA
| | - Gabriela J. Little
- Aging Institute of UPMC and the University of Pittsburgh, Pittsburgh, PA, USA
| | | | - Brenda McMahon
- Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, PA, USA
| | - Ian J. Sipula
- Center for Metabolism and Mitochondrial Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Amber M. Vandevender
- Center for Metabolism and Mitochondrial Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Byron Chuan
- Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Diana Cooke
- Orentreich Foundation for the Advancement of Science Inc., Cold Spring, NY, USA
| | - Antonio F. M. Pinto
- Mass Spectrometry Core for Proteomics and Metabolomics, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Lisa C. Flores
- Barshop Institute for Longevity and Aging Studies, San Antonio, TX, USA
| | - Hannah L. Hartman
- Renal Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Jolene K. Diedrich
- Mass Spectrometry Core for Proteomics and Metabolomics, Salk Institute for Biological Studies, La Jolla, CA, USA
| | | | - Jonathan K. Alder
- Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Krystle A. Frahm
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Laura E. Pascal
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Emma Stolt
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Hannibal Troensegaard
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Bente Øvrebø
- Department of Food Safety, Norwegian Institute of Public Health, Oslo, Norway
| | - Amany Elshorbagy
- Department of Physiology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
- Department of Pharmacology, University of Oxford, Oxford, UK
| | - Elsa Molina
- Next Generation Sequencing Core, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Kathrine J. Vinknes
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Roderick J. Tan
- Renal Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Ora A. Weisz
- Renal Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Marta Bueno
- Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Oliver Eickelberg
- Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Matthew L. Steinhauser
- Aging Institute of UPMC and the University of Pittsburgh, Pittsburgh, PA, USA
- Center for Human Integrative Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Toren Finkel
- Aging Institute of UPMC and the University of Pittsburgh, Pittsburgh, PA, USA
| | - Gene P. Ables
- Orentreich Foundation for the Advancement of Science Inc., Cold Spring, NY, USA
| | - Yuji Ikeno
- Barshop Institute for Longevity and Aging Studies, San Antonio, TX, USA
- Department of Pathology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
- Geriatric Research and Education Center, Audie L. Murphy VA Hospital South Texas Veterans Health Care System, San Antonio, TX, USA
| | - Thomas Olsen
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Alessandra Sacco
- Development, Aging, and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Michael J. Jurczak
- Center for Metabolism and Mitochondrial Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | | | - Andrey A. Parkhitko
- Aging Institute of UPMC and the University of Pittsburgh, Pittsburgh, PA, USA
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4
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Ommi NB, Mattocks DA, Kalecký K, Bottiglieri T, Nichenametla SN. Pharmacological recapitulation of the lean phenotype induced by the lifespan-extending sulfur amino acid-restricted diet. Aging (Albany NY) 2025; 17:960-981. [PMID: 40202448 PMCID: PMC12074818 DOI: 10.18632/aging.206237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 03/20/2025] [Indexed: 04/10/2025]
Abstract
Sulfur amino acid restriction (SAAR), lowering the dietary concentration of sulfur amino acids methionine and cysteine, induces strong anti-obesity effects in rodents. Due to difficulties in formulating the SAAR diet for human consumption, its translation is challenging. Since our previous studies suggest a mechanistic role for low glutathione (GSH) in SAAR-induced anti-obesity effects, we investigated if the pharmacological lowering of GSH recapitulates the lean phenotype in mice on a sulfur amino acid-replete diet. Male obese C57BL6/NTac mice were fed high-fat diets with 0.86% methionine (CD), 0.12% methionine (SAAR), SAAR diet supplemented with a GSH biosynthetic precursor, N-acetylcysteine in water (NAC), and CD supplemented with a GSH biosynthetic inhibitor, DL-buthionine-(S, R)-sulfoximine in water (BSO). The SAAR diet lowered hepatic GSH but increased Nrf2, Phgdh, and serine. These molecular changes culminated in lower hepatic lipid droplet frequency, epididymal fat depot weights, and body fat mass; NAC reversed all these changes. BSO mice exhibited all SAAR-induced changes, with two notable differences, i.e., a smaller effect size than that of the SAAR diet and a higher predilection for molecular changes in kidneys than in the liver. Metabolomics data indicate that BSO and the SAAR diet induce similar changes in the kidney. Unaltered plasma aspartate and alanine transaminases and cystatin-C indicate that long-term continuous administration of BSO is safe. Data demonstrate that BSO recapitulates the SAAR-induced anti-obesity effects and that GSH plays a mechanistic role. BSO dose-response studies in animals and pilot studies in humans to combat obesity are highly warranted.
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Affiliation(s)
- Naidu B. Ommi
- Animal Science Laboratory, Orentreich Foundation for the Advancement of Science Inc., Cold Spring-on-Hudson, NY 10516, USA
| | - Dwight A.L. Mattocks
- Animal Science Laboratory, Orentreich Foundation for the Advancement of Science Inc., Cold Spring-on-Hudson, NY 10516, USA
| | - Karel Kalecký
- Center of Metabolomics, Institute of Metabolic Disease, Baylor Scott and White Research Institute, Dallas, TX 75204, USA
| | - Teodoro Bottiglieri
- Center of Metabolomics, Institute of Metabolic Disease, Baylor Scott and White Research Institute, Dallas, TX 75204, USA
| | - Sailendra N. Nichenametla
- Animal Science Laboratory, Orentreich Foundation for the Advancement of Science Inc., Cold Spring-on-Hudson, NY 10516, USA
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5
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Souza Matos M, Sil A, Riedel G, Platt B, Delibegovic M. Effects of age and dietary methionine restriction on cognitive and behavioural phenotypes in the rTg4510 mouse model of frontotemporal dementia. Neurobiol Aging 2025; 146:24-37. [PMID: 39577250 DOI: 10.1016/j.neurobiolaging.2024.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 10/11/2024] [Accepted: 11/07/2024] [Indexed: 11/24/2024]
Abstract
Metabolic disorders such as diabetes and obesity are linked to neurodegenerative diseases, with evidence of lower brain glucose metabolism and insulin resistance in dementia patients. Dietary methionine restriction (MR) is a nutritional intervention that enhances insulin sensitivity and delays ageing-associated metabolic alterations, however, its impact on neurodegenerative diseases is not fully understood. Here, we examined the behavioural and metabolic phenotypes of a murine tauopathy model (rTg4510), which overexpresses human P301L mutated tau, at 6 and 12 months of age, assessing the impact of an 8-week dietary MR in the older group. While rTg4510 mice displayed progressive behavioural and motor impairments at both ages, MR led to significant benefits in the 12-month-old cohort, improving motor coordination, short-term memory, and social recognition. These effects were accompanied by increased glycolysis markers and FGF21R1 levels in the hippocampus, alongside unaltered glucose metabolism/adiposity. Overall, our results reveal the impact of MR on an FTD-mouse model, suggesting this as a potential therapeutic intervention to delay and/or improve the progression of tau-related disease.
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Affiliation(s)
- Marina Souza Matos
- Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom; Aberdeen Cardiovascular and Diabetes Centre, Aberdeen, United Kingdom.
| | - Annesha Sil
- Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom
| | - Gernot Riedel
- Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom
| | - Bettina Platt
- Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
| | - Mirela Delibegovic
- Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom; Aberdeen Cardiovascular and Diabetes Centre, Aberdeen, United Kingdom.
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6
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Pinheiro F, Lail H, Neves JS, Negrão R, Wanders D. Sulfur Amino Acid Restriction Mitigates High-Fat Diet-Induced Molecular Alterations in Cardiac Remodeling Primarily via FGF21-Independent Mechanisms. Nutrients 2024; 16:4347. [PMID: 39770968 PMCID: PMC11677450 DOI: 10.3390/nu16244347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 12/06/2024] [Accepted: 12/13/2024] [Indexed: 01/11/2025] Open
Abstract
Background/Objectives: Dietary sulfur amino acid restriction (SAAR) elicits various health benefits, some mediated by fibroblast growth factor 21 (FGF21). However, research on SAAR's effects on the heart is limited and presents mixed findings. This study aimed to evaluate SAAR-induced molecular alterations associated with cardiac remodeling and their dependence on FGF21. Methods: Male C57BL/6J wild-type and FGF21 knockout mice were randomized into four dietary regimens, including normal fat and high-fat diets (HFDs) with and without SAAR, over five weeks. Results: SAAR significantly reduced body weight and visceral adiposity while increasing serum FGF21 levels. In the heart, SAAR-induced molecular metabolic alterations are indicative of enhanced lipid utilization, glucose uptake, and mitochondrial biogenesis. SAAR also elicited opposing effects on the cardiac gene expression of FGF21 and adiponectin. Regarding cellular stress responses, SAAR mitigated the HFD-induced increase in the cardiac expression of genes involved in oxidative stress, inflammation, and apoptosis, while upregulating antioxidative genes. Structurally, SAAR did not induce alterations indicative of cardiac hypertrophy and it counteracted HFD-induced fibrotic gene expression. Overall, most alterations induced by SAAR were FGF21-independent, except for those related to lipid utilization and glucose uptake. Conclusions: Altogether, SAAR promotes cardiac alterations indicative of physiological rather than pathological remodeling, primarily through FGF21-independent mechanisms.
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Affiliation(s)
- Filipe Pinheiro
- Department of Nutrition, Georgia State University, 140 Decatur St SE, Atlanta, GA 30303, USA; (F.P.); (H.L.)
- Unit of Biochemistry, Department of Biomedicine, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal;
- Center for Health Technology and Services Research—CINTESIS@RISE, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
| | - Hannah Lail
- Department of Nutrition, Georgia State University, 140 Decatur St SE, Atlanta, GA 30303, USA; (F.P.); (H.L.)
- Department of Chemistry, Georgia State University, 100 Piedmont Ave., Atlanta, GA 30303, USA
| | - João Sérgio Neves
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Alameda Hernâni Monteiro, 4200-319 Porto, Portugal;
- Unit of Cardiovascular Research and Development—Unic@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Alameda Hernâni Monteiro, 4200-319 Porto, Portugal
| | - Rita Negrão
- Unit of Biochemistry, Department of Biomedicine, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal;
- Center for Health Technology and Services Research—CINTESIS@RISE, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
| | - Desiree Wanders
- Department of Nutrition, Georgia State University, 140 Decatur St SE, Atlanta, GA 30303, USA; (F.P.); (H.L.)
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7
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Wei F, Liu S, Liu J, Sun Y, Allen AE, Reid MA, Locasale JW. Separation of reproductive decline from lifespan extension during methionine restriction. NATURE AGING 2024; 4:1089-1101. [PMID: 39060538 DOI: 10.1038/s43587-024-00674-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 06/26/2024] [Indexed: 07/28/2024]
Abstract
Lifespan-extending interventions are generally thought to result in reduced fecundity. The generality of this principle and how it may extend to nutrition and metabolism is not understood. We considered dietary methionine restriction (MR), a lifespan-extending intervention linked to Mediterranean and plant-based diets. Using a chemically defined diet that we developed for Drosophila melanogaster, we surveyed the nutritional landscape in the background of MR and found that folic acid, a vitamin linked to one-carbon metabolism, notably was the lone nutrient that restored reproductive capacity while maintaining lifespan extension. In vivo isotope tracing, metabolomics and flux analysis identified the tricarboxylic cycle and redox coupling as major determinants of the MR-folic acid benefits, in part, as they related to sperm function. Together these findings suggest that dietary interventions optimized for longevity may be separable from adverse effects such as reproductive decline.
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Affiliation(s)
- Fangchao Wei
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - Shiyu Liu
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - Juan Liu
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - Yudong Sun
- Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA
| | - Annamarie E Allen
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - Michael A Reid
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - Jason W Locasale
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA.
- Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC, USA.
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Jeitner TM, Azcona JA, Ables GP, Cooke D, Horowitz MC, Singh P, Kelly JM, Cooper AJL. Cystine rather than cysteine is the preferred substrate for β-elimination by cystathionine γ-lyase: implications for dietary methionine restriction. GeroScience 2024; 46:3617-3634. [PMID: 37217633 PMCID: PMC11229439 DOI: 10.1007/s11357-023-00788-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 03/31/2023] [Indexed: 05/24/2023] Open
Abstract
Dietary methionine restriction (MR) increases longevity by improving health. In experimental models, MR is accompanied by decreased cystathionine β-synthase activity and increased cystathionine γ-lyase activity. These enzymes are parts of the transsulfuration pathway which produces cysteine and 2-oxobutanoate. Thus, the decrease in cystathionine β-synthase activity is likely to account for the loss of tissue cysteine observed in MR animals. Despite this decrease in cysteine levels, these tissues exhibit increased H2S production which is thought to be generated by β-elimination of the thiol moiety of cysteine, as catalyzed by cystathionine β-synthase or cystathionine γ-lyase. Another possibility for this H2S production is the cystathionine γ-lyase-catalyzed β-elimination of cysteine persulfide from cystine, which upon reduction yields H2S and cysteine. Here, we demonstrate that MR increases cystathionine γ-lyase production and activities in the liver and kidneys, and that cystine is a superior substrate for cystathionine γ-lyase catalyzed β-elimination as compared to cysteine. Moreover, cystine and cystathionine exhibit comparable Kcat/Km values (6000 M-1 s-1) as substrates for cystathionine γ-lyase-catalyzed β-elimination. By contrast, cysteine inhibits cystathionine γ-lyase in a non-competitive manner (Ki ~ 0.5 mM), which limits its ability to function as a substrate for β-elimination by this enzyme. Cysteine inhibits the enzyme by reacting with its pyridoxal 5'-phosphate cofactor to form a thiazolidine and in so doing prevents further catalysis. These enzymological observations are consistent with the notion that during MR cystathionine γ-lyase is repurposed to catabolize cystine and thereby form cysteine persulfide, which upon reduction produces cysteine.
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Affiliation(s)
- Thomas M Jeitner
- Department of Radiology, Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA.
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, 10595, USA.
| | - Juan A Azcona
- Department of Radiology, Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, 10595, USA
| | - Gene P Ables
- Orentreich Foundation for the Advancement of Science, Inc, 855 Route 301, Cold Spring, NY, 10516, USA
| | - Diana Cooke
- Orentreich Foundation for the Advancement of Science, Inc, 855 Route 301, Cold Spring, NY, 10516, USA
| | - Mark C Horowitz
- Department of Orthopedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, 06510, USA
| | - Pradeep Singh
- Department of Radiology, Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA
| | - James M Kelly
- Department of Radiology, Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA
- Citigroup Biomedical Imaging Center, Weill Cornell Medicine, 516 East 72Nd St, New York, NY, 10021, USA
| | - Arthur J L Cooper
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, 10595, USA
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9
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Olsen T, Elshorbagy A, Stolt E, Åsberg A, Zaré HK, Bastani NE, Refsum H, Retterstøl K, Vinknes KJ. Acute effects of oral mesna administration on the full amino acid profile and 3-methylhistidine: secondary results from the CYLOB dose-finding study. Amino Acids 2024; 56:39. [PMID: 38844567 PMCID: PMC11156715 DOI: 10.1007/s00726-024-03398-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 05/22/2024] [Indexed: 06/09/2024]
Abstract
Plasma total cysteine (tCys) is strongly associated with fat mass in humans. Mesna lowers plasma tCys in a dose-dependent manner, but it is not known whether it interferes with metabolism of other amino acids or protein. In this Phase-1 study, we show that a single dose of mesna administered at 400, 800, 1200 or 1600 mg to 6-7 individuals per dose only slightly affects amino acid profiles, with increases in plasma valine across dose levels. There were no effects of mesna on 3-methylhistidine, a marker of protein breakdown.
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Affiliation(s)
- Thomas Olsen
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.
| | - Amany Elshorbagy
- Department of Pharmacology, University of Oxford, Oxford, UK
- Department of Physiology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
| | - Emma Stolt
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Anders Åsberg
- Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
- Department of Pharmacy, University of Oslo, Oslo, Norway
| | - Hasse K Zaré
- Department of Pharmacology, Oslo University Hospital, Oslo, Norway
| | - Nasser E Bastani
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Helga Refsum
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
- Department of Physiology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
| | - Kjetil Retterstøl
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
- Department of Endocrinology, The Lipid Clinic, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway
| | - Kathrine J Vinknes
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
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10
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Xue J, Ye C. The role of lipoylation in mitochondrial adaptation to methionine restriction. Bioessays 2024; 46:e2300218. [PMID: 38616332 DOI: 10.1002/bies.202300218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 03/12/2024] [Accepted: 04/02/2024] [Indexed: 04/16/2024]
Abstract
Dietary methionine restriction (MR) is associated with a spectrum of health-promoting benefits. Being conducive to prevention of chronic diseases and extension of life span, MR can activate integrated responses at metabolic, transcriptional, and physiological levels. However, how the mitochondria of MR influence metabolic phenotypes remains elusive. Here, we provide a summary of cellular functions of methionine metabolism and an overview of the current understanding of effector mechanisms of MR, with a focus on the aspect of mitochondria-mediated responses. We propose that mitochondria can sense and respond to MR through a modulatory role of lipoylation, a mitochondrial protein modification sensitized by MR.
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Affiliation(s)
- Jingyuan Xue
- Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Cunqi Ye
- Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China
- Hainan Institute, Zhejiang University, Sanya, China
- National R&D Center for Freshwater Fish Processing, Jiangxi Normal University, Nanchang, China
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11
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Amorim T, Kumar NG, David NL, Dion W, Pagadala T, Doshi NK, Zhu B, Parkhitko A, Steinhauser ML, Fazeli PK. Methionine as a regulator of bone remodeling with fasting. JCI Insight 2024; 9:e177997. [PMID: 38780544 PMCID: PMC11383369 DOI: 10.1172/jci.insight.177997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 05/15/2024] [Indexed: 05/25/2024] Open
Abstract
Caloric restriction improves metabolic health but is often complicated by bone loss. We studied bone parameters in humans during a 10-day fast and identified candidate metabolic regulators of bone turnover. Pro-collagen 1 intact N-terminal pro-peptide (P1NP), a bone formation marker, decreased within 3 days of fasting. Whereas dual-energy x-ray absorptiometry measures of bone mineral density were unchanged after 10 days of fasting, high-resolution peripheral quantitative CT demonstrated remodeling of bone microarchitecture. Pathway analysis of longitudinal metabolomics data identified one-carbon metabolism as fasting dependent. In cultured osteoblasts, we tested the functional significance of one-carbon metabolites modulated by fasting, finding that methionine - which surged after 3 days of fasting - affected markers of osteoblast cell state in a concentration-dependent manner, in some instances exhibiting a U-shaped response with both low and high concentrations driving putative antibone responses. Administration of methionine to mice for 5 days recapitulated some fasting effects on bone, including a reduction in serum P1NP. In conclusion, a 10-day fast in humans led to remodeling of bone microarchitecture, potentially mediated by a surge in circulating methionine. These data support an emerging model that points to a window of optimal methionine exposure for bone health.
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Affiliation(s)
- Tânia Amorim
- Aging Institute of UPMC and University of Pittsburgh School of Medicine
- Neuroendocrinology Unit, Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine
- Center for Human Integrative Physiology, Aging Institute of UPMC and University of Pittsburgh School of Medicine
| | - Naveen G.V. Kumar
- Aging Institute of UPMC and University of Pittsburgh School of Medicine
| | - Natalie L. David
- Aging Institute of UPMC and University of Pittsburgh School of Medicine
- Neuroendocrinology Unit, Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine
- Center for Human Integrative Physiology, Aging Institute of UPMC and University of Pittsburgh School of Medicine
| | - William Dion
- Aging Institute of UPMC and University of Pittsburgh School of Medicine
| | - Trishya Pagadala
- Aging Institute of UPMC and University of Pittsburgh School of Medicine
| | - Nandini K. Doshi
- Aging Institute of UPMC and University of Pittsburgh School of Medicine
- Center for Human Integrative Physiology, Aging Institute of UPMC and University of Pittsburgh School of Medicine
| | - Bokai Zhu
- Aging Institute of UPMC and University of Pittsburgh School of Medicine
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine; and
| | - Andrey Parkhitko
- Aging Institute of UPMC and University of Pittsburgh School of Medicine
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine; and
| | - Matthew L. Steinhauser
- Aging Institute of UPMC and University of Pittsburgh School of Medicine
- Center for Human Integrative Physiology, Aging Institute of UPMC and University of Pittsburgh School of Medicine
- Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Pouneh K. Fazeli
- Neuroendocrinology Unit, Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine
- Center for Human Integrative Physiology, Aging Institute of UPMC and University of Pittsburgh School of Medicine
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12
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Austad SN, Smith JR, Hoffman JM. Amino acid restriction, aging, and longevity: an update. FRONTIERS IN AGING 2024; 5:1393216. [PMID: 38757144 PMCID: PMC11096585 DOI: 10.3389/fragi.2024.1393216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 04/18/2024] [Indexed: 05/18/2024]
Abstract
Various so-called dietary restriction paradigms have shown promise for extending health and life. All such paradigms rely on ad libitum (hereafter ad lib) feeding, something virtually never employed in animals whose long-term health we value, either as a control or, except for food restriction itself, for both control and treatment arms of the experiment. Even though the mechanism(s) remain only vaguely understood, compared to ad lib-fed animals a host of dietary manipulations, including calorie restriction, low protein, methionine, branched-chain amino acids, and even low isoleucine have demonstrable health benefits in laboratory species in a standard laboratory environment. The remaining challenge is to determine whether these health benefits remain in more realistic environments and how they interact with other health enhancing treatments such as exercise or emerging geroprotective drugs. Here we review the current state of the field of amino acid restriction on longevity of animal models and evaluate its translational potential.
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Affiliation(s)
- S. N. Austad
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - J. R. Smith
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - J. M. Hoffman
- Department of Biological Sciences, Augusta University, Augusta, GA, United States
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13
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Subramanian SK, Brahmbhatt B, Bailey-Lundberg JM, Thosani NC, Mutha P. Lifestyle Medicine for the Prevention and Treatment of Pancreatitis and Pancreatic Cancer. Diagnostics (Basel) 2024; 14:614. [PMID: 38535034 PMCID: PMC10968821 DOI: 10.3390/diagnostics14060614] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 02/26/2024] [Accepted: 02/27/2024] [Indexed: 04/14/2025] Open
Abstract
The incidence of pancreatitis and pancreatic cancer is on the upswing in the USA. These conditions often lead to higher healthcare costs due to the complex nature of diagnosis and the need for specialized medical interventions, surgical procedures, and prolonged medical management. The economic ramification encompasses direct healthcare expenses and indirect costs related to productivity losses, disability, and potential long-term care requirements. Increasing evidence underscores the importance of a healthy lifestyle in preventing and managing these conditions. Lifestyle medicine employs evidence-based interventions to promote health through six key pillars: embracing a whole-food, plant-predominant dietary pattern; regular physical activity; ensuring restorative sleep; managing stress effectively; removing harmful substances; and fostering positive social connections. This review provides a comprehensive overview of lifestyle interventions for managing and preventing the development of pancreatitis and pancreatic cancer.
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Affiliation(s)
- Sruthi Kapliyil Subramanian
- Center for Interventional Gastroenterology at UTHealth (iGUT), Section of Endoluminal Surgery and Interventional Gastroenterology, Division of Elective General Surgery, Department of Surgery, McGovern Medical School at UTHealth, Houston, TX 77030, USA; (S.K.S.); (P.M.)
| | - Bhaumik Brahmbhatt
- Mayo Clinic, Division of Gastroenterology and Hepatology, Jacksonville, FL 32224, USA;
| | - Jennifer M. Bailey-Lundberg
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School at UTHealth, Houston, TX 77030, USA;
| | - Nirav C. Thosani
- Center for Interventional Gastroenterology at UTHealth (iGUT), Section of Endoluminal Surgery and Interventional Gastroenterology, Division of Elective General Surgery, Department of Surgery, McGovern Medical School at UTHealth, Houston, TX 77030, USA; (S.K.S.); (P.M.)
| | - Pritesh Mutha
- Center for Interventional Gastroenterology at UTHealth (iGUT), Section of Endoluminal Surgery and Interventional Gastroenterology, Division of Elective General Surgery, Department of Surgery, McGovern Medical School at UTHealth, Houston, TX 77030, USA; (S.K.S.); (P.M.)
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14
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Cooke D, Ables GP. Physical activity of mice on dietary sulfur amino acid restriction is influenced by age of diet initiation and biological sex. Sci Rep 2023; 13:20609. [PMID: 37996548 PMCID: PMC10667228 DOI: 10.1038/s41598-023-47676-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 11/16/2023] [Indexed: 11/25/2023] Open
Abstract
Sulfur amino acid restriction (SAAR)-the reduction of methionine and cysteine concentrations either in the diet or by genetic manipulation-promotes health span and extends lifespan, but its effects on physical activity remain unclear. We investigated whether age of diet initiation and biological sex could influence physical activity in mice fed either a control diet (CF, 0.86% methionine w/w) or SAAR (0.12% methionine w/w). Quadriceps femoris muscle mass is smaller in SAAR than in CF mice. Young mice fed a chronic SAAR diet at 8 weeks of age exhibited improved wire hang and running wheel activities compared to young CF mice, while aged mice showed comparable results. The effects of chronic SAAR on physical activity was mildly influenced by sex as observed in middle-aged male SAAR mice who showed minor improvements than CF males while middle-aged females displayed no discernible effects. Muscle mass is minimally affected by changes in markers of protein synthesis, autophagy and atrophy. Improvements to physical activity in young SAAR mice could be partially attributed to increased skeletal muscle mitochondrial activity. Furthermore, SAAR in C2C12 myotubes increased citrate synthase protein expression and enhanced succinyl dehydrogenase enzyme activity compared to CF myotubes. Overall, our data reveal that SAAR can improve mouse physical activity without compromising muscle proteostasis. This is partially due to enhanced mitochondrial activity, but the effects are influenced by age of diet initiation and sex.
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Affiliation(s)
- Diana Cooke
- Orentreich Foundation for the Advancement of Science, Inc., 855 Route 301, Cold Spring, NY, 10516, USA
| | - Gene P Ables
- Orentreich Foundation for the Advancement of Science, Inc., 855 Route 301, Cold Spring, NY, 10516, USA.
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15
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Ungvari A, Gulej R, Csik B, Mukli P, Negri S, Tarantini S, Yabluchanskiy A, Benyo Z, Csiszar A, Ungvari Z. The Role of Methionine-Rich Diet in Unhealthy Cerebrovascular and Brain Aging: Mechanisms and Implications for Cognitive Impairment. Nutrients 2023; 15:4662. [PMID: 37960316 PMCID: PMC10650229 DOI: 10.3390/nu15214662] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 10/28/2023] [Accepted: 10/31/2023] [Indexed: 11/15/2023] Open
Abstract
As aging societies in the western world face a growing prevalence of vascular cognitive impairment and Alzheimer's disease (AD), understanding their underlying causes and associated risk factors becomes increasingly critical. A salient concern in the western dietary context is the high consumption of methionine-rich foods such as red meat. The present review delves into the impact of this methionine-heavy diet and the resultant hyperhomocysteinemia on accelerated cerebrovascular and brain aging, emphasizing their potential roles in cognitive impairment. Through a comprehensive exploration of existing evidence, a link between high methionine intake and hyperhomocysteinemia and oxidative stress, mitochondrial dysfunction, inflammation, and accelerated epigenetic aging is drawn. Moreover, the microvascular determinants of cognitive deterioration, including endothelial dysfunction, reduced cerebral blood flow, microvascular rarefaction, impaired neurovascular coupling, and blood-brain barrier (BBB) disruption, are explored. The mechanisms by which excessive methionine consumption and hyperhomocysteinemia might drive cerebromicrovascular and brain aging processes are elucidated. By presenting an intricate understanding of the relationships among methionine-rich diets, hyperhomocysteinemia, cerebrovascular and brain aging, and cognitive impairment, avenues for future research and potential therapeutic interventions are suggested.
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Affiliation(s)
- Anna Ungvari
- Department of Public Health, Semmelweis University, 1089 Budapest, Hungary
| | - Rafal Gulej
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (R.G.); (B.C.); (P.M.); (S.N.); (S.T.); (A.Y.); (A.C.); (Z.U.)
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Boglarka Csik
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (R.G.); (B.C.); (P.M.); (S.N.); (S.T.); (A.Y.); (A.C.); (Z.U.)
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- International Training Program in Geroscience, Department of Public Health, Doctoral School of Basic and Translational Medicine, Semmelweis University, 1089 Budapest, Hungary
| | - Peter Mukli
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (R.G.); (B.C.); (P.M.); (S.N.); (S.T.); (A.Y.); (A.C.); (Z.U.)
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- International Training Program in Geroscience, Department of Public Health, Doctoral School of Basic and Translational Medicine, Semmelweis University, 1089 Budapest, Hungary
| | - Sharon Negri
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (R.G.); (B.C.); (P.M.); (S.N.); (S.T.); (A.Y.); (A.C.); (Z.U.)
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Stefano Tarantini
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (R.G.); (B.C.); (P.M.); (S.N.); (S.T.); (A.Y.); (A.C.); (Z.U.)
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- International Training Program in Geroscience, Department of Public Health, Doctoral School of Basic and Translational Medicine, Semmelweis University, 1089 Budapest, Hungary
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK 73104, USA
- Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Andriy Yabluchanskiy
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (R.G.); (B.C.); (P.M.); (S.N.); (S.T.); (A.Y.); (A.C.); (Z.U.)
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- International Training Program in Geroscience, Department of Public Health, Doctoral School of Basic and Translational Medicine, Semmelweis University, 1089 Budapest, Hungary
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK 73104, USA
- Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Zoltan Benyo
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary;
- Cerebrovascular and Neurocognitive Disorders Research Group, Eötvös Loránd Research Network, Semmelweis University, 1094 Budapest, Hungary
| | - Anna Csiszar
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (R.G.); (B.C.); (P.M.); (S.N.); (S.T.); (A.Y.); (A.C.); (Z.U.)
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK 73104, USA
- Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- International Training Program in Geroscience, Department of Translational Medicine, Doctoral School of Basic and Translational Medicine, Semmelweis University, 1089 Budapest, Hungary
| | - Zoltan Ungvari
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (R.G.); (B.C.); (P.M.); (S.N.); (S.T.); (A.Y.); (A.C.); (Z.U.)
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- International Training Program in Geroscience, Department of Public Health, Doctoral School of Basic and Translational Medicine, Semmelweis University, 1089 Budapest, Hungary
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK 73104, USA
- Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
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16
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Thyne KM, Salmon AB. Sexually dimorphic effects of methionine sulfoxide reductase A (MsrA) on murine longevity and health span during methionine restriction. GeroScience 2023; 45:3003-3017. [PMID: 37391679 PMCID: PMC10643651 DOI: 10.1007/s11357-023-00857-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 06/17/2023] [Indexed: 07/02/2023] Open
Abstract
Methionine restriction (MR) extends lifespan in various model organisms, and understanding the molecular effectors of MR could expand the repertoire of tools targeting the aging process. Here, we address to what extent the biochemical pathway responsible for redox metabolism of methionine plays in regulating the effects of MR on lifespan and health span. Aerobic organisms have evolved methionine sulfoxide reductases to counter the oxidation of the thioether group contained in the essential amino acid methionine. Of these enzymes, methionine sulfoxide reductase A (MsrA) is ubiquitously expressed in mammalian tissues and has subcellular localization in both the cytosol and mitochondria. Loss of MsrA increases sensitivity to oxidative stress and has been associated with increased susceptibility to age-associated pathologies including metabolic dysfunction. We rationalized that limiting the available methionine with MR may place increased importance on methionine redox pathways, and that MsrA may be required to maintain available methionine for its critical uses in cellular homeostasis including protein synthesis, metabolism, and methylation. Using a genetic mutant mouse lacking MsrA, we tested the requirement for this enzyme in the effects of MR on longevity and markers of healthy aging late in life. When initiated in adulthood, we found that MR had minimal effects in males and females regardless of MsrA status. MR had minimal effect on lifespan with the exception of wild-type males where loss of MsrA slightly increased lifespan on MR. We also observed that MR drove an increase in body weight in wild-type mice only, but mice lacking MsrA tended to maintain more stable body weight throughout their lives. We also found that MR had greater benefit to males than females in terms of glucose metabolism and some functional health span assessments, but MsrA generally had minimal impact on these metrics. Frailty was also found to be unaffected by MR or MsrA in aged animals. We found that in general, MsrA was not required for the beneficial effects of MR on longevity and health span.
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Affiliation(s)
- Kevin M Thyne
- Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | - Adam B Salmon
- Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
- Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
- Geriatric Research Education and Clinical Center, Audie L. Murphy Hospital, South Texas Veterans Health Care System, San Antonio, TX, 78229, USA.
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17
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Lucienne M, Gerlini R, Rathkolb B, Calzada-Wack J, Forny P, Wueest S, Kaech A, Traversi F, Forny M, Bürer C, Aguilar-Pimentel A, Irmler M, Beckers J, Sauer S, Kölker S, Dewulf JP, Bommer GT, Hoces D, Gailus-Durner V, Fuchs H, Rozman J, Froese DS, Baumgartner MR, de Angelis MH. Insights into energy balance dysregulation from a mouse model of methylmalonic aciduria. Hum Mol Genet 2023; 32:2717-2734. [PMID: 37369025 PMCID: PMC10460489 DOI: 10.1093/hmg/ddad100] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 05/25/2023] [Accepted: 06/19/2023] [Indexed: 06/29/2023] Open
Abstract
Inherited disorders of mitochondrial metabolism, including isolated methylmalonic aciduria, present unique challenges to energetic homeostasis by disrupting energy-producing pathways. To better understand global responses to energy shortage, we investigated a hemizygous mouse model of methylmalonyl-CoA mutase (Mmut)-type methylmalonic aciduria. We found Mmut mutant mice to have reduced appetite, energy expenditure and body mass compared with littermate controls, along with a relative reduction in lean mass but increase in fat mass. Brown adipose tissue showed a process of whitening, in line with lower body surface temperature and lesser ability to cope with cold challenge. Mutant mice had dysregulated plasma glucose, delayed glucose clearance and a lesser ability to regulate energy sources when switching from the fed to fasted state, while liver investigations indicated metabolite accumulation and altered expression of peroxisome proliferator-activated receptor and Fgf21-controlled pathways. Together, these shed light on the mechanisms and adaptations behind energy imbalance in methylmalonic aciduria and provide insight into metabolic responses to chronic energy shortage, which may have important implications for disease understanding and patient management.
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Affiliation(s)
- Marie Lucienne
- Division of Metabolism and Children’s Research Center, University Children’s Hospital Zurich, University of Zurich, 8032 Zurich, Switzerland
- radiz – Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Raffaele Gerlini
- Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Birgit Rathkolb
- Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-University München, Munich, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Julia Calzada-Wack
- Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Patrick Forny
- Division of Metabolism and Children’s Research Center, University Children’s Hospital Zurich, University of Zurich, 8032 Zurich, Switzerland
| | - Stephan Wueest
- Division of Pediatric Endocrinology and Diabetology and Children’s Research Center, University Children's Hospital, University of Zurich, 8032 Zurich, Switzerland
| | - Andres Kaech
- Center for Microscopy and Image Analysis, University of Zurich, Zurich, Switzerland
| | - Florian Traversi
- Division of Metabolism and Children’s Research Center, University Children’s Hospital Zurich, University of Zurich, 8032 Zurich, Switzerland
| | - Merima Forny
- Division of Metabolism and Children’s Research Center, University Children’s Hospital Zurich, University of Zurich, 8032 Zurich, Switzerland
| | - Céline Bürer
- Division of Metabolism and Children’s Research Center, University Children’s Hospital Zurich, University of Zurich, 8032 Zurich, Switzerland
| | - Antonio Aguilar-Pimentel
- Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Martin Irmler
- Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Johannes Beckers
- Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Sven Sauer
- Division of Pediatric Neurology and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital, Heidelberg, Germany
| | - Stefan Kölker
- Division of Pediatric Neurology and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital, Heidelberg, Germany
| | - Joseph P Dewulf
- Department of Biochemistry, de Duve Institute, UCLouvain, Brussels, Belgium
- Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Brussels, Belgium
- Department of Laboratory Medicine, Cliniques universitaires Saint-Luc, UCLouvain, Brussels, Belgium
| | - Guido T Bommer
- Department of Biochemistry, de Duve Institute, UCLouvain, Brussels, Belgium
- Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Brussels, Belgium
| | - Daniel Hoces
- Institute of Food, Nutrition and Health, D-HEST, ETH Zurich, Zurich, Switzerland
| | - Valerie Gailus-Durner
- Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Helmut Fuchs
- Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Jan Rozman
- Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - D Sean Froese
- Division of Metabolism and Children’s Research Center, University Children’s Hospital Zurich, University of Zurich, 8032 Zurich, Switzerland
- radiz – Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, Zurich, Switzerland
| | - Matthias R Baumgartner
- Division of Metabolism and Children’s Research Center, University Children’s Hospital Zurich, University of Zurich, 8032 Zurich, Switzerland
- radiz – Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Martin Hrabě de Angelis
- Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Freising, Germany
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18
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Capelo-Diz A, Lachiondo-Ortega S, Fernández-Ramos D, Cañas-Martín J, Goikoetxea-Usandizaga N, Serrano-Maciá M, González-Rellan MJ, Mosca L, Blazquez-Vicens J, Tinahones-Ruano A, Fondevila MF, Buyan M, Delgado TC, Gutierrez de Juan V, Ayuso-García P, Sánchez-Rueda A, Velasco-Avilés S, Fernández-Susavila H, Riobello-Suárez C, Dziechciarz B, Montiel-Duarte C, Lopitz-Otsoa F, Bizkarguenaga M, Bilbao-García J, Bernardo-Seisdedos G, Senra A, Soriano-Navarro M, Millet O, Díaz-Lagares Á, Crujeiras AB, Bao-Caamano A, Cabrera D, van Liempd S, Tamayo-Carro M, Borzacchiello L, Gomez-Santos B, Buqué X, Sáenz de Urturi D, González-Romero F, Simon J, Rodríguez-Agudo R, Ruiz A, Matute C, Beiroa D, Falcon-Perez JM, Aspichueta P, Rodríguez-Cuesta J, Porcelli M, Pajares MA, Ameneiro C, Fidalgo M, Aransay AM, Lama-Díaz T, Blanco MG, López M, Villa-Bellosta R, Müller TD, Nogueiras R, Woodhoo A, Martínez-Chantar ML, Varela-Rey M. Hepatic levels of S-adenosylmethionine regulate the adaptive response to fasting. Cell Metab 2023; 35:1373-1389.e8. [PMID: 37527658 PMCID: PMC10432853 DOI: 10.1016/j.cmet.2023.07.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 03/30/2023] [Accepted: 07/06/2023] [Indexed: 08/03/2023]
Abstract
There has been an intense focus to uncover the molecular mechanisms by which fasting triggers the adaptive cellular responses in the major organs of the body. Here, we show that in mice, hepatic S-adenosylmethionine (SAMe)-the principal methyl donor-acts as a metabolic sensor of nutrition to fine-tune the catabolic-fasting response by modulating phosphatidylethanolamine N-methyltransferase (PEMT) activity, endoplasmic reticulum-mitochondria contacts, β-oxidation, and ATP production in the liver, together with FGF21-mediated lipolysis and thermogenesis in adipose tissues. Notably, we show that glucagon induces the expression of the hepatic SAMe-synthesizing enzyme methionine adenosyltransferase α1 (MAT1A), which translocates to mitochondria-associated membranes. This leads to the production of this metabolite at these sites, which acts as a brake to prevent excessive β-oxidation and mitochondrial ATP synthesis and thereby endoplasmic reticulum stress and liver injury. This work provides important insights into the previously undescribed function of SAMe as a new arm of the metabolic adaptation to fasting.
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Affiliation(s)
- Alba Capelo-Diz
- Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, A Coruña 15706, Spain
| | - Sofía Lachiondo-Ortega
- Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
| | - David Fernández-Ramos
- Precision Medicine and Metabolism Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain; Centro de investigación Biomedica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de salud Carlos III, 28029 Madrid, Spain
| | - Jorge Cañas-Martín
- Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, A Coruña 15706, Spain
| | - Naroa Goikoetxea-Usandizaga
- Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
| | - Marina Serrano-Maciá
- Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
| | - Maria J González-Rellan
- Department of Physiology, CIMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, A Coruña 15706, Spain
| | - Laura Mosca
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Via Luigi De Crecchio 7, 80138 Naples, Italy
| | - Joan Blazquez-Vicens
- Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, A Coruña 15706, Spain
| | - Alberto Tinahones-Ruano
- Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, A Coruña 15706, Spain
| | - Marcos F Fondevila
- Department of Physiology, CIMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, A Coruña 15706, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, A Coruña 15706, Spain
| | - Mason Buyan
- Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
| | - Teresa C Delgado
- Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
| | - Virginia Gutierrez de Juan
- Precision Medicine and Metabolism Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
| | - Paula Ayuso-García
- Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, A Coruña 15706, Spain
| | - Alejandro Sánchez-Rueda
- Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, A Coruña 15706, Spain
| | - Sergio Velasco-Avilés
- Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, A Coruña 15706, Spain
| | - Héctor Fernández-Susavila
- Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, A Coruña 15706, Spain
| | - Cristina Riobello-Suárez
- Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, A Coruña 15706, Spain
| | - Bartlomiej Dziechciarz
- Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, A Coruña 15706, Spain
| | - Cristina Montiel-Duarte
- The John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK
| | - Fernando Lopitz-Otsoa
- Precision Medicine and Metabolism Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
| | - Maider Bizkarguenaga
- Precision Medicine and Metabolism Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
| | - Jon Bilbao-García
- Precision Medicine and Metabolism Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
| | - Ganeko Bernardo-Seisdedos
- Precision Medicine and Metabolism Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
| | - Ana Senra
- CIMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, A Coruña 15706, Spain
| | - Mario Soriano-Navarro
- Electron Microscopy Core Facility, Centro de Investigación Príncipe Felipe (CIPF), Valencia 46012, Spain
| | - Oscar Millet
- Precision Medicine and Metabolism Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
| | - Ángel Díaz-Lagares
- Epigenomics Unit, Cancer Epigenomics, Translational Medical Oncology Group (ONCOMET), Health Research Institute of Santiago de Compostela (IDIS), University Clinical Hospital of Santiago (CHUS/SERGAS), Santiago de Compostela, A Coruña 15706, Spain
| | - Ana B Crujeiras
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, A Coruña 15706, Spain; Epigenomics in Endocrinology and Nutrition Group, Epigenomics Unit, Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago de Compostela (CHUS/SERGAS), 15706 Santiago de Compostela, Spain
| | - Aida Bao-Caamano
- Epigenomics in Endocrinology and Nutrition Group, Epigenomics Unit, Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago de Compostela (CHUS/SERGAS), 15706 Santiago de Compostela, Spain
| | - Diana Cabrera
- Metabolomics Platform, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
| | - Sebastiaan van Liempd
- Metabolomics Platform, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
| | - Miguel Tamayo-Carro
- Nerve Disorders Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
| | - Luigi Borzacchiello
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Via Luigi De Crecchio 7, 80138 Naples, Italy
| | - Beatriz Gomez-Santos
- Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain
| | - Xabier Buqué
- Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain
| | - Diego Sáenz de Urturi
- Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain
| | - Francisco González-Romero
- Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain
| | - Jorge Simon
- Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
| | - Rubén Rodríguez-Agudo
- Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
| | - Asier Ruiz
- Laboratory of Neurobiology, Achucarro Basque Center for Neuroscience, Department of Neurosciences, University of Basque Country (UPV/EHU), Centro de investigación Biomedica en Red de Enfermedades Neurodegenerativas (CIBERNED), 48940 Leioa, Spain
| | - Carlos Matute
- Laboratory of Neurobiology, Achucarro Basque Center for Neuroscience, Department of Neurosciences, University of Basque Country (UPV/EHU), Centro de investigación Biomedica en Red de Enfermedades Neurodegenerativas (CIBERNED), 48940 Leioa, Spain
| | - Daniel Beiroa
- Experimental Biomedicine Center (CEBEGA), University of Santiago de Compostela, A Coruña 15706, Spain
| | - Juan M Falcon-Perez
- Centro de investigación Biomedica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de salud Carlos III, 28029 Madrid, Spain; Metabolomics Platform, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Bizkaia 48009, Spain
| | - Patricia Aspichueta
- Centro de investigación Biomedica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de salud Carlos III, 28029 Madrid, Spain; Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain; Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
| | - Juan Rodríguez-Cuesta
- Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
| | - Marina Porcelli
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Via Luigi De Crecchio 7, 80138 Naples, Italy
| | - María A Pajares
- Centro de Investigaciones Biológicas Margarita Salas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain
| | - Cristina Ameneiro
- Stem Cells and Human Diseases, CIMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, A Coruña 15706, Spain
| | - Miguel Fidalgo
- Stem Cells and Human Diseases, CIMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, A Coruña 15706, Spain
| | - Ana M Aransay
- Genome Analysis Plataform, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
| | - Tomas Lama-Díaz
- DNA Repair and Genome Integrity Laboratory, CIMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, A Coruña 15706, Spain
| | - Miguel G Blanco
- DNA Repair and Genome Integrity Laboratory, CIMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, A Coruña 15706, Spain; Department of Biochemistry and Molecular Biology, University of Santiago de Compostela, Plaza do Obradoiro s/n, Santiago de Compostela, Spain
| | - Miguel López
- Department of Physiology, CIMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, A Coruña 15706, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, A Coruña 15706, Spain
| | - Ricardo Villa-Bellosta
- Department of Biochemistry and Molecular Biology, University of Santiago de Compostela, Plaza do Obradoiro s/n, Santiago de Compostela, Spain; Metabolic Homeostasis and Vascular Calcification Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela, Santiago de Compostela, A Coruña 15706, Spain
| | - Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Zentrum Munich, and German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Rubén Nogueiras
- Department of Physiology, CIMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, A Coruña 15706, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, A Coruña 15706, Spain; Oportunius Program, Galician Agency of Innovation (GAIN), Xunta de Galicia, Santiago de Compostela, A Coruña, Spain
| | - Ashwin Woodhoo
- Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, A Coruña 15706, Spain; Nerve Disorders Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Bizkaia 48009, Spain; Oportunius Program, Galician Agency of Innovation (GAIN), Xunta de Galicia, Santiago de Compostela, A Coruña, Spain; Department of Functional Biology, University of Santiago de Compostela, Plaza do Obradoiro s/n, Santiago de Compostela, Spain
| | - María Luz Martínez-Chantar
- Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain; Centro de investigación Biomedica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de salud Carlos III, 28029 Madrid, Spain.
| | - Marta Varela-Rey
- Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, A Coruña 15706, Spain; Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain; Centro de investigación Biomedica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de salud Carlos III, 28029 Madrid, Spain; Department of Biochemistry and Molecular Biology, University of Santiago de Compostela, Plaza do Obradoiro s/n, Santiago de Compostela, Spain.
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19
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Mihaylova MM, Chaix A, Delibegovic M, Ramsey JJ, Bass J, Melkani G, Singh R, Chen Z, Ja WW, Shirasu-Hiza M, Latimer MN, Mattison JA, Thalacker-Mercer AE, Dixit VD, Panda S, Lamming DW. When a calorie is not just a calorie: Diet quality and timing as mediators of metabolism and healthy aging. Cell Metab 2023; 35:1114-1131. [PMID: 37392742 PMCID: PMC10528391 DOI: 10.1016/j.cmet.2023.06.008] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 05/07/2023] [Accepted: 06/13/2023] [Indexed: 07/03/2023]
Abstract
An epidemic of obesity has affected large portions of the world, increasing the risk of developing many different age-associated diseases, including cancer, cardiovascular disease, and diabetes. In contrast with the prevailing notion that "a calorie is just a calorie," there are clear differences, within and between individuals, in the metabolic response to different macronutrient sources. Recent findings challenge this oversimplification; calories from different macronutrient sources or consumed at different times of day have metabolic effects beyond their value as fuel. Here, we summarize discussions conducted at a recent NIH workshop that brought together experts in calorie restriction, macronutrient composition, and time-restricted feeding to discuss how dietary composition and feeding schedule impact whole-body metabolism, longevity, and healthspan. These discussions may provide insights into the long-sought molecular mechanisms engaged by calorie restriction to extend lifespan, lead to novel therapies, and potentially inform the development of a personalized food-as-medicine approach to healthy aging.
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Affiliation(s)
- Maria M Mihaylova
- Department of Biological Chemistry and Pharmacology, College of Medicine, The Ohio State University, Columbus, OH, USA; The Ohio State University, Comprehensive Cancer Center, Wexner Medical Center, Arthur G. James Cancer Hospital, Columbus, OH, USA.
| | - Amandine Chaix
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT 84112, USA
| | - Mirela Delibegovic
- Aberdeen Cardiovascular and Diabetes Centre, Institute of Medical Sciences, University of Aberdeen, Foresterhill Health Campus, Aberdeen, UK
| | - Jon J Ramsey
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, USA
| | - Joseph Bass
- Department of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Girish Melkani
- Department of Pathology, Division of Molecular and Cellular Pathology, Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Rajat Singh
- Department of Medicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Zheng Chen
- Department of Biochemistry and Molecular Biology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - William W Ja
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA
| | - Michele Shirasu-Hiza
- Department of Genetics and Development, Columbia University Medical Center, New York, NY, USA
| | - Mary N Latimer
- Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Julie A Mattison
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | - Anna E Thalacker-Mercer
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Vishwa Deep Dixit
- Department of Pathology, Yale School of Medicine, New Haven, CT, USA; Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA; Yale Center for Research on Aging, Yale School of Medicine, New Haven, CT, USA
| | - Satchidananda Panda
- Regulatory Biology Lab, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Dudley W Lamming
- Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
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20
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Klatt KC, Bass K, Speakman JR, Hall KD. Chowing down: diet considerations in rodent models of metabolic disease. LIFE METABOLISM 2023; 2:load013. [PMID: 37485302 PMCID: PMC10361708 DOI: 10.1093/lifemeta/load013] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 02/28/2023] [Accepted: 04/13/2023] [Indexed: 07/25/2023]
Abstract
Diet plays a substantial role in the etiology, progression, and treatment of chronic disease and is best considered as a multifaceted set of modifiable input variables with pleiotropic effects on a variety of biological pathways spanning multiple organ systems. This brief review discusses key issues related to the design and conduct of diet interventions in rodent models of metabolic disease and their implications for interpreting experiments. We also make specific recommendations to improve rodent diet studies to help better understand the role of diet on metabolic physiology and thereby improve our understanding of metabolic disease.
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Affiliation(s)
- Kevin C Klatt
- Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, CA 94720, United States
| | - Kevin Bass
- Garrison Institute of Aging, Texas Tech University Health Science Center, Lubbock, TX 79430, United States
| | - John R Speakman
- Center for Energy Metabolism and Reproduction, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China
| | - Kevin D Hall
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, United States
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21
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Liu L, Rosen CJ. New Insights into Calorie Restriction Induced Bone Loss. Endocrinol Metab (Seoul) 2023; 38:203-213. [PMID: 37150516 PMCID: PMC10164494 DOI: 10.3803/enm.2023.1673] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 03/30/2023] [Indexed: 05/09/2023] Open
Abstract
Caloric restriction (CR) is now a popular lifestyle choice due to its ability in experimental animals to improve lifespan, reduce body weight, and lessen oxidative stress. However, more and more emerging evidence suggests this treatment requires careful consideration because of its detrimental effects on the skeletal system. Experimental and clinical studies show that CR can suppress bone growth and raise the risk of fracture, but the specific mechanisms are poorly understood. Reduced mechanical loading has long been thought to be the primary cause of weight loss-induced bone loss from calorie restriction. Despite fat loss in peripheral depots with calorie restriction, bone marrow adipose tissue (BMAT) increases, and this may play a significant role in this pathological process. Here, we update recent advances in our understanding of the effects of CR on the skeleton, the possible pathogenic role of BMAT in CR-induced bone loss, and some strategies to mitigate any potential side effects on the skeletal system.
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Affiliation(s)
- Linyi Liu
- MaineHealth Institute for Research, Scarborough, ME, USA
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22
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Zhai J, Kongsberg WH, Pan Y, Hao C, Wang X, Sun J. Caloric restriction induced epigenetic effects on aging. Front Cell Dev Biol 2023; 10:1079920. [PMID: 36712965 PMCID: PMC9880295 DOI: 10.3389/fcell.2022.1079920] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 12/31/2022] [Indexed: 01/15/2023] Open
Abstract
Aging is the subject of many studies, facilitating the discovery of many interventions. Epigenetic influences numerous life processes by regulating gene expression and also plays a crucial role in aging regulation. Increasing data suggests that dietary changes can alter epigenetic marks associated with aging. Caloric restriction (CR)is considered an intervention to regulate aging and prolong life span. At present, CR has made some progress by regulating signaling pathways associated with aging as well as the mechanism of action of intercellular signaling molecules against aging. In this review, we will focus on autophagy and epigenetic modifications to elaborate the molecular mechanisms by which CR delays aging by triggering autophagy, epigenetic modifications, and the interaction between the two in caloric restriction. In order to provide new ideas for the study of the mechanism of aging and delaying aging.
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Affiliation(s)
| | | | | | | | | | - Jie Sun
- *Correspondence: Xiaojing Wang, ; Jie Sun,
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23
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Wu G, Xu J, Wang Q, Fang Z, Fang Y, Jiang Y, Zhang X, Cheng X, Sun J, Le G. Methionine-Restricted Diet: A Feasible Strategy Against Chronic or Aging-Related Diseases. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:5-19. [PMID: 36571820 DOI: 10.1021/acs.jafc.2c05829] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
Dietary methionine restriction (MR) has been associated with multifaceted health-promoting effects. MR is conducive to prevention of several chronic diseases and cancer, and extension of lifespan. A growing number of studies on new phenotypes and mechanisms of MR have become available in the past five years, especially in angiogenesis, neurodegenerative diseases, intestinal microbiota, and intestinal barrier function. In this review, we summarize the characteristics and advantages of MR, and current knowledge on the physiological responses and effects of MR on chronic diseases and aging-associated pathologies. Potential mechanisms, in which hydrogen sulfide, fibroblast growth factor 21, gut microbiota, short-chain fatty acids, and so on are involved, are discussed. Moreover, directions for epigenetics and gut microbiota in an MR diet are presented in future perspectives. This review comprehensively summarizes the novel roles and interpretations of the mechanisms underlying MR in the prevention of chronic diseases and aging.
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Affiliation(s)
- Guoqing Wu
- School of Public Health, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Jingxuan Xu
- School of Public Health, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Qiyao Wang
- Translational Medicine Center of Pain, Emotion and Cognition, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, 315211, China
| | - Ziyang Fang
- School of Public Health, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Yucheng Fang
- School of Public Health, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Yujie Jiang
- School of Public Health, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Xiaohong Zhang
- School of Public Health, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Xiangrong Cheng
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Jin Sun
- Institute of Nutrition and Health, Qingdao University, Qingdao, 266021, China
| | - Guowei Le
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
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McGilvrey M, Fortier B, Tero B, Cooke D, Cooper E, Walker J, Koza R, Ables G, Liaw L. Effects of dietary methionine restriction on age-related changes in perivascular and beiging adipose tissues in the mouse. Obesity (Silver Spring) 2023; 31:159-170. [PMID: 36513498 PMCID: PMC9780157 DOI: 10.1002/oby.23583] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 08/13/2022] [Accepted: 08/19/2022] [Indexed: 12/15/2022]
Abstract
OBJECTIVE Perivascular adipose tissue (PVAT) regulates vascular health. Dietary methionine restriction (MetR) impacts age-related adiposity, and this study addresses its effects in PVAT. METHODS Male C57BL/6 mice at 8, 52, and 102 weeks of age were fed a standard (0.86%) or low-methionine (0.12%) diet for 52 weeks in 8-week-old and 52-week-old mice and for 15 weeks in 102-week-old mice. RESULTS Mice with dietary MetR were resistant to weight gain and maintained a healthy blood profile. Aging increased lipid accumulation, and MetR reversed this phenotype. Notch signaling in inguinal white adipose tissue (iWAT) was decreased by MetR but increased in gonadal white adipose tissue. However, the Notch phenotype of brown adipose tissue (BAT) was not affected by MetR. Uncoupling protein 1 (UCP1) was increased in PVAT, iWAT, and BAT by MetR when initiated in young mice, but this effect was lost in middle-aged mice. CONCLUSIONS Lipid in mouse PVAT peaked at 1 year of age, consistent with peak body mass. MetR reduced body weight, normalized metabolic parameters, and decreased lipid in PVAT in all age cohorts. Mice fed a MetR diet from early maturity to 1 year of age displayed an increased thermogenic adipocyte phenotype in iWAT, PVAT, and BAT, all tissues with thermogenic capacity.
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Affiliation(s)
- Marissa McGilvrey
- Center for Molecular Medicine, MaineHealth Institute for Research
- Graduate School of Biomedical Science and Engineering, University of Maine
| | - Bethany Fortier
- Center for Molecular Medicine, MaineHealth Institute for Research
- Department of Biological Sciences, University of Southern Maine
| | - Benjamin Tero
- Center for Molecular Medicine, MaineHealth Institute for Research
| | - Diana Cooke
- Orentreich Foundation for the Advancement of Science, Inc
| | - Emily Cooper
- Center for Molecular Medicine, MaineHealth Institute for Research
| | - Jeffrey Walker
- Department of Biological Sciences, University of Southern Maine
| | - Robert Koza
- Center for Molecular Medicine, MaineHealth Institute for Research
- Graduate School of Biomedical Science and Engineering, University of Maine
| | - Gene Ables
- Orentreich Foundation for the Advancement of Science, Inc
| | - Lucy Liaw
- Center for Molecular Medicine, MaineHealth Institute for Research
- Department of Biological Sciences, University of Southern Maine
- Graduate School of Biomedical Science and Engineering, University of Maine
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Lysine or Threonine Deficiency Decreases Body Weight Gain in Growing Rats despite an Increase in Food Intake without Increasing Energy Expenditure in Response to FGF21. Nutrients 2022; 15:nu15010197. [PMID: 36615854 PMCID: PMC9824894 DOI: 10.3390/nu15010197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 12/14/2022] [Accepted: 12/22/2022] [Indexed: 01/03/2023] Open
Abstract
The objective of this study is to evaluate the effects of a strictly essential amino acid (lysine or threonine; EAA) deficiency on energy metabolism in growing rats. Rats were fed for three weeks severely (15% and 25% of recommendation), moderately (40% and 60%), and adequate (75% and 100%) lysine or threonine-deficient diets. Food intake and body weight were measured daily and indirect calorimetry was performed the week three. At the end of the experimentation, body composition, gene expression, and biochemical analysis were performed. Lysine and threonine deficiency induced a lower body weight gain and an increase in relative food intake. Lysine or threonine deficiency induced liver FGF21 synthesis and plasma release. However, no changes in energy expenditure were observed for lysine deficiency, unlike threonine deficiency, which leads to a decrease in total and resting energy expenditure. Interestingly, threonine severe deficiency, but not lysine deficiency, increase orexigenic and decreases anorexigenic hypothalamic neuropeptides expression, which could explain the higher food intake. Our results show that the deficiency in one EAA, induces a decrease in body weight gain, despite an increased relative food intake, without any increase in energy expenditure despite an induction of FGF21.
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Cifuentes-Mendiola SE, Solís-Suárez DL, Martínez-Dávalos A, Perrusquía-Hernández E, García-Hernández AL. Aerobic training improves bone fragility by reducing the inflammatory microenvironment in bone tissue in type 2 diabetes. J Biomech 2022; 145:111354. [PMID: 36335825 DOI: 10.1016/j.jbiomech.2022.111354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 10/13/2022] [Accepted: 10/16/2022] [Indexed: 11/06/2022]
Abstract
Aerobic training (AT) is indicated in type 2 diabetes mellitus (T2DM) to control hyperglycaemia and inflammation. AT improves bone microarchitecture and resistance to fracture. The intensity of AT and the mechanisms that lead to the improvement in bone quality are still unknown. Using a mouse model of T2DM, we evaluated the effects of two intensities of forced AT. We divided mice into: sedentary (SED), T2DM-SED, low runners (LOW), T2DM-LOW, high runners (HIGH) and T2DM-HIGH. The AT for low was 8 m/minute (m/min); 5° slope or high 18 m/min; 15° slope for 2 months. We measured metabolic parameters, the serum cytokines concentration, lipocalin-2 (LCN-2) and adiponectin; and the tibial concentrations of LCN-2, tumour necrosis factor alpha (TNF-α) and protein carbonylation (CO). We evaluated femur morphometry and biomechanical properties. We performed multiple correlation analysis. The T2DM-LOW versus T2DM-SED group, shown an increase of interleukin (IL)-10 (417 ± 90 vs 102 ± 25 pg/mL) and improved trabecular bone (BV/TV: 31.8 ± 2.3 vs 19.25 ± 1.4%; Tb.Sp.: 1.62 ± 0.02 vs 2.0 ± 0.07 mm), by a decrease bone CO (3.4 ± 0.1 vs 6.0 ± 0.5 nmol/mg), bone TNF-α (84 ± 4 vs 239 ± 13 pg/mL) and LCN-2 (2887 ± 23 vs 3418 ± 105 pg/mL). The T2DM-HIGH versus T2DM-SED group showed a greater hypoglycaemic effect (228 ± 10 vs 408 ± 5 mg/dL), with improved cortical bone density (0.26 ± 0.012 vs 0.21 ± 0.007 mm) and fracture resistance (102 ± 8 vs 78 ± 5 MPa), by a reduction of bone TNF-α (77 ± 34 vs 239 ± 13 pg/mL); LCN-2 (2768 ± 20 vs 3418 ± 105 pg/mL) and CO (4.8 ± 0.5 vs 6.0 ± 0.5 nmol/mg). In conclusion, AT improves bone morphometry and biomechanical properties by reducing the bone inflammatory microenvironment.
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Affiliation(s)
- Saúl Ernesto Cifuentes-Mendiola
- Laboratory of Dental Research, Section of Osteoimmunology and Oral Immunology. FES Iztacala, National Autonomous University of Mexico (UNAM), Mexico; Postgraduate in Biological Sciences. National Autonomous University of Mexico (UNAM), Mexico City, Mexico
| | - Diana Laura Solís-Suárez
- Laboratory of Dental Research, Section of Osteoimmunology and Oral Immunology. FES Iztacala, National Autonomous University of Mexico (UNAM), Mexico; Postgraduate in Dentistry Sciencies. National Autonomous University of Mexico (UNAM), Mexico City, Mexico
| | | | - Elías Perrusquía-Hernández
- Laboratory of Dental Research, Neurobiology of Oral Sensations and Movements Section, FES Iztacala, National Autonomous University of Mexico (UNAM), Mexico
| | - Ana Lilia García-Hernández
- Laboratory of Dental Research, Section of Osteoimmunology and Oral Immunology. FES Iztacala, National Autonomous University of Mexico (UNAM), Mexico.
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Nichenametla SN, Mattocks DAL, Cooke D, Midya V, Malloy VL, Mansilla W, Øvrebø B, Turner C, Bastani N, Sokolová J, Pavlíková M, Richie JP, Shoveller A, Refsum H, Olsen T, Vinknes KJ, Kožich V, Ables GP. Cysteine restriction-specific effects of sulfur amino acid restriction on lipid metabolism. Aging Cell 2022; 21:e13739. [PMID: 36403077 PMCID: PMC9741510 DOI: 10.1111/acel.13739] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 10/12/2022] [Accepted: 10/21/2022] [Indexed: 11/21/2022] Open
Abstract
Decreasing the dietary intake of methionine exerts robust anti-adiposity effects in rodents but modest effects in humans. Since cysteine can be synthesized from methionine, animal diets are formulated by decreasing methionine and eliminating cysteine. Such diets exert both methionine restriction (MR) and cysteine restriction (CR), that is, sulfur amino acid restriction (SAAR). Contrarily, SAAR diets formulated for human consumption included cysteine, and thus might have exerted only MR. Epidemiological studies positively correlate body adiposity with plasma cysteine but not methionine, suggesting that CR, but not MR, is responsible for the anti-adiposity effects of SAAR. Whether this is true, and, if so, the underlying mechanisms are unknown. Using methionine- and cysteine-titrated diets, we demonstrate that the anti-adiposity effects of SAAR are due to CR. Data indicate that CR increases serinogenesis (serine biosynthesis from non-glucose substrates) by diverting substrates from glyceroneogenesis, which is essential for fatty acid reesterification and triglyceride synthesis. Molecular data suggest that CR depletes hepatic glutathione and induces Nrf2 and its downstream targets Phgdh (the serine biosynthetic enzyme) and Pepck-M. In mice, the magnitude of SAAR-induced changes in molecular markers depended on dietary fat concentration (60% fat >10% fat), sex (males > females), and age-at-onset (young > adult). Our findings are translationally relevant as we found negative and positive correlations of plasma serine and cysteine, respectively, with triglycerides and metabolic syndrome criteria in a cross-sectional epidemiological study. Controlled feeding of low-SAA, high-polyunsaturated fatty acid diets increased plasma serine in humans. Serinogenesis might be a target for treating hypertriglyceridemia.
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Affiliation(s)
- Sailendra N. Nichenametla
- Animal Science LaboratoryOrentreich Foundation for the Advancement of ScienceCold Spring‐on‐HudsonNew YorkUSA
| | - Dwight A. L. Mattocks
- Animal Science LaboratoryOrentreich Foundation for the Advancement of ScienceCold Spring‐on‐HudsonNew YorkUSA
| | - Diana Cooke
- Animal Science LaboratoryOrentreich Foundation for the Advancement of ScienceCold Spring‐on‐HudsonNew YorkUSA
| | - Vishal Midya
- Department of Environmental Medicine and Public HealthIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Virginia L. Malloy
- Animal Science LaboratoryOrentreich Foundation for the Advancement of ScienceCold Spring‐on‐HudsonNew YorkUSA
| | - Wilfredo Mansilla
- Department of Animal BioscienceUniversity of GuelphGuelphOntarioCanada
| | - Bente Øvrebø
- Department of Nutrition, Institute of Basic Medical SciencesUniversity of OsloOsloNorway
| | - Cheryl Turner
- Department of PharmacologyUniversity of OxfordOxfordUK
| | - Nasser E. Bastani
- Department of Nutrition, Institute of Basic Medical SciencesUniversity of OsloOsloNorway
| | - Jitka Sokolová
- Department of Pediatrics and Inherited Metabolic Disorders, General University Hospital in PragueCharles University‐First Faculty of MedicinePragueCzech Republic
| | - Markéta Pavlíková
- Department of Probability and Mathematical StatisticsCharles University ‐ Faculty of Mathematics and PhysicsPragueCzech Republic
| | - John P. Richie
- Departments of Public Health Sciences and PharmacologyPenn State University College of MedicineHersheyPennsylvaniaUSA
| | - Anna K. Shoveller
- Department of Animal BioscienceUniversity of GuelphGuelphOntarioCanada
| | - Helga Refsum
- Department of Nutrition, Institute of Basic Medical SciencesUniversity of OsloOsloNorway,Department of PharmacologyUniversity of OxfordOxfordUK
| | - Thomas Olsen
- Department of Nutrition, Institute of Basic Medical SciencesUniversity of OsloOsloNorway
| | - Kathrine J. Vinknes
- Department of Nutrition, Institute of Basic Medical SciencesUniversity of OsloOsloNorway
| | - Viktor Kožich
- Department of Pediatrics and Inherited Metabolic Disorders, General University Hospital in PragueCharles University‐First Faculty of MedicinePragueCzech Republic
| | - Gene P. Ables
- Animal Science LaboratoryOrentreich Foundation for the Advancement of ScienceCold Spring‐on‐HudsonNew YorkUSA
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28
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Dai Z, Zheng W, Locasale JW. Amino acid variability, tradeoffs and optimality in human diet. Nat Commun 2022; 13:6683. [PMID: 36335142 PMCID: PMC9637229 DOI: 10.1038/s41467-022-34486-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 10/27/2022] [Indexed: 11/07/2022] Open
Abstract
Studies at the molecular level demonstrate that dietary amino acid intake produces substantial effects on health and disease by modulating metabolism. However, how these effects may manifest in human food consumption and dietary patterns is unknown. Here, we develop a series of algorithms to map, characterize and model the landscape of amino acid content in human food, dietary patterns, and individual consumption including relations to health status, covering over 2,000 foods, ten dietary patterns, and over 30,000 dietary profiles. We find that the type of amino acids contained in foods and human consumption is highly dynamic with variability far exceeding that of fat and carbohydrate. Some amino acids positively associate with conditions such as obesity while others contained in the same food negatively link to disease. Using linear programming and machine learning, we show that these health trade-offs can be accounted for to satisfy biochemical constraints in food and human eating patterns to construct a Pareto front in dietary practice, a means of achieving optimality in the face of trade-offs that are commonly considered in economic and evolutionary theories. Thus this study may enable the design of human protein quality intake guidelines based on a quantitative framework.
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Affiliation(s)
- Ziwei Dai
- grid.26009.3d0000 0004 1936 7961Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710 USA ,grid.263817.90000 0004 1773 1790Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055 China
| | - Weiyan Zheng
- grid.263817.90000 0004 1773 1790Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055 China
| | - Jason W. Locasale
- grid.26009.3d0000 0004 1936 7961Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710 USA
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29
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Zhang Y, Jelleschitz J, Grune T, Chen W, Zhao Y, Jia M, Wang Y, Liu Z, Höhn A. Methionine restriction - Association with redox homeostasis and implications on aging and diseases. Redox Biol 2022; 57:102464. [PMID: 36152485 PMCID: PMC9508608 DOI: 10.1016/j.redox.2022.102464] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 08/26/2022] [Accepted: 08/30/2022] [Indexed: 10/31/2022] Open
Abstract
Methionine is an essential amino acid, involved in the promotion of growth, immunity, and regulation of energy metabolism. Over the decades, research has long focused on the beneficial effects of methionine supplementation, while data on positive effects of methionine restriction (MR) were first published in 1993. MR is a low-methionine dietary intervention that has been reported to ameliorate aging and aging-related health concomitants and diseases, such as obesity, type 2 diabetes, and cognitive disorders. In addition, MR seems to be an approach to prolong lifespan which has been validated extensively in various animal models, such as Caenorhabditis elegans, Drosophila, yeast, and murine models. MR appears to be associated with a reduction in oxidative stress via so far mainly undiscovered mechanisms, and these changes in redox status appear to be one of the underlying mechanisms for lifespan extension and beneficial health effects. In the present review, the association of methionine metabolism pathways with redox homeostasis is described. In addition, the effects of MR on lifespan, age-related implications, comorbidities, and diseases are discussed.
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Affiliation(s)
- Yuyu Zhang
- Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Julia Jelleschitz
- German Institute of Human Nutrition (DIfE) Potsdam-Rehbruecke, Department of Molecular Toxicology, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany
| | - Tilman Grune
- German Institute of Human Nutrition (DIfE) Potsdam-Rehbruecke, Department of Molecular Toxicology, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany; German Center for Diabetes Research (DZD), 85764, Muenchen-Neuherberg, Germany; NutriAct-Competence Cluster Nutrition Research Berlin-Potsdam, Nuthetal, Germany; German Center for Cardiovascular Research (DZHK), Berlin, Germany; Institute of Nutrition, University of Potsdam, Nuthetal, 14558, Germany
| | - Weixuan Chen
- Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Yihang Zhao
- Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Mengzhen Jia
- Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Yajie Wang
- Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Zhigang Liu
- Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China; German Institute of Human Nutrition (DIfE) Potsdam-Rehbruecke, Department of Molecular Toxicology, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.
| | - Annika Höhn
- German Institute of Human Nutrition (DIfE) Potsdam-Rehbruecke, Department of Molecular Toxicology, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany; German Center for Diabetes Research (DZD), 85764, Muenchen-Neuherberg, Germany.
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30
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Dong Z, Richie JP, Gao X, Al-Shaar L, Nichenametla SN, Shen B, Orentreich D. Cumulative Consumption of Sulfur Amino Acids and Risk of Diabetes: A Prospective Cohort Study. J Nutr 2022; 152:2419-2428. [PMID: 36774108 DOI: 10.1093/jn/nxac172] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 05/17/2022] [Accepted: 08/02/2022] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Cross-sectional studies have suggested that consumption of sulfur amino acids (SAAs), including methionine and cysteine, is associated with a higher risk of type 2 diabetes (T2D) in humans and with T2D-related biomarkers in animals. But whether higher long-term SAA intake increases the risk of T2D in humans remains unknown. OBJECTIVES We aimed to investigate the association between long-term dietary SAA intake and risk of T2D. METHODS We analyzed data collected from 2 different cohorts of the Framingham Heart Study, a long-term, prospective, and ongoing study. The Offspring cohort (1991-2014) included participants from fifth through ninth examinations, and the Third-Generation cohort (2002-2011) included participants from first and second examinations. After excluding participants with a clinical history of diabetes, missing dietary data, or implausible total energy intake, 3222 participants in the Offspring cohort and 3205 participants in the Third-Generation cohort were included. Dietary intake was assessed using a validated FFQ. The relations between energy-adjusted total SAA (methionine and cysteine) intake or individual SAA intake (in quintiles) and risk of incident T2D were estimated via Cox proportional hazards models after adjusting for dietary and nondietary risk factors. Associations across the 2 cohorts were determined by direct combination and meta-analysis. RESULTS During the 23 y of follow-up, 472 participants reported a new diagnosis of T2D in the 2 cohorts. In the meta-analysis, the HRs of T2D comparing the highest with the lowest intake of total SAAs, methionine, and cysteine were 1.8 (95% CI: 1.3, 2.5), 1.7 (95% CI: 1.2, 2.3), and 1.4 (95% CI: 1.0, 2.1), respectively. The association of SAA intake with T2D was attenuated after adjusting animal protein intake in sensitivity analyses. CONCLUSIONS Our findings show that excess intake of SAAs is associated with higher risk of T2D. Dietary patterns that are low in SAAs could help in preventing T2D.
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Affiliation(s)
- Zhen Dong
- Orentreich Foundation for the Advancement of Science, Inc, Cold Spring, NY, USA.
| | - John P Richie
- Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Xiang Gao
- Department of Nutritional Sciences, Pennsylvania State University, University Park, PA, USA
| | - Laila Al-Shaar
- Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA, USA
| | | | - Biyi Shen
- Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - David Orentreich
- Orentreich Foundation for the Advancement of Science, Inc, Cold Spring, NY, USA
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31
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Deeba F, Shahar Yar M, Rafi Haidar M, Sharma AK, Sharma M. Synthesis, molecular docking, and pharmacological evaluation of 5-(4-(2-(5-ethyl pyridine-2-yl) ethoxy) benzyl)-3-(phenylsulfonyl) thiazolidine-2, 4-dione against HFD-induced diabesity via interaction with the CB1 receptor. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2022; 25:1028-1036. [PMID: 36159331 PMCID: PMC9464343 DOI: 10.22038/ijbms.2022.65649.14443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 08/10/2022] [Indexed: 11/08/2022]
Abstract
Objectives CB1 antagonism arbitrates a dormant shape to the endocannabinoid system that alleviates diverse pathological incidents of diabesity. The present study pursued the synthesis and evaluation of thiazolidine derivative (BAC) having pleiotropic action on CB1R, with or without AM251 (selective antagonist of the CB1 receptor) against high-fat diet (HFD) induced diabesity in C57BL/6 mice. Materials and Methods A molecular docking study for CB1 antagonistic potential was conducted by Maestro 11.4 program (Schrodinger Inc., USA), and the thiazolidine derivative BAC was synthesized. The assessment of varied parameters including anthropometric, neurobehavioral, hyperglycemia, dyslipidemia, oxidative stress, and inflammatory cytokines was evaluated in HFD-fed animals as compared with individual and combined treatments of BAC and AM251. Results Incomparable to AM251, the treatment of BAC was reported for a significant reduction in food intake and obesity, diabetic biomarkers, lipid profile, oxidative stress, and proinflammatory cytokine release. Moreover, the BAC treatment showed no significant alteration in neurobehavioral activity, including anxiety and depression. Conclusion The preliminary in silico study suggests that BAC has a close interaction with CB1 antagonism but has no sign of neurobehavioral alteration. Simultaneously, this compound showed significant ability to ameliorate diversity by the underlying mechanisms of minimizing oxidative stress, regularizing the lipid profile, and reducing pro-inflammatory cytokines.
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Affiliation(s)
- Farah Deeba
- Department of Pharmacology, School of Pharmaceutical Education and Research, (SPER) Jamia Hamdard, Delhi-110062, India
| | - Mohammad Shahar Yar
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, (SPER) Jamia Hamdard, Delhi-110062, India
| | | | - Arun K. Sharma
- Department of Pharmacology, Amity University Haryana, Gurugram-122413, India,Corresponding authors: Manju Sharma. Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, Delhi-110062, India. , Arun K. Sharma. Department of Pharmacology, Amity University Haryana, Gurugram-122413, India.
| | - Manju Sharma
- Department of Pharmacology, School of Pharmaceutical Education and Research, (SPER) Jamia Hamdard, Delhi-110062, India,Corresponding authors: Manju Sharma. Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, Delhi-110062, India. , Arun K. Sharma. Department of Pharmacology, Amity University Haryana, Gurugram-122413, India.
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32
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High dietary methionine intake may contribute to the risk of nonalcoholic fatty liver disease by inhibiting hepatic H2S production. Food Res Int 2022; 158:111507. [DOI: 10.1016/j.foodres.2022.111507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 06/09/2022] [Accepted: 06/10/2022] [Indexed: 12/06/2022]
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Plummer JD, Johnson JE. Intermittent methionine restriction reduces IGF-1 levels and produces similar healthspan benefits to continuous methionine restriction. Aging Cell 2022; 21:e13629. [PMID: 35570387 PMCID: PMC9197402 DOI: 10.1111/acel.13629] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 04/10/2022] [Accepted: 05/01/2022] [Indexed: 11/27/2022] Open
Abstract
A sustained state of methionine restriction (MR) dramatically extends the healthspan of several model organisms. For example, continuously methionine‐restricted rodents have less age‐related pathology and are up to 45% longer‐lived than controls. Promisingly, MR is feasible for humans, and studies have suggested that methionine‐restricted individuals may receive similar benefits to rodents. However, long‐term adherence to a methionine‐restricted diet is likely to be challenging for many individuals. Prompted by this, and the fact that intermittent variants of other healthspan‐extending interventions (i.e., intermittent fasting and the cyclic ketogenic diet) are just as effective, if not more, than their continuous counterparts, we hypothesized that an intermittent form of MR might produce similar healthspan benefits to continuous MR. Accordingly, we developed two increasingly stringent forms of intermittent MR (IMR) and assessed whether mice maintained on these diets demonstrate the beneficial metabolic changes typically observed for continuous MR. To the best of our knowledge, we show for the first time that IMR produces similar beneficial metabolic effects to continuous MR, including improved glucose homeostasis and protection against diet‐induced obesity and hepatosteatosis. In addition, like continuous MR, IMR confers beneficial changes in the plasma levels of the hormones IGF‐1, FGF‐21, leptin, and adiponectin. Together, our findings demonstrate that the more practicable intermittent form of MR produces similar healthspan benefits to continuous MR, and thus may represent a more appealing alternative to the classical intervention.
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Affiliation(s)
- Jason D. Plummer
- Department of Biology Orentreich Foundation for the Advancement of Science Cold Spring New York USA
| | - Jay E. Johnson
- Department of Biology Orentreich Foundation for the Advancement of Science Cold Spring New York USA
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Metabolic benefits of methionine restriction in adult mice do not require functional methionine sulfoxide reductase A (MsrA). Sci Rep 2022; 12:5073. [PMID: 35332198 PMCID: PMC8948287 DOI: 10.1038/s41598-022-08978-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 03/11/2022] [Indexed: 11/27/2022] Open
Abstract
Methionine restriction (MR) extends lifespan and improves several markers of health in rodents. However, the proximate mechanisms of MR on these physiological benefits have not been fully elucidated. The essential amino acid methionine plays numerous biological roles and limiting its availability in the diet directly modulates methionine metabolism. There is growing evidence that redox regulation of methionine has regulatory control on some aspects of cellular function but interactions with MR remain largely unexplored. We tested the functional role of the ubiquitously expressed methionine repair enzyme methionine sulfoxide reductase A (MsrA) on the metabolic benefits of MR in mice. MsrA catalytically reduces both free and protein-bound oxidized methionine, thus playing a key role in its redox state. We tested the extent to which MsrA is required for metabolic effects of MR in adult mice using mice lacking MsrA. As expected, MR in control mice reduced body weight, altered body composition, and improved glucose metabolism. Interestingly, lack of MsrA did not impair the metabolic effects of MR on these outcomes. Moreover, females had blunted MR responses regardless of MsrA status compared to males. Overall, our data suggests that MsrA is not required for the metabolic benefits of MR in adult mice.
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Host Metabolic Changes during Mycobacterium Tuberculosis Infection Cause Insulin Resistance in Adult Mice. J Clin Med 2022; 11:jcm11061646. [PMID: 35329973 PMCID: PMC8948975 DOI: 10.3390/jcm11061646] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 03/07/2022] [Accepted: 03/14/2022] [Indexed: 02/06/2023] Open
Abstract
Tuberculosis (TB) is a highly infectious bacterial disease that primarily attacks the lungs. TB is manifested either as latent TB infection (LTBI) or active TB disease, the latter posing a greater threat to life. The risk of developing active TB disease from LTBI is three times higher in individuals with type 2 diabetes mellitus (T2DM). The association between TB and T2DM is becoming more prominent as T2DM is rapidly increasing in settings where TB is endemic. T2DM is a chronic metabolic disorder characterized by elevated blood glucose, insulin resistance, and relative insulin deficiency. Insulin resistance and stress-induced hyperglycemia have been shown to be increased by TB and to return to normal upon treatment. Previously, we demonstrated that adipocytes (or fat tissue) regulate pulmonary pathology, inflammation, and Mycobacterium tuberculosis (Mtb) load in a murine model of TB. Metabolic disturbances of adipose tissue and/or adipocyte dysfunction contribute to the pathogenesis of T2DM. Thus, pathological adipocytes not only regulate pulmonary pathology, but also increase the risk for T2DM during TB infection. However, the cellular and molecular mechanisms driving the interaction between hyperglycemia, T2DM and TB remain poorly understood. Here, we report the impact of Mtb infection on the development of insulin resistance in mice fed on a regular diet (RD) versus high-fat diet (HFD) and, conversely, the effect of hyperglycemia on pulmonary pathogenesis in juvenile and adult mouse models. Overall, our study demonstrated that Mtb persists in adipose tissue and that Mtb infection induces irregular adipocyte lipolysis and loss of fat cells via different pathways in RD- and HFD-fed mice. In RD-fed mice, the levels of TNFα and HSL (hormone sensitive lipase) play an important role whereas in HFD-fed mice, ATGL (adipose triglyceride lipase) plays a major role in regulating adipocyte lipolysis and apoptosis during Mtb infection in adult mice. We also showed that Mtb infected adult mice that were fed an RD developed insulin resistance similar to infected adult mice that were overweight due to a HFD diet. Importantly, we found that a consequence of Mtb infection was increased lipid accumulation in the lungs, which altered cellular energy metabolism by inhibiting major energy signaling pathways such as insulin, AMPK and mToR. Thus, an altered balance between lipid metabolism and glucose metabolism in adipose tissue and other organs including the lungs may be an important component of the link between Mtb infection and subsequent metabolic syndrome.
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Spann RA, Morrison CD, den Hartigh LJ. The Nuanced Metabolic Functions of Endogenous FGF21 Depend on the Nature of the Stimulus, Tissue Source, and Experimental Model. Front Endocrinol (Lausanne) 2022; 12:802541. [PMID: 35046901 PMCID: PMC8761941 DOI: 10.3389/fendo.2021.802541] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 12/09/2021] [Indexed: 01/13/2023] Open
Abstract
Fibroblast growth factor 21 (FGF21) is a hormone that is involved in the regulation of lipid, glucose, and energy metabolism. Pharmacological FGF21 administration promotes weight loss and improves insulin sensitivity in rodents, non-human primates, and humans. However, pharmacologic effects of FGF21 likely differ from its physiological effects. Endogenous FGF21 is produced by many cell types, including hepatocytes, white and brown adipocytes, skeletal and cardiac myocytes, and pancreatic beta cells, and acts on a diverse array of effector tissues such as the brain, white and brown adipose tissue, heart, and skeletal muscle. Different receptor expression patterns dictate FGF21 function in these target tissues, with the primary effect to coordinate responses to nutritional stress. Moreover, different nutritional stimuli tend to promote FGF21 expression from different tissues; i.e., fasting induces hepatic-derived FGF21, while feeding promotes white adipocyte-derived FGF21. Target tissue effects of FGF21 also depend on its capacity to enter the systemic circulation, which varies widely from known FGF21 tissue sources in response to various stimuli. Due to its association with obesity and non-alcoholic fatty liver disease, the metabolic effects of endogenously produced FGF21 during the pathogenesis of these conditions are not well known. In this review, we will highlight what is known about endogenous tissue-specific FGF21 expression and organ cross-talk that dictate its diverse physiological functions, with particular attention given to FGF21 responses to nutritional stress. The importance of the particular experimental design, cellular and animal models, and nutritional status in deciphering the diverse metabolic functions of endogenous FGF21 cannot be overstated.
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Affiliation(s)
- Redin A. Spann
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, United States
| | - Christopher D. Morrison
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, United States
| | - Laura J. den Hartigh
- Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA, United States
- Diabetes Institute, University of Washington, Seattle, WA, United States
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Navik U, Rawat K, Tikoo K. L-Methionine prevents β-cell damage by modulating the expression of Arx, MafA and regulation of FOXO1 in type 1 diabetic rats. Acta Histochem 2022; 124:151820. [PMID: 34871948 DOI: 10.1016/j.acthis.2021.151820] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 11/24/2021] [Accepted: 11/24/2021] [Indexed: 12/31/2022]
Abstract
L-Methionine (L-Met) is an essential sulphur-containing amino acid having a vital role in various key cellular processes. Here we investigated the effect of L-Met on streptozotocin-induced β-cell damage model of diabetes mellitus in Sprague Dawley rats. At the end of study biochemical parameters, immunoblotting, qRT-PCR and ChIP-qPCR are performed. L-Met was administered orally (250 and 500 mg/kg/day) to diabetic animals for 8 weeks improved plasma glucose and insulin levels. Pancreas immunohistochemistry showed significant increase in insulin expression, decrease in glucagon and Bax expression. Interestingly, L-Met inhibited the expression of Arx; upregulated MafA and FOXO1 which play a critical role in the maintenance of β-cell identity. Our data also showed a decrease in H3K27me3 and an increase in H3K4me3 ("bivalent domain" alteration) in diabetic rats and these recovered by L-Met. Furthermore, the chromatin-immunoprecipitation assay showed a decreased enrichment of H3K27me3 on the promoter of the FOXO1 gene in diabetic rats and L-Met prevents this decrease. Our results showed the first evidence of the involvement of H3K27me3 in regulating the expression of the FOXO1 gene and the prevention of β-cell injury by L-Met treatment. In conclusion, we report the involvement of L-Met in the modulation of α-cell identity marker (Arx), β-cell identity marker (MafA) and regulation of FOXO1 by histone methylation marks for the first time. We are of the opinion that this employed as a novel therapeutic approach for mitigating diabetes-induced β-cell death.
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Affiliation(s)
- Umashanker Navik
- Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar (Mohali), Punjab 160062, India; Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda 151401, India.
| | - Kajal Rawat
- Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar (Mohali), Punjab 160062, India
| | - Kulbhushan Tikoo
- Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar (Mohali), Punjab 160062, India.
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Yang Y, Qian J, Li B, Lu M, Le G, Xie Y. Metabolomics Based on 1H-NMR Reveal the Regulatory Mechanisms of Dietary Methionine Restriction on Splenic Metabolic Dysfunction in Obese Mice. Foods 2021; 10:foods10102439. [PMID: 34681487 PMCID: PMC8535630 DOI: 10.3390/foods10102439] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 10/06/2021] [Accepted: 10/12/2021] [Indexed: 12/13/2022] Open
Abstract
Methionine restriction (MR) has been reported to have many beneficial health effects, including stress resistance enhancement and lifespan extension. However, the effects of MR on the splenic metabolic dysfunction induced by obesity in mice remain unknown. This study aimed to investigate the scientific problem and clarify its possible mechanisms. C57BL/6J mice in the control group were fed a control diet (0.86% methionine, 4.2% fat) for 34 weeks, and others were fed a high-fat diet (0.86% methionine, 24% fat) for 10 weeks to establish diet-induced obese (DIO) mouse models. Then, the obtained DIO mice were randomly divided into two groups: the DIO group (DIO diet), the DIO + MR group (0.17% methionine, 24% fat) for 24 weeks. Our results indicated that MR decreased spleen weight, and spleen and plasma lipid profiles, promoted lipid catabolism and fatty acid oxidation, glycolysis and tricarboxylic acid cycle metabolism, and improved mitochondrial function and ATP generation in the spleen. Moreover, MR normalized the splenic redox state and inflammation-related metabolite levels, and increased plasma levels of immunoglobulins. Furthermore, MR increased percent lean mass and splenic crude protein levels, activated the autophagy pathway and elevated nucleotide synthesis to maintain protein synthesis in the spleen. These findings indicate that MR can ameliorate metabolic dysfunction by reducing lipid accumulation, oxidative stress, and inflammation in the spleen, and the mechanism may be the activation of autophagy pathway.
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Affiliation(s)
- Yuhui Yang
- College of Food Science and Engineering, Henan University of Technology, Zhengzhou 450001, China; (Y.Y.); (J.Q.); (M.L.)
| | - Jing Qian
- College of Food Science and Engineering, Henan University of Technology, Zhengzhou 450001, China; (Y.Y.); (J.Q.); (M.L.)
| | - Bowen Li
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (B.L.); (G.L.)
| | - Manman Lu
- College of Food Science and Engineering, Henan University of Technology, Zhengzhou 450001, China; (Y.Y.); (J.Q.); (M.L.)
| | - Guowei Le
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (B.L.); (G.L.)
| | - Yanli Xie
- College of Food Science and Engineering, Henan University of Technology, Zhengzhou 450001, China; (Y.Y.); (J.Q.); (M.L.)
- Correspondence: ; Tel.: +86-371-6775-8022
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A genetic model of methionine restriction extends Drosophila health- and lifespan. Proc Natl Acad Sci U S A 2021; 118:2110387118. [PMID: 34588310 DOI: 10.1073/pnas.2110387118] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/24/2021] [Indexed: 12/12/2022] Open
Abstract
Loss of metabolic homeostasis is a hallmark of aging and is characterized by dramatic metabolic reprogramming. To analyze how the fate of labeled methionine is altered during aging, we applied 13C5-Methionine labeling to Drosophila and demonstrated significant changes in the activity of different branches of the methionine metabolism as flies age. We further tested whether targeted degradation of methionine metabolism components would "reset" methionine metabolism flux and extend the fly lifespan. Specifically, we created transgenic flies with inducible expression of Methioninase, a bacterial enzyme capable of degrading methionine and revealed methionine requirements for normal maintenance of lifespan. We also demonstrated that microbiota-derived methionine is an alternative and important source in addition to food-derived methionine. In this genetic model of methionine restriction (MetR), we also demonstrate that either whole-body or tissue-specific Methioninase expression can dramatically extend Drosophila health- and lifespan and exerts physiological effects associated with MetR. Interestingly, while previous dietary MetR extended lifespan in flies only in low amino acid conditions, MetR from Methioninase expression extends lifespan independently of amino acid levels in the food. Finally, because impairment of the methionine metabolism has been previously associated with the development of Alzheimer's disease, we compared methionine metabolism reprogramming between aging flies and a Drosophila model relevant to Alzheimer's disease, and found that overexpression of human Tau caused methionine metabolism flux reprogramming similar to the changes found in aged flies. Altogether, our study highlights Methioninase as a potential agent for health- and lifespan extension.
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Degens H, Swaminathan A, Tallis J. A High-Fat Diet Aggravates the Age-Related Decline in Skeletal Muscle Structure and Function. Exerc Sport Sci Rev 2021; 49:253-259. [PMID: 33927161 DOI: 10.1249/jes.0000000000000261] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The age-related decline in muscle function is aggravated by a high-fat diet (HFD)-induced increase in fat mass. The hypothesis is that an HFD leads to a faster accumulation of intramyocellular lipids (IMCL) and an earlier onset of muscle dysfunction in old than in young-adult individuals. The IMCL accumulation is attenuated in young-adult organisms by an elevated oxidative capacity. Methionine restriction enhances mitochondrial biogenesis and is promising to combat obesity across the ages.
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Affiliation(s)
| | - Anandini Swaminathan
- Institute of Sport Science and Innovations, Lithuanian Sports University, Kaunas, Lithuania
| | - Jason Tallis
- Center for Sport, Exercise and Life Sciences, Alison Gingell Building, Coventry University, Coventry, UK
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Luo B, Zhou X, Tang Q, Yin Y, Feng G, Li S, Chen L. Circadian rhythms affect bone reconstruction by regulating bone energy metabolism. J Transl Med 2021; 19:410. [PMID: 34579752 PMCID: PMC8477514 DOI: 10.1186/s12967-021-03068-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Accepted: 09/02/2021] [Indexed: 01/02/2023] Open
Abstract
Metabolism is one of the most complex cellular biochemical reactions, providing energy and substances for basic activities such as cell growth and proliferation. Early studies have shown that glucose is an important nutrient in osteoblasts. In addition, amino acid metabolism and fat metabolism also play important roles in bone reconstruction. Mammalian circadian clocks regulate the circadian cycles of various physiological functions. In vertebrates, circadian rhythms are mediated by a set of central clock genes: muscle and brain ARNT like-1 (Bmal1), muscle and brain ARNT like-2 (Bmal2), circadian rhythmic motion output cycle stagnates (Clock), cryptochrome 1 (Cry1), cryptochrome2 (Cry2), period 1 (Per1), period 2 (Per2), period 3 (Per3) and neuronal PAS domain protein 2 (Npas2). Negative feedback loops, controlled at both the transcriptional and posttranslational levels, adjust these clock genes in a diurnal manner. According to the results of studies on circadian transcriptomic studies in several tissues, most rhythmic genes are expressed in a tissue-specific manner and are affected by tissue-specific circadian rhythms. The circadian rhythm regulates several activities, including energy metabolism, feeding time, sleeping, and endocrine and immune functions. It has been reported that the circadian rhythms of mammals are closely related to bone metabolism. In this review, we discuss the regulation of the circadian rhythm/circadian clock gene in osteoblasts/osteoclasts and the energy metabolism of bone, and the relationship between circadian rhythm, bone remodeling, and energy metabolism. We also discuss the therapeutic potential of regulating circadian rhythms or changing energy metabolism on bone development/bone regeneration.
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Affiliation(s)
- Beibei Luo
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Xin Zhou
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Qingming Tang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Ying Yin
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Guangxia Feng
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Shue Li
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. .,School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. .,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China.
| | - Lili Chen
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. .,School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. .,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China.
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Dong Z, Gao X, Chinchilli VM, Sinha R, Muscat J, Winkels R, Richie JP. Association of dietary sulfur amino acid intake with mortality from diabetes and other causes. Eur J Nutr 2021; 61:289-298. [PMID: 34327571 DOI: 10.1007/s00394-021-02641-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 07/12/2021] [Indexed: 11/30/2022]
Abstract
PURPOSE Sulfur amino acid (SAA) consumption in Western countries is far greater than recommended levels. In preclinical studies, reduced SAA intake enhanced longevity and reduced risk for numerous chronic diseases. The current objective was to examine for associations between the intake of total SAA, including methionine (Met) and cysteine (Cys), and all-cause and disease-specific mortality US adults. METHODS This prospective analysis included 15,083 US adult participants (mean age = 46.7 years) from the Third National Examination and Nutritional Health Survey (NHANES III, 1988-1994) with available mortality status (National Death Registry, 1988-2011). Dietary SAA intake was obtained from 24-h recall data. Associations between quintile (Q) of SAA intake (expressed as absolute intake or protein density) and mortality were assessed using Cox proportional hazard models and expressed as hazard ratio (HR). RESULTS During follow-up (mean = 16.9 years), 4636 deaths occurred. After multivariable adjustment (including demographics and traditional risk factors, such as fat and other micronutrients intake), diabetes-caused mortality rates were nearly threefold higher in the highest compared to lowest SAA intake quintiles [HRQ5-Q1 total SAA, 2.68 (1.46-4.90); HRQ5-Q1 methionine, 2.45 (1.37-4.38); HRQ5-Q1 cysteine, 2.91 (1.57-5.37)] (P < 0.01)]. Higher total SAA protein density was also associated with diabetes-caused mortality [HRQ5-Q1 1.75 (1.31-2.35)]. Associations between SAA intake and all-cause mortality, and mortality caused by other major diseases were not detected. CONCLUSION Results suggest that high-SAA diets are associated with increased risk for diabetes mortality and that lowering intake towards to Recommended Dietary Allowance levels could lead to reductions in lifetime risk.
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Affiliation(s)
- Zhen Dong
- Department of Public Health Sciences, Penn State Cancer Institute, The Pennsylvania State University College of Medicine, 500 University Drive, Mail Code CH69, Hershey, PA, 17033, USA
| | - Xiang Gao
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Vernon M Chinchilli
- Department of Public Health Sciences, Penn State Cancer Institute, The Pennsylvania State University College of Medicine, 500 University Drive, Mail Code CH69, Hershey, PA, 17033, USA
| | - Raghu Sinha
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Joshua Muscat
- Department of Public Health Sciences, Penn State Cancer Institute, The Pennsylvania State University College of Medicine, 500 University Drive, Mail Code CH69, Hershey, PA, 17033, USA
| | - Renate Winkels
- Department of Public Health Sciences, Penn State Cancer Institute, The Pennsylvania State University College of Medicine, 500 University Drive, Mail Code CH69, Hershey, PA, 17033, USA
| | - John P Richie
- Department of Public Health Sciences, Penn State Cancer Institute, The Pennsylvania State University College of Medicine, 500 University Drive, Mail Code CH69, Hershey, PA, 17033, USA.
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Bermudez Sanchez S, Pilla R, Sarawichitr B, Gramenzi A, Marsilio F, Steiner JM, Lidbury JA, Woods GRT, Suchodolski JS, German AJ. Untargeted fecal metabolome analysis in obese dogs after weight loss achieved by feeding a high-fiber-high-protein diet. Metabolomics 2021; 17:66. [PMID: 34228201 PMCID: PMC8260550 DOI: 10.1007/s11306-021-01815-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 06/15/2021] [Indexed: 01/01/2023]
Abstract
INTRODUCTION In humans and companion animals, obesity is accompanied by metabolic derangements. Studies have revealed differences in the composition of the fecal microbiome between obese dogs and those with an ideal body weight. OBJECTIVES We have previously reported that the fecal microbiome in obese dogs changes after controlled weight reduction, induced by feeding a diet high in fiber and protein. Despite these findings, it is unclear if taxonomic differences infer differences at the functional level between obese dogs and those with an ideal body weight. METHODOLOGY Untargeted fecal metabolome analysis was performed on dogs with obesity before and after weight loss achieved by feeding a high-fiber-high-protein diet. RESULTS Fecal metabolome analysis revealed a total of 13 compounds that changed in concentration in obese dogs after weight loss. Of these compounds, metabolites associated with bacterial metabolism decreased after weight loss including purine, L-(-)-methionine, coumestrol, and the alkaloids 1-methylxanthine and trigonelline. Conversely, the polyphenols (-)-epicatechin and matairesinol and the quinoline derivatives 1,5-isoquinolinediol and 2-hydroxiquinoline increased after weight loss. CONCLUSION These results suggest differences in intestinal microbiome at the functional level after weight loss, but further studies are needed to determine the role of these compounds in the etiology of obesity and weight loss.
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Affiliation(s)
- Sandra Bermudez Sanchez
- Gastrointestinal Laboratory, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA.
- Veterinary Medicine Sciences, University of Teramo, Teramo, Italy.
| | - Rachel Pilla
- Gastrointestinal Laboratory, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Benjamin Sarawichitr
- Gastrointestinal Laboratory, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | | | - Fulvio Marsilio
- Veterinary Medicine Sciences, University of Teramo, Teramo, Italy
| | - Joerg M Steiner
- Gastrointestinal Laboratory, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Jonathan A Lidbury
- Gastrointestinal Laboratory, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Georgiana R T Woods
- Institute of Life Course and Medical Sciences, University of Liverpool, Leahurst, Neston, UK
| | - Jan S Suchodolski
- Gastrointestinal Laboratory, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Alexander J German
- Institute of Life Course and Medical Sciences, University of Liverpool, Leahurst, Neston, UK
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Hsu CL, Lo YC, Kao CF. H3K4 Methylation in Aging and Metabolism. EPIGENOMES 2021; 5:14. [PMID: 34968301 PMCID: PMC8594702 DOI: 10.3390/epigenomes5020014] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/02/2021] [Accepted: 06/15/2021] [Indexed: 02/03/2023] Open
Abstract
During the process of aging, extensive epigenetic alterations are made in response to both exogenous and endogenous stimuli. Here, we summarize the current state of knowledge regarding one such alteration, H3K4 methylation (H3K4me), as it relates to aging in different species. We especially highlight emerging evidence that links this modification with metabolic pathways, which may provide a mechanistic link to explain its role in aging. H3K4me is a widely recognized marker of active transcription, and it appears to play an evolutionarily conserved role in determining organism longevity, though its influence is context specific and requires further clarification. Interestingly, the modulation of H3K4me dynamics may occur as a result of nutritional status, such as methionine restriction. Methionine status appears to influence H3K4me via changes in the level of S-adenosyl methionine (SAM, the universal methyl donor) or the regulation of H3K4-modifying enzyme activities. Since methionine restriction is widely known to extend lifespan, the mechanistic link between methionine metabolic flux, the sensing of methionine concentrations and H3K4me status may provide a cogent explanation for several seemingly disparate observations in aging organisms, including age-dependent H3K4me dynamics, gene expression changes, and physiological aberrations. These connections are not yet entirely understood, especially at a molecular level, and will require further elucidation. To conclude, we discuss some potential H3K4me-mediated molecular mechanisms that may link metabolic status to the aging process.
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Affiliation(s)
- Chia-Ling Hsu
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 11529, Taiwan;
| | - Yi-Chen Lo
- Graduate Institute of Food Science and Technology, National Taiwan University, Taipei 10617, Taiwan;
| | - Cheng-Fu Kao
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 11529, Taiwan;
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Babygirija R, Lamming DW. The regulation of healthspan and lifespan by dietary amino acids. TRANSLATIONAL MEDICINE OF AGING 2021; 5:17-30. [PMID: 34263088 PMCID: PMC8277109 DOI: 10.1016/j.tma.2021.05.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
As a key macronutrient and source of essential macromolecules, dietary protein plays a significant role in health. For many years, protein-rich diets have been recommended as healthy due to the satiety-inducing and muscle-building effects of protein, as well as the ability of protein calories to displace allegedly unhealthy calories from fats and carbohydrates. However, clinical studies find that consumption of dietary protein is associated with an increased risk of multiple diseases, especially diabetes, while studies in rodents have demonstrated that protein restriction can promote metabolic health and even lifespan. Emerging evidence suggests that the effects of dietary protein on health and longevity are not mediated simply by protein quantity but are instead mediated by protein quality - the specific amino acid composition of the diet. Here, we discuss how dietary protein and specific amino acids including methionine, the branched chain amino acids (leucine, isoleucine, and valine), tryptophan and glycine regulate metabolic health, healthspan, and aging, with attention to the specific molecular mechanisms that may participate in these effects. Finally, we discuss the potential applicability of these findings to promoting healthy aging in humans.
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Affiliation(s)
- Reji Babygirija
- William S. Middleton Memorial Veterans Hospital, Madison, WI
- Department of Medicine, University of Wisconsin-Madison, Madison, WI
- Graduate Program in Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, WI, USA
| | - Dudley W. Lamming
- William S. Middleton Memorial Veterans Hospital, Madison, WI
- Department of Medicine, University of Wisconsin-Madison, Madison, WI
- Graduate Program in Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, WI, USA
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Fang H, Stone KP, Forney LA, Sims LC, Gutierrez GC, Ghosh S, Gettys TW. Implementation of dietary methionine restriction using casein after selective, oxidative deletion of methionine. iScience 2021; 24:102470. [PMID: 34113817 PMCID: PMC8169944 DOI: 10.1016/j.isci.2021.102470] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/29/2021] [Accepted: 04/22/2021] [Indexed: 01/24/2023] Open
Abstract
Dietary methionine restriction (MR) is normally implemented using diets formulated from elemental amino acids (AA) that reduce methionine content to ∼0.17%. However, translational implementation of MR with elemental AA-based diets is intractable due to poor palatability. To solve this problem and restrict methionine using intact proteins, casein was subjected to mild oxidation to selectively reduce methionine. Diets were then formulated using oxidized casein, adding back methionine to produce a final concentration of 0.17%. The biological efficacy of dietary MR using the oxidized casein (Ox Cas) diet was compared with the standard elemental MR diet in terms of the behavioral, metabolic, endocrine, and transcriptional responses to the four diets. The Ox Cas MR diet faithfully reproduced the expected physiological, biochemical, and transcriptional responses in liver and inguinal white adipose tissue. Collectively, these findings demonstrate that dietary MR can be effectively implemented using casein after selective oxidative reduction of methionine.
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Affiliation(s)
- Han Fang
- Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA
| | - Kirsten P. Stone
- Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA
| | - Laura A. Forney
- Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA
- Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Landon C. Sims
- Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA
| | - Gabriela C. Gutierrez
- School of Nutrition and Food Sciences, Louisiana State University, Baton Rouge, LA 70809, USA
| | - Sujoy Ghosh
- Laboratory of Computational Biology, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA
- Program in Cardiovascular and Metabolic Disorders and Centre for Computational Biology, Duke-NUS Medical School, Singapore, Singapore
| | - Thomas W. Gettys
- Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA
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Jonsson WO, Margolies NS, Mirek ET, Zhang Q, Linden MA, Hill CM, Link C, Bithi N, Zalma B, Levy JL, Pettit AP, Miller JW, Hine C, Morrison CD, Gettys TW, Miller BF, Hamilton KL, Wek RC, Anthony TG. Physiologic Responses to Dietary Sulfur Amino Acid Restriction in Mice Are Influenced by Atf4 Status and Biological Sex. J Nutr 2021; 151:785-799. [PMID: 33512502 PMCID: PMC8030708 DOI: 10.1093/jn/nxaa396] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 10/19/2020] [Accepted: 11/17/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Dietary sulfur amino acid restriction (SAAR) improves body composition and metabolic health across several model organisms in part through induction of the integrated stress response (ISR). OBJECTIVE We investigate the hypothesis that activating transcription factor 4 (ATF4) acts as a converging point in the ISR during SAAR. METHODS Using liver-specific or global gene ablation strategies, in both female and male mice, we address the role of ATF4 during dietary SAAR. RESULTS We show that ATF4 is dispensable in the chronic induction of the hepatokine fibroblast growth factor 21 while being essential for the sustained production of endogenous hydrogen sulfide. We also affirm that biological sex, independent of ATF4 status, is a determinant of the response to dietary SAAR. CONCLUSIONS Our results suggest that auxiliary components of the ISR, which are independent of ATF4, are critical for SAAR-mediated improvements in metabolic health in mice.
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Affiliation(s)
- William O Jonsson
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ, USA
| | | | - Emily T Mirek
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ, USA
| | - Qian Zhang
- Department of Health and Exercise Science, Colorado State University, Ft. Collins, CO, USA
| | - Melissa A Linden
- Department of Health and Exercise Science, Colorado State University, Ft. Collins, CO, USA
- Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | - Cristal M Hill
- Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | - Christopher Link
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA
| | - Nazmin Bithi
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA
| | - Brian Zalma
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ, USA
| | - Jordan L Levy
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ, USA
| | - Ashley P Pettit
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ, USA
| | - Joshua W Miller
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ, USA
| | - Christopher Hine
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA
| | | | - Thomas W Gettys
- Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | - Benjamin F Miller
- Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Karyn L Hamilton
- Department of Health and Exercise Science, Colorado State University, Ft. Collins, CO, USA
| | - Ronald C Wek
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Tracy G Anthony
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ, USA
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Du S, Lv Y, Li N, Huang X, Liu X, Li H, Wang C, Jia YF. Biological investigations on therapeutic effect of chitosan encapsulated nano resveratrol against gestational diabetes mellitus rats induced by streptozotocin. Drug Deliv 2021; 27:953-963. [PMID: 32611265 PMCID: PMC8216480 DOI: 10.1080/10717544.2020.1775722] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The chitosan encapsulation with bioactive compounds (resveratrol) is a significant method that can be used to raise the stability and effectiveness of substances in gestational diabetes management. In this study, the resveratrol–zinc oxide complex is encapsulated with chitosan (CS–ZnO–RS). The synthesized CS–ZnO–RS could be used to deliver the resveratrol with minimized side effects and also improved bioavailability. CS–ZnO–RS were characterized by various techniques such as particle size analyzer, DSC, FT-IR, TEM, SEM, and AFM. The electron microscopic and particle analyzer confirmed that the synthesized CS–ZnO–RS were monodispersed, spherical and its average size was 38 nm. The drug-releasing profile showed that 95% of RS is released from CS–ZnO–RS within 24 h. In vitro studies confirmed that α-glucosidase and α-amylase inhibitory activities were closely related to the concentration of CS–ZnO–RS. The highest inhibition of α-glucosidase (77.32%) and α-amylase (78.4%) was observed at 500 μg/mL. Furthermore, the treatment of CS–ZnO–RS significantly decreased the blood glucose levels in gestational diabetes mellitus induced rats and maintained the lipid content toward the normal rats. In addition, the CS–ZnO–RS reduced the level of inflammation factors (IL-6 and MCP-1) and endoplasmic reticulum stress (GRP78, p-IRE1α, p-eIF2α, and p-PERK).
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Affiliation(s)
- Shengye Du
- Department of Obstetrics, Jinan City People's Hospital, Jinan, PR China
| | - Yan Lv
- Gynecological Reproductive Clinic, Jinan City People's Hospital, Jinan, PR China
| | - Na Li
- Department of Gynecology and Traditional Chinese Medicine, Jinan City People's Hospital, Jinan, PR China
| | - Xianxia Huang
- Department of Obstetrics, Jinan City People's Hospital, Jinan, PR China
| | - Xuemei Liu
- Department of Obstetrics, Jinan City People's Hospital, Jinan, PR China
| | - Hui Li
- Department of Obstetrics, Jinan City People's Hospital, Jinan, PR China
| | - Chao Wang
- Department of Obstetrics, Jinan City People's Hospital, Jinan, PR China
| | - Yi-Fang Jia
- Center of Prenatal Diagnosis, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, PR China
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Plummer JD, Postnikoff SD, Tyler JK, Johnson JE. Selenium supplementation inhibits IGF-1 signaling and confers methionine restriction-like healthspan benefits to mice. eLife 2021; 10:62483. [PMID: 33783357 PMCID: PMC8009673 DOI: 10.7554/elife.62483] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 03/16/2021] [Indexed: 12/14/2022] Open
Abstract
Methionine restriction (MR) dramatically extends the healthspan of several organisms. Methionine-restricted rodents have less age-related pathology and increased longevity as compared with controls, and recent studies suggest that humans might benefit similarly. Mechanistically, it is likely that the decreased IGF-1 signaling that results from MR underlies the benefits of this regimen. Thus, we hypothesized that interventions that decrease IGF-1 signaling would also produce MR-like healthspan benefits. Selenium supplementation inhibits IGF-1 signaling in rats and has been studied for its putative healthspan benefits. Indeed, we show that feeding mice a diet supplemented with sodium selenite results in an MR-like phenotype, marked by protection against diet-induced obesity, as well as altered plasma levels of IGF-1, FGF-21, adiponectin, and leptin. Selenomethionine supplementation results in a similar, albeit less robust response, and also extends budding yeast lifespan. Our results indicate that selenium supplementation is sufficient to produce MR-like healthspan benefits for yeast and mammals.
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Affiliation(s)
- Jason D Plummer
- Department of Biology, Orentreich Foundation for the Advancement of Science, Cold Spring, United States
| | - Spike Dl Postnikoff
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United States
| | - Jessica K Tyler
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United States
| | - Jay E Johnson
- Department of Biology, Orentreich Foundation for the Advancement of Science, Cold Spring, United States
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Inglis A, Ubungen R, Farooq S, Mata P, Thiam J, Saleh S, Shibin S, Al-Mohanna FA, Collison KS. Strain-based and sex-biased differences in adrenal and pancreatic gene expression between KK/HlJ and C57BL/6 J mice. BMC Genomics 2021; 22:180. [PMID: 33711921 PMCID: PMC7953684 DOI: 10.1186/s12864-021-07495-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 02/26/2021] [Indexed: 11/15/2022] Open
Abstract
Background The ever-increasing prevalence of diabetes and associated comorbidities serves to highlight the necessity of biologically relevant small-animal models to investigate its etiology, pathology and treatment. Although the C57BL/6 J model is amongst the most widely used mouse model due to its susceptibility to diet-induced obesity (DIO), there are a number of limitations namely [1] that unambiguous fasting hyperglycemia can only be achieved via dietary manipulation and/or chemical ablation of the pancreatic beta cells. [2] Heterogeneity in the obesogenic effects of hypercaloric feeding has been noted, together with sex-dependent differences, with males being more responsive. The KK mouse strain has been used to study aspects of the metabolic syndrome and prediabetes. We recently conducted a study which characterized the differences in male and female glucocentric parameters between the KK/HlJ and C57BL/6 J strains as well as diabetes-related behavioral differences (Inglis et al. 2019). In the present study, we further characterize these models by examining strain- and sex-dependent differences in pancreatic and adrenal gene expression using Affymetrix microarray together with endocrine-associated serum analysis. Results In addition to strain-associated differences in insulin tolerance, we found significant elevations in KK/HlJ mouse serum leptin, insulin and aldosterone. Additionally, glucagon and corticosterone were elevated in female mice of both strains. Using 2-factor ANOVA and a significance level set at 0.05, we identified 10,269 pancreatic and 10,338 adrenal genes with an intensity cut-off of ≥2.0 for all 4 experimental groups. In the pancreas, gene expression upregulated in the KK/HlJ strain related to increased insulin secretory granule biofunction and pancreatic hyperplasia, whereas ontology of upregulated adrenal differentially expressed genes (DEGs) related to cell signaling and neurotransmission. We established a network of functionally related DEGs commonly upregulated in both endocrine tissues of KK/HlJ mice which included the genes coding for endocrine secretory vesicle biogenesis and regulation: PCSK2, PCSK1N, SCG5, PTPRN, CHGB and APLP1. We also identified genes with sex-biased expression common to both strains and tissues including the paternally expressed imprint gene neuronatin. Conclusion Our novel results have further characterized the commonalities and diversities of pancreatic and adrenal gene expression between the KK/HlJ and C57BL/6 J strains as well as differences in serum markers of endocrine physiology. Supplementary Information The online version contains supplementary material available at 10.1186/s12864-021-07495-4.
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Affiliation(s)
- Angela Inglis
- Department of Cell Biology, King Faisal Specialist Hospital & Research Centre, PO BOX 3354, Riyadh, 11211, Saudi Arabia
| | - Rosario Ubungen
- Department of Cell Biology, King Faisal Specialist Hospital & Research Centre, PO BOX 3354, Riyadh, 11211, Saudi Arabia
| | - Sarah Farooq
- Department of Cell Biology, King Faisal Specialist Hospital & Research Centre, PO BOX 3354, Riyadh, 11211, Saudi Arabia
| | - Princess Mata
- Department of Cell Biology, King Faisal Specialist Hospital & Research Centre, PO BOX 3354, Riyadh, 11211, Saudi Arabia
| | - Jennifer Thiam
- Department of Cell Biology, King Faisal Specialist Hospital & Research Centre, PO BOX 3354, Riyadh, 11211, Saudi Arabia
| | - Soad Saleh
- Department of Cell Biology, King Faisal Specialist Hospital & Research Centre, PO BOX 3354, Riyadh, 11211, Saudi Arabia
| | - Sherin Shibin
- Department of Cell Biology, King Faisal Specialist Hospital & Research Centre, PO BOX 3354, Riyadh, 11211, Saudi Arabia
| | - Futwan A Al-Mohanna
- Department of Cell Biology, King Faisal Specialist Hospital & Research Centre, PO BOX 3354, Riyadh, 11211, Saudi Arabia
| | - Kate S Collison
- Department of Cell Biology, King Faisal Specialist Hospital & Research Centre, PO BOX 3354, Riyadh, 11211, Saudi Arabia.
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