Modulation of Energy Sensing by Leucine Synergy with Natural Sirtuin Activators: Effects on Health Span
Abstract
Sirt1 and 5′ adenosine monophosphate-activated protein kinase (AMPK) are energy-sensing systems that work cooperatively and regulate mitochondrial biogenesis and fuel metabolism, and mediate, in part, the salutary effects of caloric restriction on lifespan and healthspan. We have shown that leucine activates Sirt1 and enables synergy with sirtuin co-activators. Resveratrol is a widely recognized activator of Sirt1; however, poor bioavailability and rapid metabolism limit effective clinical translation of promising animal data. However, we found that combining low resveratrol doses with leucine increased skeletal muscle and adipocyte Sirt1 activity, mitochondrial biogenesis and fatty acid oxidation; these effects result in increased lifespan and marked reductions in insulin resistance, inflammatory markers, body weight, and visceral adiposity in preclinical models. To translate these data to humans, we assessed the effects of resveratrol (50 mg)/leucine (1.11 g) on glucose dynamics in a 4-week placebo-controlled trial of 36 prediabetic subjects. Leucine-resveratrol reduced insulin resistance (homeostatic model assessment for insulin resistance) 33% with corresponding reductions in glucose and insulin area under the curve in oral glucose tolerance tests. We extended these concepts in preclinical studies using both direct Sirt1 activators and Sirt1 pathway activators. Low-dose (10 nM) NAD+ precursors (nicotinic acid, nicotinamide mononucleotide, and nicotinamide riboside) synergized with leucine to increase Sirt1 activity in adipocytes, hepatocytes, and muscle cells (30–100%, P < .01) and lifespan in Caenorhabditis elegans (25%, P = .025) and to significantly regress atherosclerotic lesion size and macrophage infiltration in a mouse model of atherosclerosis. Thus, synergistic activation of Sirt1 using leucine and a co-activator exerts pleiotropic effects impacting cardiometabolic endpoints.
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A human clinical trial of leucine-resveratrol combinations improved glucose homeostasis and insulin sensitivity in patients with prediabetes.
“Interestingly, a human clinical trial testing leucine–resveratrol combinations showed improved glucose homeostasis and insulin sensitivity in patients with prediabetes, suggesting that synergistic approaches might be a good alternative to treat age-associated metabolic diseases250.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [250]
Cites
AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity
Cantó, C., Gerhart-Hines, Z., Feige, J. N., Lagouge, M., Noriega, L., Milne, J. C., Elliott, P. J., Puigserver, P., & Auwerx, J. (2009) · Nature · doi:10.1038/nature07813 · Cited by 3,300 · see citing works
PGC-1α, SIRT1 and AMPK, an energy sensing network that controls energy expenditure
Cantó, C., & Auwerx, J. (2009) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e328328d0a4 · Cited by 1,624 · see citing works
Effects of intermittent fasting on health, aging, and disease
de Cabo, R., & Mattson, M. P. (2019) · New England Journal of Medicine · doi:10.1056/nejmra1905136 · Cited by 1,605 · see citing works
Price, N. L., Gomes, A. P., Ling, A. J. Y., Duarte, F. V., Martin-Montalvo, A., North, B. J., Agarwal, B., Ye, L., Ramadori, G., Teodoro, J. S., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.04.003 · Cited by 1,602 · see citing works
Promoting Health and Longevity through Diet: From Model Organisms to Humans
Fontana, L., & Partridge, L. (2015) · Cell · doi:10.1016/j.cell.2015.02.020 · Cited by 1,245 · see citing works
SIRT1 and other sirtuins in metabolism
Chang, H.-C., & Guarente, L. (2014) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2013.12.001 · Cited by 1,138 · see citing works
Purushotham, A., Schug, T. T., Xu, Q., Surapureddi, S., Guo, X., & Li, X. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.02.006 · Cited by 1,112 · see citing works
Sirt1 protects against high-fat diet-induced metabolic damage
Pfluger, P. T., Herranz, D., Velasco-Miguel, S., Serrano, M., & Tschöp, M. H. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0802917105 · Cited by 928 · see citing works
Katsanos, C. S., Kobayashi, H., Sheffield-Moore, M., Aarsland, A., & Wolfe, R. R. (2006) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00488.2005 · Cited by 923 · see citing works
Mattagajasingh, I., Kim, C.-S., Naqvi, A., Yamamori, T., Hoffman, T. A., Jung, S.-B., DeRicco, J., Kasuno, K., & Irani, K. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0704329104 · Cited by 881 · see citing works
AMPK, insulin resistance, and the metabolic syndrome
Ruderman, N. B., Carling, D., Prentki, M., & Cacicedo, J. M. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67227 · Cited by 877 · see citing works
Brandhorst, S., Choi, I. Y., Wei, M., Cheng, C. W., Sedrakyan, S., Navarrete, G., Dubeau, L., Yap, L. P., Park, R., Vinciguerra, M., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.05.012 · Cited by 850 · see citing works
SIRT1 Modulation of the Acetylation Status, Cytosolic Localization, and Activity of LKB1
Lan, F., Cacicedo, J. M., Ruderman, N., & Ido, Y. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m805711200 · Cited by 825 · see citing works
Flipping the Metabolic Switch: Understanding and Applying the Health Benefits of Fasting
Anton, S. D., Moehl, K., Donahoo, W. T., Marosi, K., Lee, S. A., Mainous, A. G., Leeuwenburgh, C., & Mattson, M. P. (2017) · Obesity · doi:10.1002/oby.22065 · Cited by 782 · see citing works
SIRT1 Regulates Hepatocyte Lipid Metabolism through Activating AMP-activated Protein Kinase
Hou, X., Xu, S., Maitland-Toolan, K. A., Sato, K., Jiang, B., Ido, Y., Lan, F., Walsh, K., Wierzbicki, M., Verbeuren, T. J., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m802187200 · Cited by 778 · see citing works
AMP-activated protein kinase: the current landscape for drug development
Steinberg, G. R., & Carling, D. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0019-2 · Cited by 757 · see citing works
Sparks, L. M., Xie, H., Koza, R. A., Mynatt, R., Hulver, M. W., Bray, G. A., & Smith, S. R. (2005) · Diabetes · doi:10.2337/diabetes.54.7.1926 · Cited by 629 · see citing works
Martens, C. R., Denman, B. A., Mazzo, M. R., Armstrong, M. L., Reisdorph, N., McQueen, M. B., Chonchol, M., & Seals, D. R. (2018) · Nature Communications · doi:10.1038/s41467-018-03421-7 · Cited by 588 · see citing works
Nicotinic acid: the broad‐spectrum lipid drug. A 50th anniversary review
Carlson, L. A. (2005) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2005.01528.x · Cited by 586 · see citing works
Wei, M., Brandhorst, S., Shelehchi, M., Mirzaei, H., Cheng, C. W., Budniak, J., Groshen, S., Mack, W. J., Guen, E., Di Biase, S., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aai8700 · Cited by 553 · see citing works
Gowans, G. J., Hawley, S. A., Ross, F. A., & Hardie, D. G. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.08.019 · Cited by 531 · see citing works
Elhassan, Y. S., Kluckova, K., Fletcher, R. S., Schmidt, M. S., Garten, A., Doig, C. L., Cartwright, D. M., Oakey, L., Burley, C. V., Jenkinson, N., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.07.043 · Cited by 448 · see citing works
Resveratrol and Its Human Metabolites—Effects on Metabolic Health and Obesity
Springer, M., & Moco, S. (2019) · Nutrients · doi:10.3390/nu11010143 · Cited by 293 · see citing works
Sirtuins and Type 2 Diabetes: Role in Inflammation, Oxidative Stress, and Mitochondrial Function
Kitada, M., Ogura, Y., Monno, I., & Koya, D. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00187 · Cited by 289 · see citing works
A Molecular Mechanism for Direct Sirtuin Activation by Resveratrol
Gertz, M., Nguyen, G. T. T., Fischer, F. F., Suenkel, B., Schlicker, C., Fränzel, B., Tomaschewski, J., Aladini, F., Becker, C., Wolters, D. A., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0049761 · Cited by 286 · see citing works
Dollerup, O. L., Christensen, B., Svart, M., Schmidt, M. S., Sulek, K., Ringgaard, S., Stødkilde-Jørgensen, H., Møller, N., Brenner, C., Treebak, J. T., et al. (2018) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqy132 · Cited by 282 · see citing works
NAD metabolism: Implications in aging and longevity
Yaku, K., Okabe, K., & Nakagawa, T. (2018) · Ageing Research Reviews · doi:10.1016/j.arr.2018.05.006 · Cited by 269 · see citing works
Obesity May Accelerate the Aging Process
Salvestrini, V., Sell, C., & Lorenzini, A. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00266 · Cited by 260 · see citing works
Dellinger, R. W., Santos, S. R., Morris, M., Evans, M., Alminana, D., Guarente, L., & Marcotulli, E. (2017) · npj Aging and Mechanisms of Disease · doi:10.1038/s41514-017-0016-9 · Cited by 181 · see citing works
High-fat diet feeding impairs both the expression and activity of AMPKa in rats’ skeletal muscle
Liu, Y., Wan, Q., Guan, Q., Gao, L., & Zhao, J. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.11.068 · Cited by 136 · see citing works
Bruckbauer, A., Zemel, M. B., Thorpe, T., Akula, M. R., Stuckey, A. C., Osborne, D., Martin, E. B., Kennel, S. J., & Wall, J. S. (2012) · Nutrition & Metabolism · doi:10.1186/1743-7075-9-77 · Cited by 128 · see citing works
Self-citationChallenges of Translating Basic Research Into Therapeutics: Resveratrol as an Example
Smoliga, J. M., Vang, O., & Baur, J. A. (2011) · The Journals of Gerontology Series A · doi:10.1093/gerona/glr062 · Cited by 111 · see citing works
Koopman, R., Verdijk, L. B., Beelen, M., Gorselink, M., Kruseman, A. N., Wagenmakers, A. J. M., Kuipers, H., & van Loon, L. J. C. (2008) · British Journal Of Nutrition · doi:10.1017/s0007114507812013 · Cited by 104 · see citing works
Koka, S., Aluri, H. S., Xi, L., Lesnefsky, E. J., & Kukreja, R. C. (2014) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00865.2013 · Cited by 97 · see citing works
de la Rubia, J. E., Drehmer, E., Platero, J. L., Benlloch, M., Caplliure-Llopis, J., Villaron-Casales, C., de Bernardo, N., AlarcÓn, J., Fuente, C., Carrera, S., et al. (2019) · Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration · doi:10.1080/21678421.2018.1536152 · Cited by 92 · see citing works
Kantartzis, K., Fritsche, L., Bombrich, M., Machann, J., Schick, F., Staiger, H., Kunz, I., Schoop, R., Lehn‐Stefan, A., Heni, M., et al. (2018) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.13268 · Cited by 87 · see citing works
Bruckbauer, A., & Zemel, M. B. (2014) · PLoS ONE · doi:10.1371/journal.pone.0089166 · Cited by 82 · see citing works
Self-citationZemel, M. B., & Bruckbauer, A. (2012) · Nutrients · doi:10.3390/nu4060529 · Cited by 67 · see citing works
Self-citationmTOR Inhibitor Therapy and Metabolic Consequences: Where Do We Stand?
Kezić, A., Popović, L., & Lalic, K. S. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/2640342 · Cited by 67 · see citing works
Zullo, A., Simone, E., Grimaldi, M., Musto, V., & Mancini, F. P. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19040928 · Cited by 64 · see citing works
Effects of dairy consumption on SIRT1 and mitochondrial biogenesis in adipocytes and muscle cells
Bruckbauer, A., & Zemel, M. B. (2011) · Nutrition & Metabolism · doi:10.1186/1743-7075-8-91 · Cited by 53 · see citing works
Self-citationMatsumoto, T., Nakamura, K., Matsumoto, H., Sakai, R., Kuwahara, T., Kadota, Y., Kitaura, Y., Sato, J., & Shimomura, Y. (2014) · SpringerPlus · doi:10.1186/2193-1801-3-35 · Cited by 52 · see citing works
Fu, L., Bruckbauer, A., Li, F., Cao, Q., Cui, X., Wu, R., Shi, H., Zemel, M. B., & Xue, B. (2015) · Metabolism · doi:10.1016/j.metabol.2015.03.007 · Cited by 42 · see citing works
Self-citationChalasani, N., Vuppalanchi, R., Rinella, M. E., Middleton, M. S., Siddiqui, M. S., Barritt, A. S., Kolterman, O., Flores, O., Alonso, C., Iruarrizaga‐Lejarreta, M., et al. (2018) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.14674 · Cited by 40 · see citing works
Self-citationWipperman, M. F., Montrose, D. C., Gotto, A. M., & Hajjar, D. P. (2019) · American Journal Of Pathology · doi:10.1016/j.ajpath.2018.11.013 · Cited by 40 · see citing works
Steinberg, G. R. (2018) · Diabetes · doi:10.2337/dbi17-0039 · Cited by 27 · see citing works
Zemel, M. B., & Bruckbauer (2013) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s49623 · Cited by 19 · see citing works
Self-citationZemel, M. B., Kolterman, O., Rinella, M., Vuppalanchi, R., Flores, O., Barritt, A. S., Siddiqui, M., & Chalasani, N. (2019) · Obesity · doi:10.1002/oby.22346 · Cited by 19 · see citing works
Self-citationAMPK ↔ Sirt1: From a signaling network to a combination drug
Dagon, Y., Mantzoros, C. S., & Kim, Y. (2016) · Metabolism · doi:10.1016/j.metabol.2016.07.014 · Cited by 14 · see citing works
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- Authors
- Zemel, M. B.
- Affiliations
- NuSirt Biopharma, Research and Development, Knoxville, Tennessee, USA.
- Corresponding author
- Zemel, Michael B.
- ORCID
- Zemel, Michael B.
- Venue
- Journal of Medicinal Food
- Publisher
- SAGE Publications
- Published
- 2020-11-01
- Volume
- 23
- Issue
- 11
- Pages
- 1129-1135
- ISSN
- 1096-620X (ISSN-L)
- 1557-7600
- OpenAlex
- W3047837124
- Cited by
- 12
- References
- 49
- Citations by year
- 2025: 1 · 2023: 4 · 2022: 5 · 2021: 1 · 2020: 1
- FWCI
- 1.45
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Food (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- leucine, SIRT1, resveratrol, AMPK, NAD+ precursors, nicotinamide mononucleotide, nicotinamide riboside, nicotinic acid, healthspan, lifespan, insulin resistance, prediabetes, glucose tolerance, mitochondrial biogenesis, fatty acid oxidation, atherosclerosis, visceral fat, energy sensing, Caenorhabditis elegans
- MeSH terms
- Resveratrol, Animals, Humans, Insulin Resistance, Leucine, Longevity, Mice, Obese, Prediabetic State, Stilbenes, AMP-Activated Protein Kinases, Sirtuin 1
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