From bedside to battlefield: intersection of ketone body mechanisms in geroscience with military resilience.
Aging
Geroscience
Ketone bodies
Metabolism
Sarcopenia
TBI
Journal
GeroScience
ISSN: 2509-2723
Titre abrégé: Geroscience
Pays: Switzerland
ID NLM: 101686284
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
received:
05
08
2020
accepted:
22
09
2020
pubmed:
3
10
2020
medline:
2
7
2021
entrez:
2
10
2020
Statut:
ppublish
Résumé
Ketone bodies are endogenous metabolites that are linked to multiple mechanisms of aging and resilience. They are produced by the body when glucose availability is low, including during fasting and dietary carbohydrate restriction, but also can be consumed as exogenous ketone compounds. Along with supplying energy to peripheral tissues such as brain, heart, and skeletal muscle, they increasingly are understood to have drug-like protein binding activities that regulate inflammation, epigenetics, and other cellular processes. While these energy and signaling mechanisms of ketone bodies are currently being studied in a variety of aging-related diseases such as Alzheimer's disease and type 2 diabetes mellitus, they may also be relevant to military service members undergoing stressors that mimic or accelerate aging pathways, particularly traumatic brain injury and muscle rehabilitation and recovery. Here we summarize the biology of ketone bodies relevant to resilience and rehabilitation, strategies for translational use of ketone bodies, and current clinical investigations in this area.
Identifiants
pubmed: 33006708
doi: 10.1007/s11357-020-00277-y
pii: 10.1007/s11357-020-00277-y
pmc: PMC8190215
doi:
Substances chimiques
Ketone Bodies
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
1071-1081Subventions
Organisme : NIA NIH HHS
ID : R01 AG067333
Pays : United States
Organisme : NIA NIH HHS
ID : K08AG048354
Pays : United States
Références
Veech RL, Bradshaw PC, Clarke K, Curtis W, Pawlosky R, King MT. Ketone bodies mimic the life span extending properties of caloric restriction. IUBMB Life. 2017;69(5):305–14.
pubmed: 28371201
Newman JC, Verdin E. beta-Hydroxybutyrate: a signaling metabolite. Annu Rev Nutr. 2017;37:51–76.
pubmed: 28826372
pmcid: 6640868
Han YM, Ramprasath T, Zou MH. β-Hydroxybutyrate and its metabolic effects on age-associated pathology. Exp Mol Med. 2020;52(4):548–55.
pubmed: 32269287
pmcid: 7210293
Mattson MP, Moehl K, Ghena N, Schmaedick M, Cheng A. Intermittent metabolic switching, neuroplasticity and brain health. Nat Rev Neurosci. 2018;19(2):63–80.
pubmed: 29321682
pmcid: 5913738
Miller MW, Sadeh N. Traumatic stress, oxidative stress and post-traumatic stress disorder: neurodegeneration and the accelerated-aging hypothesis. Mol Psychiatry. 2014;19(11):1156–62.
pubmed: 25245500
pmcid: 4211971
Tamman AJF, Montalvo-Ortiz JL, Southwick SM, Krystal JH, Levy BR, Pietrzak RH. Accelerated DNA methylation aging in U.S. military veterans: results from the National Health and Resilience in Veterans Study. Am J Geriatr Psychiatry. 2019;27(5):528–32.
pubmed: 30792041
Veitch DP, Friedl KE, Weiner MW. Military risk factors for cognitive decline, dementia and Alzheimer's disease. Curr Alzheimer Res. 2013;10(9):907–30.
pubmed: 23906002
Songer TJ, LaPorte RE. Disabilities due to injury in the military. Am J Prev Med. 2000;18(3 Suppl):33–40.
pubmed: 10736539
Feuerstein M, Berkowitz SM, Peck CA Jr. Musculoskeletal-related disability in US Army personnel: prevalence, gender, and military occupational specialties. J Occup Environ Med. 1997;39(1):68–78.
pubmed: 9029434
Sivanandam TM, Thakur MK. Traumatic brain injury: a risk factor for Alzheimer's disease. Neurosci Biobehav Rev. 2012;36(5):1376–81.
pubmed: 22390915
Robinson AM, Williamson DH. Physiological roles of ketone-bodies as substrates and signals in mammalian-tissues. Physiol Rev. 1980;60(1):143–87.
pubmed: 6986618
Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev. 1999;15(6):412–26.
pubmed: 10634967
Cahill GF Jr. Fuel metabolism in starvation. Annu Rev Nutr. 2006;26:1–22.
pubmed: 16848698
Rich AJ. Ketone bodies as substrates. Proc Nutr Soc. 1990;49(3):361–73.
pubmed: 2080169
Krebs HA. The regulation of the release of ketone bodies by the liver. Adv Enzym Regul. 1966;4:339–54.
Wheless, J.W., Chapter 2—History and origin of the ketogenic diet. Epilepsy and the ketogenic diet. 2004: Humana Press Inc.
Branco AF, Ferreira A, Simões RF, Magalhães-Novais S, Zehowski C, Cope E, et al. Ketogenic diets: from cancer to mitochondrial diseases and beyond. Eur J Clin Investig. 2016;46(3):285–98.
Weber DD, Aminzadeh-Gohari S, Tulipan J, Catalano L, Feichtinger RG, Kofler B. Ketogenic diet in the treatment of cancer—where do we stand? Mol Metab. 2020;33:102–21.
pubmed: 31399389
Burke LM. Re-examining high-fat diets for sports performance: did we call the “Nail in the Coffin” too soon? Sports Med. 2015;45(Suppl 1):S33–49.
pubmed: 26553488
Burke L and Kiens B., “fat adaptations” for athletic performance: the nail in the coffin? J Appl Physiol, 2006. 100.
Athinarayanan SJ, et al., Long-term effects of a novel continuous remote care intervention including nutritional ketosis for the management of type 2 diabetes: a 2-year non-randomized clinical trial. Front Endocrinol, 2019. 10(348).
Diamond DM, O'Neill BJ, Volek JS. Low carbohydrate diet: are concerns with saturated fat, lipids, and cardiovascular disease risk justified? Curr Opin Endocrinol Diabetes Obes. 2020;27(5):291–300.
pubmed: 32773573
Volek JS, Freidenreich DJ, Saenz C, Kunces LJ, Creighton BC, Bartley JM, et al. Metabolic characteristics of keto-adapted ultra-endurance runners. Metabolism. 2016;65(3):100–10.
pubmed: 26892521
LaFountain RA, Miller VJ, Barnhart EC, Hyde PN, Crabtree CD, McSwiney FT, et al. Extended ketogenic diet and physical training intervention in military personnel. Mil Med. 2019;184(9–10):e538–47.
pubmed: 30877806
Poff AM, Koutnik AP, Egan B. Nutritional ketosis with ketogenic diets or exogenous ketones: features, convergence, and divergence. Curr Sports Med Rep. 2020;19(7):251–9.
pubmed: 32692060
Cahill G, Veech RL. Ketoacids? Good medicine? Trans Am Clin Climatol Assoc. 2003;114(0065–7778 (Print)):149–61 discussion 162-3.
pubmed: 12813917
pmcid: 2194504
Gavrilovici C and Rho JM, Metabolic epilepsies amenable to ketogenic therapies: indications, Contra-indications and underlying mechanisms. J Inherit Metab Dis, 2020.
Stubbs B, et al., On the metabolism of exogenous ketones in humans. Front Physiol 2017.
Vandenberghe, C., et al., Tricaprylin alone increases plasma ketone response more than coconut oil or other medium-chain triglycerides: an acute crossover study in healthy adults. Curr Dev Nutr, 2017. 1(4).
Croteau E, Castellano CA, Richard MA, Fortier M, Nugent S, Lepage M, et al. Ketogenic medium chain triglycerides increase brain energy metabolism in Alzheimer's disease. J Alzheimers Dis. 2018;64(2):551–61.
pubmed: 29914035
Fortier M, Castellano CA, Croteau E, Langlois F, Bocti C, St-Pierre V, et al. A ketogenic drink improves brain energy and some measures of cognition in mild cognitive impairment. Alzheimers Dement. 2019;15(5):625–34.
pubmed: 31027873
Eckel RH, Hanson AS, Chen AY, Berman JN, Yost TJ, Brass EP. Dietary substitution of medium-chain triglycerides improves insulin-mediated glucose metabolism in NIDDM subjects. Diabetes. 1992;41(5):641–7.
pubmed: 1568535
Clegg ME. Medium-chain triglycerides are advantageous in promoting weight loss although not beneficial to exercise performance. Int J Food Sci Nutr. 2010;61(7):653–79.
pubmed: 20367215
Ööpik V, Timpmann S, Medijainen L, Lemberg H. Effects of daily medium-chain triglyceride ingestion on energy metabolism and endurance performance capacity in well-trained runners. Nutr Res. 2001;21(8):1125–35.
Thomas DD, Stockman MC, Yu L, Meshulam T, McCarthy AC, Ionson A, et al. Effects of medium chain triglycerides supplementation on insulin sensitivity and beta cell function: a feasibility study. PLoS One. 2019;14(12):e0226200.
pubmed: 31869355
pmcid: 6927614
Misell, L.M., et al., Chronic medium-chain trilgycerol onsumption and endurance performance in trained runners. J Sports Med Phys Fitness, 2001. 41(2).
Thorburn MS, et al. Attenuated gastric distress but no benefit to performance with adaptation to octanoate-rich esterified oils in well-trained male cyclists. J Appl Physiol (1985). 2006;101(6):1733–43.
Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, le Moan N, et al. Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science. 2013;339(6116):211–4.
pubmed: 23223453
Xie Z, Zhang D, Chung D, Tang Z, Huang H, Dai L, et al. Metabolic regulation of gene expression by histone lysine beta-hydroxybutyrylation. Mol Cell. 2016;62(2):194–206.
pubmed: 27105115
pmcid: 5540445
Wei T, Tian W, Liu F, Xie G. Protective effects of exogenous β-hydroxybutyrate on paraquat toxicity in rat kidney. Biochem Biophys Res Commun. 2014;447(4):666–71.
pubmed: 24755084
Izuta Y, Imada T, Hisamura R, Oonishi E, Nakamura S, Inagaki E, et al. Ketone body 3-hydroxybutyrate mimics calorie restriction via the Nrf2 activator, fumarate, in the retina. Aging Cell. 2018;17(1):e12699.
Meroni E, et al., Metabolic responses in endothelial cells following exposure to ketone bodies. Nutrients, 2018. 10(2).
Kim DY, Davis LM, Sullivan PG, Maalouf M, Simeone TA, Brederode J, et al. Ketone bodies are protective against oxidative stress in neocortical neurons. J Neurochem. 2007;101(5):1316–26.
pubmed: 17403035
Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, le Moan N, et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science. 2013;339(6116):211–4.
pubmed: 23223453
Kong G, Huang Z, Ji W, Wang X, Liu J, Wu X, et al. The ketone metabolite β-Hydroxybutyrate attenuates oxidative stress in spinal cord injury by suppression of class I histone deacetylases. J Neurotrauma. 2017;34(18):2645–55.
pubmed: 28683591
Han Y-M, et al. β-Hydroxybutyrate prevents vascular senescence through hnRNP A1-mediated upregulation of Oct4. Mol Cell. 2018;71(6):1064–1078.e5.
pubmed: 30197300
pmcid: 6230553
Miyamoto J, Ohue-Kitano R, Mukouyama H, Nishida A, Watanabe K, Igarashi M, et al. Ketone body receptor GPR43 regulates lipid metabolism under ketogenic conditions. Proc Natl Acad Sci. 2019;116(47):23813–21.
pubmed: 31685604
Zou X, Meng J, Li L, Han W, Li C, Zhong R, et al. Acetoacetate accelerates muscle regeneration and ameliorates muscular dystrophy in mice. J Biol Chem. 2016;291(5):2181–95.
pubmed: 26645687
Juge N, Gray JA, Omote H, Miyaji T, Inoue T, Hara C, et al. Metabolic control of vesicular glutamate transport and release. Neuron. 2010;68(1):99–112.
pubmed: 20920794
pmcid: 2978156
Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. 2015;21(3):263–9.
pubmed: 25686106
pmcid: 4352123
Goldberg EL, Asher JL, Molony RD, Shaw AC, Zeiss CJ, Wang C, et al. Beta-hydroxybutyrate deactivates neutrophil NLRP3 inflammasome to relieve gout flares. Cell Rep. 2017;18(9):2077–87.
pubmed: 28249154
pmcid: 5527297
Stubbs, B.J., et al., Investigating ketone bodies as immunometabolic countermeasures against respiratory viral infections. Medicine
Swanson KV, Deng M, Ting JP. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol. 2019;19(8):477–89.
pubmed: 31036962
pmcid: 7807242
Sepehri Z, Kiani Z, Afshari M, Kohan F, Dalvand A, Ghavami S. Inflammasomes and type 2 diabetes: an updated systematic review. Immunol Lett. 2017;192:97–103.
pubmed: 29079203
Forsythe CE, Phinney SD, Fernandez ML, Quann EE, Wood RJ, Bibus DM, et al. Comparison of low fat and low carbohydrate diets on circulating fatty acid composition and markers of inflammation. Lipids. 2008;43(1):65–77.
pubmed: 18046594
Rajman L, Chwalek K, Sinclair DA. Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell Metab. 2018;27(3):529–47.
pubmed: 29514064
pmcid: 6342515
Mouchiroud L, Houtkooper RH, Moullan N, Katsyuba E, Ryu D, Cantó C, et al. The NAD(+)/Sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell. 2013;154(2):430–41.
pubmed: 23870130
pmcid: 3753670
Veech RL, Todd King M, Pawlosky R, Kashiwaya Y, Bradshaw PC, Curtis W. The “great” controlling nucleotide coenzymes. IUBMB Life. 2019;71(5):565–79.
pubmed: 30624851
pmcid: 6850382
Elia M, Wood S, Khan K, Pullicino E. Ketone body metabolism in lean male adults during short-term starvation, with particular reference to forearm muscle metabolism. Clin Sci (Lond). 1990;78(6):579–84.
Kashiwaya Y, King MT, Veech RL. Substrate signaling by insulin: a ketone bodies ratio mimics insulin action in heart. Am J Cardiol. 1997;80(3a):50a–64a.
pubmed: 9293956
Pawlosky RJ, Kemper MF, Kashiwaya Y, King MT, Mattson MP, Veech RL. Effects of a dietary ketone ester on hippocampal glycolytic and tricarboxylic acid cycle intermediates and amino acids in a 3xTgAD mouse model of Alzheimer's disease. J Neurochem. 2017;141(2):195–207.
pubmed: 28099989
pmcid: 5383517
Ang QY, et al. Ketogenic diets alter the gut microbiome resulting in decreased intestinal Th17 cells. Cell. 2020;181(6):1263–1275.e16.
pubmed: 32437658
Nagpal R, Neth BJ, Wang S, Craft S, Yadav H. Modified Mediterranean-ketogenic diet modulates gut microbiome and short-chain fatty acids in association with Alzheimer's disease markers in subjects with mild cognitive impairment. EBioMedicine. 2019;47:529–42.
pubmed: 31477562
pmcid: 6796564
Nagpal R, Neth BJ, Wang S, Mishra SP, Craft S, Yadav H. Gut mycobiome and its interaction with diet, gut bacteria and alzheimer's disease markers in subjects with mild cognitive impairment: a pilot study. EBioMedicine. 2020;59:102950.
pubmed: 32861197
pmcid: 7475073
Olson CA, et al. The gut microbiota mediates the anti-seizure effects of the ketogenic diet. Cell. 2018;173(7):1728–1741.e13.
pubmed: 29804833
pmcid: 6003870
Puchalska P, et al. Hepatocyte-macrophage acetoacetate shuttle protects against tissue fibrosis. Cell Metab. 2019;29(2):383–398.e7.
pubmed: 30449686
Uchihashi, M., et al., Cardiac-specific Bdh1 overexpression ameliorates oxidative stress and cardiac remodeling in pressure overload-induced heart failure. Circ Heart Fail, 2017. 10(12).
García-Caballero M, Zecchin A, Souffreau J, Truong ACK, Teuwen LA, Vermaelen W, et al. Role and therapeutic potential of dietary ketone bodies in lymph vessel growth. Nat Metab. 2019;1(7):666–75.
pubmed: 32694649
Cheng CW, et al. Ketone body signaling mediates intestinal stem cell homeostasis and adaptation to diet. Cell. 2019;178(5):1115–1131.e15.
pubmed: 31442404
pmcid: 6732196
Horton JL, Davidson MT, Kurishima C, Vega RB, Powers JC, Matsuura TR, et al. The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense. JCI insight. 2019;4(4):e124079.
pmcid: 6478419
Byrne Nikole J, et al. Chronically elevating circulating ketones can reduce cardiac inflammation and blunt the development of heart failure. Circ Heart Fail. 2020;13(6):e006573.
pubmed: 32493060
Uchihashi M, et al. Cardiac-specific Bdh1 overexpression ameliorates oxidative stress and cardiac remodeling in pressure overload–induced heart failure. Circ Heart Fail. 2017;10(12):e004417.
pubmed: 29242353
Selvaraj S, Kelly DP, Margulies KB. Implications of altered ketone metabolism and therapeutic ketosis in heart failure. Circulation. 2020;141(22):1800–12.
pubmed: 32479196
pmcid: 7304522
Nielsen R, Møller N, Gormsen LC, Tolbod LP, Hansson NH, Sorensen J, et al. Cardiovascular effects of treatment with the ketone body 3-hydroxybutyrate in chronic heart failure patients. Circulation. 2019;139(18):2129–41.
pubmed: 30884964
pmcid: 6493702
Gormsen LC, et al., Ketone body infusion with 3-hydroxybutyrate reduces myocardial glucose uptake and increases blood flow in humans: a positron emission tomography study. J Am Heart Assoc, 2017. 6(3).
Song JP, et al., Elevated plasma β-hydroxybutyrate predicts adverse outcomes and disease progression in patients with arrhythmogenic cardiomyopathy. Sci Transl Med, 2020. 12(530).
Yoshino A, Hovda DA, Kawamata T, Katayama Y, Becker DP. Dynamic changes in local cerebral glucose utilization following cerebral concussion in rats: evidence of a hyper- and subsequent hypometabolic state. Brain Res. 1991;561(1):106–19.
pubmed: 1797338
Roberts MN, et al. A ketogenic diet extends longevity and healthspan in adult mice. Cell Metab. 2017;26(3):539–546.e5.
pubmed: 28877457
pmcid: 5609489
Newman JC, et al. Ketogenic diet reduces midlife mortality and improves memory in aging mice. Cell Metab. 2017;26(3):547–557.e8.
pubmed: 28877458
pmcid: 5605815
Wood TR, Stubbs BJ, Juul SE. Exogenous ketone bodies as promising neuroprotective agents for developmental brain injury. Dev Neurosci. 2018;40(5–6):451–62.
pubmed: 31085911
Gano LB, Patel M, Rho JM. Ketogenic diets, mitochondria, and neurological diseases. J Lipid Res. 2014;55(11):2211–28.
pubmed: 24847102
pmcid: 4617125
Yang H, Shan W, Zhu F, Wu J, Wang Q. Ketone bodies in neurological diseases: focus on neuroprotection and underlying mechanisms. Front Neurol. 2019;10:585.
pubmed: 31244753
pmcid: 6581710
Prins ML, Matsumoto JH. The collective therapeutic potential of cerebral ketone metabolism in traumatic brain injury. J Lipid Res. 2014;55(12):2450–7.
pubmed: 24721741
pmcid: 4242438
Arora N, Mehta TR. Role of the ketogenic diet in acute neurological diseases. Clin Neurol Neurosurg. 2020;192:105727.
pubmed: 32087500
McDougall A, Bayley M, Munce SE. The ketogenic diet as a treatment for traumatic brain injury: a scoping review. Brain Inj. 2018;32(4):416–22.
pubmed: 29359959
Prins ML. Cerebral metabolic adaptation and ketone metabolism after brain injury. J Cereb Blood Flow Metab : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2008;28(1):1–16.
Neth BJ, Mintz A, Whitlow C, Jung Y, Solingapuram Sai K, Register TC, et al. Modified ketogenic diet is associated with improved cerebrospinal fluid biomarker profile, cerebral perfusion, and cerebral ketone body uptake in older adults at risk for Alzheimer's disease: a pilot study. Neurobiol Aging. 2020;86:54–63.
pubmed: 31757576
Grammatikopoulou MG, et al., To keto or not to keto? A systematic review of randomized controlled trials assessing the effects of ketogenic therapy on Alzheimer disease. Adv Nutr, 2020.
Felig P, Owen OE, Wahren J, Cahill GF Jr. Amino acid metabolism during prolonged starvation. J Clin Invest. 1969;48(3):584–94.
pubmed: 5773094
pmcid: 535724
Koutnik AP, D'Agostino DP, Egan B. Anticatabolic effects of ketone bodies in skeletal muscle. Trends Endocrinol Metab. 2019;30(4):227–9.
pubmed: 30712977
Koutnik AP, et al., Ketone bodies attenuate wasting in models of atrophy. J Cachexia Sarcopenia Muscle 2020
Shukla SK, Gebregiworgis T, Purohit V, Chaika NV, Gunda V, Radhakrishnan P, et al. Metabolic reprogramming induced by ketone bodies diminishes pancreatic cancer cachexia. Cancer Metab. 2014;2:18.
pubmed: 25228990
pmcid: 4165433
Fearon KC, Borland W, Preston T, Tisdale MJ, Shenkin A, Calman KC. Cancer cachexia: influence of systemic ketosis on substrate levels and nitrogen metabolism. Am J Clin Nutr. 1988;47(1):42–8.
pubmed: 3122552
Nair KS, Welle SL, Halliday D, Campbell RG. Effect of beta-hydroxybutyrate on whole-body leucine kinetics and fractional mixed skeletal muscle protein synthesis in humans. J Clin Invest. 1988;82(1):198–205.
pubmed: 3392207
pmcid: 303494
Vandoorne T, de Smet S, Ramaekers M, van Thienen R, de Bock K, Clarke K, et al. Intake of a ketone ester drink during recovery from exercise promotes mTORC1 signaling but not glycogen resynthesis in human muscle. Front Physiol. 2017;8:310.
pubmed: 28588499
pmcid: 5440563
Covinsky KE, Pierluissi E, Johnston CB. Hospitalization-associated disability: “she was probably able to ambulate, but I’m not sure.”. Jama. 2011;306(16):1782–93.
pubmed: 22028354
Church, D.D., et al., Mitigation of muscle loss in stressed physiology: military relevance. Nutrients, 2019. 11(8).
Corona BT, Rivera JC, Owens JG, Wenke JC, Rathbone CR. Volumetric muscle loss leads to permanent disability following extremity trauma. J Rehabil Res Dev. 2015;52(7):785–92.
pubmed: 26745661
Owen OE, Morgan AP, Kemp HG, Sullivan JM, Herrera MG, Cahill GF Jr. Brain metabolism during fasting. J Clin Invest. 1967;46(10):1589–95.
pubmed: 6061736
pmcid: 292907
Owen OE, Felig P, Morgan AP, Wahren J, Cahill GF Jr. Liver and kidney metabolism during prolonged starvation. J Clin Invest. 1969;48(3):574–83.
pubmed: 5773093
pmcid: 535723
Sherwin RS, Hendler RG, Felig P. Effect of ketone infusions on amino acid and nitrogen metabolism in man. J Clin Invest. 1975;55(6):1382–90.
pubmed: 1133179
pmcid: 301893
Maiz A, Moldawer LL, Bistrian BR, Birkhahn RH, Long CL, Blackburn GL. Monoacetoacetin and protein metabolism during parenteral nutrition in burned rats. Biochem J. 1985;226(1):43–50.
pubmed: 3977880
pmcid: 1144675
Phinney S, et al. The human metabolic response to chronic ketosis without caloric restriction: preservation of submaximal exercise capability with reduced carbohydrate oxidation. Metabolism. 1983;32(8):769–76.
pubmed: 6865776
Thomsen HH, Rittig N, Johannsen M, Møller AB, Jørgensen JO, Jessen N, et al. Effects of 3-hydroxybutyrate and free fatty acids on muscle protein kinetics and signaling during LPS-induced inflammation in humans: anticatabolic impact of ketone bodies. Am J Clin Nutr. 2018;108(4):857–67.
pubmed: 30239561
Tisdale MJ, Brennan RA, Fearon KC. Reduction of weight loss and tumour size in a cachexia model by a high fat diet. Br J Cancer. 1987;56(1):39–43.
pubmed: 3620317
pmcid: 2001676
Nakamura, K., et al., A Ketogenic formula prevents tumor progression and cancer cachexia by attenuating systemic inflammation in colon 26 tumor-bearing mice. Nutrients, 2018. 10(2).
Tomita I, Kume S, Sugahara S, Osawa N, Yamahara K, Yasuda-Yamahara M, et al. SGLT2 inhibition mediates protection from diabetic kidney disease by promoting ketone body-induced mTORC1 inhibition. Cell Metab. 2020;32:404–419.e6.
pubmed: 32726607
Sengupta S, Peterson TR, Laplante M, Oh S, Sabatini DM. mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature. 2010;468(7327):1100–4.
pubmed: 21179166
Balasse EO, Fery F. Ketone-body production and disposal—effects of fasting, diabetes, and exercise. Diabetes Metab Rev. 1989;5(3):247–70.
pubmed: 2656155
Fery F, Balasse EO. Ketone-body production and disposal in diabetic ketosis—a comparison with fasting ketosis. Diabetes. 1985;34(4):326–32.
pubmed: 3918903
Kackley ML, Short JA, Hyde PN, LaFountain RA, Buga A, Miller VJ, et al. A pre-workout supplement of ketone salts, caffeine, and amino acids improves high-intensity exercise performance in keto-naïve and keto-adapted individuals. J Am Coll Nutr. 2020;39(4):290–300.
pubmed: 32330107