β-hydroxybutyrate and its metabolic effects on age-associated pathology

Young-Min Han, Tharmarajan Ramprasath, Ming-Hui Zou, Young-Min Han, Tharmarajan Ramprasath, Ming-Hui Zou

Abstract

Aging is a universal process that renders individuals vulnerable to many diseases. Although this process is irreversible, dietary modulation and caloric restriction are often considered to have antiaging effects. Dietary modulation can increase and maintain circulating ketone bodies, especially β-hydroxybutyrate (β-HB), which is one of the most abundant ketone bodies in human circulation. Increased β-HB has been reported to prevent or improve the symptoms of various age-associated diseases. Indeed, numerous studies have reported that a ketogenic diet or ketone ester administration alleviates symptoms of neurodegenerative diseases, cardiovascular diseases, and cancers. Considering the potential of β-HB and the intriguing data emerging from in vivo and in vitro experiments as well as clinical trials, this therapeutic area is worthy of attention. In this review, we highlight studies that focus on the identified targets of β-HB and the cellular signals regulated by β-HB with respect to alleviation of age-associated ailments.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1. Alleviation of age-associated disease symptoms…
Fig. 1. Alleviation of age-associated disease symptoms and improvement of health outcomes by increased β-HB.
Aging is the leading risk factor for the development of various cancers, neurodegenerative diseases, and cardiovascular disease. Dietary manipulation, such as calorie restriction or a ketogenic diet, alleviates these age-associated diseases through upregulation of circulating β-HB. The increase in β-HB, as depicted by the redshift of the arrow in the figure, improves metabolic complications caused by insulin resistance, reduces cellular aging phenotypes, including senescence and inflammation, and regenerates sciatic nerves.
Fig. 2. Dietary manipulation or supplementation to…
Fig. 2. Dietary manipulation or supplementation to induce β-HB elevation.
There are multiple ways to increase β-HB in circulation. The β-HB level is controlled by lipolysis in adipose tissue. A ketogenic diet and calorie restriction are the most well-known dietary manipulations used to stimulate lipolysis. Lipolysis-induced FFA is converted to β-HB through β-oxidation in the liver. SGLT2 inhibition also elevates β-HB levels by shifting substrate utilization from carbohydrate to ketone bodies through lipolysis or glucosuria. KEs have recently been developed as a commercially available β-HB supplement.
Fig. 3. Inhibition, activation, and posttranslational modification…
Fig. 3. Inhibition, activation, and posttranslational modification by β-HB.
β-HB directly or indirectly interacts with many cellular proteins in different organelles. β-HB acts as an agonist or antagonist to the two GPCRs FFAR3 and HCAR2 in the plasma membrane. β-HB directly binds to hnRNP A1 to regulate Oct4 mRNA stability. β-HB suppresses inflammation through inhibition of NRLP3 inflammasome formation or its activity. Specifically, β-HB also regulates nuclear proteins. β-HB is an HDAC inhibitor that also regulates histones and p53 through β-hydroxybutyrylation.
Fig. 4. The overall molecular mechanisms underlying…
Fig. 4. The overall molecular mechanisms underlying the β-HB-associated effects on aging.
Target molecules and cellular signaling of β-HB are associated with the aging process, which is accelerated by senescence and inflammation. β-HB delays senescence via HDAC inhibition, hnRNP A1-mediated Oct4 expression, and β-hydroxybutyrylation on p53. Furthermore, β-HB suppresses inflammation by NLRP3 inhibition or HCAR2 activation and reduces the contribution to aging-associated diseases.

References

    1. UN. (2015).
    1. UN Department of Economic and Social Affairs. World Population Ageing 2013, (2013).
    1. Fielding RA, et al. The paradox of overnutrition in aging and cognition. Ann. N. Y. Acad. Sci. 2013;1287:31–43.
    1. Sundrum A. Metabolic disorders in the transition period indicate that the dairy cows’ ability to adapt is overstressed. Animals (Basel) 2015;5:978–1020.
    1. Nettle D, Andrews C, Bateson M. Food insecurity as a driver of obesity in humans: the insurance hypothesis. Behav. Brain Sci. 2017;40:e105.
    1. Heilbronn LK, Ravussin E. Calorie restriction and aging: review of the literature and implications for studies in humans. Am. J. Clin. Nutr. 2003;78:361–369.
    1. Meynet O, Ricci JE. Caloric restriction and cancer: molecular mechanisms and clinical implications. Trends Mol. Med. 2014;20:419–427.
    1. Witte AV, Fobker M, Gellner R, Knecht S, Floel A. Caloric restriction improves memory in elderly humans. Proc. Natl Acad. Sci. USA. 2009;106:1255–1260.
    1. Goldenberg RM, et al. SGLT2 inhibitor-associated diabetic ketoacidosis: clinical review and recommendations for prevention and diagnosis. Clin. Ther. 2016;38:2654–2664 e2651.
    1. Cox PJ, et al. Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. Cell Metab. 2016;24:256–268.
    1. Veech RL, et al. Ketone bodies mimic the life span extending properties of caloric restriction. IUBMB Life. 2017;69:305–314.
    1. Evans M, Cogan KE, Egan B. Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation. J. Physiol. 2017;595:2857–2871.
    1. Roberts MN, et al. A ketogenic diet extends longevity and healthspan in adult mice. Cell Metab. 2018;27:1156.
    1. Edwards C, et al. D-beta-hydroxybutyrate extends lifespan in C. elegans. Aging (Albany NY) 2014;6:621–644.
    1. Han YM, et al. beta-hydroxybutyrate prevents vascular senescence through hnRNP A1-mediated upregulation of Oct4. Mol. Cell. 2018;71:1064–1078 e1065.
    1. Newman JC, et al. Ketogenic diet reduces midlife mortality and improves memory in aging mice. Cell Metab. 2017;26:547–557 e548.
    1. Singh PB, Newman AG. Age reprogramming and epigenetic rejuvenation. Epigenetics Chromatin. 2018;11:73.
    1. Liskiewicz A, et al. Sciatic nerve regeneration in rats subjected to ketogenic diet. Nutr. Neurosci. 2016;19:116–124.
    1. Stumpf SK, et al. Ketogenic diet ameliorates axonal defects and promotes myelination in Pelizaeus-Merzbacher disease. Acta Neuropathol. 2019;138:147–161.
    1. Cheng CW, et al. Ketone body signaling mediates intestinal stem cell homeostasis and adaptation to diet. Cell. 2019;178:1115–1131 e1115.
    1. Aunan JR, Cho WC, Soreide K. The biology of aging and cancer: a brief overview of shared and divergent molecular hallmarks. Aging Dis. 2017;8:628–642.
    1. Kumari S, Badana AK, Gmm GS, Malla R. Reactive oxygen species: a key constituent in cancer survival. Biomark. Insights. 2018;13:1177271918755391.
    1. Allen BG, et al. Ketogenic diets as an adjuvant cancer therapy: history and potential mechanism. Redox Biol. 2014;2:963–970.
    1. Klement RJ, Champ CE, Otto C, Kammerer U. Anti-tumor effects of ketogenic diets in mice: a meta-analysis. PLoS ONE. 2016;11:e0155050.
    1. Poff AM, Ari C, Seyfried TN, D’Agostino DP. The ketogenic diet and hyperbaric oxygen therapy prolong survival in mice with systemic metastatic cancer. PLoS ONE. 2013;8:e65522.
    1. Otto C, et al. Growth of human gastric cancer cells in nude mice is delayed by a ketogenic diet supplemented with omega-3 fatty acids and medium-chain triglycerides. BMC Cancer. 2008;8:122.
    1. Klement RJ, Kammerer U. Is there a role for carbohydrate restriction in the treatment and prevention of cancer? Nutr. Metab. (Lond.) 2011;8:75.
    1. Fine EJ, et al. Targeting insulin inhibition as a metabolic therapy in advanced cancer: a pilot safety and feasibility dietary trial in 10 patients. Nutrition. 2012;28:1028–1035.
    1. Gluschnaider U, et al. Long-chain fatty acid analogues suppress breast tumorigenesis and progression. Cancer Res. 2014;74:6991–7002.
    1. Varshneya K, Carico C, Ortega A, Patil CG. The efficacy of ketogenic diet and associated hypoglycemia as an adjuvant therapy for high-grade gliomas: a review of the literature. Cureus. 2015;7:e251.
    1. Jansen N, Walach H. The development of tumours under a ketogenic diet in association with the novel tumour marker TKTL1: a case series in general practice. Oncol. Lett. 2016;11:584–592.
    1. Champ CE, et al. Targeting metabolism with a ketogenic diet during the treatment of glioblastoma multiforme. J. Neurooncol. 2014;117:125–131.
    1. Klement RJ, Sweeney RA. Impact of a ketogenic diet intervention during radiotherapy on body composition: I. Initial clinical experience with six prospectively studied patients. BMC Res. Notes. 2016;9:143.
    1. Schmidt M, Pfetzer N, Schwab M, Strauss I, Kammerer U. Effects of a ketogenic diet on the quality of life in 16 patients with advanced cancer: a pilot trial. Nutr. Metab. (Lond.) 2011;8:54.
    1. Sen A, Capelli V, Husain M. Cognition and dementia in older patients with epilepsy. Brain. 2018;141:1592–1608.
    1. Vossel KA, Tartaglia MC, Nygaard HB, Zeman AZ, Miller BL. Epileptic activity in Alzheimer’s disease: causes and clinical relevance. Lancet Neurol. 2017;16:311–322.
    1. Wu Q, et al. Ketogenic diet effects on 52 children with pharmacoresistant epileptic encephalopathy: a clinical prospective study. Brain Behav. 2018;8:e00973.
    1. Appavu B, Vanatta L, Condie J, Kerrigan JF, Jarrar R. Ketogenic diet treatment for pediatric super-refractory status epilepticus. Seizure. 2016;41:62–65.
    1. Kossoff EH, Wang HS. Dietary therapies for epilepsy. Biomed. J. 2013;36:2–8.
    1. Neal EG, et al. The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol. 2008;7:500–506.
    1. Olson CA, et al. The gut microbiota mediates the anti-seizure effects of the ketogenic diet. Cell. 2018;174:497.
    1. Cao W, Zheng H. Peripheral immune system in aging and Alzheimer’s disease. Mol. Neurodegener. 2018;13:51.
    1. Kashiwaya Y, et al. A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer’s disease. Neurobiol. Aging. 2013;34:1530–1539.
    1. Brownlow ML, Benner L, D’Agostino D, Gordon MN, Morgan D. Ketogenic diet improves motor performance but not cognition in two mouse models of Alzheimer’s pathology. PLoS ONE. 2013;8:e75713.
    1. Beckett TL, Studzinski CM, Keller JN, Paul Murphy M, Niedowicz DM. A ketogenic diet improves motor performance but does not affect beta-amyloid levels in a mouse model of Alzheimer’s disease. Brain Res. 2013;1505:61–67.
    1. Hertz L, Chen Y, Waagepetersen HS. Effects of ketone bodies in Alzheimer’s disease in relation to neural hypometabolism, beta-amyloid toxicity, and astrocyte function. J. Neurochem. 2015;134:7–20.
    1. Newport MT, VanItallie TB, Kashiwaya Y, King MT, Veech RL. A new way to produce hyperketonemia: use of ketone ester in a case of Alzheimer’s disease. Alzheimers Dement. 2015;11:99–103.
    1. Cheng B, et al. Ketogenic diet protects dopaminergic neurons against 6-OHDA neurotoxicity via up-regulating glutathione in a rat model of Parkinson’s disease. Brain Res. 2009;1286:25–31.
    1. Tieu K, et al. D-beta-hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease. J. Clin. Invest. 2003;112:892–901.
    1. Jura M, Kozak LP. Obesity and related consequences to ageing. Age (Dordr.) 2016;38:23.
    1. Brehm BJ, Seeley RJ, Daniels SR, D’Alessio DA. A randomized trial comparing a very low carbohydrate diet and a calorie-restricted low fat diet on body weight and cardiovascular risk factors in healthy women. J. Clin. Endocrinol. Metab. 2003;88:1617–1623.
    1. Moreno B, et al. Comparison of a very low-calorie-ketogenic diet with a standard low-calorie diet in the treatment of obesity. Endocrine. 2014;47:793–805.
    1. Yancy WS, Jr, Olsen MK, Guyton JR, Bakst RP, Westman EC. A low-carbohydrate, ketogenic diet versus a low-fat diet to treat obesity and hyperlipidemia: a randomized, controlled trial. Ann. Intern. Med. 2004;140:769–777.
    1. Dashti HM, et al. Long-term effects of a ketogenic diet in obese patients. Exp. Clin. Cardiol. 2004;9:200–205.
    1. Gibson AA, et al. Do ketogenic diets really suppress appetite? A systematic review and meta-analysis. Obes. Rev. 2015;16:64–76.
    1. Kinzig KP, Honors MA, Hargrave SL. Insulin sensitivity and glucose tolerance are altered by maintenance on a ketogenic diet. Endocrinology. 2010;151:3105–3114.
    1. Kalyani RR, Egan JM. Diabetes and altered glucose metabolism with aging. Endocrinol. Metab. Clin. North Am. 2013;42:333–347.
    1. Yancy WS, Jr, Foy M, Chalecki AM, Vernon MC, Westman EC. A low-carbohydrate, ketogenic diet to treat type 2. diabetes Nutr. Metab. (Lond.) 2005;2:34.
    1. Farres J, et al. Revealing the molecular relationship between type 2 diabetes and the metabolic changes induced by a very-low-carbohydrate low-fat ketogenic diet. Nutr. Metab. (Lond.) 2010;7:88.
    1. Hussain TA, et al. Effect of low-calorie versus low-carbohydrate ketogenic diet in type 2 diabetes. Nutrition. 2012;28:1016–1021.
    1. Bertolotti M, et al. Nonalcoholic fatty liver disease and aging: epidemiology to management. World J. Gastroenterol. 2014;20:14185–14204.
    1. Browning JD, et al. Short-term weight loss and hepatic triglyceride reduction: evidence of a metabolic advantage with dietary carbohydrate restriction. Am. J. Clin. Nutr. 2011;93:1048–1052.
    1. Tendler D, et al. The effect of a low-carbohydrate, ketogenic diet on nonalcoholic fatty liver disease: a pilot study. Dig. Dis. Sci. 2007;52:589–593.
    1. Pasyukova EG, Vaiserman AM. HDAC inhibitors: a new promising drug class in anti-aging research. Mech. Ageing Dev. 2017;166:6–15.
    1. Shimazu T, et al. Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science. 2013;339:211–214.
    1. Huang C, et al. The ketone body metabolite beta-hydroxybutyrate induces an antidepression-associated ramification of microglia via HDACs inhibition-triggered Akt-small RhoGTPase activation. Glia. 2018;66:256–278.
    1. Gao Z, et al. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes. 2009;58:1509–1517.
    1. Chriett S, et al. Prominent action of butyrate over beta-hydroxybutyrate as histone deacetylase inhibitor, transcriptional modulator and anti-inflammatory molecule. Sci. Rep. 2019;9:742.
    1. Taggart, A. K. et al. (D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J. Biol. Chem. 280, 26649–26652 (2005) .
    1. Dobbins RL, et al. GSK256073, a selective agonist of G-protein coupled receptor 109A (GPR109A) reduces serum glucose in subjects with type 2 diabetes mellitus. Diabetes Obes. Metab. 2013;15:1013–1021.
    1. Rahman M, et al. The beta-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages. Nat. Commun. 2014;5:3944.
    1. Kimura I, et al. Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41) Proc. Natl Acad. Sci. USA. 2011;108:8030–8035.
    1. Wang H, et al. hnRNP A1 antagonizes cellular senescence and senescence-associated secretory phenotype via regulation of SIRT1 mRNA stability. Aging Cell. 2016;15:1063–1073.
    1. Zhu D, Xu G, Ghandhi S, Hubbard K. Modulation of the expression of p16INK4a and p14ARF by hnRNP A1 and A2 RNA binding proteins: implications for cellular senescence. J. Cell Physiol. 2002;193:19–25.
    1. Deng H, Gao K, Jankovic J. The role of FUS gene variants in neurodegenerative diseases. Nat. Rev. Neurol. 2014;10:337–348.
    1. Thomas-Jinu S, et al. Non-nuclear pool of splicing factor SFPQ regulates axonal transcripts required for normal motor development. Neuron. 2017;94:322–336 e325.
    1. Johnson JB, et al. Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma. Free Radic. Biol. Med. 2007;42:665–674.
    1. Youm YH, et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat. Med. 2015;21:263–269.
    1. Xie Z, et al. Metabolic regulation of gene expression by histone lysine beta-Hydroxybutyrylation. Mol. Cell. 2016;62:194–206.
    1. Liu K, et al. p53 beta-hydroxybutyrylation attenuates p53 activity. Cell Death Dis. 2019;10:243.
    1. Abmayr SM, Workman JL. Histone lysine de-beta-hydroxybutyrylation by SIRT3. Cell Res. 2019;29:694–695.

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