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Β-Hydroxybutyrate and Its Metabolic Effects on Age-Associated Pathology Young-Min Han 1, Tharmarajan Ramprasath 1 and Ming-Hui Zou1

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Β-Hydroxybutyrate and Its Metabolic Effects on Age-Associated Pathology Young-Min Han 1, Tharmarajan Ramprasath 1 and Ming-Hui Zou1 Han et al. Experimental & Molecular Medicine (2020) 52:548–555 https://doi.org/10.1038/s12276-020-0415-z Experimental & Molecular Medicine REVIEW ARTICLE Open Access β-hydroxybutyrate and its metabolic effects on age-associated pathology Young-Min Han 1, Tharmarajan Ramprasath 1 and Ming-Hui Zou1 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. Introduction opportunities for its application as a therapeutic target for Aging, along with its associated ailments, including the treatment or prevention of human diseases. Based on β 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; cardiovascular disease, cancer, arthritis, dementia, catar- the potential of -HB, this review describes the direct and acts, osteoporosis, diabetes, hypertension, and Alzhei- indirect effects of β-HB on the regulation of signals mer’s disease, is a primary health concern. Accumulating involved in inflammation, senescence, and apoptosis. This data demonstrate that a ketogenic diet elevates the levels review also describes the effect of ketogenic diets and/or of β-hydroxybutyrate (β-HB), improving many age-related ketone ester (KE) treatment as well as the molecular diseases (Fig. 1). Indeed, β-HB appears to act as a reg- mechanisms and targets of these interventions on aging- ulator of cellular signaling via numerous pathways in related diseases, such as cancer, cardiovascular disease, various cellular organelles in a manner that is indepen- and neurodegenerative diseases. dent of nicotinamide adenine dinucleotide (NAD) levels. Reports have verified that β-HB controls many cellular Aging epidemics and the global public health signals via its function as a ligand, regulates gene emergency expression, inhibits or activates protein functions, and A worldwide increase in the elderly population caused plays a role in neuronal functions. Thus, identification of by declining fertility and increased life expectancy is the molecular targets of β-HB will provide a better thought to represent one of the most significant global understanding of how calorie restriction or a ketogenic health emergencies of the 21st century. Geriatric syn- diet improves age-related disease symptoms. Stemming dromes that affect this aging population are characterized from the current evidence, investigation of the detailed by the emergence of several complex health states that molecular capacity of β-HB will provide new render individuals vulnerable to many disease conditions. The number of people aged 65 years or older is projected to increase from an estimated 524 million in 2010 to Correspondence: Young-Min Han ([email protected]) nearly 1.5 billion in 2050, with the majority of the increase 1Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA, USA occurring in developing countries. While the invention of These authors contributed equally: Young-Min Han, Tharmarajan Ramprasath © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Korean Society for Biochemistry and Molecular Biology Han et al. Experimental & Molecular Medicine (2020) 52:548–555 549 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 fi the gure, improves metabolic complications caused by insulin Fig. 2 Dietary manipulation or supplementation to induce β-HB resistance, reduces cellular aging phenotypes, including senescence elevation. There are multiple ways to increase β-HB in circulation. The fl and in ammation, and regenerates sciatic nerves. 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 modern therapies extends life expectancy, these levels by shifting substrate utilization from carbohydrate to ketone advancements also increase aging-based noncommunic- bodies through lipolysis or glucosuria. KEs have recently been able diseases that impose a considerable burden on the developed as a commercially available β-HB supplement. global population1,2. Reducing severe disability from dis- ease is key to minimizing health and social costs as the population increases. ketone body reabsorption in the kidney, and increased β-HB9. KEs are hydrolyzed by nonspecific gut esterases in Feeding-fasting effects on aging the small intestine and liberate β-HB and (R)-1,3-butane- At all stages of life, nutrient requirements are essential; diol, thus increasing the level of β-HB in the circulation10. however, overnutrition is strongly associated with serious Since ketone body metabolism is highly activated dur- health conditions and an enhanced aging process3. Var- ing calorie restriction or in glucose-deprived metabolic ious species of animals have developed diverse nutritional conditions, ketone bodies are considered crucial meta- and metabolic mechanisms to adapt to sudden nutritional bolites for calorie restriction-induced antiaging pheno- changes4. In particular, these diverse metabolic control types11. Therefore, in-depth research is required to mechanisms provide a resilient or flexible adaptation to establish the effects of ketone body-associated ther- stress from food insecurity as well as overeating5. Food apeutic intervention on aging and age-related diseases. availability has a very close and direct effect on health. Physiologically produced ketones travel to peripheral Specifically, calorie restriction or intermittent fasting is tissues and are used as an energy source as an alternative currently the most effective dietary intervention to pro- to glucose. In particular, β-HB is the most abundant long a healthy lifespan6 and prevent cancer development7. ketone body absorbed as an alternative energy source by Moreover, studies have demonstrated that caloric peripheral tissues, such as the muscles, heart, and brain, restriction improves memory in elderly humans8. in various animal species. β-HB is derived in the liver from the β-oxidation of free fatty acids (FFAs) that are β-HB levels contribute to antiaging phenotypes produced via lipolysis of adipose tissues during periods of Approaches to increase circulating β-HB by dietary glucose deficiency. Circulating β-HB is converted to manipulation or ingestion of supplements have been acetyl-CoA via the ketosis pathway in the muscles, heart, examined via four different routes: a ketogenic diet, calorie and brain, and this intermediate is then further used to restriction, KE administration, and sodium-glucose trans- generate adenosine triphosphate (ATP) via the citric acid port protein 2 (SGLT2) inhibition (Fig. 2). The ketogenic cycle12. Although numerous studies have been conducted diet, calorie restriction, and SGLT2 inhibition induce on the function of β-HB as an alternative energy source, ketogenesis in the liver through lipolysis. In particular, the role of β-HB as a signaling metabolite during some SGLT2 inhibition decreases insulin secretion from β cells, pathophysiological conditions remains an unclear, albeit resulting in lipolysis in adipose tissues, regulation of very interesting, topic. Official journal of the Korean Society for Biochemistry and Molecular Biology Han et al. Experimental & Molecular Medicine (2020) 52:548–555 550 Benefits of β-HB on aging and associated diseases aerobic glycolysis, known
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