Re: 음식 치료제(항암제) 베타 하이드로뷰티르산 2023년 논문

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케톤 생성법

1. 탄수화물 차단식이요법 + 지방식이

2. 90분 격렬한 운동  

3. 케톤생성 아미노산(류신, 리신)

A ketogenic amino acid is an amino acid that can be degraded directly into acetyl-CoA, which is the precursor of ketone bodies and myelin, particularly during early childhood, when the developing brain requires high rates of myelin synthesis.[1] This is in contrast to the glucogenic amino acids, which are converted into glucose. Ketogenic amino acids are unable to be converted to glucose as both carbon atoms in the ketone body are ultimately degraded to carbon dioxide in the citric acid cycle.

In humans, two amino acids – leucine and lysine – are exclusively ketogenic. Five more are both ketogenic and glucogenic: phenylalanine, isoleucine, threonine, tryptophan and tyrosine. The remaining thirteen are exclusively glucogenic.[2]

Review article

Function and treatment strategies of β-hydroxybutyrate in aging

Author links open overlay panelYang Xiang a e 1, Qi-Quan Wang a 1, Xin-Qiang Lan a, Hui-Jie Zhang a, Dai-Xu Wei b c d

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Abstract

Metabolic intermediates serve as precursors for bioactive molecule synthesis, the energy source for life activities, and signals for environmental adaptation. Ketone bodies are important metabolic intermediates produced in the liver by the degradation of fatty acids, acting as an alternative energy source for extrahepatic tissues when glucose is short in supply (especially during starvation). β-hydroxybutyric acid, with its conjugate base β-hydroxybutyrate, constitutes approximately 70% of ketone bodies. A growing number of studies have demonstrated the beneficial effects of β-hydroxybutyrate, especially in delaying aging, intervening in aging-related disease, and promoting longevity.

대사 중간체는 생명 활동의 에너지원이자, 환경 적응을 위한 신호인 생리활성 분자 합성의 전구체 역할을 합니다. 케톤체는 지방산이 분해되어 간에서 생성되는 중요한 대사 중간체로, 포도당 공급이 부족할 때(특히 기아 상태) 간외 조직의 대체 에너지원으로 작용합니다. β-하이드록시부티르산은 공액 염기인 β-하이드록시부티레이트와 함께 케톤체의 약 70%를 구성합니다. β-하이드록시부티레이트의 유익한 효과, 특히 노화 지연, 노화 관련 질병에 대한 개입 및 수명 촉진에 대한 연구가 점점 더 많이 입증되고 있습니다. 

This review systematically reviews the role of β-hydroxybutyrate in aging hallmarks, shedding light on the possible molecular mechanism by which β-hydroxybutyrate supports healthy aging. Higher circulating β-hydroxybutyrate can be achieved by lifestyle modification (ketogenic diet or caloric restriction) or exogenous β-hydroxybutyrate (or β-hydroxybutyrate precursors, derivates and agonists) supplementation. We will also discuss the pros and cons of different ways to upregulate β-hydroxybutyrate, emphasizing the promising future clinical use of poly-β-hydroxybutyrate, the polymers of β-hydroxybutyrate, which can be easily produced via a microbial platform and synthetic biology.

이 리뷰에서는 노화 특징에서 β-하이드록시부티레이트의 역할을 체계적으로 검토하여 β-하이드록시부티레이트가 건강한 노화를 지원하는 가능한 분자 메커니즘에 대해 조명합니다. β-하이드록시부티레이트는 생활 습관 수정(케토제닉 식단 또는 칼로리 제한) 또는 외인성 β-하이드록시부티레이트(또는 β-하이드록시부티레이트 전구체, 유도체 및 작용제) 보충을 통해 더 높은 순환 β-하이드록시부티레이트 수치를 달성할 수 있습니다. 또한 미생물 플랫폼과 합성 생물학을 통해 쉽게 생산할 수 있는 β-하이드록시부티레이트의 고분자인 폴리-β-하이드록시부티레이트의 유망한 미래 임상 사용을 강조하면서 β-하이드록시부티레이트의 상향 조절을 위한 다양한 방법의 장단점에 대해 논의할 예정입니다.

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Keywords

β-hydroxybutyrate

Aging

Aging hallmarks

Poly-β-hydroxybutyrate

1. Introduction

Life feeds on negative entropy to maintain homeostatic processes [1]. Aging is characterized by a degenerative change in homeostatic processes over time, resulting in functional decline and an increased risk for diseases and death. Metabolism plays a central role in aging and longevity [2]. Metabolic manipulation by lifestyle modification has been demonstrated to delay aging, prevent aging-related disease and promote longevity. As early as 1935, McCay reported that reduced intake of nutrients without malnutrition (caloric restriction, CR) could increase the mean and maximum lifespan of rats [3,4]. CR has been proven to delay aging and promote longevity among various species, from yeast to primates [5]. A ketogenic diet, with very low carbohydrate intake, was shown to extend lifespan in mammals [6]. A variety of other lifestyle modifications, for example, the Atkins diet, intermittent and periodic fasting are beneficial for healthy aging. Lifestyle modifications generally change the structure of energy sources, which may contribute to their effect on aging and longevity [7]. Study on successfully aging individuals – centenarians, by integrated pathway analysis showed that metabolic pathways including starch, sucrose and xenobiotic metabolism are highly associated with longevity in Han Chinese [8].

생명체는 항상성 과정을 유지하기 위해 마이너스 엔트로피를 사용합니다[1]. 노화는 시간이 지남에 따라 항상성 과정의 퇴행성 변화로 인해 기능이 저하되고 질병과 사망 위험이 증가하는 특징이 있습니다. 신진대사는 노화와 장수의 핵심적인 역할을 합니다[2]. 생활 습관 교정을 통한 신진대사 조절은 노화를 지연시키고 노화 관련 질병을 예방하며 장수를 촉진하는 것으로 입증되었습니다. 일찍이 1935년에 McCay는 영양실조 없이 영양소 섭취를 줄이면(칼로리 제한, CR) 쥐의 평균 수명과 최대 수명을 늘릴 수 있다고 보고했습니다[3,4]. CR은 효모에서 영장류에 이르기까지 다양한 종에서 노화를 지연시키고 장수를 촉진하는 것으로 입증되었습니다 [5]. 탄수화물 섭취량이 매우 낮은 케톤 생성 식단은 포유류의 수명을 연장하는 것으로 나타났습니다 [6]. 앳킨스 다이어트, 간헐적 단식, 주기적 단식 등 다양한 다른 생활 습관 수정은 건강한 노화에 도움이 됩니다. 라이프스타일 수정은 일반적으로 에너지원의 구조를 변화시켜 노화와 장수에 영향을 미칠 수 있습니다[7]. 통합 경로 분석을 통한 성공적인 노화 개인(100세 노인)에 대한 연구에 따르면 전분, 자당 및 이종 생물 대사를 포함한 대사 경로가 한족의 장수와 관련이 높은 것으로 나타났습니다[8].

Metabolic intermediates play a pivotal role in the beneficial effect of these health-promoting lifestyles. The tricarboxylic acid (TCA) cycle intermediates α-ketoglutarate and citrate have been proven to extend lifespan or improve aging-related diseases [9,10]. The crucial role of these metabolic intermediates in aging and longevity opens a novel path for aging-delaying and longevity drugs or drug leads. 

대사 중간체는 이러한 건강 증진 생활 방식의 유익한 효과에 중추적인 역할을 합니다. 트리카르복실산(TCA) 사이클 중간체 α-케토글루타레이트와 구연산염은 수명을 연장하거나 노화 관련 질병을 개선하는 것으로 입증되었습니다[9,10]. 노화와 수명에 있어 이러한 대사 중간체의 중요한 역할은 노화 지연 및 장수 약물 또는 약물 리드를 위한 새로운 경로를 열어줍니다. 

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Ketone bodies, including acetoacetate, β-hydroxybutyrate and acetone, are well known as alternative energy sources for extrahepatic tissues when glucose is short in supply. β-hydroxybutyric acid, with its conjugate base β-hydroxybutyrate, constitutes approximately 70% of ketone bodies. Numerous studies have demonstrated the beneficial effect of β-hydroxybutyrate in delaying aging, intervening in aging-related disease and promoting longevity. We will review the regulation of β-hydroxybutyrate production and utilization, the role of β-hydroxybutyrate in aging hallmarks and how circulating β-hydroxybutyrate is upregulated and further improves its beneficial health effects in this review.

아세토아세테이트, β-하이드록시부티레이트, 아세톤을 포함한 케톤체는 포도당 공급이 부족할 때 간외 조직을 위한 대체 에너지원으로 잘 알려져 있습니다. β-하이드록시부티르산은 공액 염기인 β-하이드록시부티레이트와 함께 케톤체의 약 70%를 구성합니다. 수많은 연구에서 β-하이드록시부티레이트가 노화를 지연시키고 노화 관련 질병에 개입하며 장수를 촉진하는 유익한 효과가 입증되었습니다. 이번 리뷰에서는 β-하이드록시부티레이트 생산 및 활용의 조절, 노화 특징에서 β-하이드록시부티레이트의 역할, 순환하는 β-하이드록시부티레이트가 어떻게 상향 조절되고 건강에 유익한 효과를 더욱 향상시키는지에 대해 살펴봅니다.

2. Regulation of β-hydroxybutyrate (BHB) production and utilization

BHB is mainly produced by the liver and utilized as an alternative fuel by extrahepatic tissues under certain circumstances, such as starvation. As mentioned above, BHB constitutes approximately 70% of ketone bodies [11]. The production of ketone bodies in the liver of human beings is well known to occur by the breakdown of fatty acids and ketogenic amino acids [11]. Under specific metabolic conditions, such as fasting, carbohydrate-restrictive diets, starvation, and prolonged strenuous exercise, two molecules of acetyl-CoA derived from fatty acid β-oxidation or ketogenic amino acids are condensed to form acetoacetyl-CoA. 3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) is formed when acetoacetyl-CoA is conjugated to another molecule of acetyl-CoA under the catalysis of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2). HMG-CoA is also the intermediate for the meval‎onate pathway for cholesterol synthesis. The ketone body acetoacetate is formed under the catalysis of 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL) by releasing one acetyl-CoA molecule. Part of the acetoacetate can be reduced to BHB under the catalysis of hydroxybutyrate dehydrogenase (HBDH).

BHB는 주로 간에서 생성되며 굶주림과 같은 특정 상황에서 간외 조직에서 대체 연료로 활용됩니다. 위에서 언급했듯이 BHB는 케톤체의 약 70%를 구성합니다[11]. 인간의 간에서 케톤체의 생성은 지방산의 분해와 케톤 생성 아미노산에 의해 발생하는 것으로 잘 알려져 있습니다 [11]. 단식, 탄수화물 제한 식단, 굶주림, 장기간의 격렬한 운동과 같은 특정 대사 조건에서 지방산 β-산화 또는 케톤 생성 아미노산에서 파생된 두 분자의 아세틸-CoA가 응축되어 아세토아세틸-CoA를 형성합니다. 3-하이드록시-3-메틸글루타릴-CoA(HMG-CoA)는 3-하이드록시-3-메틸글루타릴-CoA 신타제 2(HMGCS2)의 촉매 작용으로 아세토아세틸-CoA가 다른 아세틸-CoA 분자와 접합될 때 형성됩니다. HMG-CoA는 콜레스테롤 합성을 위한 메발로네이트 경로의 중간체이기도 합니다. 케톤체 아세토아세테이트는 3-하이드록시-3-메틸글루타릴-CoA 리아제(HMGCL)의 촉매 작용에 의해 하나의 아세틸-CoA 분자를 방출하여 형성됩니다. 아세토아세테이트의 일부는 하이드록시부티레이트 탈수소효소(HBDH)의 촉매 작용에 의해 BHB로 환원될 수 있습니다.

Both acetoacetate and BHB can enter the bloodstream and are readily taken up by extrahepatic tissues, including the brain, heart, and muscle. A low proportion of acetoacetate can be nonenzymatically decarboxylated to produce acetone, a volatile ketone that can appear in the breath [12] (Fig. 1a). That BHB can only be synthesized in the liver has been assumed for a long time because the key enzyme for ketogenesis, HMGCS2, is only found expressed in hepatocytes. However, recent studies during the last decade showed that BHB and other ketone bodies could also be produced by astrocytes of the central nervous system [13], the kidney [14], pancreatic β cells [15], retinal pigment epithelium [16] and tumor cells [17] under certain circumstances.

아세토아세테이트와 BHB는 모두 혈류로 들어가 뇌, 심장, 근육을 포함한 간외 조직에 쉽게 흡수될 수 있습니다. 소량의 아세토아세테이트는 비효소적으로 탈카르복실화되어 호흡에 나타날 수 있는 휘발성 케톤인 아세톤을 생성할 수 있습니다[12](그림 1a). 케톤 생성의 핵심 효소인 HMGCS2가 간세포에서만 발현되기 때문에 BHB는 간에서만 합성될 수 있다고 오랫동안 추정되어 왔습니다. 그러나 지난 10년간의 최근 연구에 따르면 특정 상황에서 중추신경계[13], 신장[14], 췌장 베타세포[15], 망막 색소 상피[16], 종양 세포[17]에서도 BHB 및 기타 케톤체가 생성될 수 있다는 사실이 밝혀졌습니다.

With advances in single-cell omics sequencing technologies, whether other specific cell types in extrahepatic tissues that produce ketone bodies can be identified is unknown [18]. Notably, BHB can further be used to synthesize poly(BHB) (PHB) in bacteria for energy storage, like polysaccharides, lipids, and proteins [19]. As a polymer of BHB, PHB, the simplest member in polyhydroxyalkanoates (PHAs), provides novel therapeutics for ketone body generation for health intervention [20]. Similarly, other PHAs as PHB derivatives can be designed as medical devices for tissue regeneration [[21], [22], [23], [24]] and drug carriers [[25], [26], [27], [28]], which showed excellent biocompatibility in regenerative medicine. These polymers released self-degraded monomer (BHB) are more beneficial for specific applications in tissue engineering [[29], [30], [31], [32]], which is superior to other scaffolds with addition of external bioactive factors [[33], [34], [35], [36], [37], [38]].

단일 세포 오믹스 시퀀싱 기술의 발전으로 케톤체를 생성하는 간외 조직의 다른 특정 세포 유형을 식별할 수 있는지 여부는 알려지지 않았습니다[18]. 특히, BHB는 다당류, 지질, 단백질과 같은 에너지 저장을 위해 박테리아에서 폴리(BHB)(PHB)를 합성하는 데 추가로 사용될 수 있습니다 [19]. 폴리하이드록시알카노에이트(PHA)에서 가장 단순한 구성 요소인 PHB는 BHB의 중합체로서 건강 개입을 위한 케톤체 생성을 위한 새로운 치료제를 제공합니다[20]. 마찬가지로, PHB 유도체로서 다른 PHA는 조직 재생용 의료기기[[21], [22], [23], [24]] 및 약물 운반체[[25], [26], [27], [28]]로 설계될 수 있으며 재생 의학에서 우수한 생체 적합성을 보여주었습니다. 이러한 폴리머는 자가분해 단량체(BHB)를 방출하여 조직공학의 특정 응용 분야에 더 유리하며[[29], [30], [31], [32]], 외부 생리활성 인자를 첨가한 다른 스캐폴드보다 우수합니다[[33], [34], [35], [36], [37], [38]].

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Fig. 1. Ketone body production and utilization.

a Hepatic ketogenesis and its regulation. β-Hydroxylbutyrate is produced from fatty acids or ketogenic amino acids (such as leucine) and enters the bloodstream through monocarboxylate transporters (MCTs). The enzymes are shown in blue. Factors for activation (transcriptional or posttranslational, green) or inhibition (posttranslational, red) of the key enzyme HMGCS2 are listed.

b Extrahepatic ketone body utilization and regulation. Extrahepatic tissues take up β-hydroxybutyrate via MCTs and utilize it as an energy source to enter the TCA cycle. Tyrosine nitration inhibits SCOT activity. mThiolase, mitochondrial thiolase; thiolase activity is encoded by at least 6 genes: ACAA1, ACAA2, ACAT1, ACAT2, HADHA, and HADHB.

Circulating BHB can be taken up and used as fuel to generate ATP by extrahepatic tissues, such as the heart, brain and muscle. In the cells of these extrahepatic tissues, BHB is first converted to acetoacetate by 3-hydroxy-n-butyrate dehydrogenase (BDH1) and then converted to acetoacetyl-CoA by succinyl-CoA:3-oxoacid-CoA transferase (SCOT). Mitochondrial acetoacetyl-CoA thiolase generates two acetyl-CoAs from acetoacetyl-CoAs and then enters the TCA cycle or is diverted to the lipogenesis or sterol synthesis pathways [39] (Fig. 1b). BHB cannot be utilized by the liver because hepatocytes lack the enzyme SCOT and mitochondrial acetoacetyl-CoA thiolase and are thus unable to metabolize BHB [40].

순환하는 BHB는 심장, 뇌, 근육과 같은 간외 조직에서 ATP를 생성하기 위한 연료로 흡수되어 사용될 수 있습니다. 이러한 간외 조직의 세포에서 BHB는 먼저 3-하이드록시-n-부티레이트 탈수소효소(BDH1)에 의해 아세토아세테이트로 전환된 다음, 숙시닐-CoA:3-옥소산-CoA 전이효소(SCOT)에 의해 아세토아세틸-CoA로 전환됩니다. 미토콘드리아 아세토아세틸-CoA 티올라제는 아세토아세틸-CoA에서 두 개의 아세틸-CoA를 생성한 다음 TCA 주기로 들어가거나 지방 생성 또는 스테롤 합성 경로로 전환됩니다[39](그림 1b). 간세포에는 효소 SCOT와 미토콘드리아 아세토아세틸-CoA 티올라제가 부족하여 BHB를 대사할 수 없기 때문에 간에서 BHB를 이용할 수 없습니다[40].

Ketone body generation and utilization are tightly regulated at the transcriptional, translational and posttranslational levels [41,42]. Because of the critical role of ketone bodies in energy metabolism during fasting, fasting-regulated transcription factors generally regulate both the production and utilization of ketone bodies. For example, the rate-limiting enzyme HMGCS2 is transcriptionally regulated by the forkhead box transcription factor FOXA2 and peroxisome proliferator-activated receptor alpha (PPARα), both of which are key transcription factors during fasting. FOXA2 directly binds to the promoter of HMGCS2 to activate its transcription to boost ketogenesis [43]. PPARα directly stimulates the transcription of HMGCS2 too, and mice lacking PPARα have reduced levels of ketogenesis [44]. The activity of HMGCS2 is also posttranslationally modified by acetylation, succinylation and palmitoylation. Both acetylation and succinylation reduced the activity of HMGCS2 [45]. Deacetylation of HMGCS2 at lysines 310, 447, and 473 by SIRT3 enhances its enzymatic activity [46]. In comparison, palmitoylation of HMGCS2 enhances its interaction with PPARα and transcription [47]. HMGCS2 is also identified to be β-hydroxybutyrylated by its terminal product BHB as a feedback [48]. Enzymes for BHB degradation in extrahepatic tissues are also posttranslationally regulated. Deacetylation sites were identified in BDH1 [49]. Tyrosine nitration resulted in inhibition of SCOT activity [50].

케톤체 생성 및 이용은 전사, 번역 및 번역 후 수준에서 엄격하게 조절됩니다[41,42]. 공복 중 에너지 대사에서 케톤체가 중요한 역할을 하기 때문에 공복 조절 전사인자는 일반적으로 케톤체의 생성과 활용을 모두 조절합니다. 예를 들어, 속도 제한 효소인 HMGCS2는 포크헤드 박스 전사인자 FOXA2와 퍼옥시좀 증식 촉진제 활성화 수용체 알파(PPARα)에 의해 전사적으로 조절되는데, 이 두 가지 전사인자는 공복 시 주요 전사인자입니다. FOXA2는 HMGCS2의 프로모터에 직접 결합하여 전사를 활성화하여 케톤 생성을 촉진합니다[43]. PPARα도 HMGCS2의 전사를 직접 자극하며, PPARα가 결핍된 마우스는 케톤 생성 수준이 감소합니다 [44]. HMGCS2의 활성은 아세틸화, 숙시닐화 및 팔미토일화에 의해 번역 후에도 변형됩니다. 아세틸화와 숙시닐화는 모두 HMGCS2의 활성을 감소시켰습니다 [45]. SIRT3에 의한 라이신 310, 447, 473에서 HMGCS2의 탈세틸화는 효소 활성을 향상시킵니다[46]. 이에 비해 HMGCS2의 팔미토일화는 PPARα 및 전사와의 상호 작용을 향상시킵니다 [47]. HMGCS2는 또한 피드백으로 말단 생성물인 BHB에 의해 β-하이드록시부티릴화되는 것으로 확인되었습니다 [48]. 간외 조직에서 BHB 분해를 위한 효소도 번역 후 조절됩니다. BDH1에서 탈세틸화 부위가 확인되었습니다 [49]. 티로신 질화는 SCOT 활성의 억제를 초래했습니다 [50].

Genetic mutations in genes encoding enzymes for ketone body production and utilization result in metabolic disorders. Patients with HMGCS2 deficiency present with hypoketotic hypoglycemia, encephalopathy and hepatomegaly, which usually occur and are aggravated by an intercurrent infection or prolonged fasting [51]. SCOT deficiency (caused by a mutation in the OXCT1 gene) resulted in intermittent ketoacidosis leading to infant death at six months [52]. Mutations in the OXCT1 gene have been reported in several populations [53]. However, healthy aging populations (centenarians, nonagenarians) possess rare coding variants on HMGCS2, OXCT1, HMGCL, and BDH1 that would result in functional alterations [54]. Whether mild perturbation (increased or decreased production) of ketone body metabolism in human can delay aging and extend lifespan in humans is a fascinating question. In mice models, the beneficial roles have been demonstrated in mice overexpressing Hmgcs2. Hmgcs2 heterozygous adult mice exhibited lower ketogenic activity, were more susceptible to diet-induced NAFLD development, but HMGCS2 overexpression‎ in NAFLD mice improved hepatosteatosis and glucose homeostasis [55].

케톤체 생성 및 활용을 위한 효소를 코딩하는 유전자의 유전적 돌연변이는 대사 장애를 초래합니다. HMGCS2 결핍 환자는 저칼륨성 저혈당증, 뇌병증 및 간 비대가 나타나며, 이는 일반적으로 동시 감염 또는 장기간의 금식으로 인해 발생하고 악화됩니다 [51]. SCOT 결핍(OXCT1 유전자의 돌연변이로 인해 발생)은 간헐적 케톤산증을 유발하여 6개월에 영아 사망으로 이어졌습니다[52]. OXCT1 유전자의 돌연변이는 여러 집단에서 보고되었습니다[53]. 그러나 건강한 노화 인구(100세 노인, 비노화 노인)는 기능적 변화를 초래할 수 있는 HMGCS2, OXCT1, HMGCL 및 BDH1의 드문 코딩 변이를 가지고 있습니다[54]. 인간의 케톤체 대사에 가벼운 교란(생산 증가 또는 감소)이 노화를 지연시키고 수명을 연장할 수 있는지 여부는 흥미로운 질문입니다. 마우스 모델에서 Hmgcs2가 과발현된 마우스에서 유익한 역할이 입증되었습니다. Hmgcs2 이형 접합성 성인 마우스는 케톤 생성 활성이 낮고 식이 요법으로 유도된 NAFLD 발병에 더 취약했지만, NAFLD 마우스에서 HMGCS2 과발현은 간지방증과 포도당 항상성을 개선했습니다[55].

The genetic variations, especially those rare variants, may affect HMGCS2 and other key enzymes at least by four ways: (1) variations in transcriptional regulatory elements such as promoters result in altered transcription efficiency; (2) variations in 3′ UTR or 5’ UTR result in altered mRNA stability; (3) synonymous mutations at protein coding region translation efficiency due to the codon preference; (4) nonsynonymous mutations result in increased or decreased enzymatic activities. The genetic variations and mutations which affect ketone body production and utilization suggest that individual differences should be considered during health interventions with BHB. Novel genetic variations will also provide clues for the development of agonists or inhibitors for key enzymes in ketone body metabolism.

유전적 변이, 특히 희귀 변이는 적어도 네 가지 방식으로 HMGCS2 및 기타 주요 효소에 영향을 미칠 수 있습니다: (1) 프로모터와 같은 전사 조절 요소의 변이는 전사 효율의 변화를 초래하고, (2) 3′ UTR 또는 5′ UTR의 변이는 mRNA 안정성의 변화를 초래하며, (3) 코돈 선호도로 인한 단백질 코딩 영역 번역 효율의 동의어 변이; (4) 비동의어 변이는 효소 활성의 증가 또는 감소를 초래합니다. 케톤체 생성 및 이용에 영향을 미치는 유전적 변이와 돌연변이는 BHB를 통한 건강 개입 시 개인차를 고려해야 함을 시사합니다. 새로운 유전적 변이는 케톤체 대사의 주요 효소에 대한 작용제 또는 억제제 개발에 대한 단서를 제공할 것입니다.

3. BHB as a signal metabolite

As the most abundant ketone body in mammals, apart from being alternative fuel sources and precursors of the synthesis of other metabolites (lipid acids and cholesterol) in extrahepatic tissues (reviewed by Patrycja Puchalska and Peter A. Crawford [56]), BHB is also a vital signal metabolite (reviewed by John C Newman and Eric Verdin [57]).

포유류에서 가장 풍부한 케톤체로서 간외 조직에서 대체 연료 공급원이자 다른 대사산물(지질산 및 콜레스테롤) 합성의 전구체(Patrycja Puchalska 및 Peter A. Crawford [56] 검토)일 뿐만 아니라 BHB는 중요한 신호 대사물질(John C Newman 및 Eric Verdin [57] 검토)이기도 합니다.

BHB can act as a cell membrane receptor agonist or antagonist. It directly binds at least two cell surface G-protein-coupled receptors, including HCAR2 and FFAR3. HCAR2 activation by BHB resulted in decelerated lipolysis in adipose tissue as negative feedback [58]. HCAR2 activation is beneficial for lowering circulating plasma free fatty acids and glucose in patients with type 2 diabetes [59]. HCAR2 activation by BHB is involved in anti-inflammation and neuroprotection [57]. Loss of GPR109A/HCAR2 induces aging-associated hepatic steatosis [60], indicating a role of HCAR2 activation by BHB in aging-related diseases. Another membrane GPCR, GPR41 (also known as FFAR3), can be antagonized by BHB to inhibit sympathetic activity [61]. The controversial role of BHB on GPR41 was also reported in that it acts as an agonist of GPR41 to regulate voltage-dependent calcium channels [62]. Thus, further work is needed to confirm‎ the activity of BHB on GPR41. BHB acts on histone deacetylases (HDACs) to regulate histone posttranslational modification [63] and as a substrate for histone lysine β-hydroxybutyrylation [64].

BHB는 세포막 수용체 작용제 또는 길항제로 작용할 수 있습니다. HCAR2 및 FFAR3를 포함하여 적어도 두 개의 세포 표면 G 단백질 결합 수용체와 직접 결합합니다. BHB에 의한 HCAR2 활성화는 부정적인 피드백으로 지방 조직에서 지방 분해를 감소시켰습니다 [58]. HCAR2 활성화는 제2형 당뇨병 환자의 순환 혈장 유리 지방산과 포도당을 낮추는 데 도움이 됩니다[59]. BHB에 의한 HCAR2 활성화는 항염증 및 신경 보호에 관여합니다 [57]. GPR109A/HCAR2의 손실은 노화 관련 간 지방증을 유도하며[60], 이는 노화 관련 질환에서 BHB에 의한 HCAR2 활성화의 역할을 나타냅니다. 또 다른 막 GPCR인 GPR41(FFAR3라고도 함)은 BHB에 의해 길항되어 교감 활동을 억제할 수 있습니다[61]. 논란의 여지가 있는 GPR41에 대한 BHB의 역할은 전압 의존성 칼슘 채널을 조절하기 위해 GPR41의 작용제로 작용한다는 점에서 보고되었습니다 [62]. 따라서 GPR41에 대한 BHB의 활성을 확인하기 위해서는 추가 연구가 필요합니다. BHB는 히스톤 탈아세틸화 효소(HDAC)에 작용하여 히스톤 번역 후 변형을 조절하고[63] 히스톤 라이신 β-하이드록시부티릴화의 기질로 작용합니다[64].

4. BHB in aging and longevity

The multidimensional roles of BHB in energy metabolism and signaling regulation make it widely involved in aging, longevity, and aging-related diseases. BHB has been widely accepted to promote longevity in model organisms such as worms [65] and fruit flies [66]. Both KD [67] and CR [68], which promote the production and circulating level of BHB, are demonstrated to be beneficial for delaying and preventing aging-related disease and promote longevity, but to what extent the beneficial effect is contributed by BHB needs further investigation. However, proteomics analysis has found that lysine β-hydroxybutyrylation is involved in ketogenesis influencing liver metabolism [48]. Mild elevation of blood ketone bodies also occurs during the process of chronological aging [69], and it is unknown whether it is involved in counteracting chronological aging. Young-Min Han et al. systematically reviewed BHB in aging-related diseases [70]. We will review the relationship between BHB and aging hallmarks.

에너지 대사와 신호 조절에서 BHB의 다차원적인 역할로 인해 노화, 수명 및 노화 관련 질병에 광범위하게 관여합니다. BHB는 벌레[65] 및 초파리[66]와 같은 모델 유기체에서 장수를 촉진하는 것으로 널리 인정받고 있습니다. BHB의 생성과 순환 수준을 촉진하는 KD [67]와 CR [68]은 모두 노화 관련 질병을 지연 및 예방하고 장수를 촉진하는 데 유익한 것으로 입증되었지만, BHB가 어느 정도까지 유익한 효과에 기여하는지는 추가 연구가 필요합니다. 그러나 단백질체학 분석에 따르면 라이신 β-하이드록시부티릴화가 간 대사에 영향을 미치는 케톤 생성에 관여하는 것으로 밝혀졌습니다[48]. 혈중 케톤체의 경미한 상승은 시간적 노화 과정에서도 발생하며[69], 이것이 시간적 노화에 대응하는 데 관여하는지 여부는 알려져 있지 않습니다. 한영민 등은 노화 관련 질환에서 BHB를 체계적으로 검토한 바 있습니다[70]. 본 논문에서는 BHB와 노화 특징 사이의 관계를 검토해 보겠습니다.

5. BHB in aging hallmarks

Although many theories have been proposed to explain the aging processes, modern biological theories of aging fall into two main categories: programmed and damage or error theories. The programmed theories imply that gene expression‎ controls the systems responsible for maintenance, repair, and defense responses; thus, individuals follow a biological timetable. The damage or error theories emphasize environmental assaults on living organisms that induce cumulative damage at various levels as the cause of aging [71].

노화 과정을 설명하기 위해 많은 이론이 제안되었지만, 현대 생물학적 노화 이론은 프로그램 이론과 손상 또는 오류 이론의 두 가지 주요 범주로 나뉩니다. 프로그램된 이론은 유전자 발현이 유지, 복구 및 방어 반응을 담당하는 시스템을 제어하므로 개인은 생물학적 시간표를 따른다는 것을 의미합니다. 손상 또는 오류 이론은 노화의 원인으로 다양한 수준에서 누적 손상을 유발하는 생물체에 대한 환경적 공격을 강조합니다[71].

In 2013, Carlos López-Otín et al. proposed nine hallmarks of aging at the cellular and molecular levels, including (1) genomic instability, (2) telomere attrition, (3) epigenetic alterations, (4) loss of proteostasis, (5) deregulated nutrient sensing, (6) mitochondrial dysfunction, (7) cellular senescence, (8) stem cell exhaustion, and (9) altered intercellular communication (Fig. 2).

2013년에 Carlos López-Otín 등은 (1) 게놈 불안정성, (2) 텔로미어 소실, (3) 후성유전학적 변화, (4) 단백질 안정성 상실, (5) 영양분 감지 기능 저하, (6) 미토콘드리아 기능 장애, (7) 세포 노화, (8) 줄기세포 고갈, (9) 세포 간 통신 변화 등 세포 및 분자 수준에서 노화의 9가지 특징을 제안했습니다(그림 2).

They can be classified into three categories: primary hallmarks, antagonistic hallmarks, and integrative hallmarks. Primary hallmarks, including genomic instability, telomere attrition, epigenetic alterations and loss of proteostasis, are all unequivocally negative to health. The antagonistic hallmarks, including deregulated nutrient sensing, mitochondrial dysfunction, and cellular senescence, are generally beneficial to health at low levels but harmful to health at high levels. Integrative hallmarks, including stem cell exhaustion and altered intercellular communication, directly affect tissue homeostasis and function. At the organ level, different organs show quite different rates of aging according to a multi-omics study [72]. Organ crosstalk also plays a pivotal role in aging [73]. We will describe the specific role of BHB in each aging hallmark below.

이러한 증상은 일차적 특징, 길항적 특징, 통합적 특징의 세 가지 범주로 분류할 수 있습니다. 게놈 불안정성, 텔로미어 감소, 후성유전학적 변화, 단백질 안정성 상실을 포함한 일차적 특징은 모두 건강에 부정적인 영향을 미칩니다. 조절된 영양소 감지 기능 저하, 미토콘드리아 기능 장애, 세포 노화 등 길항성 특징은 일반적으로 낮은 수준에서는 건강에 유익하지만 높은 수준에서는 건강에 해로울 수 있습니다. 줄기세포 고갈, 세포 간 통신 변화 등 통합적인 특징은 조직 항상성과 기능에 직접적인 영향을 미칩니다. 다중 오믹스 연구[72]에 따르면 장기 수준에서 장기마다 노화 속도가 상당히 다르게 나타납니다. 장기 누화는 또한 노화에서 중추적인 역할을 합니다 [73]. 아래에서는 각 노화 특징에서 BHB의 구체적인 역할에 대해 설명합니다.

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Fig. 2. BHB in aging hallmarks.

The nine hallmarks of aging and the modulation of BHB on these aging hallmarks are listed in the pie chart as reported by Carlos López-Otín et al. [93]. To show the influences of BHB on these aging hallmarks, the up arrow (↑) and down arrow (↓) indicate that BHB increases or decreases the corresponding biological processes. Meanwhile, a question mark (?) means that it is still unclear or controversial for these processes.

5.1. Genomic instability

Genomic instability is a result of nuclear and mitochondrial DNA damage and further alters the nuclear architecture. There is no evidence that BHB directly reduces nuclear DNA damage during chronological aging. Reactive oxygen species are well recognized as mediators of DNA damage. BHB is widely involved in reactive oxygen species (ROS) metabolism [74]. It functions not only as a direct antioxidant for hydroxyl radicals [75] but also as an inhibitor of mitochondrial ROS production in stressed neurons by facilitating NADH oxidation [76]. For mitochondrial DNA, ketone bodies, including BHB supplementation in a mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) cell model increased the mtDNA copy number to increase ATP synthesis and alleviate mitochondrial dysfunction [77]. In an in vitro experiment on a cybrid cell line, 5 ​mM BHB treatment reduced the percentage of the m.13094 ​T ​> ​C heteroplasmic mutation [78].

게놈 불안정성은 핵 및 미토콘드리아 DNA 손상의 결과이며 핵 구조를 더욱 변화시킵니다. BHB가 노화 과정에서 핵 DNA 손상을 직접적으로 감소시킨다는 증거는 아직 없습니다. 활성 산소 종은 DNA 손상의 매개체로 잘 알려져 있습니다. BHB는 활성 산소종(ROS) 대사에 광범위하게 관여합니다[74]. 하이드록실 라디칼에 대한 직접적인 항산화제 역할을 할 뿐만 아니라 [75] 스트레스를 받은 뉴런에서 NADH 산화를 촉진하여 미토콘드리아 ROS 생성을 억제하는 역할도 합니다 [76]. 미토콘드리아 DNA의 경우, 미토콘드리아 뇌근병증, 젖산증 및 뇌졸중 유사 에피소드(MELAS) 세포 모델에서 BHB 보충제를 포함한 케톤체가 mtDNA 복제 수를 증가시켜 ATP 합성을 증가시키고 미토콘드리아 기능 장애를 완화했습니다[77]. 하이브리드 세포주에 대한 시험관 내 실험에서 5mM BHB 처리는 m.13094 T > C 이종질체 돌연변이의 비율을 감소시켰습니다[78].

The effect of dietary patterns that produce BHB on DNA mutations has been studied more. KD directly reduces DNA damage in the hippocampus by modulating NAD ​+ ​-dependent enzymes [79]. CR, which also promotes BHB, promotes genomic stability by reducing ROS production to decrease DNA damage or augment DNA repair [80]. Whether these beneficial effects of KD and CR are exerted by BHB is unknown.

BHB를 생성하는 식이 패턴이 DNA 돌연변이에 미치는 영향은 더 많이 연구되었습니다. KD는 NAD + - 의존성 효소를 조절하여 해마에서 DNA 손상을 직접적으로 감소시킵니다 [79]. 또한 BHB를 촉진하는 CR은 ROS 생성을 감소시켜 DNA 손상을 줄이거나 DNA 복구를 강화함으로써 게놈 안정성을 촉진합니다 [80]. KD와 CR의 이러한 유익한 효과가 BHB에 의해 발휘되는지 여부는 알려져 있지 않습니다.

5.2. Telomere attrition

Unlike other chromosomal regions, telomeres are much more susceptible to age-related deterioration. Telomeres are shortened along with cell proliferation when telomerase is unavailable. When exposed to genotoxic agents, telomeres are generally more easily damaged than other regions [81]. Telomere shortening is observed during normal aging in both humans and mice [82,83]. Activation of telomerase, which results in telomere lengthening, has become a possible method of aging intervention [84]. CR decreases the rate of telomere shortening with chronological aging in mice [85]. However, it is more complicated in studies with humans. Pérez L. M et al. systematically reviewed 2128 studies and concluded that the available evidence suggests no effect of diet on telomere length. This may be a result of the strong heterogeneity in the type and duration of dietary interventions [86]. There is no definite link between KD and telomere length, but as an “anti-inflammatory diet”, BHB at least is proposed to reduce inflammation and ROS-induced telomere damage [87]. Another method of lengthening telomeres is to activate telomerase, thus decelerating aging and preventing aging-related diseases [88]. To date, there are no reports on whether BHB directly influences telomerase activity.

다른 염색체 영역과 달리 텔로미어는 노화와 관련된 기능 저하에 훨씬 더 취약합니다. 텔로머레이스가 작동하지 않으면 세포 증식과 함께 텔로미어가 짧아집니다. 유전 독성 물질에 노출되면 텔로미어는 일반적으로 다른 부위보다 더 쉽게 손상됩니다 [81]. 텔로미어 단축은 인간과 생쥐 모두에서 정상적인 노화 과정에서 관찰됩니다 [82,83]. 텔로미어 연장을 초래하는 텔로머라제의 활성화는 노화 개입의 가능한 방법이 되었습니다 [84]. CR은 생쥐의 시간적 노화에 따른 텔로미어 단축 속도를 감소시킵니다 [85]. 그러나 인간을 대상으로 한 연구에서는 더 복잡합니다. 2128개의 연구를 체계적으로 검토한 결과, 이용 가능한 증거는 식단이 텔로미어 길이에 미치는 영향이 없다는 결론을 내렸습니다. 이는 식이 요법의 유형과 기간의 강한 이질성 때문일 수 있습니다[86]. KD와 텔로미어 길이 사이에는 명확한 연관성이 없지만 "항염증제 식단"으로서 BHB는 적어도 염증과 ROS에 의한 텔로미어 손상을 줄이기 위해 제안되었습니다 [87]. 텔로미어를 연장하는 또 다른 방법은 텔로머라아제를 활성화하여 노화를 늦추고 노화 관련 질병을 예방하는 것입니다 [88]. 현재까지 BHB가 텔로머라제 활성에 직접적인 영향을 미치는지에 대한 보고는 없습니

5.3. Epigenetic alterations

Aging is significantly influenced by epigenetic alterations, including DNA methylation, posttranslational modification of histones, and chromatin remodeling. The DNA methylation characteristics of aging include global hypomethylation and region-specific hypermethylation [89]. The DNA methylation reaction is catalyzed by DNA methyltransferases (DNMTs), which transfer a methyl group from S-adenosyl-l-methionine to the C5 of a cytosine [90]. There is no evidence of whether BHB is directly involved in DNA methylation regulation. However, CR delays age-related methylation drift [91]. KD also affects DNA methylation [92]. This may be much more like a secondary effect by posttranslational modification of histones. H4K16 acetylation, H4K20 trimethylation or H3K4 trimethylation are increased, and H3K9 methylation or H3K27 trimethylation are decreased during aging [93]. BHB is an endogenous inhibitor of many protein deacetylases (HDACs). High levels of BHB induced by fasting or CR decrease global histone acetylation through inhibition of class I histone deacetylases (HDACs) (HDAC1, HDAC2, HDAC3, and HDAC8) in mice, thus changing the posttranslational modification of histones and subsequently upregulating the well-known longevity-promoting gene Foxo3a to promote oxidative stress resistance [94].

노화는 DNA 메틸화, 히스톤의 번역 후 변형, 염색질 리모델링을 포함한 후성유전학적 변화에 의해 크게 영향을 받습니다. 노화의 DNA 메틸화 특성에는 전 세계적인 저메틸화 및 지역별 과메틸화가 포함됩니다[89]. DNA 메틸화 반응은 S-아데노실-l-메티오닌에서 사이토신의 C5로 메틸기를 전달하는 DNA 메틸전달효소(DNMT)에 의해 촉매됩니다[90]. BHB가 DNA 메틸화 조절에 직접적으로 관여하는지에 대한 증거는 아직 없습니다. 그러나 CR은 노화와 관련된 메틸화 드리프트를 지연시킵니다 [91]. KD는 또한 DNA 메틸화에 영향을 미칩니다 [92]. 이는 히스톤의 번역 후 변형에 의한 이차적 효과와 비슷할 수 있습니다. 노화 중에는 H4K16 아세틸화, H4K20 트리메틸화 또는 H3K4 트리메틸화가 증가하고, H3K9 메틸화 또는 H3K27 트리메틸화가 감소합니다 [93]. BHB는 많은 단백질 탈아세틸화 효소(HDAC)의 내인성 억제제입니다. 공복 또는 CR에 의해 유도된 높은 수준의 BHB는 생쥐에서 클래스 I 히스톤 탈아세틸화 효소(HDAC)(HDAC1, HDAC2, HDAC3 및 HDAC8)의 억제를 통해 전체 히스톤 아세틸화를 감소시켜 히스톤의 번역 후 변형을 변화시키고 잘 알려진 장수 촉진 유전자 Foxo3a를 상향 조절하여 산화 스트레스 저항성을 촉진합니다[94].

BHB also acts as a substrate for the acylation of the amino group of the lysine side chain, similar to acetylation. In 2016, Zhongyu Xie et al. reported the identification of lysine β-hydroxybutyrylation (Kbhb) of histones as a new type of histone epigenetic regulatory mark [64]. Elevation of BHB in vitro and in vivo both promoted histone lysine β-hydroxybutyrylation. Increased H3K9bhb levels during fasting are associated with upregulated genes in starvation-responsive metabolic pathways, which favor organismal longevity [95]. A recent study also showed that lysine Kbhb improves stability of COVID-19 antibody, suggesting a possible conserved beneficial role and mechanism of BHB [96]. The role and mechanism of β-hydroxybutyrylation during chronological aging needs further investigation to develop new pharmacological interventions for the amelioration of a variety of pathological conditions during aging.

DNA methylation and histone posttranslational modification mediate the remodeling of chromatin. Aging factors regulate transcriptome changes related to the aging process through chromatin remodeling to accelerate or decelerate the aging process [97]. BHB has also been reported to inhibit age- and oxidative stress-induced heterochromatin instability in Drosophila [98].

BHB는 또한 아세틸화와 유사하게 라이신 측쇄의 아미노기 아실화를 위한 기질로도 작용합니다. 2016년에 Zhongyu Xie 등은 새로운 유형의 히스톤 후성유전학적 조절 마크로서 히스톤의 라이신 β-하이드록시부티릴화(Kbhb)를 확인했다고 보고했습니다[64]. 시험관 내 및 생체 내 BHB의 상승은 모두 히스톤 라이신 β-하이드록시부티릴화를 촉진했습니다. 단식 중 H3K9bhb 수치의 증가는 기아 반응성 대사 경로에서 상향 조절된 유전자와 관련이 있으며, 이는 유기체 수명에 유리합니다 [95]. 최근 연구에 따르면 라이신 Kbhb는 COVID-19 항체의 안정성을 개선하여 BHB의 보존된 유익한 역할과 메커니즘 가능성을 시사합니다 [96]. 시간적 노화 동안 β- 하이드 록시 부티릴 화의 역할과 메커니즘은 노화 동안 다양한 병리학 적 상태를 개선하기위한 새로운 약리학 적 개입을 개발하기 위해 추가 조사가 필요합니다.



DNA 메틸화와 히스톤 번역 후 변형은 염색질 리모델링을 매개합니다. 노화 인자는 염색질 리모델링을 통해 노화 과정과 관련된 전사체 변화를 조절하여 노화 과정을 가속화하거나 감속합니다 [97]. BHB는 또한 초파리에서 노화 및 산화 스트레스로 인한 이종 염색질 불안정성을 억제하는 것으로 보고되었습니다 [98].

5.4. Loss of proteostasis

Proteostasis, or protein homeostasis, is the dynamic regulation of a balanced, functional proteome within the cell to ensure the health of the organism [99]. It is maintained by a network comprising molecular chaperones and proteolytic machineries and their regulators. The molecular chaperones, most prominently the heat-shock family of proteins (HSPs), ensure the stabilization of correctly folded proteins. Proteasomes or lysosomes mediate the degradation of damaged proteins [93]. Aging is accompanied by loss of proteostasis, especially with reduced proteasome and lysosome activity, which results in accumulation of misfolded or aggregated proteins to contribute to the development of aging-related diseases, such as Alzheimer's disease and Parkinson's disease [100]. Activation of HSPs by pharmacological agonists or the specific transcription factor HSF-1 resulted in longevity of model organisms [101]. We previously found that handelin, a selective activator of HSP70 [102], extends the lifespan of nematodes [103] and alleviates cell death induced by high osmotic pressure [104]. Transcriptome analysis of centenarians revealed that autophagy promotes longevity in human beings [105] in addition to having the same effect on various model organisms [106]. Proteasome activation also leads to lifespan extension in nematodes [107].

단백질 항상성 또는 단백질 항상성은 유기체의 건강을 보장하기 위해 세포 내에서 균형 잡힌 기능적 단백질체를 동적으로 조절하는 것입니다[99]. 이는 분자 샤프론과 단백질 분해 기계 및 조절기로 구성된 네트워크에 의해 유지됩니다. 분자 샤프론, 가장 대표적으로 열충격 단백질(HSP) 계열은 올바르게 접힌 단백질의 안정화를 보장합니다. 프로테아좀 또는 리소좀은 손상된 단백질의 분해를 매개합니다[93]. 노화는 특히 프로테아좀 및 리소좀 활성 감소와 함께 단백질 정체성 상실을 동반하며, 이로 인해 잘못 접히거나 응집된 단백질이 축적되어 알츠하이머병 및 파킨슨병과 같은 노화 관련 질병의 발병에 기여합니다 [100]. 약리 작용제 또는 특정 전사인자 HSF-1에 의한 HSP의 활성화는 모델 유기체의 수명을 연장하는 결과를 가져왔습니다[101]. 우리는 이전에 HSP70의 선택적 활성화제인 핸델린[102]이 선충의 수명을 연장하고[103], 높은 삼투압에 의해 유도된 세포 사멸을 완화한다는 사실을 발견했습니다[104]. 100세 노인의 전사체 분석 결과 오토파지가 인간의 장수를 촉진하는 것으로 밝혀졌으며[105], 다양한 모델 유기체에서도 동일한 효과를 나타냈습니다[106]. 프로테아좀 활성화는 선충의 수명 연장으로도 이어집니다 [107].

Ketone bodies, including BHB, are reported to activate chaperone-mediated autophagy (CMA) during prolonged starvation [108]. CMA selectively degrades KFERQ-like motif-bearing proteins via chaperone HSC70 and cochaperones. There is no report on whether BHB promotes the expression‎ of other HSPs, such as HSP70. However, in a shrimp cell model, the BHB polymer PHB increased HSP70 protein levels to counteract vibriosis [109]. Approximately three decades ago, hsp70 mRNA levels were reported to be increased in the proximal gut of young and old rats with either acute fasting or calorie restriction [110]. Recently, in a human cohort study, HSP70 and other heat shock proteins were reported to be increased post long-term CR in skeletal muscle to ensure proteostasis [111]. Whether and how BHB enhances the expression‎ or activity of heat shock proteins is still a question needing further investigation.

BHB를 포함한 케톤체는 장기간 굶는 동안 샤페론 매개 자가포식(CMA)을 활성화하는 것으로 보고되었습니다[108]. CMA는 샤프론 HSC70과 코카페론을 통해 KFERQ 유사 모티프 보유 단백질을 선택적으로 분해합니다. BHB가 HSP70과 같은 다른 HSP의 발현을 촉진하는지에 대한 보고는 없습니다. 그러나 새우 세포 모델에서 BHB 폴리머 PHB는 HSP70 단백질 수준을 증가시켜 진동증에 대응했습니다 [109]. 약 30년 전, 급성 단식 또는 칼로리 제한을 한 젊은 쥐와 늙은 쥐의 근위 장에서 hsp70 mRNA 수치가 증가한다고 보고되었습니다 [110]. 최근 인간 코호트 연구에서 골격근에서 장기간의 CR 후 HSP70 및 기타 열충격 단백질이 증가하여 단백질 정체성을 보장하는 것으로 보고되었습니다 [111]. BHB가 열충격 단백질의 발현 또는 활성을 향상시키는지 여부와 그 방법은 아직 추가 연구가 필요한 문제입니다.

It is widely accepted that either CR or KD induces multiorgan autophagy [112,113]. Apart from promoting CMA, BHB also promotes macroautophagy [114] and mitophagy [115]. Macroautophagy activation by BHB will help cells acquire nutrients [116,117], while mitophagy is more involved in mitochondrial quantity and quality control. Considering its role in autophagy activation, BHB is demonstrated to prevent neuronal death [118] and delay vascular aging to act as a vasodilator [119].

CR 또는 KD가 다기관 자가포식을 유도한다는 사실은 널리 알려져 있습니다[112,113]. CMA를 촉진하는 것 외에도 BHB는 매크로 오토파지[114] 및 미토파지[115]도 촉진합니다. BHB에 의한 매크로 오토파지 활성화는 세포가 영양분을 획득하는 데 도움이 되며[116,117], 미토파지는 미토콘드리아의 양과 질 조절에 더 많이 관여합니다. 자가포식 활성화에 대한 역할을 고려할 때, BHB는 신경세포 사멸을 예방하고[118] 혈관 노화를 지연시켜 혈관 확장제 역할을 하는 것으로 입증되었습니다[119].

5.5. Deregulated nutrient sensing

In his famous book What Is Life? Schrödinger originally stated that life feeds on negative entropy [1]. Energy is required for negative entropy by degradation of macronutrients for heterotrophic organisms. Sensing and responding to fluctuations in environmental nutrient levels is requisite for all kingdoms of organisms. Sensors and pathways that detect intracellular and extracellular levels of macronutrients such as sugars, lipids, and amino acids can ensure the precise regulation of anabolism and catabolism [120]. At the organismal level, the growth hormone–insulin growth factor 1 (GH/IGF-1) axis regulates postnatal growth and metabolism [121]. The GH/IGF-1 signal progressively declines after puberty and GH/IGF-1. However, prohibition of GH/IGF-1 signaling has been shown to promote longevity among species including yeast, worms, fruit flies and mammals [122]. Genetic variation in GH/IGF-1 signaling is positively correlated with human longevity [123].

슈뢰딩거는 그의 유명한 저서 <생명이란 무엇인가? 슈뢰딩거는 원래 생명은 음의 엔트로피를 먹고 산다고 말했습니다[1]. 마이너스 엔트로피에는 종속 영양 생물의 다량 영양소 분해에 의한 에너지가 필요합니다. 환경 영양소 수준의 변동을 감지하고 이에 대응하는 것은 모든 생물계에서 필수적입니다. 당, 지질, 아미노산과 같은 다량 영양소의 세포 내 및 세포 외 수준을 감지하는 센서와 경로는 동화 작용과 이화 작용의 정확한 조절을 보장할 수 있습니다[120]. 유기체 수준에서는 성장 호르몬-인슐린 성장 인자 1(GH/IGF-1) 축이 출생 후 성장과 신진대사를 조절합니다[121]. 사춘기 이후에는 GH/IGF-1 신호가 점진적으로 감소합니다. 그러나 효모, 벌레, 초파리, 포유류 등의 종에서 GH/IGF-1 신호의 억제가 수명을 촉진하는 것으로 나타났습니다 [122]. GH/IGF-1 신호의 유전적 변이는 인간의 수명과 양의 상관관계가 있습니다[123].

At the cellular level, there are three mast regulators of nutrients and energy: mTOR, AMPK and sirtuins. They sense intracellular amino acids, AMP and NAD+, respectively. The inhibition of mTOR signaling decelerates aging and promotes longevity from yeast to mammals [124]. Sirtuins are class III NAD ​+ ​-dependent histone deacetylases that also participate in posttranslational modifications of other proteins. Sirtuins can be activated during CR to promote longevity [125]. AMPK senses high levels of intracellular AMP, and its activation contributes to longevity and is conserved among species [126].

 세포 수준에는 영양분과 에너지의 세 가지 마스트 조절인자인 mTOR, AMPK, 시르투인이 있습니다. 이들은 각각 세포 내 아미노산인 AMP와 NAD+를 감지합니다. mTOR 신호의 억제는 노화를 늦추고 효모에서 포유류에 이르기까지 장수를 촉진합니다[124]. 시르투인은 다른 단백질의 번역 후 변형에도 관여하는 클래스 III NAD +-의존성 히스톤 탈아세틸화 효소입니다. 시르투인은 CR 동안 활성화되어 장수를 촉진할 수 있습니다 [125]. AMPK는 높은 수준의 세포 내 AMP를 감지하며, 그 작용은 다음과 같습니다.

CR resulted in reduced signal levels of GH/IGF-1 [127]. A carbohydrate-restricted diet (similar to a KD) resulted in decreased IGF-1 levels in the human population [128]. CR has been proven to activate sirtuins and AMPK while inhibiting mTOR both in vitro and in vivo in mammals [129]. KD also inhibits mTOR [130] and activates AMPK [131]. But BHB supplementation showed controversial results on mTOR. Intake of a ketone ester drink during recovery from exercise promotes mTORC1 signaling in human skeletal muscle [132]. BHB efficiently reduce muscle atrophy by facilitating positive balance of proteins and nucleotides with enhanced accumulation of glutamate and decreased uric acid in wasting muscles in a hindlimb unloaded mouse model too [133]. An in vitro experiment on hepatocytes showed that BHB supplementation activated SIRT1 to protect the cells from endoplasmic reticulum stress [134]. BHB administration activated AMPK in HepG2 cells through GPR109A in another report [135]. Notably, a BHB-producing diet (CR or KD) or BHB supplementation may result in different concentrations of BHB in different tissues and cells, resulting in quite different tolerances to BHB.

CR은 GH/IGF-1의 신호 수준을 감소시켰습니다 [127]. 탄수화물 제한 식단(KD와 유사)은 인간 집단에서 IGF-1 수치를 감소시켰습니다[128]. CR은 포유류에서 시험관 내 및 생체 내에서 mTOR를 억제하면서 시르투인 및 AMPK를 활성화하는 것으로 입증되었습니다 [129]. KD는 또한 mTOR을 억제하고[130] AMPK를 활성화합니다[131]. 그러나 BHB 보충제는 mTOR에 대한 논란의 여지가 있는 결과를 보여주었습니다. 운동 후 회복 중에 케톤 에스테르 음료를 섭취하면 인간 골격근에서 mTORC1 신호가 촉진됩니다 [132]. BHB는 뒷다리가 없는 마우스 모델에서도 단백질과 뉴클레오타이드의 긍정적인 균형을 촉진하여 글루타메이트 축적을 증가시키고 소모성 근육의 요산을 감소시켜 근육 위축을 효율적으로 감소시켰습니다 [133]. 간세포를 대상으로 한 시험관 내 실험에서 BHB 보충제는 SIRT1을 활성화하여 소포체 스트레스로부터 세포를 보호하는 것으로 나타났습니다 [134]. 또 다른 보고서에서 BHB 투여는 GPR109A를 통해 HepG2 세포에서 AMPK를 활성화했습니다 [135]. 특히, BHB를 생성하는 식단(CR 또는 KD) 또는 BHB 보충제는 조직과 세포에 따라 BHB의 농도가 달라질 수 있으며, 그 결과 BHB에 대한 내성이 상당히 달라질 수 있습니다.

5.6. Mitochondrial dysfunction

Mitochondria generate most of the chemical energy needed to power the cell's biochemical reactions. Organismal and cellular aging are accompanied by diminished efficacy of the respiratory chain, increasing electron leakage and reducing ATP production [136]. Because of the impaired integrity, mitochondria from aging tissue and cells produce more ROS, which will further amplify the harmful effect, such as increased mitochondrial DNA mutation and reduced biogenesis of mitochondria [137]. Strategies to reduce mitochondrial DNA mutation, improve mitochondrial quality (by mitophagy) and quantity, and extinguish mitochondrial-derived ROS are among the most prominent ways to delay aging and promote longevity [138].

미토콘드리아는 세포의 생화학 반응에 필요한 화학 에너지의 대부분을 생성합니다. 유기체 및 세포의 노화는 호흡기 사슬의 효율성 감소, 전자 누출 증가 및 ATP 생산 감소를 동반합니다[136]. 손상된 완전성으로 인해 노화된 조직과 세포의 미토콘드리아는 더 많은 ROS를 생성하여 미토콘드리아 DNA 돌연변이 증가 및 미토콘드리아의 생체 생성 감소와 같은 유해한 영향을 더욱 증폭시킵니다 [137]. 미토콘드리아 DNA 돌연변이를 줄이고, 미토콘드리아의 질(미토파지에 의한)과 양을 개선하며, 미토콘드리아 유래 ROS를 소멸시키는 전략은 노화를 지연하고 장수를 촉진하는 가장 두드러진 방법 중 하나입니다 [138].

Approximately two decades ago, CR was reported to induce mitochondrial biogenesis and bioenergetic efficiency in vitro in HeLa cells and primary hepatocytes [139]. In vivo experiments on mice showed that lifelong CR in mice prevents age-related loss of mitochondrial oxidative capacity and efficiency on muscle fibers without increasing mitochondrial biogenesis [140]. In a mitochondrial dysfunctional mouse model, a KD improves mitochondrial biogenesis and bioenergetics via the PGC1α-SIRT3-UCP2 axis [141]. However, a recent study reported that prolonged KD exposure induced cardiac fibrosis by reducing both the biogenesis and bioenergetics of cardiomyocytes [142]. BHB supplementation was reported to elicit favorable mitochondrial changes in C2C12 skeletal muscle cells [143]. BHB mineral salt (3.2%) supplementation improved mitochondrial function in skeletal muscle in mice to increase exercise capacity [144]. For the alteration of mitochondria, the role of BHB may largely depend on its dose and duration applied.

약 20년 전, CR은 HeLa 세포와 원발성 간세포에서 시험관 내에서 미토콘드리아 생성과 생체 에너지 효율을 유도하는 것으로 보고되었습니다[139]. 생쥐를 대상으로 한 생체 내 실험에 따르면 생쥐에서 평생 CR을 투여하면 미토콘드리아 생성을 증가시키지 않으면서 노화와 관련된 미토콘드리아 산화 능력 및 근육 섬유의 효율성 손실을 방지하는 것으로 나타났습니다 [140]. 미토콘드리아 기능 장애 마우스 모델에서 KD는 PGC1α-SIRT3-UCP2 축을 통해 미토콘드리아 생체 생성과 생체 에너지를 개선합니다 [141]. 그러나 최근 연구에 따르면 장기간 KD에 노출되면 심근세포의 생체 생성과 생체 에너지가 모두 감소하여 심장 섬유화가 유발된다고 보고했습니다[142]. BHB 보충제는 C2C12 골격근 세포에서 유리한 미토콘드리아 변화를 유도하는 것으로 보고되었습니다 [143]. BHB 미네랄 소금(3.2%) 보충제는 생쥐의 골격근에서 미토콘드리아 기능을 개선하여 운동 능력을 증가시켰습니다[144]. 미토콘드리아의 변화에서 BHB의 역할은 적용된 용량과 기간에 따라 크게 달라질 수 있습니다.

5.7. Cellular senescence

Cellular senescence is defined as a stable arrest of the cell cycle coupled with stereotyped phenotypic changes [93]. Apart from telomere shortening-induced cellular senescence, which is described as the “Hayflick limit” [145], the senescence of cells can be caused by genomic damage, strong mitogen-associated signals, epigenomic damage, and the activation of tumor suppressors [146]. Cellular senescence contributes to organ dysfunction and age-related diseases through mechanisms including damaging senescent cell-derived tissue functions and producing a complex secretome senescence-associated secretory phenotype (SASP) to systematically influence aging [147]. Delaying cell senescence is a way to deccerate systematic aging [148]. A better strategy is to kill senescent cells to eliminate the systematic negative effect (via SASP) by “senolytis” [149].

세포 노화는 정형화된 표현형 변화와 함께 세포 주기가 안정적으로 정지되는 것으로 정의됩니다 [93]. "헤이플릭 한계"[145]로 설명되는 텔로미어 단축에 의한 세포 노화 외에도 유전체 손상, 강력한 미토겐 관련 신호, 후성 유전체 손상 및 종양 억제제의 활성화로 인해 세포 노화가 발생할 수 있습니다[146]. 세포 노화는 노화 세포 유래 조직 기능을 손상하고 노화에 체계적으로 영향을 미치는 복잡한 분비물 노화 관련 분비 표현형(SASP)을 생성하는 등의 메커니즘을 통해 장기 기능 장애 및 노화 관련 질병에 기여합니다[147]. 세포 노화를 지연시키는 것은 체계적인 노화를 억제하는 방법입니다 [148]. 더 나은 전략은 노화 세포를 사멸시켜 "세노리티스"[149]에 의한 체계적인 부정적 영향(SASP를 통해)을 없애는 것입니다.

CR is reported to prevent the accumulation of senescent cells in both mice and humans [150], but whether the beneficial effect on reducing the senescent cell proportion is exerted by directly delaying cell senescence or via a “senolytic effect” is unknown. There is no report on whether a ketogenic diet reduces senescent cell accumulation in vivo. Supplementation with BHB at 4 ​mM inhibits both stress-induced premature senescence and replicative senescence through p53-independent mechanisms in primary human umbilical vein endothelial cells (HUVECs) and human aortic smooth muscle cells (hASMCs) [151]. However, at a concentration of 2.4 ​mM, BHB induced bovine hepatocyte apoptosis via the ROS-p38 signaling pathway [152]. These controversial results remind us that different tissues, species, and BHB concentrations should be considered when investigating the role of BHB in cellular senescence.

CR은 생쥐와 사람 모두에서 노화 세포의 축적을 방지하는 것으로 보고되었지만[150], 노화 세포 비율을 줄이는 데 유익한 효과가 세포 노화를 직접 지연시킴으로써 발휘되는지 아니면 "세놀리티스 효과"를 통해 발휘되는지는 알려져 있지 않습니다. 케토제닉 식단이 생체 내 노화 세포 축적을 감소시키는지에 대한 보고는 아직 없습니다. 4 mM의 BHB 보충제는 일차 인간 제대 정맥 내피 세포 (HUVEC)와 인간 대동맥 평활근 세포 (hASMC)에서 p53 독립적 메커니즘을 통해 스트레스에 의한 조기 노화와 복제 노화를 모두 억제합니다 [151]. 그러나 2.4mM 농도에서 BHB는 ROS-p38 신호 경로를 통해 소 간세포 세포 사멸을 유도했습니다[152]. 이러한 논란의 여지가 있는 결과는 세포 노화에서 BHB의 역할을 조사할 때 다양한 조직, 종, BHB 농도를 고려해야 한다는 점을 상기시켜 줍니다.

5.8. Stem cell exhaustion

Aging is generally accompanied by the accumulation of DNA damage and mutations, which leads to stem cell aging. The stem cell theory of aging is one of the earliest theories of aging [153]. Stem cell exhaustion is first a result of the senescence of the cells by replication and stress induction. Second, excessive proliferation of stem and progenitor cells can also be deleterious by accelerating the exhaustion of stem cell niches during aging [154]. Stem cell exhaustion results in a decline in the regenerative potential of tissues, which is one of the most obvious characteristics of systematic aging.

노화는 일반적으로 DNA 손상과 돌연변이의 축적을 동반하며, 이는 줄기세포 노화로 이어집니다. 줄기세포 노화 이론은 노화에 대한 가장 초기의 이론 중 하나입니다[153]. 줄기세포 고갈은 첫째, 복제와 스트레스 유도에 의한 세포 노화의 결과입니다. 둘째, 줄기세포와 전구세포의 과도한 증식은 노화 과정에서 줄기세포 틈새의 고갈을 가속화하여 해로울 수 있습니다[154]. 줄기세포의 고갈은 조직의 재생 잠재력을 감소시키는데, 이는 체계적인 노화의 가장 명백한 특징 중 하나입니다.

CR is reported to increase intestinal and muscle stem functions via nonautonomous cells dependent on mTORC1 [155,156]. A recent study showed that self-renewing Lgr5(+) intestine stem cells (ISCs) produce ketone bodies to maintain their stemness by inhibiting HDACs to reinforce Notch signaling for self-renewal and lineage decisions [157]. This study directly linked the role of BHB in stem cell function. Hmgcs2 loss depletes BHB levels in Lgr5(+) ISCs and impairs their differentiation toward secretory cells, but this can be rescued by exogenous administration of BHB. A recent study on skeletal muscle stem cells and satellite cells showed quite different results. BHB directly promotes MuSC deep quiescence via a nonmetabolic mechanism by acetylation and activation of the HDAC1 target protein p53 [158]. Poly(3-hydroxybutyrate-co-3-hydroxyvalerate), which can release BHB after degradation, is reported to improve adipose-derived mesenchymal stem cell neuronal differentiation and promote peripheral nerve regeneration [159].

CR은 mTORC1에 의존하는 비자율 세포를 통해 장 및 근육 줄기 기능을 증가시키는 것으로 보고되었습니다 [155,156]. 최근 연구에 따르면 자가 재생 Lgr5(+) 장 줄기세포(ISC)는 케톤체를 생성하여 HDAC를 억제하여 자가 재생 및 계통 결정을 위한 Notch 신호를 강화함으로써 줄기성을 유지하는 것으로 나타났습니다 [157]. 이 연구는 줄기세포 기능에서 BHB의 역할을 직접적으로 연결했습니다. Hmgcs2의 손실은 Lgr5(+) ISC에서 BHB 수준을 고갈시키고 분비 세포로의 분화를 손상시키지만, 이는 BHB의 외인성 투여로 회복될 수 있습니다. 골격근 줄기세포와 위성 세포에 대한 최근 연구에서는 상당히 다른 결과가 나타났습니다. BHB는 HDAC1 표적 단백질 p53의 아세틸화 및 활성화에 의한 비대사적 메커니즘을 통해 MuSC 깊은 정지를 직접적으로 촉진합니다 [158]. 분해 후 BHB를 방출할 수 있는 폴리(3-하이드록시부티레이트-co-3-하이드록시발레이트)는 지방유래 중간엽 줄기세포의 신경 분화를 개선하고 말초신경 재생을 촉진하는 것으로 보고되고 있습니다 [159].

5.9. Altered intercellular communication

Multicellular organisms need intercellular communications to maintain physiological functions. For mammals, intercellular communication is achieved canonically through nerves of the nervous system and hormones of endocrine organs or glands. However, various noncanonical regulators of intercellular and inter-organ communication have been identified [160]. For example, as a nonendocrine organ, the liver produces FGF21 and BHB to adapt to starvation, reprogramming the metabolic profile of other organs, including the brain, skeletal muscle and heart [161]. The gut microbiota produces short-chain fatty acids (SCFAs) to regulate the aging of the brain, skeletal muscle, adipose tissue, liver and heart via the “gut-X axis” [162]. Immune system-derived immune cells and cytokines play important roles in intercellular and inter-organ communication in aging and aging-related diseases, with a typical characteristic of upregulated innate immunity, reduced adaptive immunity and chronic inflammation [163].

다세포 유기체는 생리적 기능을 유지하기 위해 세포 간 통신이 필요합니다. 포유류의 경우, 세포 간 통신은 신경계의 신경과 내분비 기관 또는 샘의 호르몬을 통해 표준적으로 이루어집니다. 그러나 세포 간 및 기관 간 통신의 다양한 비규범적 조절자가 확인되었습니다 [160]. 예를 들어, 비내분비 기관으로서 간은 기아에 적응하기 위해 FGF21과 BHB를 생성하여 뇌, 골격근 및 심장을 포함한 다른 기관의 대사 프로필을 재프로그래밍합니다 [161]. 장내 미생물은 "장-X 축"을 통해 뇌, 골격근, 지방 조직, 간, 심장의 노화를 조절하는 단쇄 지방산(SCFA)을 생성합니다[162]. 면역계 유래 면역세포와 사이토카인은 노화 및 노화 관련 질환에서 세포 간 및 기관 간 소통에 중요한 역할을 하며, 선천 면역 조절, 적응 면역 감소 및 만성 염증이라는 전형적인 특징을 가지고 있습니다[163].

As mentioned above, BHB is mainly produced by the liver and utilized by extrahepatic tissues, making it a prominent chemical for intercellular and inter-organ communications. Long-term moderate CR was reported to inhibit inflammation without impairing cell-mediated immunity in a randomized controlled trial in humans [164]. KD is generally regarded as an “anti-inflammatory diet” [165]. BHB supplementation is reported to reduce inflammatory cytokine production via inhibition of NLRP3 inflammasomes [166]. Further investigation of the direct role and mechanism of BHB in intercellular and inter-organ communication will facilitate clinical application of BHB.

위에서 언급했듯이 BHB는 주로 간에서 생성되고 간외 조직에서 활용되므로 세포 간 및 장기 간 통신에 중요한 화학 물질입니다. 사람을 대상으로 한 무작위 대조 시험에서 장기간의 중등도 CR은 세포 매개 면역을 손상시키지 않고 염증을 억제하는 것으로 보고되었습니다[164]. KD는 일반적으로 "항염증 식단"으로 간주됩니다[165]. BHB 보충제는 NLRP3 인플라마좀의 억제를 통해 염증성 사이토카인 생성을 감소시키는 것으로 보고되었습니다 [166]. 세포 간 및 장기 간 통신에서 BHB의 직접적인 역할과 메커니즘에 대한 추가 조사는 BHB의 임상 적용을 용이하게 할 것입니다.

6. Elevating circulating BHB: from “ketogenic” to “keto-supplementary” methods

The concentration of circulating ketone bodies varies from 50 ​μM to 25 ​mM (subjects with diabetic ketoacidosis). It is generally accepted that the normal level of ketone bodies for healthy human beings should be no more than 0.5 ​mM [167]. After a single overnight fast, the circulating concentrations of ketone bodies are approximately 0.1–0.5 ​mM, just below the “threshold” for ketosis. After 48 ​h of fasting, ketone bodies can reach 1–2 ​mM. Five days of fasting can increase ketone body levels to above 5 ​mM [168,169]. The ratio of circulating BHB to acetoacetate is not stable under different conditions, with approximately 1 after a meal, but increases to approximately 6 after prolonged fasting. As summarized above, elevated BHB levels contribute to counteracting aging hallmarks. For humans, BHB can be elevated in various ways: (1) lifestyle modification, including CR and KD; (2) exogenous BHB administration; and (3) BHB derivates or agonists administration (Fig. 3).

순환 케톤체의 농도는 50 μM에서 25 mM까지 다양합니다 (당뇨병성 케톤산증이있는 피험자). 일반적으로 건강한 사람의 케톤체 정상 수치는 0.5mM 이하로 유지되어야 한다고 알려져 있습니다[167]. 하룻밤 금식 후 케톤체의 순환 농도는 케톤증의 "역치" 바로 아래인 약 0.1-0.5mM입니다. 48시간 금식 후 케톤체는 1~2mM에 도달할 수 있습니다. 5일간 금식하면 케톤체 수치가 5mM 이상으로 높아질 수 있습니다[168,169]. 순환하는 BHB와 아세토 아세테이트의 비율은 식사 후 약 1로 다른 조건에서 안정적이지 않지만 장기간 금식 후에는 약 6으로 증가합니다. 위에서 요약한 바와 같이, BHB 수치가 높아지면 노화 징후에 대응하는 데 도움이 됩니다. 

사람의 경우, 

(1) CR 및 KD를 포함한 라이프스타일 수정, 

(2) 외인성 BHB 투여, 

(3) BHB 유도체 또는 작용제 투여 등 다양한 방법으로 BHB 수치를 높일 수 있습니다(그림 3).

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Fig. 3. Methods of elevating circulating BHB.

Circulating BHB can be elevated by (1) lifestyle modification, including a ketogenic diet, caloric restriction, intermittent fasting and periodic fasting. (2) Chemicals including salt and esters of BHB, BHB precursors or BHB enantiomers. (3) Novel approaches: poly-BHB (PHB) supplementation, PHB-producing gut microbiota and HMGCS2 agonists.

(1) 케톤 생성 식단, 칼로리 제한, 간헐적 단식, 주기적 단식 등의 생활 습관 교정을 통해 혈중 BHB를 높일 수 있습니다. 

(2) BHB의 염 및 에스테르, BHB 전구체 또는 BHB 거울상 이성질체를 포함한 화학 물질. 

(3) 새로운 접근법: 폴리-BHB(PHB) 보충제, PHB를 생성하는 장내 미생물 및 HMGCS2 작용제.

6.1. Lifestyle modification

Short-term or long-term lifestyle modification, in particular changes in behaviors related to eating or physical activity, can effectively increase the circulating levels of BHB and acetoacetate.

단기 또는 장기적인 생활 습관 수정, 특히 식습관이나 신체 활동과 관련된 행동의 변화는 BHB와 아세토아세테이트의 순환 수치를 효과적으로 증가시킬 수 있습니다.

KD is the most efficient diet that promotes the production of ketone bodies, with approximately 1.5–3 ​mM circulating ketone bodies. A ketogenic diet was first used for the treatment of epileptic seizures [56,170]. For aging and aging-related diseases, a ketogenic diet contributes to a longer lifespan in mice [6]. A ketogenic diet also improved the motor performance of aged mice [171]. Metabolic syndrome aggravates systematic aging, but a ketogenic diet can be beneficial for insulin resistance and metabolic syndrome [172]. CR is another way to increase circulating ketone bodies, which are preval‎ently researched and accepted for anti-aging and pro-longevity diets [173]. Other types of CR, such as intermittent and periodic fasting, also showed beneficial roles in aging and aging-related diseases to promote longevity [174]. Bigu-Style fasting, an ancient Chinese diet of avoiding grains and fasting for several days, definitely increases ketone body concentrations to relatively high levels and improves metabolic health by modulating taurine, glucose and cholesterol homeostasis [175].

케톤 생성 식단은 케톤체 생성을 촉진하는 가장 효율적인 식단으로, 약 1.5~3mm의 케톤체가 순환합니다. 케톤 생성 식단은 간질 발작 치료에 처음 사용되었습니다 [56,170]. 노화 및 노화 관련 질병의 경우 케톤 생성 식단은 생쥐의 수명을 연장하는 데 기여합니다 [6]. 케토제닉 식단은 또한 노령 쥐의 운동 능력을 개선했습니다 [171]. 대사 증후군은 전신 노화를 악화시키지만 케톤 생성 식단은 인슐린 저항성과 대사 증후군에 도움이 될 수 있습니다 [172]. CR은 순환 케톤체를 증가시키는 또 다른 방법으로, 노화 방지 및 장수 식단을 위해 널리 연구되고 받아들여지고 있습니다[173]. 간헐적 단식 및 주기적 단식과 같은 다른 유형의 CR도 노화 및 노화 관련 질병에 유익한 역할을하여 장수를 촉진하는 것으로 나타났습니다 [174]. 곡물을 피하고 며칠 동안 금식하는 고대 중국의 식단인 비구식 단식은 케톤체 농도를 상대적으로 높은 수준으로 확실히 증가시키고 타우린, 포도당 및 콜레스테롤 항상성을 조절하여 대사 건강을 개선합니다[175].

Although lifestyle changes were shown to delay aging and may even promote longevity, it is still unknown to what extent these beneficial effects are directly contributed by ketone bodies, especially BHB. There are also some problems with using lifestyle modification to produce ketone bodies. First, CR, KD, intermittent and periodic fasting, and Bigu are difficult to sustain for most individuals. Second, a number of side effects have been reported. For example, kidney stones, hepatic steatosis, hypoproteinemia, or low levels of protein in the blood are reported as the side effects of KD [176]. This makes ketone body supplementation an alternative way of elevating circulating BHB.

생활 습관의 변화가 노화를 지연시키고 장수를 촉진하는 것으로 나타났지만, 이러한 유익한 효과가 케톤체, 특히 BHB에 의해 직접적으로 어느 정도 기여하는지는 아직 밝혀지지 않았습니다. 케톤체를 생성하기 위해 생활 습관 교정을 사용하는 데에는 몇 가지 문제도 있습니다. 첫째, CR, KD, 간헐적 단식 및 주기적 단식, 비구는 대부분의 개인이 지속하기 어렵습니다. 둘째, 여러 가지 부작용이 보고되었습니다. 예를 들어, 신장 결석, 간 지방증, 저 단백 혈증 또는 혈중 단백질 수치가 낮은 것이 KD의 부작용으로 보고되었습니다 [176]. 따라서 케톤체 보충제는 순환하는 BHB를 높이는 대안이 될 수 있습니다.

6.2. Exogenous BHB, BHB precursors, derivates and agonists administration

Administration of exogenous ketone bodies, including β-hydroxybutyric acid and β-hydroxybutyrate, increases the circulating level of BHB. However, for the short half-lives of ketone bodies, it is difficult to achieve a therapeutic level of BHB without influencing the sodium load [56]. BHB precursor administration generally increases the half-life of circulating BHB levels. As a BHB precursor, R/S-1,3-butanediol is a nontoxic dialcohol that is readily oxidized in the liver to yield D/L-BHB [177]. Ketone esters (KEs) degrade under the catalysis of esterase in the intestine or liver to elevate circulating BHB levels [169]. KEs, including R-3-hydroxybutyl R-bOHB [178], glyceryl-mono-bOHB, glyceryl-tris-bOHB [179] and R,S-1,3-butanediol acetoacetate diester [180], have been widely studied for ketone body supplementation. R-3-hydroxybutyl R-bOHB, the monoester of BHB, provides the highest (more than 3 ​mM) levels of blood BHB rapidly within 30 ​min of ingestion [178]. One advantage of KEs over ketone body salts is that they are salt-free, without incurring sodium (or potassium, calcium) loads. BHB is chiral (β-C), with the R-enantiomer (R-β-HB or D-β-HB) being the predominant circulating BHB. The half-life of S-β-HB in circulation is longer than that of R-β-HB because of the lower degradation rate. However, it showed a similar biological effect as D-β-HB, at least in the inhibition of NLRP3 inflammasome activation [181].

β- 하이드 록시 부티르산 및 β- 하이드 록시 부티레이트와 같은 외인성 케톤체를 투여하면 BHB의 순환 수준이 증가합니다. 그러나 케톤체의 반감기가 짧기 때문에 나트륨 부하에 영향을 미치지 않고 치료 수준의 BHB를 달성하기는 어렵습니다 [56]. BHB 전구체 투여는 일반적으로 순환하는 BHB 수준의 반감기를 증가시킵니다. BHB 전구체로서 R/S-1,3-부탄디올은 간에서 쉽게 산화되어 D/L-BHB를 생성하는 무독성 다이알코올입니다[177]. 케톤 에스테르(KE)는 장이나 간에서 에스테라아제의 촉매 작용으로 분해되어 순환하는 BHB 수치를 높입니다[169]. R-3-하이드록시부틸 R-bOHB[178], 글리세릴-모노-bOHB, 글리세릴-트리스-bOHB[179], R,S-1,3-부탄디올 아세토아세테이트 다이스테르[180]를 포함한 KE는 케톤체 보충을 위해 널리 연구되고 있습니다. 

BHB의 모노에스테르인 R-3-하이드록시부틸 R-bOHB는 섭취 후 30분 이내에 혈중 BHB 농도를 가장 높은 수준(3mM 이상)으로 빠르게 증가시킵니다[178]. 케톤 체염에 비해 KE의 한 가지 장점은 나트륨(또는 칼륨, 칼슘) 부하를 유발하지 않고 무염이라는 점입니다. BHB는 키랄(β-C)이며, R 거울상 이성질체(R-β-HB 또는 D-β-HB)가 주로 순환하는 BHB입니다. 순환하는 S-β-HB의 반감기는 분해 속도가 더 낮기 때문에 R-β-HB보다 더 깁니다. 그러나 적어도 NLRP3 인플라마좀 활성화 억제에서는 D-β-HB와 유사한 생물학적 효과를 보였습니다 [181].

The aforementioned BHB precursors or derivatives are generally chemically synthesized. However, one prominent biosynthetic precursor of BHB is poly-β-hydroxybutyrate (PHB). As mentioned above, for bacteria, BHB can further be used to synthesize PHB in bacteria for energy storage, such as polysaccharides, lipids, and proteins [19]. Based on the chain length, PHB can be classified into three types: 1) PHB consists of 10,000 to >1,000,000 β-OHB residues (storage PHB), 2) PHB has a medium chain length consisting of 100–300 residues (oligo-PHB), and 3) PHB (cPHB) has a short chain (≤30 residues) conjugated to proteins. Stored PHB is not found in eukaryotes. Oligo PHB and cPHB can be found in eukaryotes, including human beings. The physiological and pathological relevance of PHB in human health was reviewed by Elena N. Dedkova and Lothar A. Blatter [20]. oligo-PHB can be found in mitochondrial membranes [182] and in very-low-density and low-density lipoproteins [183]. cPHB is widely distributed in all cell compartments of prokaryotes and eukaryotes [184]. cPHB is found in atherosclerotic plaques and is also elevated in STZ-induced type 1 diabetic rats [185], but whether PHB conjugation to proteins is a cause of disease or serves as an antagonistic mechanism is unclear. The potential beneficial role of PHB administration on human health has not been widely investigated. However, in a European sea bass model, PHB administration improved larval survival and altered the larval-associated microbiota composition [186]. Our data also showed that PHB administration increased the level of BHB both in the worm Caenorhabditis elegans and mice (unpublished data), suggesting that PHB is a prominent agent for elevating circulating BHB. The excellent biocompatibility of PHB and PHB derived biomaterials [33,187] make them prominent agent for boosting BHB level. PHB is well known as biodegradable plastics. And it can be efficiently degraded by environmental bacteria with intracellular or secreted PHB depolymerases [188]. PHB-degrading bacteria have also been isolated from the gastrointestinal tract of aquatic animals [189]. Recent study on a rat model for colorectal cancer showed that oral administration of PHB resulted in elevated BHB concentration in plasma (>1 ​mM) and brain (>0.2 ​mM), suggesting an efficient degradation of PHB in the gastrointestinal tract of mammals [190]. Genetically modified bacteria with an enhanced capacity to produce BHB or PHB can be a low-cost and sustainable method for “keto-supplementation”.

앞서 언급한 BHB 전구체 또는 유도체는 일반적으로 화학적으로 합성됩니다. 그러나 BHB의 대표적인 생합성 전구체 중 하나는 폴리-β-하이드록시부티레이트(PHB)입니다. 위에서 언급했듯이 박테리아의 경우, 박테리아에서 다당류, 지질 및 단백질과 같은 에너지 저장을 위해 BHB를 합성하는 데 추가로 사용할 수 있습니다 [19]. 

사슬 길이에 따라 PHB는 세 가지 유형으로 분류할 수 있습니다: 1) 10,000~1,000,000개 이상의 β-OHB 잔기로 구성된 PHB(저장 PHB), 2) 100~300개의 잔기로 구성된 중간 사슬 길이의 PHB(올리고-PHB), 3) 단백질에 접합된 짧은 사슬(≤30개 잔기)의 PHB(cPHB)가 있습니다. 저장된 PHB는 진핵생물에서 발견되지 않습니다. 올리고 PHB와 cPHB는 인간을 포함한 진핵생물에서 발견할 수 있습니다. 인체 건강에서 PHB의 생리적 및 병리학적인 관련성은 엘레나 N. 데드코바와 로타르 로타르에 의해 검토되었습니다. 올리고-PHB는 미토콘드리아 막 [182] 및 초저밀도 및 저밀도 지단백질 [183]에서 발견될 수 있습니다. cPHB는 원핵생물과 진핵생물의 모든 세포 구획에 널리 분포되어 있습니다 [184]. cPHB는 죽상 경화성 플라크에서 발견되며 STZ로 유도된 1형 당뇨병 쥐에서도 증가하지만[185], 단백질에 대한 PHB 결합이 질병의 원인인지 아니면 길항 메커니즘으로 작용하는지는 불분명합니다. PHB 투여가 인체 건강에 미치는 잠재적인 유익한 역할은 널리 조사되지 않았습니다. 그러나 유럽 농어 모델에서 PHB 투여는 유충 생존율을 개선하고 유충 관련 미생물군 구성을 변화시켰습니다[186]. 또한 우리의 데이터에 따르면 PHB 투여는 웜 Caenorhabditis elegans와 마우스(미공개 데이터) 모두에서 BHB 수치를 증가시켰으며, 이는 PHB가 순환 BHB를 높이는 데 탁월한 약제임을 시사합니다. PHB 및 PHB 유래 생체 물질의 우수한 생체 적합성[33,187]은 BHB 수치를 높이는 데 중요한 역할을 합니다. PHB는 생분해성 플라스틱으로 잘 알려져 있습니다. 그리고 세포 내 또는 분비된 PHB 분해효소를 가진 환경 박테리아에 의해 효율적으로 분해될 수 있습니다[188]. PHB 분해 박테리아는 수생 동물의 위장관에서도 분리되었습니다 [189]. 대장암 쥐 모델에 대한 최근 연구에 따르면 PHB를 경구 투여하면 혈장(> 1mM)과 뇌(> 0.2mM)의 BHB 농도가 상승하여 포유류의 위장관에서 PHB가 효율적으로 분해되는 것으로 나타났습니다[190]. BHB 또는 PHB 생산 능력이 향상된 유전자 변형 박테리아는 "케토 보충제"를 위한 저비용의 지속 가능한 방법이 될 수 있습니다.

Compounds that promote intrinsic BHB production is another approach to elevated circulating BHB level. As the key enzyme for BHB production, HMGCS2 expression‎ was shown to be sufficient to induce ketone body production in vitro [191]. Firstly, upstream activation of transcription factors for HMGCS2 can increase its expression‎. For example, both PPARγ agonist clofibrate [192] and PPARα agonist WY14643 [193] efficiently increase the expression‎ of HMGCS2. Secondly, HMGCS2 activity is tightly regulated by posttranslational modification, including acetylation of lysines 310, 447, and 473, which results in inhibited enzyme activity. Searching for molecules that inhibiting the acetylation on those sites will also be a way to increase HMGCS2 activity. Thirdly, allosteric agonists directly act on HMGCS2 can increase its activilty. But to date no HMGCS2 allosteric agonist has been developed, though allosteric inhibitor has been identified, such as succinyl-CoA [45]. Searching for gain-of-function mutations in HMGCS2 will shed light on novel sites for HMGCS2 allosteric agonists development.

내재적 BHB 생성을 촉진하는 화합물은 순환 BHB 수치를 높이는 또 다른 접근법입니다. BHB 생성의 핵심 효소인 HMGCS2 발현은 시험관 내에서 케톤체 생성을 유도하기에 충분한 것으로 나타났습니다 [191]. 

첫째, HMGCS2에 대한 전사인자의 업스트림 활성화는 그 발현을 증가시킬 수 있습니다. 예를 들어, PPARγ 작용제인 클로피브레이트[192]와 PPARα 작용제인 WY14643[193]은 모두 HMGCS2의 발현을 효율적으로 증가시킵니다. 

둘째, HMGCS2 활성은 라이신 310, 447, 473의 아세틸화를 포함한 번역 후 변형에 의해 엄격하게 조절되며, 이는 효소 활성을 억제하는 결과를 초래합니다. 이러한 부위에서 아세틸화를 억제하는 분자를 찾는 것도 HMGCS2 활성을 높이는 방법이 될 수 있습니다. 

셋째, 알로스테릭 작용제는 HMGCS2에 직접 작용하여 활성을 증가시킬 수 있습니다. 그러나 현재까지 숙시닐-CoA [45]와 같은 알로스테릭 억제제는 확인되었지만 HMGCS2 알로스테릭 작용제는 아직까지 개발되지 않았습니다. HMGCS2에서 기능 이득 돌연변이를 검색하면 HMGCS2 알로스테릭 작용제 개발을위한 새로운 부위를 밝힐 수 있습니다.

7. Production of BHB via a microbial platform and synthetic biology

As we mentioned above, BHB is a conserved energy source among species. For bacteria, the polymer of BHB, PHB, is even an energy storage form. Therefore, apart from the economical production of chiral BHB via chemical synthesis, biosynthesis is also an efficient pathway with three different strategies (Fig. 4a): (1) in vivo depolymerization of PHAs in microbes [194], (2) in vitro depolymerization of PHAs after purification from microbes [195] or (3) direct biosynthesis of BHB without any PHA intermediate [[196], [197], [198], [199]], as shown in Figure 4a. Ruth et al. explored an efficient method to prepare enantiomerically pure (R)-3-hydroxycarboxylic acids (containing BHB) from bacterial PHAs accumulated by Pseudomonas putida GPo1 [196]. Eight (R)-3-hydroxycarboxylic acids of over 95 ​wt% were secreted into the extracellular environment and purified by acidic precipitation. Ren et al. produced chiral hydroxyalkanoic acid monomers from PHA in Pseudomonas putida in phosphate buffer at a pH of 8–11 with an efficiency of over 90% (w/w) in 9 ​h [197,198].

위에서 언급했듯이 BHB는 종들 사이에서 보존된 에너지원입니다. 박테리아의 경우, BHB의 중합체인 PHB는 에너지 저장 형태이기도 합니다. 따라서 화학 합성을 통한 키랄 BHB의 경제적인 생산 외에도 생합성은 세 가지 다른 전략을 가진 효율적인 경로입니다(그림 4a): 

(1) 미생물에서 PHA의 생체 내 해중합 [194], 

(2) 미생물로부터 정제 후 PHA의 시험관 내 해중합 [195] 또는 

(3) PHA 중간체 없이 BHB의 직접 생합성 [[196], [197], [198], [199]], 그림 4a와 같이]. 

Ruth 등은 슈도모나스 퍼티다 GPo1에 의해 축적된 박테리아 PHA로부터 거울상 이성질체로 순수한 (R)-3-하이드록시 카르복실산(BHB 함유)을 제조하는 효율적인 방법을 탐구했습니다[196]. 95 중량 % 이상의 8 (R)-3- 하이드 록시 카르 복실 산을 세포 외 환경으로 분비하고 산성 침전에 의해 정제했습니다. Ren 등은 8-11 pH의 인산염 완충액에서 슈도모나스 푸티다의 PHA로부터 키랄 하이드록시 알카노산 단량체를 9시간에 90%(w/w) 이상의 효율로 생산했습니다[197,198].

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Fig. 4. Production of BHB and metabolic pathway of BHB biosynthesis in microorganisms.

aThree strategies of BHB production: 1) in vivo depolymerization of PHAs in microbes, 2) in vitro depolymerization of PHAs after purification from microbes and 3) direct biosynthesis of BHB without any PHA intermediate.

b Metabolic pathways of BHB biosynthesis in microorganisms. PhaA, Acetoacetyl-CoA thiolase; Thl, Acetoacetyl-CoA thiolase; BktB, Acetoacetyl-CoA thiolase; PhaB, (R)-BHB-CoA dehydrogenase; Hbd, (S)–BHB-CoA dehydrogenase; Ptb, phosphotransbutyrylase; Buk, Butyrate kinase; TesB, Acyl-CoA thioesterase II.

However, based on considerations of cost and BHB purity degraded from PHAs, the direct biosynthesis of BHB from glucose is the optimal choice. In E. coli (Figure 4b), the biosynthesis of BHB contains three steps and begins with the condensation of two molecules of acetyl-CoA, catalyzed by the thiolase, to obtain acetoacetyl-CoA. Acetoacetyl-CoA is then catalyzed to (R)-3-hydroxybutyryl-CoA by an NADPH-dependent (R)-3-hydroxybutyryl-CoA dehydrogenase (PhaB). (R)-3HBCoA can be further modified via a suitable CoA removal reaction to (R)-BHB in the third step. Moreover, (S)–BHB was also accumulated via similar pathways with (S)-3-hydroxybutyryl-CoA dehydrogenase (Hbd) in step 2. Engineered E. coli can produce enantiomerically pure BHB at a final concentration of up to 12 ​g/L in culture after 48 ​h based on a synthetic biology platform for simultaneously expressing β-ketothiolase (phaA) and acetoacetyl-CoA reductase (phaB) from R. eutropha H16 for early catalysis and phosphotransbutyrylase (ptb) and encoding butyrate kinase (buk) from Clostridium acetobutylicum ATCC 824 for the 3rd step [198]. Similarly, thioesterase II (tesB) from E. coli has also been employed for the hydrolysis of BHB-CoA to obtain BHB [199]. Moreover, Tseng et al. profiled three thiolase homologs (BktB, Thl, and PhaA) and two coenzyme A (CoA) removal mechanisms (Ptb-Buk and TesB) for activity optimization of BHB in two E. coli strains, BL21 Star (DE3) and MG1655(DE3) [200]. The results showed that the engineered strains achieved titers of (R)-BHB and (S)–BHB as high as 2.92 ​g/L and 2.08 ​g/L, respectively, in shake flask cultures within 2 days. In addition to exogenous BHB supplementation via oral or intravenous injection, the probiotic E. coli Nissle 1917 (EcN) was also engineered to produce sustainable BHB in the gut lumen of mice suffering from colitis, and it produced the highest BHB of 0.6 ​g/L under microaerobic conditions [201]. It also offers new strategies for BHB supplementation in aging.

그러나 비용과 PHA에서 분해되는 BHB 순도를 고려할 때 포도당으로부터 BHB를 직접 생합성하는 것이 최적의 선택입니다. 대장균(그림 4b)에서 BHB의 생합성은 세 단계로 이루어지며, 티올라제에 의해 촉매되는 아세틸-CoA 두 분자의 축합으로 시작하여 아세토아세틸-CoA를 얻습니다. 그런 다음 아세토아세틸-CoA는 NADPH 의존성 (R)-3-하이드록시부티릴-CoA 탈수소효소(PhaB)에 의해 (R)-3-하이드록시부티릴-CoA로 촉매 작용을 합니다. (R)-3HBCoA는 세 번째 단계에서 적절한 CoA 제거 반응을 통해 (R)-BHB로 추가 변형될 수 있습니다. 또한, (S)-BHB는 2단계에서 (S)-3-하이드록시부티릴-CoA 탈수소효소(Hbd)와 유사한 경로를 통해 축적되었습니다. 엔지니어링 대장균은 β-케토티올라제(phaA)와 아세토아세틸-CoA 환원효소(phaB)를 동시에 발현하는 합성 생물학 플랫폼을 기반으로 48시간 후 배양에서 최종 농도 최대 12g/L의 거울상 이성질체로 순수한 BHB를 생산할 수 있습니다. 초기 촉매를 위한 유트로파 H16과 포스포트랜스부틸라제(ptb), 3단계로 클로스트리디움 아세토부틸리쿰 ATCC 824의 부티레이트 키나아제(buk)를 인코딩합니다[198]. 마찬가지로 대장균의 티오에스테라아제 II(tesB)도 BHB-CoA를 가수분해하여 BHB를 얻는 데 사용되었습니다 [199]. 또한 Tseng 등은 두 개의 대장균 균주인 BL21 Star(DE3)와 MG1655(DE3)에서 BHB의 활성 최적화를 위해 세 가지 티오에스테라아제 동종체(BktB, Thl, PhaA)와 두 가지 코엔자임 A(CoA) 제거 메커니즘(Ptb-Buk 및 TesB)을 프로파일링했습니다[200]. 그 결과, 엔지니어링된 균주는 2일 이내에 쉐이크 플라스크 배양에서 각각 2.92g/L 및 2.08g/L의 높은 (R)-BHB 및 (S)-BHB 역가를 달성했습니다. 경구 또는 정맥 주사를 통한 외인성 BHB 보충 외에도 대장염을 앓고 있는 생쥐의 장 내강에서 지속 가능한 BHB를 생산하도록 설계된 프로바이오틱스 대장균 니슬 1917(EcN)은 미세 혐기성 조건에서 0.6 g/L의 가장 높은 BHB를 생산했습니다[201]. 또한 노화에서 BHB 보충을 위한 새로운 전략을 제시합니다.

8. Conclusion and prospects

Both lifestyle modification (KD, CR, intermittent and periodic fasting, and Bigu-Style fasting) and exogenous BHB administration show beneficial roles in healthy aging by counteracting aging hallmarks to promote longevity. This makes BHB and its derivatives a new therapeutic option for aging-related diseases.

라이프스타일 수정(KD, CR, 간헐적 및 주기적 단식, 비구 스타일 단식)과 외인성 BHB 투여는 모두 노화 특징에 대응하여 장수를 촉진함으로써 건강한 노화에 유익한 역할을 하는 것으로 나타났습니다. 따라서 BHB와 그 유도체는 노화 관련 질병에 대한 새로운 치료 옵션이 될 수 있습니다. 

The following factors need to be considered: (1) The differences between BHB generating lifestyle modifications and BHB supplementation. Many reported beneficial role of BHB are exerted by applying BHB generating lifestyle modifications, but to what extent these beneficial effects are contributed directly by BHB needs further investigation. (2) Individual differences: the production and utilization rates of BHB are different from each other because of different metabolic programming (whether insulin resistant). One neglected factor is the single-nucleotide variations in the gene encoding ketone body production and utilization, especially those rare (with minor allele frequency <1%) variants on coding sequences of rate-limiting enzymes for ketone body production. Precision medicine using whole-genome sequencing or whole-exome sequencing will help understand the individual differences in BHB metabolism, thus helping optimize BHB administration. (3) Concentrations of BHB and BHB derivates need to be optimized for different diseases considering different target tissues and organs. Different tissues and organs have different sensitivities to BHB. Optimization of the therapeutic dose of BHB via pharmacokinetic studies in vivo will help solve this problem. (4) A targeted delivery strategy may be useful to improve the specificity of BHB on specific tissues and organs. (5) Chemicals and novel materials that target enzymes to promote ketone body production can be developed. Based on the cellular and molecular mechanisms by which BHB counteracts aging and promotes longevity, the development of novel BHB mimics that cannot be metabolized quickly will be a proposed direction. With more randomized controlled trials for BHB, BHB derivates, BHB mimics, and BHB-producing diets, novel precise BHB-related interventions will facilitate the development of strategies for delaying aging and treating aging-related diseases.

다음 요소를 고려해야 합니다: 

(1) 생활습관 교정을 통한 BHB와 BHB 보충제의 차이점. BHB의 유익한 역할에 대한 많은 보고가 생활 습관 교정을 통해 이루어지고 있지만, 이러한 유익한 효과가 BHB에 의해 직접적으로 어느 정도 기여하는지는 추가 조사가 필요합니다. 

(2) 개인차: 대사 프로그램(인슐린 저항성 여부)이 다르기 때문에 BHB의 생산 및 이용률은 서로 다릅니다. 한 가지 무시된 요인은 케톤체 생산 및 활용을 코딩하는 유전자의 단일 뉴클레오티드 변이, 특히 케톤체 생산 속도 제한 효소의 코딩 서열에서 드문 (대립 유전자 빈도 <1 %) 변이입니다. 전체 게놈 시퀀싱 또는 전체 엑솜 시퀀싱을 사용하는 정밀 의학은 BHB 대사의 개인차를 이해하는 데 도움이되므로 BHB 투여를 최적화하는 데 도움이됩니다. 

(3) 표적 조직과 장기가 다른 점을 고려하여 질병에 따라 BHB 및 BHB 유도체 농도를 최적화해야 합니다. 조직과 장기에 따라 BHB에 대한 민감도가 다릅니다. 생체 내 약동학 연구를 통해 BHB의 치료 용량을 최적화하면 이 문제를 해결하는 데 도움이 될 것입니다. 

(4) 표적 전달 전략은 특정 조직 및 기관에 대한 BHB의 특이성을 개선하는 데 유용할 수 있습니다. 

(5) 케톤체 생성을 촉진하는 효소를 표적으로 하는 화학물질과 새로운 물질을 개발할 수 있습니다. BHB가 노화에 대응하고 장수를 촉진하는 세포 및 분자 메커니즘을 기반으로 빠르게 대사되지 않는 새로운 BHB 모방 물질을 개발하는 것이 제안 된 방향이 될 것입니다. BHB, BHB 유도체, BHB 모방체, BHB 생성 식단에 대한 더 많은 무작위 대조군 임상시험을 통해 새로운 정밀한 BHB 관련 중재를 통해 노화를 지연시키고 노화 관련 질병을 치료하는 전략을 개발할 수 있을 것입니다.

CRediT authorship contribution statement

Yang Xiang: Conceptualization, Writing – original draft, Writing – review & editing. Qi-Quan Wang: Conceptualization, Writing – original draft. Xin-Qiang Lan: Writing – original draft. Hui-Jie Zhang: Writing – review & editing. Dai-Xu Wei: Conceptualization, Writing – original draft, Writing – review & editing.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

We thank the National Key R&D Program, Ministry of Science and Technology of China (2020YFC2002900), the National Natural Science Foundation of China (81873814, 31900950 and 91649120) and Jiangxi Province (20192BCB23004, 2018ACB21036, 20181BCD40001) for their financial support.

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