The Beneficial and Adverse Effects of Autophagic Response to Caloric Restri

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Adv Nutr. 2023 Sep; 14(5): 1211–1225.

Published online 2023 Jul 30. doi: 10.1016/j.advnut.2023.07.006

PMCID: PMC10509423

PMID: 37527766

The Beneficial and Adverse Effects of Autophagic Response to Caloric Restriction and Fasting

Roya Shabkhizan,1,2,† Sanya Haiaty,1,† Marziyeh Sadat Moslehian,1,2 Ahad Bazmani,1 Fatemeh Sadeghsoltani,3 Hesam Saghaei Bagheri,4 Reza Rahbarghazi,5,6,∗# and Ebrahim Sakhinia1,2,∗∗#

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Abstract

Each cell is equipped with a conserved housekeeping mechanism, known as autophagy, to recycle exhausted materials and dispose of injured organelles via lysosomal degradation. Autophagy is an early-stage cellular response to stress stimuli in both physiological and pathological situations. It is thought that the promotion of autophagy flux prevents host cells from subsequent injuries by removing damaged organelles and misfolded proteins. As a correlate, the modulation of autophagy is suggested as a therapeutic approach in diverse pathological conditions.

Accumulated evidence suggests that intermittent fasting or calorie restriction can lead to the induction of adaptive autophagy and increase longevity of eukaryotic cells. However, prolonged calorie restriction with excessive autophagy response is harmful and can stimulate a type II autophagic cell death. Despite the existence of a close relationship between calorie deprivation and autophagic response in different cell types, the precise molecular mechanisms associated with this phenomenon remain unclear. Here, we aimed to highlight the possible effects of prolonged and short-term calorie restriction on autophagic response and cell homeostasis.

각 세포에는 

리소좀 분해를 통해 소진된 물질을 재활용하고 

손상된 세포 소기관을 처리하는 자가포식이라는 

보존된 청소 메커니즘이 있습니다. 

오토파지는 생리적 및 병리적 상황에서 

스트레스 자극에 대한 초기 단계의 세포 반응입니다. 

자가포식 플럭스의 촉진은 

손상된 세포 소기관과 

잘못 접힌 단백질을 제거하여 

숙주 세포의 후속 손상을 방지하는 것으로 생각됩니다. 

이와 관련하여 다양한 병리학적 조건에서 

자가포식 조절이 치료적 접근법으로 제시되고 있습니다. 

축적된 증거에 따르면 

간헐적 단식이나 칼로리 제한이 

적응성 자가포식을 유도하고

 진핵세포의 수명을 늘릴 수 있다고 합니다. 

그러나 

과도한 자가포식 반응을 동반한 장기간의 칼로리 제한은 해로우며 

제2형 자가포식 세포 사멸을 자극할 수 있습니다. 

다양한 세포 유형에서 칼로리 부족과 

자가포식 반응 사이에 밀접한 관계가 존재함에도 불구하고 

이 현상과 관련된 정확한 분자 메커니즘은 아직 명확하지 않습니다. 

이 연구에서는 

장단기 칼로리 제한이 

자가포식 반응과 세포 항상성에 미칠 수 있는 영향을 

중점적으로 살펴보고자 했습니다.

Keywords: short-term and long-term, calorie restriction, autophagy, cellular homeostasis, therapeutic effects

Statement of Significance

This review article presents the evidence supporting the modulatory effects of calorie restriction on autophagic flux under physiological and pathological conditions. Both adaptive (useful) and excessive (harmful) autophagic responses can be stimulated, depending on the metabolic status, by short- and long-term diet programs. Attention should be taken to the application of calorie restriction along with therapeutic protocols under pathological conditions.

이 리뷰 기사에서는 생리적 및 병리학적 조건에서 칼로리 제한이 자가포식 플럭스에 미치는 조절 효과를 뒷받침하는 증거를 제시합니다. 

신진대사 상태에 따라 

단기 및 장기 다이어트 프로그램을 통해

 적응성(유용한) 자가포식 반응과 

과도한(해로운) 자가포식 반응이 모두 자극될 수 있습니다. 

병리학적인 조건에서 

치료 프로토콜과 함께 칼로리 제한을 적용하는데 

주의를 기울여야 합니다.

Introduction

The term autophagy refers to cellular mechanisms associated with self-eating and diverse homeostatic phenomena. Activation of autophagy helps the host cells to eliminate misfolded, aggregated proteins and injured organelles [1]. Besides its role in cellular homeostasis, autophagy is actively involved in the development, differentiation, and regenerative potential of several embryonic and adult cells [2,3]. In eukaryotes, the autophagy machinery and proteasomes are the 2 main degradation systems for the elimination of digested molecular cargo [4]. In contrast to proteasomal degradation, autophagy is the only way to eliminate entire injured organelles [2]. To date, 3 different types of autophagy mechanisms, namely macroautophagy, microautophagy, and chaperone-mediated autophagy, have been indicated in eukaryotic cells [2].

오토파지라는 용어는 

자가 포식 및 다양한 항상성 현상과 관련된 

세포 메커니즘을 의미합니다. 

오토파지의 활성화는 

숙주 세포가 잘못 접혀서 응집된 단백질과 

손상된 세포 소기관을 제거하는 데 도움이 됩니다[1]. 

세포 항상성에서의 역할 외에도 오토파지는 

여러 배아 및 성체 세포의 발달, 분화, 재생 잠재력에도 

적극적으로 관여합니다[2,3]. 

진핵생물에서 

오토파지 기계와 프로테아좀은 

소화된 분자화물을 제거하는 두 가지 주요 분해 시스템입니다[4]. 

프로테아좀 분해와 달리 오토파지는 

손상된 세포 소기관 전체를 제거하는 유일한 방법입니다[2]. 

현재까지 진핵세포에서 

거시적 자가포식, 

미세 자가포식, 

샤프론 매개 자가포식 등 3가지 유형의 자가포식 메커니즘이 밝혀졌습니다 [2].

Recent works have established that macroautophagy is the main autophagy mechanism in most cell types and is hereafter referred to as autophagy. From ultrastructural aspects, the autophagic response is initiated by the formation of double-membrane vesicles named autophagosomes [5]. In the latter steps, autophagosomes translocate and fuse with lysosomes for enzymatic degradation via the activity of several acidic hydrolases [6]. Compared to macroautophagy, microautophagy is thought of as a nxxxxonselective process and is initiated by the direct engulfment and sequestration of cytosolic components via the lysosomal membrane. In the last autophagy type (chaperone-mediated autophagy), a complex of chaperone proteins and target proteins are directed into the lysosomes via the activity of LAMP-2A [7].

최근 연구에 따르면 

대부분의 세포 유형에서 

매크로오토파지가 주요 자가포식 메커니즘으로 밝혀졌으며, 

이후 이를 자가포식이라고 부릅니다. 

초구조적 측면에서 보면, 

오토파지 반응은 

오토파지좀이라는 이중막 소포의 형성에 의해 시작됩니다 [5]. 

후자의 단계에서 오토파지는 

여러 산성 가수분해 효소의 활성을 통해 효소 분해를 위해 

리소좀으로 이동하고 융합합니다[6]. 

거대 오토파지에 비해 

미세 오토파지는 비선택적 과정으로 간주되며, 

리소좀 막을 통해 세포질 성분을 

직접 포획하고 격리함으로써 시작됩니다. 

마지막 

자가포식 유형(샤페론 매개 자가포식)에서는 

샤페론 단백질과 표적 단백질의 복합체가 LAMP-2A의 활성을 통해 

리소좀으로 유도됩니다[7].

Despite the protective role of autophagy on injured cells, abnormal or excessive autophagic responses cause several pathological outcomes via the stimulation of programmed cell death such as apoptosis, pyroptosis, etc. [[8], [9], [10], [11]]. Likewise, a severe reduction in autophagy activity can contribute to diverse pathological conditions such as genome instability, anaplastic changes, infection, premature aging, and metabolic disease [[12], [13], [14], [15], [16]]. Due to the mutual crosstalk between several autophagy constituents and other signaling cascades, pleiotropic effects have been attributed to the autophagy machinery [17,18]. The existence of complex autophagy machinery and shared molecular effectors lead to different simultaneous reaction cascades [19]. Along with these descriptions, it is logical to hypothesize that specific metabolic conditions can regulate the autophagic response either in physiological or pathological situations [20]. Molecular investigations have revealed that low energy levels or deprivation of essential nutrients like amino acids and glucose can lead to ATP depletion and increased AMP/ATP ratio, resulting in autophagy induction [21]. Under these conditions, the autophagy machinery is recalled to compensate for ATP limitation, whereas the promotion of autophagic efflux and subsequent biological events are closely linked to the consumption of ATP [22]. The exact relevance of the duration of starvation and activation of adaptive or excessive autophagy remains unknown. Here, we collected recent data associated with the possible therapeutic/detrimental effects of fasting on the autophagic response in terms of cellular homeostasis.

손상된 세포에 대한 자가포식의 보호 역할에도 불구하고 

비정상적이거나 과도한 자가포식 반응은 

세포 사멸, 

열성화(pyroptosis) 등 프로그램된 세포 사멸을 자극하여 

여러 가지 병리학적인 결과를 초래합니다. [[8], [9], [10], [11]]. 

마찬가지로 

자가포식 활동의 심각한 감소는 

유전체 불안정성, 

역형성 변화, 

감염, 

조기 노화, 

대사성 질환 등 다양한 병리적 상태를 유발할 수 있습니다[[12], [13], [14], [15], [16]]. 

여러 오토파지 구성 요소와 다른 신호 캐스케이드 간의 상호 누화로 인해, 

플레오트로픽 효과는 

오토파지 기계에 기인합니다 [17,18]. 

복잡한 오토파지 메커니즘과 

공유 분자 이펙터의 존재는 

서로 다른 동시 반응 캐스케이드로 이어집니다 [19]. 

이러한 설명과 함께 

특정 대사 조건이 생리적 또는 병리적 상황에서 

자가포식 반응을 조절할 수 있다는 가설을 세우는 것이 

합리적입니다 [20]. 

분자 연구에 따르면 

에너지 수준이 낮거나 

아미노산 및 포도당과 같은 필수 영양소가 부족하면 

ATP가 고갈되고 

AMP/ATP 비율이 증가하여 오토파지가 유도될 수 있습니다 [21]. 

이러한 조건에서 

자가포식 기계는 

ATP 제한을 보상하기 위해 호출되는 반면, 

자가포식 유출의 촉진과 그에 따른 생물학적 사건은 

ATP 소비와 밀접하게 연관되어 있습니다 [22]. 

기아 기간과 적응성 또는 

과도한 자가포식 활성화의 정확한 관련성은 아직 밝혀지지 않았습니다. 

여기에서는 세포 항상성 측면에서 단식이 자가포식 반응에 미칠 수 있는 치료적/해로운 영향과 관련된 최근 데이터를 수집했습니다.

As abovementioned, the autophagic response is initiated by the formation of double-membrane vesicles, namely autophagosomes. This biological phenomenon depends on the activity of nearly 16 Atgs and 2 distinct ubiquitin-like conjugation systems (Figure 1) [23]. Two complexes are required to promote the formation of autophagosomes. The first complex is composed of type III PI3K, Vps34, Atg14, Atg6/Beclin1, and Vps15/p150.73, and the second complex is associated with the activity of the serine/threonine kinase Atg1 [24]. In yeast, Atg8 or Atg13 and Atg17 are essential for the kinase activity of Atg1 whereas in mammals, LC3, which is an ortholog of Atg8, can promote the activity of Atg1 along with GATE-16 and GABARAP [25]. In the next step, autophagosomes become elongated via the activity of ubiquitin-like conjugation pathways. For this purpose, cells can use 2 pathways consisting of LC3/GABARAP/GATE-16 and Atg12 [26]. Due to the proteolytic activity of Atg4 on the Atg8 (carboxyl terminus), a glycine residue is exposed to generate the autophagosome [27]. After that, phosphatidyl ethanolamine is covalently attached to Atg8 (lipidated LC3-II in mammals) [28]. With the progression of autophagosome formation, the Atg16-Atg5-Atg12 complex is separated from the autophagosomal membrane, and complete autophagosomes can fuse with lysosomes [29]. The procedure is followed by the formation of autophagolysosomes in which autophagic cargo is degraded via lysosomal activity. In an alternative pathway, autophagosomes fuse with late endosomes and form amphisomes [30]. Molecular investigations have indicated that both amphisomes and autophagosomes converge eventually in lysosomes to digest and recycle their contents [31]. Several factors like Rab and Arf proteins with GTPase activity, tethering proteins like SNAREs, tethering adaptors, along with motor proteins promote the direct interaction of autophagosomes with lysosomes [31]. Autophagocytosed macromolecules are recycled into the cytosol to maintain bioenergetic homeostasis or are secreted out of the cells [32]. It should not be forgotten that the increase of autophagosomes (known also as autophagy flux) can reflect both increased autophagic response and abnormal reduction of autophagolysosome formation [33]. Therefore, the increase of intracellular autophagosomes does not necessarily reflect a complete autophagy response.

위에서 언급한 바와 같이 

자가포식 반응은 

이중막 소포, 즉 오토파지솜의 형성에 의해 시작됩니다. 

이 생물학적 현상은 약 16개의 Atgs와 2개의 서로 다른 유비퀴틴 유사 접합 시스템의 활성에 따라 달라집니다(그림 1) [23]. 오토파지좀의 형성을 촉진하려면 두 개의 복합체가 필요합니다. 

첫 번째 복합체는 

유형 III PI3K, Vps34, Atg14, Atg6/Beclin1, Vps15/p150.73으로 구성되며, 

두 번째 복합체는 

세린/트레오닌 키나아제 Atg1의 활성과 관련이 있습니다 [24]. 

효모에서는 Atg8 또는 Atg13과 Atg17이 Atg1의 키나아제 활성에 필수적인 반면, 포유류에서는 Atg8의 상동체인 LC3가 GATE-16 및 GABARAP과 함께 Atg1의 활성을 촉진할 수 있습니다 [25]. 

다음 단계에서는 

유비퀴틴 유사 접합 경로의 활성을 통해 

오토파지솜이 길어집니다. 

이를 위해 세포는 

LC3/GABARAP/GATE-16 및 Atg12로 구성된 

두 가지 경로를 사용할 수 있습니다 [26]. 

Atg8(카르복실 말단)에서 Atg4의 단백질 분해 활성으로 인해 

글리신 잔기가 노출되어 

오토파지솜이 생성됩니다 [27]. 

그 후, 포스파티딜 에탄올아민은

 Atg8(포유류의 지질화된 LC3-II)에 공유 결합됩니다[28]. 

자가포식체 형성이 진행됨에 따라

 Atg16-Atg5-Atg12 복합체는 

자가포식체 막에서 분리되고 

완전한 자가포식체는 리소좀과 융합 할 수 있습니다 [29]. 

이 절차에 이어 

자가포식화물이 

리소좀 활동을 통해 분해되는 자가포식 리소좀이 형성됩니다.

다른 경로에서 오토파지는

후기 엔도좀과 융합하여 암피좀을 형성합니다[30].

분자 연구에 따르면 앰피솜과 오토파지솜은

모두 결국 리소좀으로 수렴하여

내용물을 소화하고 재활용합니다[31].

GTPase 활성을 가진

Rab 및 Arf 단백질,

SNARE와 같은 테더링 단백질,

테더링 어댑터,

모터 단백질과 같은 여러 인자가 오토파지와

리소좀의 직접적인 상호 작용을 촉진합니다 [31].

자가포식된 거대분자는

생체 에너지 항상성을 유지하기 위해

세포질로 재활용되거나

세포 밖으로 분비됩니다[32].

자가포식 플럭스라고도 하는 자가포식소체의 증가는

자가포식 반응의 증가와

자가포식 리소좀 형성의 비정상적인 감소를 모두 반영할 수 있다는 사실을 잊지 말아야 합니다[33].

따라서

세포 내 오토파지솜의 증가가

반드시 완전한 오토파지 반응을 반영하는 것은 아닙니다.

FIGURE 1

Autophagy molecular machinery. The process of autophagy consists of several consequent molecular and subcellular morphological changes. In the early steps, the activation of autophagy upstream molecules leads to phagophore formation and expansion. These units sequester the damaged organelles, aggregated proteins, etc. By the activation of several Atgs, phagophores mature into autophagosomes followed by fusion with lysosomes and the formation of autophagolysosomes. Inside the autophagolysosomes, enzymatic digestion is orchestrated via varied hydrolases, leading to massive enzymatic digestion. The digested cargo is recycled into the cytosol or protrudes out of the host cells. Atg, autophagy-related protein; mTOR, mammalian target of rapamycin.

오토파지 분자 기계. 

오토파지 과정은 

여러 가지 분자 및 아세포 형태학적 변화로 구성됩니다. 

초기 단계에서 오토파지 상류 분자의 활성화는 

식세포 형성 및 확장으로 이어집니다. 

이러한 단위는 

손상된 세포 소기관, 

응집된 단백질 등을 격리합니다. 

여러 Atgs의 활성화에 의해 식세포는 

오토파지로 성숙하고 

리소좀과 융합하여 오토파지리소좀을 형성합니다. 

자가포식소체 내부에서는 

다양한 가수분해효소를 통해 

효소 소화가 조율되어 대량의 효소 소화가 이루어집니다. 

소화된 화물은 

세포질로 재활용되거나 

숙주 세포 밖으로 돌출됩니다. A

tg, 자가포식 관련 단백질; mTOR, 라파마이신의 포유류 표적.

In this review article, we aimed to highlight the possible effects of prolonged and short-term calorie deprivation on autophagic response and cell homeostasis. The molecular mechanisms by which calorie restriction can mediate both adaptive and excessive autophagic responses are discussed in detail. Whether and how autophagy modulation by calorie restriction can help the host cells to circumvent insulting conditions is at the center of the debate.

이 리뷰 기사에서는 

장단기 칼로리 결핍이 

자가포식 반응과 

세포 항상성에 미칠 수 있는 영향을 강조하고자 했습니다. 

칼로리 제한이 

적응성 및 과도한 자가포식 반응을 모두 매개할 수 있는 

분자적 메커니즘에 대해 자세히 논의합니다. 

칼로리 제한에 의한 자가포식 조절이 

숙주 세포가 모욕적인 조건을 회피하는 데 도움이 되는지 여부와 

그 방법이 논쟁의 중심에 있습니다.

Health Benefits of Intermittent Fasting

The term intermittent fasting (IF) includes different short- and long-term diet programs with regular cycles between the time of eating and fasting [[34], [35], [36]]. Calorie-restricted programs can usually last for 24 h to 3 wk, providing 30% of total energy demands [37]. Along with several programs recommended by nutritionists, IF is complete or partial abstinence from all drinks and foods in religious disciplines [38]. For decades, different forms of IF regimes have been used in several studies [39]. In the alternate-day fasting protocol, fasting is done every other day, and the consumption of energy-generating food products is prevented, whereas during feeding time (d) the studied groups are allowed access to food ad libitum. Of note, alternate-day modified fasting is a type of alternate-day fasting in which total energy intake reaches below 25% to 30% and is done in a limited period (open eating window: 2–4 h). A modified fasting regimen is another type of IF that supports 20% to 25% of daily energy using regular fasting days. This method is based on 5:2 diet, with 2 fasting days per week and usual eating on other days. Time-restricted feeding includes specific time frames of eating and fasting. Ramadan, with time-restricted eating rules, restricts Muslims to eat from dawn to sunset. During the eating time (4–10 h), the energy amount is not limited [37,39].

간헐적 단식(IF)이라는 용어는 

식사 시간과 단식 시간 사이에 규칙적인 주기가 있는 

다양한 단기 및 장기 다이어트 프로그램을 포함합니다[[34], [35], [36]]. 

칼로리 제한 프로그램은 

일반적으로 24시간에서 3주 동안 지속될 수 있으며, 

총 에너지 요구량의 30%를 공급합니다[37]. 

영양사가 권장하는 여러 프로그램과 함께 

IF는 종교적 규율에서 모든 음료와 음식을 완전히 

또는 부분적으로 금하는 것입니다 [38]. 

수십 년 동안 여러 연구에서 

다양한 형태의 IF 체제가 사용되었습니다 [39]. 

격일 단식 프로토콜에서는 

격일로 단식을 하고 

에너지를 생성하는 식품의 섭취를 막는 반면, 

수유 시간(d)에는 연구 대상 그룹이 음식을 자유로이 섭취할 수 있도록 허용합니다. 

참고로, 격일 변형 단식은 

총 에너지 섭취량을 25~30% 미만으로 제한하고 

제한된 기간(식사 시간: 2~4시간)에 시행하는 단식의 한 유형입니다. 

변형 단식 요법은 

일반 단식일에 일일 에너지의 20~25%를 섭취하는 또 다른 유형의 IF입니다. 

이 방법은 5:2 식단을 기본으로 하며, 

일주일에 2일은 금식하고 

다른 날은 평소와 같이 식사합니다. 

시간 제한 식단에는 

특정 식사 및 금식 시간대가 포함됩니다. 

시간 제한 식사 규칙이 있는 라마단에서는 무슬림이 새벽부터 일몰까지 식사를 제한합니다. 

식사 시간(4-10시간) 동안에는 에너지 양이 제한되지 않습니다[37,39].

Several findings are consistent with the fact that calorie restriction is linked to longevity and enhances protection against chronic pathologies by the regulation of anti-inflammatory responses [40]. IF may be an alternative method to conventional therapeutic regimes by exerting oncostatic properties and even increasing cancer patients' tolerance to chemotherapy. In support of this notion, healthy cells are more resistant to chemotherapy-induced injury; therefore, the intensity of off-target side effects is less in cancer patients who have undergone fasting [41]. To be specific, the exposure of normal cells to calorie restriction leads to the consumption of energy (ATP) for maintenance and regeneration purposes rather than proliferation. In tumor cells, the activation of several oncogenes such as the IGF-1R, Ras, and AKT/mTOR molecular pathways increases the proliferation rate and thus cell sensitivity to chemo/radiotherapy protocols [42]. Several works have provided evidence of bulk changes in metabolic status under regular starvation conditions [36].

칼로리 제한이 

장수와 관련이 있고 

항염증 반응의 조절을 통해 

만성 병리에 대한 보호를 강화한다는 사실과 일치하는 몇 가지 발견이 있습니다 [40]. 

IF는 

종양 억제 효과를 발휘하고 

화학 요법에 대한 암 환자의 내성을 증가시킴으로써 

기존 치료 요법의 대안이 될 수 있습니다. 

이러한 개념을 뒷받침하는 근거로, 

건강한 세포는 

화학요법으로 인한 손상에 대한 저항력이 더 강하기 때문에 

금식을 한 암 환자에서 표적 외 부작용의 강도가 더 적습니다 [41]. 

구체적으로 말하면, 

정상 세포가 칼로리 제한에 노출되면 

증식보다는 유지 및 재생을 위해 에너지(ATP)를 소비하게 됩니다. 

종양 세포에서 

IGF-1R, Ras, AKT/mTOR 분자 경로와 같은 

여러 종양 유전자의 활성화는 증식 속도를 증가시켜 

화학/방사선 치료 프로토콜에 대한 세포 민감도를 높입니다 [42]. 

여러 연구에서 

규칙적인 기아 조건에서 

대사 상태의 대량 변화에 대한 증거를 제공했습니다 [36].

In about the first 10 h after starvation, the stored glycogen in hepatic tissues is consumed followed by the breakdown of the fatty acids in muscles and adipose tissue. As a consequence, significant quantities of free fatty acids and amino acids are produced [36]. Importantly, IF alleviates inflammatory responses and leads to several ameliorative outcomes in individuals affected by asthma, rheumatoid arthritis, etc. [40]. An example is the production of IL-4, -5, and -13 by type 2 CD4+ lymphocytes to increase macrophage polarization toward M2 phenotypes, resulting in anti-inflammatory properties [43]. Beneficial effects of IF on gut microbiota and immune system activity may take place in patients with multiple sclerosis [44]. The molecular identity of the peripheral mononuclear cells in 21 volunteers with 24-h fasting and 3-h refeeding revealed the activation of CD4+ Th2 cells in healthy groups and asthmatic counterparts [45,46].

기아 후 약 10 시간 동안 

간 조직에 저장된 글리코겐이 소비되고 

근육과 지방 조직에서 지방산이 분해됩니다. 

결과적으로 

상당한 양의 유리 지방산과 아미노산이 생성됩니다 [36]. 

중요한 것은 

IF가 염증 반응을 완화하고 

천식, 류마티스 관절염 등의 영향을받는 개인에서 

몇 가지 개선 된 결과를 가져온다는 것입니다. [40]. 

예를 들어, 

2형 CD4+ 림프구에 의한 IL-4, -5, -13의 생산은 

M2 표현형에 대한 대식세포 분극을 증가시켜 

항염증 작용을 일으킵니다 [43]. 

장내 미생물 및 면역계 활동에 대한 IF의 유익한 효과는 

다발성 경화증 환자에서 발생할 수 있습니다 [44]. 

21명의 지원자를 대상으로 

24시간 금식 및 3시간 재수유를 실시한 후 

말초 단핵세포의 분자적 정체성을 연구한 결과, 

건강한 그룹과 천식 환자에서 CD4+ Th2 세포가 활성화된 것으로 나타났습니다[45,46].

The exact relevance of fasting and immunomodulatory effects is associated with the activation of FOXO4 and its canonical target FK506-binding protein 5. These factors are thought of as fasting-response elements in terms of the immune system with the potential to regulate the production and release of inflammatory cytokines from Th1 and Th17 lymphocytes [47]. In a similar experiment, time-restricted fasting significantly reduced the number of CD16+ and CD56+ natural killer cells without any effects on circulating CD3+, CD4+, and CD8+ lymphocytes [48]. Fasting may increase the activity of the antioxidant system against oxidative stress. For instance, SOD, an enzyme involved in the neutralization of ROS, is stimulated in cells subjected to IF [49]. Data indicated that the absolute protein concentrations of soluble intracellular adhesion molecule-1, LDL, and T3 hormone are reduced in middle-aged populations subjected to short- and long-term alternate-day fasting [50]. Biochemical studies demonstrated that 49 metabolites exhibited a 20% reduction and these values were ∼44.9% in amino acids.

단식과 면역 조절 효과의 정확한 관련성은 

FOXO4 및 그 표준 표적인 FK506 결합 단백질 5의 활성화와 

관련이 있습니다. 

이러한 인자들은 

면역계 측면에서 공복 반응 요소로 생각되며, 

Th1 및 Th17 림프구에서 

염증성 사이토카인의 생산과 방출을 조절할 수 있는 

잠재력을 가지고 있습니다 [47]. 

유사한 실험에서 

시간 제한 단식은 순환하는 

CD3+, CD4+, CD8+ 림프구에는 영향을 미치지 않으면서 

CD16+ 및 CD56+ 자연 살해 세포의 수를 현저히 감소시켰습니다 [48]. 

단식은 

산화 스트레스에 대항하는 

항산화 시스템의 활동을 증가시킬 수 있습니다. 

예를 들어, 

ROS의 중화에 관여하는 효소인 SOD는 

IF를 받은 세포에서 자극을 받습니다 [49]. 

데이터에 따르면 

장단기 격일제 단식을 하는 중년층에서 

가용성 세포 내 부착 분자-1, 

LDL, T

3 호르몬의 절대 단백질 농도가 감소하는 것으로 나타났습니다 [50]. 

생화학적 연구에 따르면 

49개의 대사 산물이 20% 감소했으며, 

이 수치는 아미노산에서 ∼44.9% 감소한 것으로 나타났습니다.

The apparent reduction of certain amino acids like methionine, a pro-aging factor, can postpone the aging procedure [51]. Another antiaging benefit of IF is related to the regulation of stem cell dynamic growth and function [52,53]. These cells can restore the function of damaged cells and replace lost cells. The conduction of fasting programs in animal models can lead to the elimination of age-related changes like AD and accelerated healing capacity under ischemic stroke [40]. Based on the histological examination, the proliferation of rodent hippocampus neural stem cells is increased ∼3 wk after IF. These changes are consistent with the local distribution of BDNF [54]. Of note, stimulation of the mTOR axis reduces telomere shortening and maintains pluripotency potential under IF conditions [55,56].

노화 촉진 인자인 

메티오닌과 같은 특정 아미노산의 명백한 감소는 

노화 과정을 지연시킬 수 있습니다 [51]. 

IF의 또 다른 노화 방지 효과는 

줄기세포의 동적 성장 및 기능 조절과 관련이 있습니다[52,53]. 

이러한 세포는 

손상된 세포의 기능을 회복하고 손

실 된 세포를 대체 할 수 있습니다. 

동물 모델에서 단식 프로그램을 실시하면

 AD와 같은 노화 관련 변화를 제거하고 

허혈성 뇌졸중에서 치유 능력을 가속화 할 수 있습니다 [40]. 

조직 학적 검사에 따르면 

설치류 해마 신경 줄기 세포의 증식은

 IF 후 ∼ 3 주 후에 증가합니다. 

이러한 변화는

 BDNF의 국소 분포와 일치합니다 [54]. 

주목할 점은, 

mTOR 축의 자극은 

텔로미어 단축을 감소시키고 

IF 조건 하에서 다능성 잠재력을 유지한다는 것입니다 [55,56].

IF and Autophagy

Mechanisms of IF-induced autophagy

Emerging data have indicated a close relationship between IF and autophagic response. How and by which mechanisms IF can regulate the autophagy machinery is the subject of debate [57]. Sun and coworkers [58] found a close relationship between starvation and autophagy induction via the deacetylation of ATG4B and further interaction with pro-LC3. It confirmed that starvation in mice led to simultaneous reduction of P300 and induction of SIRT2 activity, resulting in deacetylation of ATG4B [58]. Under normal conditions, the acetyltransferase activity of P300 contributes to the nuclear localization of the ATG8–PE ubiquitin system and autophagy inhibition in Bombyx mori (Figure 2) [59]. Based on the data, a 2-d period of starvation in Sirt2−/− mice led to a reduction of LC3-II, an increase in acetylated ATGB4 in hepatic tissue, and a suppression of the autophagic response, suggesting a close relationship between autophagy and SIRT2 activity (Figure 3) [58].

새로운 데이터에 따르면 

IF와 자가포식 반응 사이에 

밀접한 관계가 있는 것으로 나타났습니다. 

IF가 

오토파지 메커니즘을 조절하는 방법과 

메커니즘은 논쟁의 대상입니다 [57]. 

Sun과 동료 연구자[58]는 

ATG4B의 탈아세틸화와 프로-LC3와의 추가 상호작용을 통한 

기아 및 오토파지 유도 사이의 밀접한 관계를 발견했습니다. 

생쥐의 기아가 P300의 감소와 SIRT2 활성의 유도를 동시에 유도하여 ATG4B의 탈아세틸화를 초래한다는 것을 확인했습니다 [58]. 정상적인 조건에서 P300의 아세틸 트랜스퍼라제 활성은 봄빅스 모리에서 ATG8-PE 유비퀴틴 시스템의 핵 국소화와 오토파지 억제에 기여합니다(그림 2) [59]. 데이터에 따르면, Sirt2-/- 마우스에서 2일간 굶긴 결과 LC3-II가 감소하고 간 조직에서 아세틸화된 ATGB4가 증가하며 자가포식 반응이 억제되어 자가포식과 SIRT2 활성 사이에 밀접한 관계가 있음을 시사합니다(그림 3) [58].

Once the intracellular concentrations of ATP and glucose drop below the normal values, the elevation of AMP promotes the allosteric changes in AMPK and thus its enzymatic activity [60]. In such conditions, the AMPK activity inhibits mTORC1 and protein synthesis to minimize ATP consumption by controlling anabolic and catabolic processes [61]. Further reduction of fructose-1, 6-bisphosphate concentrations activate lysosomal AMPK via vacuolar H+‒ATPase-aldolase complex. Along with these changes, the AXIN-vacuolar H+‒ATPase complex regulates the activity of LKB1, resulting in the phosphorylation of AMPK [61]. To minimize fatty acid synthesis, AMPK recalls acetyl-CoA carboxylases to trigger the oxidation of fatty acids. Furthermore, the phosphorylation of SREBP-1c by AMPK leads to the suppression of fatty acid synthesis at the expression‎ level [61]. Direct phosphorylation of ULK1 (the ortholog of yeast Atg1) and BCLN1 by AMPK initiates several Atgs related to the autophagy signaling pathway [62].

세포 내 ATP 및 포도당 농도가 정상치 이하로 떨어지면 

AMP의 상승은 AMPK의 알로스테릭 변화를 촉진하여 

효소 활성을 촉진합니다 [60]. 

이러한 조건에서 

AMPK 활성은 

단백 동화 및 이화 과정을 제어하여 

ATP 소비를 최소화하기 위해 

mTORC1 및 단백질 합성을 억제합니다 [61]. 

과당-1, 6-비스포스페이트 농도가 더 감소하면 

액포 H+-ATPase-알돌라제 복합체를 통해 

리소좀 AMPK가 활성화됩니다. 

이러한 변화와 함께 

AXIN-소포체 H+-ATPase 복합체는 

LKB1의 활성을 조절하여 

AMPK의 인산화를 초래합니다 [61]. 

지방산 합성을 최소화하기 위해 

AMPK는 아세틸-CoA 카르복실화 효소를 호출하여

 지방산의 산화를 촉발합니다. 

또한 AMPK에 의한 SREBP-1c의 인산화는 

발현 수준에서 지방산 합성을 억제합니다 [61]. 

AMPK에 의한 ULK1(효모 Atg1의 상동체) 및 BCLN1의 직접 인산화는 자가포식 신호 경로와 관련된 여러 Atgs를 개시합니다[62].

FIGURE 2

Monitoring protein concentrations of BmSqstm1, BmAtg3, and BmAtg8 in Bombyx mori using western blotting (A) and immunofluorescence staining in fat body after treatment with BmAtg4 RNAi for 24 h (A’; Scale bar: 10 μm). Measuring the protein concentrations of BmSqstm1, BmAtg3, and BmAtg8 using western blotting in the fat body after treatment with BmAtg7 RNAi for 24 h (B). At the same time point, protein concentrations of BmAtg3 and BmAtg8 were studied using immunofluorescence staining (B’; Scale bar: 10 μm). Acetylated BmAtg4-V5 after 4-h starvation (C). Acetylated BmAtg7-HA concentrations after 4 h (D). BmAtg8, BmSqstm1, and BmAtg4-V5 concentrations were analyzed using western blotting (E) and immunofluorescence staining (E’; Scale bar: 10 μm) after treatment with 20-hydroxyecdysone (20E) or 4-h starvation. Protein contents of BmSqstm1, BmAtg7-HA, and BmAtg8 were assessed using western blotting (F), and immunofluorescence staining (F’; Scale bar: 10 μm) was used to detect BmAtg7-HA concentrations after treatment with 20E or 4-h starvation. Acetylated levels of BmAtg4-V5 were measured after treatment with 5 μM 20E, 800 nM C646 (selective inhibitor of P300), 20 μM TSA (deacetylase Rpd3 inhibitor), and 20 μM CTB (P300 activator) after 6 h in BmN cells (G). Acetylated levels of BmAtg7-HA in BmN cells after treatment with the same conditions mentioned in panel G (H). Adapted with permission [59]. Copyright Cell Death Discovery 2021 (https://doi.org/10.1038/s41420-021-00513-0). Atg, autophagy-related protein; TSA, Trichostatin A.

FIGURE 3

Studying the effect of SIRT2 on ATG4B deacetylation and autophagy regulation in in vivo conditions. Sirt2−/− C57BL/6N mice were starved for 2 d, and hepatic tissue was analyzed and compared with the wild-type control group. Immunohistochemical analysis of SIRT2, Ac-ATG4BK39, and LC3 (A). Positive cells were counted and calculated per 1000 cells. Ac-ATG4BK39 concentrations were analyzed using immunofluorescence staining (B; Scale bar: 25 μm). Measuring protein concentrations of Ac-ATG4BK39, Ac-α-tubulinK40 using western blotting (C). The activity of ATG4B (D). The analyses were done in triplicate. One-factor ANOVA with Tukey’s multiple comparisons tests. ∗∗∗P < 0.001; and ∗∗∗∗P < 0.0001. Adapted with permission [58]. Copyright Science Advances 2022 (https://doi.org/10.1126/sciadv.abo0412). ATG, autophagy-related protein; SIRT2, sirtuin 2.

Regulation of autophagy by insulin signaling

The insulin signaling pathway has a critical role in the regulation of anabolic and catabolic mechanisms under physiological and pathological conditions [63]. Insulin hormone can bind to membrane-associated receptors INSR-1, -2, and IGF1R, which have tyrosine kinase activity, to trigger signals associated with energy homeostasis [64]. Unlike hypoglycemic conditions, the activation of INSR-1, -2, and IGF1R increase glucose uptake via the PI3K/Akt axis [63,64]. Along with these changes, glycolysis, glycogenesis, and lipogenesis mechanisms are induced by the activation of phosphofructokinase‒2 and inhibition of GSK3β [63,64]. Gluconeogenesis is reduced in the presence of insulin following the phosphorylation of FOXO1 [65,66]. Data support the fact that insulin inhibits the autophagy machinery via the activation of mTORC1, phosphorylation of ULK1, and suppression of FOXO1 expression‎ [67].

인슐린 신호 경로는 

생리적 및 병리학적인 조건에서 

동화 작용과 이화 작용 메커니즘을 조절하는 데 

중요한 역할을 합니다[63]. 

인슐린 호르몬은 

티로신 키나아제 활성을 갖는 

막 관련 수용체 INSR-1, -2 및 IGF1R에 결합하여 

에너지 항상성과 관련된 신호를 유발할 수 있습니다 [64]. 

저혈당 상태와 달리 

INSR-1, -2, IGF1R의 활성화는 

PI3K/Akt 축을 통해 포도당 흡수를 증가시킵니다[63,64]. 

이러한 변화와 함께 

해당 작용, 

글리코겐 생성 및 지방 생성 메커니즘은 

포스포프락토키나제-2의 활성화와 

GSK3β의 억제에 의해 유도됩니다 [63,64]. 

포도당 생성은 

FOXO1의 인산화 후 인슐린이 존재할 때 

감소합니다 [65,66]. 

데이터는 

인슐린이 

mTORC1의 활성화, 

ULK1의 인산화 및 FOXO1 발현 억제를 통해 

자가포식 메커니즘을 억제한다는 사실을 뒷받침합니다 [67].

Recent works have reported that Akt regulates the phosphorylation of mTORC1 and FOXO1/3 factors, indicating the reciprocal interaction of autophagy and insulin signaling pathways [67]. Results showed a moderate to high increase of aging-related factors like p53, p21, and p16 and β-galactosidase activity in chondrocytes exposed to hyperglycemic conditions [68]. By increasing the glucose contents, intracellular p62 and ROS concentrations are increased, and this coincides with the suppression of LC3II/I and the phosphorylated-AMPK/AMPK ratio [68]. Of course, it should not be forgotten that the autophagy machinery is stimulated in the early stages after the exposure of cells to high glucose conditions. However, it is possible that the continuity of hyperglycemic conditions leads to an abnormal (excessive) autophagic response [9,69]. Taken together, these data suggested the presence of common effectors between the glucose metabolism, insulin signaling pathway, and autophagy response and their mutual interaction under several conditions.

최근 연구에 따르면 

Akt는 mTORC1 및 FOXO1/3 인자의 인산화를 조절하여 

자가포식과 인슐린 신호 경로의 상호 작용을 나타내는 것으로 보고되었습니다 [67]. 

그 결과 고혈당 상태에 노출된 연골세포에서 

p53, p21, p16과 같은 노화 관련 인자와 

β-갈락토시다제 활성이 중간에서 높은 수준으로 증가하는 것으로 나타났습니다[68]. 

포도당 함량이 증가하면 

세포 내 p62 및 ROS 농도가 증가하며, 이

는 LC3II/I 및 인산화-AMPK/AMPK 비율의 억제와 일치합니다 [68]. 

물론 세포가 

고포도당 조건에 노출된 후 초기 단계에서 

자가포식 기계가 자극된다는 사실을 잊지 말아야 합니다. 

그러나 

고혈당 상태가 지속되면 

비정상적인 (과도한) 자가포식 반응이 발생할 수 있습니다 [9,69]. 

이러한 데이터를 종합하면 

포도당 대사, 

인슐린 신호 전달 경로 및 

자가포식 반응 사이에 공통된 인자가 존재하며 

여러 조건에서 상호 작용한다는 것을 알 수 있습니다.

Role of IF on Autophagic Response under Pathological Conditions

The apparent and early-stage activity of the autophagy machinery has been indicated in several pathologies [70]. In line with this claim, evidence for the participation of autophagy as an early-stage protective response has been obtained in different neurodegenerative diseases like Huntington’s disease, AD, Parkinson's disease, etc. [71]. With the progression of neurodegenerative disease, the accumulation of misfolded proteins and peptides increases the possibility of proteotoxicity [72,73]. The physiological significance of autophagy is related to scavenging deleterious proteins and the prohibition of neuronal proteotoxicity [74]. Commensurate with these descriptions, it is thought that autophagy activation using diverse stimuli like regular food starvation and varied exogenous compounds is a therapeutic strategy in patients [75,76]. An experiment conducted by Alirezaei et al. [76] confirmed that short-term fasting (24–48 h) induces an autophagic response in murine hepatic tissues and neuronal cells. Based on the data, the number of hepatic cell autophagosomes (evidenced as GFP-LC3 puncta) was increased in the early 24 h post-food restriction, and these values reached maximum concentrations after 48 h [76]. A similar pattern was obtained in the cortical neurons of food-restricted mice compared with those of the control group. Both the number and size of autophagosomes were increased in food-restricted mice. Interestingly, these conditions can promote retrograde traffic of autophagosomes from neurites toward cell somata, indicating the formation of autophagolysosomes and lysosomal degradation [76].

오토파지 기계의 명백하고 초기 단계의 활동은 여러 병리에서 나타났습니다 [70]. 이러한 주장에 따라 헌팅턴병, 알츠하이머병, 파킨슨병 등과 같은 다양한 신경 퇴행성 질환에서 초기 단계의 보호 반응으로서 오토파지의 참여에 대한 증거가 발견되었습니다. [71]. 

신경 퇴행성 질환이 진행됨에 따라 

잘못 접힌 단백질과 펩타이드의 축적은 

단백질 독성의 가능성을 증가시킵니다 [72,73]. 

오토파지의 생리적 중요성은 

해로운 단백질 제거 및 

신경세포 단백질 독성 방지와 관련이 있습니다 [74]. 

이러한 설명에 상응하여, 

규칙적인 음식 결핍 및 다양한 외인성 화합물과 같은 

다양한 자극을 이용한 자가포식 활성화가 

환자의 치료 전략으로 생각되고 있습니다 [75,76]. 

Alirezaei 등[76]이 수행한 실험에서 

단기간의 단식(24-48시간)이 쥐 간 조직과 신경세포에서 

자가포식 반응을 유도한다는 것을 확인했습니다. 

데이터에 따르면, 

간세포 오토파지솜의 수(GFP-LC3 푼타로 입증됨)는 

음식 제한 후 초기 24시간 동안 증가했으며, 

이 값은 48시간 후에 최대 농도에 도달했습니다[76]. 

음식 제한 쥐의 피질 뉴런에서도 

대조군과 비슷한 패턴이 관찰되었습니다. 

음식 제한 마우스에서 

오토파지솜의 수와 크기가 모두 증가했습니다. 

흥미롭게도 이러한 조건은 

뉴런에서 세포 소마타로 향하는 오토파지솜의 역행 교통을 촉진하여 

오토파지리소좀의 형성과 리소좀 분해를 나타낼 수 있습니다 [76].

Likewise, the existence of reticular perinuclear patterns in Purkinje cells indicated active autophagosome-lysosome fusion after food restriction [76]. As such, it was suggested that reduced p70S6 kinase activity and phosphorylated S6RP in nonfed mice were associated with the inhibition of mTOR and the autophagic response [76]. These data show that food restriction can improve neuronal injury associated with proteotoxicity and changes in intracellular inclusion via the lysosomal degradation system. In support of this notion, SIRT1-mediated deacetylation of FoxO affects the activity of ROCK1, which in turn promotes α-secretase and reduces Aβ deposition [77]. It has been shown that α-secretase, a metalloproteinase, can degrade amyloid precursor protein within the Aβ domain and inhibits the accumulation of insoluble Aβ in the extracellular matrix [78]. These data indicate the potential clinical relevance and neuroprotective effects of calorie restriction on neurological disorders via the modulation of autophagy. Toxic protein aggregates can be removed via therapeutics (drugs) or certain food regimes that target autophagy machinery. Because calorie restriction is an inexpensive and suitable alternate to drug administration and available medications, it seems that calorie restriction can be used as a prophylactic and therapeutic approach in patients with neurological disorders. Despite the beneficial effects of food restriction in the alleviation of neurodegenerative disease, there are some conflicting and inconsistent results [79,80]. Every-other-day feeding of 5XFAD mice (AD model) not only did not reduce plaque formation in brain parenchyma but also promoted a cortical neuroinflammatory response and reduced protein concentrations of factors associated with synaptic plasticity [80]. This apparent discrepancy may be related to several factors, such as food components, experimental protocol, period of dietary restrictions, genetic traits, and age of studied groups [81]. A plethora of documents have indicated compromised autophagy flux and reduced lysosomal proteolysis under calorie restriction conditions [82]. That said, calorie restriction in the elderly may not be a good strategy to eliminate the intracellular inclusion bodies because of the compromised autophagy machinery. Furthermore, cells can adapt themselves with regulated energy reduction, acute depletion in a short time, or severe ATP reduction in a prolonged time, which inhibit vacuolar hydrolysis. Under these circumstances, macroautophagy is integral to the progression of pathological changes [83]. Even the significant and hostile depletion of ATP forces the cells toward necrotic changes rather than apoptosis and/or autophagic death [84]. Rapid ATP depletion activates excessive autophagy flux, which exceeds the degradation capacity of lysosomes, resulting in the accumulation of autophagosomes and cell death [8,85]. It should not be forgotten that some treatment protocols are not applicable in in vivo conditions with prolonged fasting. For example, in rats subjected to overnight fasting, local brain calcium contents were abnormally increased after systemic administration in which refeeding with glucose led to return of brain calcium to normal concentrations [86]. One reason for these effects may be that chronic starvation can lead to blood-brain-barrier leakage due to rapid ATP depletion and loss of cell homeostasis. Thus, attention should be given when certain starvation protocols are suggested for patients with conventional therapeutic modalities.

마찬가지로, 

푸르킨예 세포에서 

망상 핵주위 패턴의 존재는 

음식 제한 후 활발한 자가포식소체-리소좀 융합을 나타냅니다 [76]. 

따라서 먹이를 먹지 않은 마우스에서 감소된 p70S6 키나아제 활성과 인산화된 S6RP는 mTOR의 억제 및 자가포식 반응과 관련이 있다고 제안되었습니다 [76]. 

이러한 데이터는 

음식 제한이 리소좀 분해 시스템을 통해 

단백질 독성 및 세포 내 포함의 변화와 관련된 신경 손상을 

개선할 수 있음을 보여줍니다. 

이러한 개념을 뒷받침하듯, 

SIRT1을 매개로 한 FoxO의 탈아세틸화는 

ROCK1의 활성에 영향을 미쳐 

α-세크레타제를 촉진하고 

Aβ 침착을 감소시킵니다 [77]. 

금속 단백질 분해 효소인 α-세크레타제는 Aβ 도메인 내에서 아밀로이드 전구체 단백질을 분해하고 세포 외 기질에 불용성 Aβ의 축적을 억제할 수 있는 것으로 나타났습니다 [78]. 

이러한 데이터는 

칼로리 제한이 자가포식 조절을 통해 

신경학적 장애에 미치는 잠재적인 임상적 관련성과 

신경 보호 효과를 나타냅니다. 

독성 단백질 응집체는 

자가포식 메커니즘을 표적으로 하는 치료제(약물) 또는 

특정 식이요법을 통해 제거할 수 있습니다. 

칼로리 제한은 

약물 투여 및 사용 가능한 약물에 대한 저렴하고 적절한 대안이기 때문에 

신경 장애 환자의 예방 및 치료 접근법으로 

칼로리 제한을 사용할 수 있는 것으로 보입니다. 

신경 퇴행성 질환의 완화에 음식 제한의 유익한 효과에도 불구하고 

일부 상충되고 일관되지 않은 결과가 있습니다 

[79,80]. 5XFAD 마우스(AD 모델)를 격일로 먹이는 것은 뇌 실질의 플라크 형성을 감소시키지 않았을 뿐만 아니라 피질 신경염증 반응을 촉진하고 시냅스 가소성과 관련된 인자의 단백질 농도를 감소시켰습니다 [80]. 이러한 명백한 불일치는 식품 성분, 실험 프로토콜, 식이 제한 기간, 유전적 특성 및 연구 그룹의 연령과 같은 여러 요인과 관련이 있을 수 있습니다 [81]. 수많은 문서에서 칼로리 제한 조건에서 자가포식 플럭스가 손상되고 리소좀 단백질 분해가 감소하는 것으로 나타났습니다 [82]. 즉, 노인의 칼로리 제한은 손상된 자가포식 기계로 인해 세포 내 봉입체를 제거하기 위한 좋은 전략이 아닐 수 있습니다. 또한, 세포는 조절된 에너지 감소, 단시간의 급성 고갈 또는 장기간의 심각한 ATP 감소로 스스로 적응하여 액포 가수분해를 억제할 수 있습니다. 이러한 상황에서 거시 오토파지는 병리학적인 변화의 진행에 필수적입니다 [83]. ATP의 현저하고 적대적인 고갈조차도 세포를 세포 사멸 및/또는 자가포식 사멸이 아닌 괴사성 변화로 유도합니다 [84]. 급속한 ATP 고갈은 리소좀의 분해 능력을 초과하는 과도한 자가포식 플럭스를 활성화하여 자가포식체의 축적과 세포 사멸을 초래합니다 [8,85]. 일부 치료 프로토콜은 장기간 단식하는 생체 내 조건에서는 적용 할 수 없다는 것을 잊지 말아야합니다. 예를 들어, 밤새 단식한 쥐의 경우, 포도당을 전신 투여한 후 국소 뇌 칼슘 함량이 비정상적으로 증가하여 포도당을 다시 먹이면 뇌 칼슘이 정상 농도로 회복되었습니다 [86]. 이러한 효과의 한 가지 이유는 만성적 인 기아가 빠른 ATP 고갈과 세포 항상성 상실로 인해 혈액-뇌 장벽 누출로 이어질 수 있기 때문일 수 있습니다. 따라서 기존 치료 방식을 사용하는 환자에게 특정 기아 프로토콜을 제안할 때는 주의를 기울여야 합니다.

Like the central nervous system, autophagy flux has a crucial role in heart function and cardiomyocyte homeostasis [87]. The activation of AMPK in ischemic cardiomyocytes is a housekeeping protective mechanism to save the injured cells [88,89]. IF in ECs mediates functional activity and reduces injury rates in obese individuals by regulating certain biomarkers and the autophagic response [90]. Godar and coworkers [91] demonstrated the cardioprotective role of IF on ischemia-reperfusion injury in a mouse model. Six-week alternate-day fasting increased autophagy flux (autophagosomes↑) and reduced infarct area compared to nonfasted mice. They claimed that the inhibition of autophagosome-lysosome fusion using chloroquine led to the accumulation of LC3-II and SQSTM1/p62 [91]. Suppression of lysosomal Lamp2 increased punctate GFP-LC3 and SQSTM1/p62 such that IF worsens ventricular remodeling and cardiomyocyte toxicity in Lamp2-/- mice [91].

중추 신경계와 마찬가지로 

자가포식 플럭스는 

심장 기능 및 심근 세포 항상성에 중요한 역할을 합니다 [87]. 

허혈성 심근세포에서 AMPK의 활성화는 

손상된 세포를 구하기 위한 보호 메커니즘입니다 [88,89]. 

심근세포의 IF는 

특정 바이오마커와 자가포식 반응을 조절하여 

기능적 활동을 매개하고 비만한 사람의 부상률을 감소시킵니다[90]. 

Godar와 동료 연구자[91]는 마우스 모델에서 허혈-재관류 손상에 대한 IF의 심장 보호 역할을 입증했습니다. 6주 동안 하루를 번갈아 단식한 쥐는 단식하지 않은 쥐에 비해 자가포식 플럭스(오토파지↑)가 증가하고 경색 면적이 감소했습니다. 연구팀은 클로로퀸을 사용하여 자가포식체-리소좀 융합을 억제하면 LC3-II와 SQSTM1/p62가 축적된다고 주장했습니다 [91]. 리소좀 Lamp2를 억제하면 점상 GFP-LC3와 SQSTM1/p62가 증가하여 IF가 Lamp2-/- 마우스에서 심실 리모델링과 심근세포 독성을 악화시켰습니다 [91].



이러한 특징은 IF에 따른 자가포식을 통한 리소좀 분해 메커니즘의 활성화가 허혈성 변화의 발생과 함께 심장 조직에서 재생 효과를 발휘할 수 있음을 나타냅니다. 주목할 점은 굶주린 심근 세포의 활성 Atg5 발현과 자가포식 플럭스가 허혈성 조건에 대한 저항에 기여한다는 것입니다 [92]. 이소프로테레놀로 급성 심근경색을 일으킨 늙은 쥐에게 4주간 IF를 투여한 결과, Atg5의 상향 조절과 심장 크레아틴 키나아제, MDA, TNF-α 및 FBS의 감소가 나타났습니다 [92]. 간 조직 내에서 자가포식 기능은 고유한 대사 상태와 특정 기능으로 인해 매우 중요합니다 [93]. 따라서 약간 모욕적 인 조건과 대사 장애가 간세포 내부의자가 포식 활성화로 이어질 수 있다는 가설을 세우는 것이 합리적입니다 [94]. 자가 포식 반응이 결핍되면 비 알코올성 지방 간염, 바이러스 성 질환 및 다양한 암종과 같은 여러 병리가 진행될 수 있습니다 [93]. 8주 동안 주당 72시간 금식을 하면 사료 펠렛을 먹인 쥐에 비해 고지방 사료를 먹인 쥐의 간에서 LC3, LAMP1, BCLN1의 유도를 통해 지방량을 감소시킬 수 있다고 제안되었습니다 [57]. 골격근의 자가포식 상태에서는 유의미한 차이가 발견되지 않았습니다 [57]. 그 이유 중 하나는 간이 기아 상태에서 케톤체가 생성되고 축적되는 주요 부위이며 자가포식 상태와 케톤체 농도 사이에 밀접한 관계가 있기 때문일 수 있습니다 [95]. Atg7의 하향 조절은 PPAR-α 핵심 조절자인 NCoR1의 세포 내 축적, PPAR의 억제 및 지방산 β 산화 감소와 관련이 있습니다 [96]. 따라서 IF에 대한 조직의 민감도는 다양한 자가포식 반응에 따라 달라질 수 있습니다 [57]. 주목할 점은 IF는 허혈성 조건에 반응하여 적응성 자가포식을 활성화하기 위해 다양한 신호 전달 인자를 통합한다는 것입니다 [97]. 간 조직 허혈성 재관류 손상을 입은 금식 마우스에서 IF에 따른 시간 의존적 보호를 무시해서는 안됩니다 [97]. 간세포가 손상된 1일 단식 마우스에서 Tnfα, Il1b, Il6, Ccl2와 같은 전 염증성 유전자의 전사 및 증가 된 전신 HMGB1 농도가 완화되는 것으로 밝혀진 반면, 2일 및 3일 단식 프로토콜은 보호 효과를 발휘하지 못했습니다 [97]. 이러한 효과는 간 조직 내 상주 쿠퍼 세포의 조절 및 허혈성 손상에 대한 호중구 침윤과 관련이 있습니다. 이러한 변화와 함께, 태아 소 혈청 농도 감소에 노출된 LPS 처리 마우스 생쥐 264-7 대식세포에서는 ROS 및 TNF-α의 생산이 증가하지 않았습니다 [97]. 데이터에 따르면 대조군과 비교하여 공복 마우스에서 LC3, BCLN1, SIRT1 및 HMGB1의 세포 내 응집이 증가한 것으로 나타났습니다 [97]. 자가포식 메커니즘은 염증성 HMGB1을 분해하고 혈액으로의 추가 분비 및 식세포의 활성화를 억제하는 것으로 생각됩니다 [97,98].

These features indicate that the activation of the lysosomal degradative machinery via autophagy following IF can exert regenerative outcomes in cardiac tissue with the occurrence of ischemic changes. Of note, active Atg5 expression‎ and autophagic flux in starved cardiomyocytes contribute to resistance against ischemic conditions [92]. In aged rats subjected to acute myocardial infarction with isoproterenol, 4-wk IF led to upregulation of Atg5 and reduction of cardiac creatine kinase, MDA, TNF-α, and FBS [92]. Within hepatic tissue, autophagy function is very important due to its unique metabolic status and specific function [93]. Therefore, it is logical to hypothesize that slightly insulting conditions and metabolic disorders can lead to the activation of autophagy inside hepatocytes [94]. A deficient autophagic response can lead to the progression of several pathologies such as nonalcoholic steatohepatitis, viral diseases, and varied carcinomas [93]. It was suggested that 72 h fasting per week for 8 wk can reduce fat mass in mouse liver fed with a high-fat diet by the induction of LC3, LAMP1, and BCLN1 compared to the feed pellets–fed mice [57]. No significant differences were found in terms of autophagy status in the skeletal muscles [57]. One reason would be that the liver is the primary site for the production and accumulation of ketone bodies during starvation and there is a close relationship between autophagy status and ketone body concentrations [95]. The downregulation of Atg7 is associated with the intracellular accumulation of NCoR1, a PPAR-α coregulator, inhibition of PPAR, and reduction of fatty acid β-oxidation [96]. Therefore, the sensitivity of tissue to IF can be different, with varied autophagic responses [57]. Of note, IF integrates a multiplicity of signaling effectors to activate adaptive autophagy in response to ischemic conditions [97]. In fasted mice subjected to hepatic tissue ischemic reperfusion injury, time-dependent protection following IF should not be neglected [97]. The transcription of proinflammatory genes such as Tnfα, Il1b, Il6, and Ccl2 and increased systemic HMGB1 concentrations were found to be mitigated in 1-d fasted mice with injured hepatocytes, whereas 2- and 3-d fasting protocols did not exert protective effects [97]. These effects are associated with the regulation of resident Kupffer cells within the hepatic tissue and neutrophil infiltration in response to ischemic injury. Along with these changes, the production of ROS and TNF-α was not increased in LPS-treated mouse Raw 264-7 macrophages exposed to decreasing concentration of fetal bovine serum [97]. Data indicated the increase of LC3, BCLN1, SIRT1, and intracellular aggregation of HMGB1 in the fasted mice as compared to the control-matched groups [97]. Autophagy machinery is thought to degrade proinflammatory HMGB1 and prohibits further secretion into the blood and activation of phagocytes [97,98].

이러한 특징은 

IF에 따른 자가포식을 통한 리소좀 분해 메커니즘의 활성화가

 허혈성 변화의 발생과 함께 심장 조직에서 재생 효과를 발휘할 수 있음을 나타냅니다. 

주목할 점은 굶주린 심근 세포의 활성 Atg5 발현과 자가포식 플럭스가 허혈성 조건에 대한 저항에 기여한다는 것입니다 [92]. 이소프로테레놀로 급성 심근경색을 일으킨 늙은 쥐에게 4주간 IF를 투여한 결과, Atg5의 상향 조절과 심장 크레아틴 키나아제, MDA, TNF-α 및 FBS의 감소가 나타났습니다 [92]. 간 조직 내에서 자가포식 기능은 고유한 대사 상태와 특정 기능으로 인해 매우 중요합니다 [93]. 따라서 약간 모욕적 인 조건과 대사 장애가 간세포 내부의자가 포식 활성화로 이어질 수 있다는 가설을 세우는 것이 합리적입니다 [94]. 자가 포식 반응이 결핍되면 비 알코올성 지방 간염, 바이러스 성 질환 및 다양한 암종과 같은 여러 병리가 진행될 수 있습니다 [93]. 8주 동안 주당 72시간 금식을 하면 사료 펠렛을 먹인 쥐에 비해 고지방 사료를 먹인 쥐의 간에서 LC3, LAMP1, BCLN1의 유도를 통해 지방량을 감소시킬 수 있다고 제안되었습니다 [57]. 골격근의 자가포식 상태에서는 유의미한 차이가 발견되지 않았습니다 [57]. 그 이유 중 하나는 간이 기아 상태에서 케톤체가 생성되고 축적되는 주요 부위이며 자가포식 상태와 케톤체 농도 사이에 밀접한 관계가 있기 때문일 수 있습니다 [95]. Atg7의 하향 조절은 PPAR-α 핵심 조절자인 NCoR1의 세포 내 축적, PPAR의 억제 및 지방산 β 산화 감소와 관련이 있습니다 [96]. 따라서 IF에 대한 조직의 민감도는 다양한 자가포식 반응에 따라 달라질 수 있습니다 [57]. 주목할 점은 IF는 허혈성 조건에 반응하여 적응성 자가포식을 활성화하기 위해 다양한 신호 전달 인자를 통합한다는 것입니다 [97]. 간 조직 허혈성 재관류 손상을 입은 금식 마우스에서 IF에 따른 시간 의존적 보호를 무시해서는 안됩니다 [97]. 간세포가 손상된 1일 단식 마우스에서 Tnfα, Il1b, Il6, Ccl2와 같은 전 염증성 유전자의 전사 및 증가 된 전신 HMGB1 농도가 완화되는 것으로 밝혀진 반면, 2일 및 3일 단식 프로토콜은 보호 효과를 발휘하지 못했습니다 [97]. 이러한 효과는 간 조직 내 상주 쿠퍼 세포의 조절 및 허혈성 손상에 대한 호중구 침윤과 관련이 있습니다. 이러한 변화와 함께, 태아 소 혈청 농도 감소에 노출된 LPS 처리 마우스 생쥐 264-7 대식세포에서는 ROS 및 TNF-α의 생산이 증가하지 않았습니다 [97]. 데이터에 따르면 대조군과 비교하여 공복 마우스에서 LC3, BCLN1, SIRT1 및 HMGB1의 세포 내 응집이 증가한 것으로 나타났습니다 [97]. 자가포식 메커니즘은 염증성 HMGB1을 분해하고 혈액으로의 추가 분비 및 식세포의 활성화를 억제하는 것으로 생각됩니다 [97,98].

Therefore, one can hypothesize that regular fasting can activate the autophagic response in ischemic hepatocytes, thus permitting direct degradation of proinflammatory factors and reducing their release into the extracellular matrix. In a comparable study, Chen and colleagues [99] extended our understanding of the potential impact of IF on hormonal regulation of lysosomal degradation capacity. They observed the elevation of systemic FGF21,which can elevate fatty acid β-oxidation rate, and autophagic response (GFP-LC3 puncta↑) in mice subjected to 12- and 24-h fasting protocols [99]. Using Fgf21−/− mice, it was indicated that intracellular LC3-II and p62 concentrations were significantly elevated, coincident with the inhibition of Lamp1 and the lysosomal-autophagic pathway [99]. In wild-type mice, fasting can inhibit mTORC1, leading to the reduction of phosphorylated TFEB factor and sequestration inside the cytosol. Dephosphorylated TFEB translocates into the nucleus and stimulates autophagy and lysosomal activity. It is noteworthy to mention that the ablation of Fgf21 can increase the activity of Mid1 and phosphorylation of TFEB. Given the intricate connection between fasting and lipid metabolism, it is likely that IF can regulate autophagic flux via the regulation of lysosomal function. Recently, it was suggested that calorie restriction along with the stimulation of autophagy can change the type of cell death and reduce consequent pathological outcomes [100]. It was indicated that the promotion of autophagy via rapamycin can reduce the severity of caerulein-induced acute pancreatitis in mice via the increase of Caspase-3 (an apoptosis-related factor) and reduction of HMGB1 (a necrosis-related factor). Amylase activity and systemic concentrations of proinflammatory factors such as IL-6, TNF-α, MCP-1, and GM-CSF were also diminished.

따라서 

규칙적인 단식이 

허혈성 간세포에서 자가포식 반응을 활성화하여 

전 염증성 인자를 직접 분해하고 

세포 외 기질로의 방출을 감소시킬 수 있다는 가설을 세울 수 있습니다. 

비슷한 연구에서 Chen과 동료들[99]은 리소좀 분해 능력의 호르몬 조절에 대한 IF의 잠재적 영향에 대한 이해를 넓혔습니다. 이들은 12시간 및 24시간 금식 프로토콜을 적용한 마우스에서 지방산 β산화율을 높일 수 있는 전신 FGF21의 상승과 자가포식 반응(GFP-LC3 puncta↑)을 관찰했습니다[99]. Fgf21-/- 마우스를 사용한 결과, 세포 내 LC3-II 및 p62 농도가 유의미하게 증가했으며, 이는 Lamp1 및 리소좀-자가포식 경로의 억제와 일치하는 것으로 나타났습니다 [99]. 야생형 마우스의 경우, 단식은 mTORC1을 억제하여 인산화 TFEB 인자의 감소와 세포질 내 격리를 유도할 수 있습니다. 탈인산화된 TFEB는 핵으로 이동하여 자가포식 및 리소좀 활동을 자극합니다. Fgf21을 제거하면 Mid1의 활성과 TFEB의 인산화가 증가할 수 있다는 점은 주목할 만합니다. 공복과 지질 대사 사이의 복잡한 연관성을 고려할 때, IF는 리소좀 기능 조절을 통해 자가포식 플럭스를 조절할 수 있을 것으로 보입니다. 최근에는 칼로리 제한과 자가포식 자극이 세포 사멸의 유형을 변화시키고 그에 따른 병리학적 결과를 감소시킬 수 있다고 제안되었습니다 [100]. 라파마이신을 통한 자가포식 촉진은 카스파제-3(세포사멸 관련 인자)의 증가와 HMGB1(괴사 관련 인자)의 감소를 통해 생쥐에서 카세룰린에 의한 급성 췌장염의 중증도를 감소시킬 수 있다는 것이 밝혀졌습니다. 아밀라아제 활성과 IL-6, TNF-α, MCP-1, GM-CSF와 같은 염증성 인자의 전신 농도도 감소했습니다.

Myocytes differ fundamentally from other cells due to the presence of a specific system that provides energy in stressful conditions via the conversion of protein to amino acids [101]. Therefore, autophagolysosomes are basic degradation sites for the production of essential amino acids [101]. Findings are consistent with the fact that fasting can contribute to phenylalanine release from skeletal tissue in an mTOR-dependent axis. Furthermore, fasting can suppress mTORC1 activity and thus reduce phosphorylated ULK1 and 4EBP1. These alterations are concurrent with a simultaneous increase of intracellular concentrations of LC3B, p62, and FOXO3a [102]. Data have indicated opposite effects in the presence of insulin in which this hormone can reverse these conditions and near-to-normal conditions.

근세포는 

스트레스 상황에서 단백질을 아미노산으로 전환하여 

에너지를 공급하는 특정 시스템이 존재하기 때문에 

다른 세포와 근본적으로 다릅니다 [101]. 

따라서 

자가포식소체는 

필수 아미노산 생성을 위한 기본 분해 부위입니다[101]. 

이러한 연구 결과는 

단식이 mTOR 의존 축에서 골격 조직에서 

페닐알라닌 방출에 기여할 수 있다는 사실과 일치합니다. 

또한, 단식은 

mTORC1 활성을 억제하여 

인산화 된 ULK1 및 4EBP1을 감소시킬 수 있습니다. 

이러한 변화는 

LC3B, p62 및 FOXO3a의 세포 내 농도가 동시에 증가하는 것과 동시에 일어납니다 [102]. 

데이터에 따르면 인슐린을 투여하면 이러한 상태를 정상에 가깝게 되돌릴 수 있는 인슐린이 존재할 때 반대의 효과가 나타납니다.

IF and autophagy in cancers

A crucial role of calorie restriction and IF in terms of cancer development and growth has been indicated in numerous experiments [103,104]. On this basis, several forms of calorie restrictions such as dietary restriction, IF, and caloric restriction tout court have been applied to control the development and progression of various cancer types. Furthermore, the “caloric restriction mimetics” with limited calories provide calorie restriction-like conditions without the necessity for strict diets in cancer patients [105]. Several pieces of evidence revealed that low energetic diets can affect tumor cells’ metabolism and microenvironment per se, leading to a reduction of growth and metastasis rate [105]. Of note, diets with low carbohydrate and protein contents and high-fat content have several benefits in cancer patients in terms of survival rate and tolerating chemotherapy side effects [106]. It is believed that amino acids such as methionine, leucine, glutamine, arginine etc., as well as glucose have pivotal roles in dynamic growth of tumor cells and motility related to normal cell type. Thus, these features make cancer cells as frontline cells exposed to calorie restriction and starvation [105]. However, the exact impact of IF on anaplastic conditions remains greatly unknown and is under intense investigation [107,108]. Of course, calorie restriction cannot be an authoritative cancer treatment and is thought of as a supportive method to increase the therapeutic efficiency of chemotherapeutics [109] even though several studies in animal models have revealed the cancer-preventative relevance of IF [110].

Due to the inevitable role of IF on dynamic tumor cell growth, recent clinical studies have focused on the application of formulated and tolerable diets with certain fasting protocols in cancer patients [[111], [112], [113]]. Clinical observations have uncovered insulin and selected compounds such as IGF1 and glucose are reduced in individuals subjected to a 5-d fasting-mimicking diet [114]. Such a metabolic profile can lead to the reduction of cancer rate, obesity, and inflammatory conditions in a mouse model [115]. As aforementioned, IF and calorie restriction can provoke autophagy signaling after cell exposure to insulting conditions, leading to the deactivation of mTORC1 [[116], [117], [118]]. Anti-tumor mechanisms such as those exerted by E-cadherin, the adiponectin/leptin ratio, metalloproteinases, chemokines and cytokines, Caspase-3, and Histone H2AX (an enzyme associated with DNA repair) are induced under starvation [[119], [120], [121], [122], [123]]. Furthermore, in vitro and in vivo starvation protocols can adjust the host cell’s sensitivity to insulin [124].

Preclinical data have indicated that short-period caloric restriction in cancer patients before or during the radiation course can increase tumoricidal properties [125]. Interestingly, Icard and coworkers [125] claimed that nonisocaloric ketogenic diets can contribute to conflicting effects in patients undergoing calorie restriction and radiotherapy compared with patients fed isocaloric diets. In vitro analyses indicated that the culture of several cancer cells such as HepG2 [hepatocellular carcinoma] and HuH6-clone5 [hepatoblastoma cells] in serum-free medium for 6 to 24 h increased radiosensitivity via the activation of mTOR and accumulation of ROS [126]. The exposure of human A549 cells to hypoglycemic conditions (2.8 mmol/L) for 24 h reduced clonogenic properties and increased DNA fragmentation after radiation, whereas normal HSF7 fibroblasts exhibited no sensitivity to glucose deprivation [127]. One reason may be that the basal metabolism status is carefully controlled by suppressive control checkpoints like SIRT3, PTEN, etc. in response to energy stress, making the normal cells flexible, whereas these factors are commonly inactive in cancer cells [128]. Of note, it seems the type of diet and period of calorie restriction can affect the dynamic growth of tumor cells [125]. Despite the stimulatory effect of ketogenic diets on the activation of autophagy response and healing mechanisms [129], the use of calorie restriction and therapeutic regimes in cancer patients with ketogenic diets can result in more conflicting outcomes [125]. In most cancer cells, protein concentrations of enzymes catabolizing ketone bodies such as SCOT and 3β-OHBD are reduced compared to normal cells [130], and ketogenic diets are used for the prevention of weight loss in cancer patients undergoing therapeutic medications [131]. It was suggested that specific tumor cells from different tissues such as blood, breast, brain, etc. can promote the activity of SCOT and 3β-OHBD enzymes to catabolize fatty acids to increase tumor size. Thus, the application of unintended calorie restriction in cancer patients subjected to therapeutic protocols may lead to additional confounding bias [132]. In an experiment, 6-h fasting in rats fed with a ketogenic diet for 4 wk led to the reduction of LC3II and ULK and increase of serum creatinine and renal fibrosis [133]. High concentrations of triglycerides and cholesterol can affect the fusion of autophagosomes with lysosomes, resulting in the accumulation of autophagosomes and incomplete autophagic response. Besides these effects, excessive lipid intake with insufficient glucose can lead to abnormal glycolipid protein metabolism and the possibility of vascular tissue complications [133].

The activation of autophagy in cancer cells after IF may exert both detrimental and beneficial outcomes. The autophagy machinery prohibits cellular damage by the promotion of DNA repair systems and antioxidant mechanisms, whereas it accelerates tumor cell death under specific conditions. Interestingly, the activation of autophagy response in certain cancer cells is also associated with proliferation and metastasis [134,135]. These data indicate the double-edged sword activity of autophagy in terms of tumor dynamic growth. Whether and how autophagy orchestrates the protective and inhibitory mechanisms inside cancer cells should be elucidated. The suppression of BCLN1 is related to the possibility of varied cancer types in tissues such as the ovaries, breasts, and testes. The ablation of BCLN1 in mice led to the development of hepatic and pulmonary cancers because of a partially deficient autophagic response [116]. Of note, BCLN1 and BRCA1 (a tumor suppressor gene) are physically close to each other, and deletion of BRCA1 in breast cancer patients can affect BCLN1 [136]. Interestingly, certain tumor cells like several Ras-transformed anaplastic changes in the bladder, pancreas, colon, etc. exhibit stimulated autophagic responses related to normal cells. Therefore, modulation of autophagy is a strategic approach to the control of these cancer types [137]. The promotion of the GTPase KRAS is tightly correlated with autophagy. Of note, in some tumor cells, mutation of Ras genes (H-RasV12 or K-RasV12) can lead to elevated autophagic flux despite the activation of mTORC1 [137]. It has been shown that reduced calorie intake can make tumor cells susceptible to apoptosis via the stimulation of CD8 lymphocytes [138]. Under fasting conditions, the inhibition of mTORC1 (AMP/ATP↑) can lead to the activation of autophagy, promotion of ketogenesis, and inhibition of glycolysis and glutaminolysis in tumor cells [139]. Calorie restriction can diminish serum concentrations of IGF-1 with the potential to suppress the PI3K/Akt/mTOR axis and thus glycolysis in cancer cells [139]. Of note, the reduction of glycolytic capacity in cancer cells is integral to lowering the proliferation rate [140]. Along with these changes, the differentiation rate toward Th1, Th17 lymphocytes and M1 macrophages is increased [139]. IF may reduce the density of CD3+/CD4+/CD25+ T regulatory cells within the tumor parenchyma [141]. In response to calorie restriction, the sensitivity of natural killer cells to tumor cells is also heightened.

Of note, the induction of certain oncogenes such as PI3K, Akt1, and Bcl2 suppresses the autophagic response. The downregulation of varied proteins (DAPK, PTEN, TSC1, TSC2, and LKB1/STK11) is associated with lysosomal degradation capacity in cancer cells [142]. Upon exposure to calorie restriction and lack of sufficient ATP, cells try to adapt themselves to insulting conditions (ie, chemotherapy) via the activation of autophagy, which is not activated in cancer cells, and therefore predisposes them to cell injury [143]. In an experiment, the effect of calorie restriction (70% of normal food intake) was investigated in the dynamic growth activity of human colorectal HCT116 tumor cells in a mouse xenograft model [144]. It was suggested that inhibition of ATG4B cysteine protease activity using S130 along with calorie restriction led to the accumulation of LC3-II (increased delipidated LC3) and p62 inside the cancer cells in tumor-bearing mice, resulting in apoptotic death via Caspase-3 activity (Figure 4) [144]. In vitro analysis indicated that the culture of MCF-7 and HCT116 cells under calorie restriction conditions led to the upregulation and activation of protein kinase CK2 (isoforms CK2α and CK2β), SIRT1, and phosphorylated AMPK [145]. These features coincide with the activation of autophagy molecular machinery (Atg5, Atg7, LC3BII, BCLIN1, and Ulk1). Calorie restriction can intensify the inhibitory effect of siRNA on protein kinase CK2 and inhibition of autophagic response in these cancer cell lines [145]. Data confirmed that the growth of Atg5+/+ kidney epithelial cells was reduced in nude mice fed with a calorie-restriction diet compared to the group fed with a standard regime [146]. In this regard, Lashinger and coworkers [146] claimed that the reduction of systemic glucose and amino acids and the concurrent increase of ketone bodies can abrogate the normal autophagic flux. Interestingly, the dynamic growth of Atg5-/- kidney epithelial cells was profoundly reduced in situations exposed to calorie restriction. These data showed that the modulation of autophagy along with calorie restriction can affect the expansion of tumor cells in in vivo conditions. Although calorie restriction can reduce the proliferation of Atg5-expressing cancer cells, these effects were intensified with simultaneous inhibition of the autophagy molecular machinery. Sun and colleagues [147] demonstrated that alternate-day fasting for 14 d can exert tumoricidal effects in the murine colorectal carcinoma CT26 cell line. Data indicated that tumor size and M2 polarization of tumor-associated macrophages were reduced under restricted calorie conditions. Along with the induction of autophagy (Atg5↑, and LC3II/I ratio↑) in fasting mice, the expression‎ of CD73 and adenosine production were also diminished [147]. Recently, it has been indicated that induction of excessive ROS and nitrogen species production using cold atmospheric pressure plasma led to autophagic and apoptotic death in B16 melanoma cells after being inoculated subcutaneously in mice [148]. Starvation of mice for 24 h (3 times per 5 d) led to prominent tumoricidal effects compared to mice subjected to cold atmospheric pressure plasma. Based on the data, excessive autophagy response (LC3↑, and ATG5↑) initiated apoptotic changes that coincided with the activation of proapoptotic factors such as Bax and Caspase-3 [148]. The overactivity of Atg5 promotes its cleavage by calpain and further interaction with Bcl-X, resulting in apoptosis [149].

FIGURE 4

The role of ATG4B inhibitor, S130, on the dynamic growth of colorectal cancer cells (A–F). HeLa cells were incubated with 1 and 25 μM of S130 and clonogenic properties were assessed using crystal violet staining (A). Panels B–E indicate the combined effects of S130 (i.p. 20 mg/kg) and calorie restriction on the body weights (B), tumor volume (C), tumor images, and weights (D–E) in mice with HCT116 xenografts. Hematoxylin–eosin staining of tumor mass in different groups (F). Student 2-tailed t test. Data are expressed as mean ± SEM (n = 6). ∗P < 0.05; ∗∗P < 0.01; and ∗∗∗P < 0.001 relative to VC. Mice were subjected to calorie restriction with 70% food intake. Adapted with permission [144]. Copyright Autophagy 2019 (https://doi.org/10.1080/15548627.2018.1517073). ATG, autophagy-related protein; CR, calorie restriction; VC, vehicle.

In conclusion, in this review, the protective/detrimental effects of calorie restriction-modulated autophagy were discussed. Data support the fact that adaptive and excessive autophagy can be activated depending on the intensity and duration of calorie restriction programs. It seems that controlled calorie restriction or IF can exert protection on different cellular functions by a modulation of autophagy in response to several pathological conditions (Figure 5). By the activation of adaptive autophagy and relevant downstream effects, IF or calorie restriction can lead to lifespan-extending and antiaging effects via the regulation of adequate homeostasis. Moderate calorie restriction for short- and long-term or IF practiced in various religions in young and middle-aged individuals can be used with no prominent adverse effects [150]. Despite the advantages, insufficient energy intake and dehydration are the risk factors in volunteers with calorie restrictions that should be carefully monitored. Under these conditions, defective (excessive) autophagy response not only does protect the host cells but also forces the cells toward autophagic cell death and apoptosis. Numerous investigations are mandatory to address underlying mechanisms related to autophagy modulation in individuals practicing IF. Despite the modulatory effects of calorie restriction on the autophagy signaling pathway, the underlying mechanisms associated with the activation of adaptive/excessive autophagy have not been addressed. The advances in molecular biology will enable us to monitor real-time changes in autophagy response in individuals under different IF programs. Due to the lack of sufficient data associated with the safety and side effects of IF programs in patients, calorie restriction should be used in clinical settings with great caution. The combination of autophagy inducers and certain calorie restrictions under specific pathological conditions can help clinicians to develop de novo therapeutic protocols.

결론적으로, 이 리뷰에서는 

칼로리 제한 조절 오토파지의 보호 효과와 

해로운 효과에 대해 논의했습니다. 

데이터는 칼로리 제한 프로그램의 강도와 기간에 따라 

적응성 및 과도한 자가포식이 활성화될 수 있다는 

사실을 뒷받침합니다. 

칼로리 제한 또는 IF를 조절하면 

여러 병리학적인 조건에 대한 반응으로 

자가포식을 조절하여 다양한 세포 기능을 보호할 수 있는 것으로 보입니다(그림 5). 

적응성 자가포식의 활성화와 관련 하류 효과에 의해 

IF 또는 칼로리 제한은 

적절한 항상성 조절을 통해 수명 연장 및 노화 방지 효과로 이어질 수 있습니다. 

다양한 종교에서 젊은이와 중장년층을 대상으로 장단기적으로 시행하는 적당한 칼로리 제한 또는 IF는 눈에 띄는 부작용 없이 사용할 수 있습니다[150]. 이러한 장점에도 불구하고, 불충분한 에너지 섭취와 탈수증은 칼로리 제한을 받는 자원자의 위험 요소이므로 주의 깊게 모니터링해야 합니다. 

이러한 조건에서 

결함이 있는 (과도한) 자가포식 반응은 

숙주 세포를 보호할 뿐만 아니라 

세포를 자가포식 세포 사멸 및 세포 사멸로 유도합니다. 

IF를 실행하는 개인의 자가포식 조절과 관련된 근본적인 메커니즘을 다루기 위해서는 수많은 조사가 필수적입니다. 칼로리 제한이 오토파지 신호 경로에 미치는 조절 효과에도 불구하고, 적응성/과도한 오토파지의 활성화와 관련된 근본적인 메커니즘은 밝혀지지 않았습니다. 

분자생물학의 발전으로 다양한 IF 프로그램 하에서 개인의 자가포식 반응 변화를 실시간으로 모니터링할 수 있게 되었습니다. 환자의 IF 프로그램의 안전성 및 부작용과 관련된 충분한 데이터가 부족하기 때문에 칼로리 제한은 임상 환경에서 매우 신중하게 사용해야 합니다. 특정 병리학적 조건에서 자가포식 유도제와 특정 칼로리 제한을 조합하면 임상의가 새로운 치료 프로토콜을 개발하는 데 도움이 될 수 있습니다.

FIGURE 5

Possible effects of calorie restriction on autophagic response, cell stress, and immune cell activity.

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Acknowledgments

We thank the personnel of the Infectious and Tropical Diseases Research Center for their help and guidance.

Author contributions

The authors’ responsibilities were as follows—RS, SH, MSM, AB, FS, HSB: conducted the literature search, extracted the data, and drafted the relative data parts; RR, ES: supervised the study; and all authors: read and approved the final manuscript.

Conflict of interest

The authors report no conflicts of interest.

Funding

This is a report of the database from an MSc thesis registered in Tabriz University of Medical Sciences with the Number 67863 (Ethical code: IR.TBZMED.VCR.REC.1401.11).

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