암, 치매 난치병 최적의 운동법 --일주기 리듬을 고려한 운동법..

[문형철]

세상에는 감사할 일이 참 많다. 서울대 생명공학과 '곽태환' 가끔 내게 최신 논문 중 중요한 개념을 설명해주고, 논문을 보내준다. 

오랫동안 생체역학을 기반으로한 치료적 운동을 연구, 실천, 환자적용을 하고 있다.

부상을 당하지 않는 운동법, 치유를 촉진하는 운동법..

방법과 강도의 측면으로만 시각을 고정해버리니 한계가 있는듯 했다.

일주기 리듬을 고려한 운동법을 탐구중이다.

Int J Environ Res Public Health. 2021 Dec; 18(24): 12949.

Published online 2021 Dec 8. doi: 10.3390/ijerph182412949

PMCID: PMC8702158

PMID: 34948558

Exercise as a Peripheral Circadian Clock Resynchronizer in Vascular and Skeletal Muscle Aging

Bruna Spolador de Alencar Silva,1 Juliana Souza Uzeloto,1 Fábio Santos Lira,1,* Telmo Pereira,2,3 Manuel J. Coelho-E-Silva,4 and Armando Caseiro3,5,6,*

Paul B. Tchounwou, Academic Editor

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Abstract

Aging is characterized by several progressive physiological changes, including changes in the circadian rhythm. Circadian rhythms influence behavior, physiology, and metabolic processes in order to maintain homeostasis; they also influence the function of endothelial cells, smooth muscle cells, and immune cells in the vessel wall. A clock misalignment could favor vascular damage and indirectly also affect skeletal muscle function. In this review, we focus on the dysregulation of circadian rhythm due to aging and its relationship with skeletal muscle changes and vascular health as possible risk factors for the development of sarcopenia, as well as the role of physical exercise as a potential modulator of these processes.

노화는 일주기 리듬의 변화를 포함한 여러 가지 점진적인 생리적 변화를 특징으로 합니다. 일주기 리듬은 항상성을 유지하기 위해 행동, 생리학 및 대사 과정에 영향을 미치며 혈관벽의 내피 세포, 평활근 세포 및 면역 세포의 기능에도 영향을 미칩니다. 생체 시계가 잘못 정렬되면 혈관 손상을 촉진하고 골격근 기능에도 간접적으로 영향을 미칠 수 있습니다. 이 리뷰에서는 노화로 인한 일주기 리듬의 조절 장애와 근감소증 발병의 위험 요인으로서 골격근 변화 및 혈관 건강과의 관계, 그리고 이러한 과정을 잠재적으로 조절할 수 있는 신체 운동의 역할에 중점을 둡니다.

Keywords: sarcopenia, inflammation, circadian rhythms, clock genes, vascular disfunction, skeletal muscle disfunction

1. Introduction

Aging is characterized by several progressive physiological alterations, such as hormonal imbalance, impaired proteostasis, mitochondrial dysfunction, and cellular senescence, which lead to functionality loss and increased risk of death [1]. The circadian rhythm also undergoes significant age-related disturbances, which can contribute to the development of several morbidities [2].

노화는 호르몬 불균형, 단백질 안정성 장애, 미토콘드리아 기능 장애, 세포 노화와 같은 여러 가지 점진적인 생리적 변화를 특징으로 하며, 이는 기능 상실과 사망 위험 증가로 이어집니다 [1]. 일주기 리듬은 또한 노화와 관련하여 심각한 교란을 겪으며, 이는 여러 가지 질병의 발병에 기여할 수 있습니다 [2].

Circadian rhythms involve biological rhythms that work by the interaction of several exogenous and endogenous factors, which together influence behavior, physiology, and metabolic processes in order to maintain homeostasis. The suprachiasmatic nucleus (SCN), together with other autonomous clocks, present in virtually all cells of the body, is responsible for controlling the central and peripheral circadian rhythm. However, the so-called synchronizers (also known as “zeitgebers”), such as external factors, can influence the functioning of these rhythms. The main synchronizer for SCN is the light–dark cycle that, through the retinohypothalamic tract, provides information to the SCN, which, by means of neurohumoral signaling and core body temperature oscillating, leads to the synchronization of peripheral clocks [3]. However, there are also non-photic synchronizers such as food, physical activity, and stress [4].

일주기 리듬은 항상성을 유지하기 위해 행동, 생리학 및 대사 과정에 영향을 미치는 여러 외인성 및 내인성 요인의 상호 작용에 의해 작용하는 생물학적 리듬을 포함합니다. 시교차상핵(SCN)은 신체의 거의 모든 세포에 존재하는 다른 자율 시계와 함께 중추 및 말초 일주기 리듬을 조절하는 역할을 담당합니다. 그러나 외부 요인과 같은 소위 동기화 장치("자이트게버"라고도 함)는 이러한 리듬의 기능에 영향을 미칠 수 있습니다. SCN의 주요 동기화 장치는 망막 시상하부를 통해 신경 체액 신호와 심부 체온 진동을 통해 말초 시계의 동기화를 유도하는 SCN에 정보를 제공하는 명암 주기입니다 [3]. 그러나 음식, 신체 활동, 스트레스와 같은 비광학적 동기화 요인도 있습니다[4].

Two main elements control the activity of the molecular clock—circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like protein 1 (BMAL1), which activate the transcription of the period 1,2 and 3 (Per) proteins and cryptochrome 1 and 2 (Cry) that, when migrating to the cell nucleus, inhibit the initial dimerization of CLOCK-BMAL1, closing a cycle of approximately 24 h. The circadian oscillation of BMAL1 is also up- and downregulated by retinoid-related orphan receptors RORs (α, β, and γ) and REV-ERBs (α and β), respectively [5]. This daily self-sustaining circuit of gene expression‎ controls several physiological processes, essential for the organism [3].

두 가지 주요 요소는 분자 시계-일주기 운동 출력 주기인 카풋(CLOCK)과 뇌 및 근육 ARNT 유사 단백질 1(BMAL1)의 활성을 제어하며, 이는 주기 1,2 및 3(Per) 단백질과 크립토크롬 1 및 2(Cry)의 전사를 활성화하여 세포 핵으로 이동할 때 CLOCK-BMAL1의 초기 이합체화를 억제하여 약 24시간의 사이클을 닫습니다. BMAL1의 일주기 진동은 레티노이드 관련 고아 수용체 ROR(α, β, γ)과 REV-ERB(α, β)에 의해서도 각각 상향 및 하향 조절됩니다[5]. 이 일상적인 자립적 유전자 발현 회로는 유기체에 필수적인 여러 생리적 과정을 제어합니다[3].

Some physiological changes related to the aging process favor central and peripheral rhythms impairment [6] such as reduction in the total secretion of melatonin [2,7] and metabolism-related rhythms (glucose control, lipid metabolism, and xenobiotic detoxification), controlled by clocks in the liver and pancreas, which can contribute to the development of metabolic diseases [8].

In muscle tissue, endogenous clock alteration can influence myogenic capacity, making it difficult to transcribe mTOR and impairing the development and growth of skeletal muscles [9]. Evidence shows that the loss of CLOCK-BMAL1 molecular rhythm function is associated with metabolic inefficiency with protein catabolism and the replacement of glucose metabolism by lipids [10,11]. Still, there may be changes in the types of muscle fiber, reduction in mitochondria, and damage to mitochondrial breathing, and in the structure and function of sarcomeres, causing severe muscle damage [8,12]. Therefore, clock gene misalignment alters muscle composition and function, which has a strong association with health status, with low strength and muscle mass being independent factors for the development of sarcopenia, which is strongly associated with breaking the circadian rhythm regardless of age; in the elderly, this factor is enhanced, which leads to functional incapacities, falls, osteoporosis, dyslipidemia, increased cardiovascular risk, metabolic syndrome, immunosuppression, and increased risk of mortality [13].

노화 과정과 관련된 일부 생리적 변화는 멜라토닌의 총 분비 감소 [2,7] 및 간과 췌장의 시계에 의해 제어되는 대사 관련 리듬 (포도당 조절, 지질 대사 및 이종 생물 해독)과 같은 중추 및 말초 리듬 손상 [6]을 선호하여 대사 질환의 발병에 기여할 수 있습니다 [8].

근육 조직에서 내인성 시계 변화는 근성장에 영향을 미쳐 mTOR의 전사를 어렵게 만들고 골격근의 발달과 성장을 저해할 수 있습니다[9]. 증거에 따르면 CLOCK-BMAL1 분자 리듬 기능의 상실은 단백질 이화 작용 및 지질에 의한 포도당 대사의 대체로 인한 대사 비효율과 관련이 있습니다 [10,11]. 그럼에도 불구하고 근육 섬유의 유형, 미토콘드리아의 감소, 미토콘드리아 호흡의 손상, 육종의 구조와 기능에 변화가 생겨 심각한 근육 손상을 유발할 수 있습니다 [8,12]. 따라서 시계유전자 오정렬은 근육의 구성과 기능을 변화시켜 건강 상태와 밀접한 관련이 있으며, 낮은 근력과 근육량은 근감소증 발생의 독립적인 요인으로 연령에 관계없이 일주기 리듬을 깨는 것과 밀접한 관련이 있고, 노인에서는 이 요인이 강화되어 기능 장애, 낙상, 골다공증, 이상지질혈증, 심혈관 위험 증가, 대사 증후군, 면역 억제 및 사망 위험 증가로 이어진다[13].

An inherent factor in aging that can also affect clock genes and muscle functions is chronic low-grade inflammation. Among other factors, it can be developed as a result of the immunosenescence process. It is known that the senescence of immune cells can reflect changes in skeletal muscle function, such as muscle regeneration and repair [14,15]. In addition, senescent immune cells accumulated during aging generally express senescence-associated inflammatory factors (SASP) with overexpression‎ of IL1β, IL-6, IL-8, TNF-α, IFN-γ, etc. [16]. These factors associated with resident muscle cells can also modulate the expression‎ of other surface molecules in muscle cells and promote an inflammatory environment [14], which, in turn, can negatively influence the local clock, making it a vicious cycle.

시계 유전자와 근육 기능에도 영향을 미칠 수 있는 노화의 내재적 요인은 만성 염증입니다. 다른 요인 중에서도 면역 노화 과정의 결과로 발생할 수 있습니다. 면역 세포의 노화는 근육 재생 및 회복과 같은 골격근 기능의 변화를 반영할 수 있는 것으로 알려져 있습니다[14,15]. 또한 노화 과정에서 축적된 노화 면역세포는 일반적으로 IL1β, IL-6, IL-8, TNF-α, IFN-γ 등의 과발현과 함께 노화 관련 염증 인자(SASP)를 발현합니다. [16]. 상주 근육 세포와 관련된 이러한 인자들은 또한 근육 세포의 다른 표면 분자의 발현을 조절하고 염증 환경을 촉진할 수 있으며[14], 이는 다시 국소 시계에 부정적인 영향을 미쳐 악순환을 일으킬 수 있습니다.

It is suggested that the decrease in vascular health also causes clock activity in the skeletal muscle. There is a decrease in vascular health with aging, such as increased stiffness of the large elastic arteries and endothelial dysfunction [17]. The dysfunction of peripheral arteries decreases blood flow to the body extremities, which can lead to decreased calf muscle area and strength [18]. Circadian rhythms also influence the function of endothelial cells, smooth muscle cells, and immune cells in the vessel wall, so a clock misalignment could favor vascular damage (e.g., impair vessel contractility and endothelial integrity [19]) and indirectly also affect skeletal muscle function.

혈관 건강의 감소는 골격근의 시계 활동에도 영향을 미치는 것으로 추정됩니다. 큰 탄성 동맥의 강성 증가 및 내피 기능 장애와 같은 노화와 함께 혈관 건강이 감소합니다 [17]. 말초 동맥의 기능 장애는 사지로의 혈류를 감소시켜 종아리 근육 면적과 근력을 감소시킬 수 있습니다 [18]. 일주기 리듬은 혈관 벽의 내피 세포, 평활근 세포 및 면역 세포의 기능에도 영향을 미치므로 시계가 잘못 정렬되면 혈관 손상(예: 혈관 수축성 및 내피 완전성 손상 [19])이 촉진되고 간접적으로 골격근 기능에도 영향을 미칠 수 있습니다.

In this sense, several studies attempt to elucidate the role of circadian rhythm in the inflammatory process (and vice versa) related to aging. In this review, we focus on the dysregulation of circadian rhythm due to aging (mainly from an inflammatory perspective) and its relationship with skeletal muscle changes and vascular health as possible risk factors for the development of sarcopenia (Figure 1), as well as the role of physical exercise as a potential modulator of these processes (Figure 2).

이러한 의미에서 여러 연구에서 노화와 관련된 염증 과정(또는 그 반대의 경우)에서 일주기 리듬의 역할을 규명하려고 시도하고 있습니다. 이 리뷰에서는 노화로 인한 일주기 리듬의 조절 장애(주로 염증 관점에서)와 근감소증 발병의 위험 요인으로서 골격근 변화 및 혈관 건강과의 관계(그림 1)와 이러한 과정의 잠재적 조절자로서 신체 운동의 역할(그림 2)에 중점을 둡니다.

Figure 1

Aging relationship with circadian rhythm disruption as possible influencers of sarcopenia.

Figure 2

The role of physical exercise as a potential positive modulator of circadian rhythm and sarcopenia.

2. Sarcopenia: Concept and Relationship with Inflammation

The reduction in muscle strength and mass are important morphological changes that occur as a result of aging, and when associated, characterize a muscle disease called sarcopenia [20]. Sarcopenia is associated with a greater likelihood of adverse outcomes, such as falls, fractures, physical disability, development of chronic diseases, and mortality [20]. Primarily, its development is related to aging, but other causal factors contributing to the disease include a sedentary lifestyle, inadequate nutrition, and inflammation [21,22,23].

근력과 질량의 감소는 노화의 결과로 발생하는 중요한 형태학적 변화이며, 근감소증이라는 근육 질환의 특징입니다 [20]. 근감소증은 낙상, 골절, 신체 장애, 만성 질환 발병, 사망률과 같은 부작용의 가능성이 높아지는 것과 관련이 있습니다[20]. 주로 노화와 관련이 있지만 질병을 유발하는 다른 원인 요인으로는 앉아서 생활하는 생활 방식, 부적절한 영양 섭취, 염증 등이 있습니다[21,22,23].

Chronic low-grade inflammation is characterized by an increase in circulating concentrations of tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), IL-1 β, etc., and is present in numerous chronic diseases [24,25,26], including sarcopenia [27]. Among the causal factors of inflammation associated with aging (inflammaging) are the accumulation of adipose tissue, mainly visceral adipose tissue (VAT), common in the elderly due to hormonal changes, unbalanced diet, and reduced physical activity [28]. VAT produces and releases pro-inflammatory cytokines and chemokines, influencing, in addition to body weight, the onset of and increase in inflammation [29]. Another causal factor of inflammation associated with age may be the decline in the functionality and efficiency of immune cells during the aging process, called immunosenescence [30]. The constant ineffective signaling of senescent cells favors a continuous stimulus for the inflammatory response in the elderly [31].

만성 저등급 염증은 종양괴사인자 α(TNF-α), 인터루킨 6(IL-6), IL-1 β 등의 순환 농도가 증가하는 것이 특징이며, 근육감소증[24,25,26]을 포함한 수많은 만성 질환[27]에 존재합니다. 노화(염증)와 관련된 염증의 원인 요인 중에는 호르몬 변화, 불균형한 식단, 신체 활동 감소로 인해 노인에게 흔히 나타나는 지방 조직, 주로 내장 지방 조직(VAT)의 축적이 있습니다[28]. VAT는 전 염증성 사이토카인과 케모카인을 생성 및 방출하여 체중 외에도 염증의 시작과 증가에 영향을 미칩니다 [29]. 나이와 관련된 염증의 또 다른 인과적 요인은 면역 노화라고 하는 노화 과정에서 면역 세포의 기능과 효율성이 저하되는 것일 수 있습니다[30]. 노화 세포의 지속적인 비효율적 신호는 노인의 염증 반응에 대한 지속적인 자극을 선호합니다 [31].

High plasma concentrations of pro-inflammatory cytokines, such as IL-6 and TNF-α, among other disorders, are associated with lower strength and MM in the elderly [32], as they provoke the stimulation of protein catabolism and suppression of muscle synthesis [27,33,34]. Positive regulation of TNF-α activates the expression‎ of proteolytic enzymes (e.g., muscle ring finger1 (MuRF1) and atrogin-1) that, via ubiquitin-proteasome (UbP) or mitogen-activated p38 protein kinase (p38MAPK), increase protein degradation [35,36,37]. IL-6 already acts in a pleiotropic manner, and when expressed by immune cells (such as CD4/CD8-TEMRA cells), it has a pro-inflammatory function that can impair muscle anabolism and energy homeostasis, and directly mediate muscle catabolism through STAT3-IL-6 signaling [14,38].

However, when expressed through muscle contraction, it has an anti-inflammatory function, by promoting the increase in an important anti-inflammatory cytokine, IL-10 [39]. IL-10 can also be expressed in response to the presence of overregulation of cytokines pro-inflammatory, blocking (via inhibition of the transcription factor NF-kB) the expression‎ of pro-inflammatory cytokines, such as TNF-α, IL-6, etc. [40].

IL-6 및 TNF-α와 같은 전 염증성 사이토 카인의 높은 혈장 농도는 다른 장애 중에서도 단백질 이화 작용의 자극과 근육 합성의 억제를 유발하기 때문에 노인의 근력 및 MM 감소와 관련이 있습니다 [32] [27,33,34]. TNF-α의 양성 조절은 유비퀴틴-프로테아좀(UbP) 또는 미토겐 활성화 p38 단백질 키나아제(p38MAPK)를 통해 단백질 분해를 증가시키는 단백질 분해 효소(예: 근육 약지1(MuRF1) 및 아트로긴-1)의 발현을 활성화합니다[35,36,37]. IL-6는 이미 다발성 방식으로 작용하며, 면역 세포(예: CD4/CD8-TEMRA 세포)에 의해 발현될 경우 근육 동화 작용과 에너지 항상성을 손상시킬 수 있는 전염증성 기능을 가지고 있으며, STAT3-IL-6 신호를 통해 근육 이화 작용을 직접 매개할 수 있습니다[14,38]. 그러나 근육 수축을 통해 발현되면 중요한 항염증 사이토카인인 IL-10의 증가를 촉진하여 항염증 기능이 있습니다 [39]. IL-10은 또한 전 염증성 사이토 카인의 과잉 조절에 반응하여 발현 될 수 있으며, TNF-α, IL-6 등과 같은 전 염증성 사이토 카인의 발현을 차단 (전사인자 NF-kB의 억제를 통해)합니다. [40].

2.1. Crosstalk between Skeletal Muscle and Immune Cells

Skeletal muscle remodeling is dependent on the interaction between skeletal muscle and immune cells; thus, the immunosenescence process alone can also negatively influence skeletal muscle morphology and regenerative capacity [14]. Although the skeletal muscle has “resident” immune cells, after an acute effect, such as injury, the peripheral blood circulation immune cells are recruited into the muscle by chemotactic signals to assist tissue repair [41]. The signaling of CXCL1 or CXCL5 by muscle cells are potential candidates to act as early activators of the inflammatory response to acute muscle injury [42]. Both chemokines are chemoattractive to neutrophils, which rise significantly in the muscle shortly after injury and help to boost the inflammatory response.

골격근 리모델링은 골격근과 면역 세포 간의 상호 작용에 의존하므로 면역 노화 과정만으로는 골격근 형태와 재생 능력에 부정적인 영향을 미칠 수 있습니다 [14]. 골격근에는 "상주" 면역 세포가 있지만, 부상과 같은 급성 영향이 발생한 후에는 말초 혈액 순환 면역 세포가 화학 주성 신호에 의해 근육으로 모집되어 조직 회복을 지원합니다 [41]. 근육 세포에 의한 CXCL1 또는 CXCL5의 신호는 급성 근육 손상에 대한 염증 반응의 초기 활성화제로 작용할 수 있는 잠재적 후보입니다[42]. 두 케모카인 모두 호중구에 대한 화학적 유인력이 있으며, 부상 직후 근육에서 크게 증가하여 염증 반응을 촉진하는 데 도움이 됩니다.

Neutrophils are the first immune cells that infiltrate muscle lesions, and their presences are required for an optimal muscle regeneration process [42]. Following neutrophil infiltration, there is a monocyte migration in response to chemokines secreted. At this moment, the expressed cytokines characterize a Th1 response (e.g., interferon-γ (IFN-γ) and TNF-α) that lead to the activation of macrophages to an M1 (pro-inflammatory) phenotype capable of continuing the inflammatory response. Macrophages, in addition to attracting satellite cells to the injury site and stimulating their proliferation, also produce cytokines (e.g., TNF-α, IL-6) that also stimulate satellite cell proliferation [43]. After the M1 macrophages perform their function and reach their peak, they are replaced by M2 macrophages (anti-inflammatory) that act to decrease inflammation and promote tissue repair. These are activated by Th2 cytokines, interleukin-4 (IL-4), IL-13 (wound healing and tissue repair), IL-10 (inhibition of the M1 phenotype), or by other molecules that enable the release of anti-inflammatory cytokines [44]. T lymphocytes also influence other immune cells or muscle satellite cells and play a pleiotropic role in the process of muscle regeneration and repair [14,15]. T cells affect the proliferation and migration of satellite muscle cells [45]. In damaged muscles, CD8+ T cells stimulate the recruitment of macrophages, thus promoting the proliferation of myoblasts [46], and regulatory T cells can release growth factors and promote muscle growth in response to specific cytokines [47].

호중구는 근육 병변에 침투하는 최초의 면역 세포이며, 최적의 근육 재생 과정을 위해 호중구의 존재가 필요합니다[42]. 호중구 침윤 후 분비된 케모카인에 반응하여 단핵구 이동이 일어납니다. 이때 발현된 사이토카인은 염증 반응을 지속할 수 있는 M1(전염성) 표현형으로 대식세포를 활성화하는 Th1 반응(예: 인터페론-γ(IFN-γ) 및 TNF-α)을 특징짓습니다. 대식세포는 손상 부위로 위성 세포를 끌어들여 증식을 자극하는 것 외에도 위성 세포 증식을 자극하는 사이토카인(예: TNF-α, IL-6)을 생성합니다[43]. M1 대식세포가 기능을 수행하고 최고치에 도달하면 염증을 줄이고 조직 회복을 촉진하는 M2 대식세포(항염증제)로 대체됩니다. 이들은 Th2 사이토카인, 인터루킨-4(IL-4), IL-13(상처 치유 및 조직 복구), IL-10(M1 표현형 억제) 또는 항염증 사이토카인의 방출을 가능하게 하는 기타 분자에 의해 활성화됩니다[44]. T 림프구는 또한 다른 면역 세포나 근육 위성 세포에 영향을 미치며 근육 재생 및 회복 과정에서 다발성 역할을 합니다[14,15]. T 세포는 위성 근육 세포의 증식과 이동에 영향을 미칩니다 [45]. 손상된 근육에서 CD8+ T 세포는 대식세포의 모집을 자극하여 근아세포의 증식을 촉진하고[46], 조절 T 세포는 특정 사이토카인에 반응하여 성장 인자를 방출하고 근육 성장을 촉진할 수 있습니다[47].

In this sense, temporal immune response (acute inflammation) is necessary for muscle stem cell activation and proliferation during regeneration; however, a continued immune response, as explained above (Section 2), triggers protein catabolism and impairments anabolic processes of skeletal muscle in the long-term leading to sarcopenia [48]. With aging, there may be a possibility of prolonged accumulation of neutrophils in skeletal muscle during muscle recovery, an abundance of inflammatory monocytes, and impaired macrophage polarization, which would affect their function in muscle repair [49]. The impaired signaling of some aging-related cytokines can also significantly impact the immune system and consequently the skeletal muscle. The impairment in IL-15 signaling impairs the proliferation and survival of naïve T cells on CD8 T cells, as well as the migration and phagocytosis of neutrophils [14]. Impairment in IL-7 signaling affects the development and maintenance of T- and B lymphocytes, failing to support the thymic function that has already decreased with age [50].

In addition, senescent T cells accumulated during aging usually overexpress pro-inflammatory cytokines [16], which, in addition to enhanced skeletal muscle wasting, can modulate the expression‎ of other surface molecules in muscle cells and favor a possible establishment of a local inflammatory environment [14]. Furthermore, the impairment of immune cell function as a result of aging itself affects skeletal muscle repair function, which can also contribute to the development of sarcopenia.

이러한 의미에서 일시적인 면역 반응(급성 염증)은 재생 중 근육 줄기세포 활성화 및 증식에 필요하지만, 위에서 설명한 바와 같이(섹션 2) 지속적인 면역 반응은 단백질 이화 작용을 유발하고 장기적으로 골격근의 동화 과정을 손상시켜 근육감소증을 유발합니다[48]. 노화가 진행되면 근육 회복 중에 골격근에 호중구가 장기간 축적되고 염증성 단핵구가 풍부해지며 대식세포 분극이 손상되어 근육 회복 기능에 영향을 줄 수 있습니다[49]. 일부 노화 관련 사이토카인의 신호 전달 장애도 면역 체계와 결과적으로 골격근에 큰 영향을 미칠 수 있습니다. IL-15 신호 전달의 장애는 CD8 T 세포에서 순진한 T 세포의 증식과 생존뿐만 아니라 호중구의 이동과 식균 작용을 손상시킵니다 [14]. IL-7 신호 전달의 손상은 T 및 B 림프구의 발달과 유지에 영향을 미치며, 나이가 들면서 이미 감소한 흉선 기능을 지원하지 못합니다 [50]. 또한 노화 중에 축적된 노화 T 세포는 일반적으로 전 염증성 사이토카인을 과발현하는데[16], 이는 골격근 소모를 증가시킬 뿐만 아니라 근육 세포에서 다른 표면 분자의 발현을 조절하고 국소 염증 환경의 형성을 촉진할 수 있습니다[14]. 또한 노화로 인한 면역 세포 기능의 손상은 골격근 회복 기능에도 영향을 미쳐 근감소증의 발병에 기여할 수 있습니다.

2.2. Inflammation and Circadian Misalignment: A Two-Way Road in Contributing to Sarcopenia

Chronic low-grade inflammation could also influence the dysregulation of circadian rhythm controlling genes. Studies indicate that cytokines affected the expression‎ of core clock genes expressed by the peripheral clocks, despite the intrinsic mechanisms are still unknown. Cavadini et al. suggested that pro-inflammatory cytokines (TNF-alpha and IL-1beta) impair the function of clock genes in fibroblasts of mice [51]. In synovial cells, TNF-alpha promotes an increase in the expression‎ of BMAL1 and Rorα, while decreasing Rev-erbα [52].

만성 염증은 일주기 리듬을 조절하는 유전자의 조절 장애에도 영향을 미칠 수 있습니다. 연구에 따르면 사이토카인이 말초 시계에 의해 발현되는 핵심 시계 유전자의 발현에 영향을 미치지만, 그 본질적인 메커니즘은 아직 밝혀지지 않았습니다. Cavadini 등은 전 염증성 사이토카인(TNF-알파 및 IL-1베타)이 생쥐의 섬유아세포에서 클럭 유전자의 기능을 손상시킨다고 제안했습니다[51]. 활막 세포에서 TNF-알파는 BMAL1과 Rorα의 발현을 증가시키는 반면, Rev-erbα는 감소시킵니다 [52].

Conversely, the deregulation of clock genes also affects inflammation. Deletion of clock genes in macrophages induces upregulation of pro-inflammatory cytokines production, which can be accompanied by a rise in oxidative stress [53]. In BMAL1-deficient mice, there is a pro-inflammatory increase due to upregulation of NF-κB-mediated by CLOCK, which may result in chronic inflammation [54]. In the same sense, the absence of Cry proteins upregulates the expression‎ of pro-inflammatory cytokines, through NF-κB activation through phosphorylation of p65 [55]. Studies show that BMAL1 KO mice have a short lifespan, have advanced aging phenotypes, and favor the emergence of chronic diseases [56]. In this sense, the power of clock genes on the inflammatory profile (and vice versa) can be a key point for the development of treatment strategies for the adverse effects of aging.

반대로, 시계 유전자의 조절 완화는 염증에도 영향을 미칩니다. 대식세포에서 시계 유전자를 제거하면 전 염증성 사이토카인 생산의 상향 조절이 유도되며, 이는 산화 스트레스의 증가를 동반할 수 있습니다 [53]. BMAL1 결핍 마우스에서는 CLOCK에 의해 매개되는 NF-κB의 상향 조절로 인해 전 염증성 증가가 발생하여 만성 염증을 유발할 수 있습니다 [54]. 같은 맥락에서, Cry 단백질의 부재는 p65의 인산화를 통한 NF-κB 활성화를 통해 염증성 사이토카인의 발현을 상향 조절합니다 [55]. 연구에 따르면 BMAL1 KO 마우스는 수명이 짧고, 노화 표현형이 진행되며, 만성 질환의 출현에 유리합니다 [56]. 이러한 의미에서 염증 프로파일에 대한 시계 유전자의 힘(또는 그 반대)은 노화의 부작용에 대한 치료 전략 개발의 핵심 포인트가 될 수 있습니다.

The age-related circadian rhythm disruption relationship with inflammation could indirectly promote negative influence in skeletal muscle tissue, in addition to direct disorders in the skeletal muscle intrinsic molecular clock itself. Several studies have found specific changes in clock genes with different muscle disorders, including changes in structural and metabolic processes (decreased glucose uptake and insulin sensitivity, impaired oxidative capacity, mitochondrial decrease, atrophy, and impaired regeneration (reviewed in [9])) As examples, deficiency in BMAL1 clock gene promotes severe sarcopenia with age [57]. BMAL1 and Sirtuin1 (SIRT1) are downregulated in skeletal muscle of mice maintained in constant abstaining from light [58]. Furthermore, regardless of age, circadian rhythm disruption associated with shift work may contribute to an increased risk of sarcopenia [59]. In this sense, muscle clock genes regulate the expression‎ of several genes that act on the local metabolism, and a change in these clocks could cause losses in insulin sensitivity and loss of muscle mass, contributing to the development of sarcopenia [8,58].

노화와 염증과의 일주기 리듬 교란 관계는 골격근 내재 분자 시계 자체의 직접적인 장애 외에도 골격근 조직에 간접적으로 부정적인 영향을 미칠 수 있습니다. 여러 연구에서 구조 및 대사 과정의 변화(포도당 흡수 및 인슐린 민감성 감소, 산화 능력 손상, 미토콘드리아 감소, 위축, 재생 장애 등)를 포함하여 다양한 근육 질환에 따른 클럭 유전자의 특정 변화를 발견했습니다([9]에서 검토). 예를 들어, BMAL1 시계 유전자의 결핍은 나이가 들어감에 따라 심각한 근감소증을 촉진합니다 [57]. 빛을 지속적으로 차단한 생쥐의 골격근에서는 BMAL1과 시르투인1(SIRT1)이 하향 조절됩니다 [58]. 또한 연령에 관계없이 교대 근무와 관련된 일주기 리듬 장애는 근감소증 위험 증가에 기여할 수 있습니다 [59]. 이러한 의미에서 근육 시계 유전자는 국소 대사에 작용하는 여러 유전자의 발현을 조절하며, 이러한 시계의 변화는 인슐린 감수성 손실과 근육량 감소를 유발하여 근감소증의 발병에 기여할 수 있습니다 [8,58].

Despite the current understanding of the role of the molecular clock in preventing age-related sarcopenia, investigations into the potential modulating effect of physical exercise on physiological mechanisms, including the maintenance of skeletal muscle growth and function, are emerging.

2.3. Vascular Disfunction and Sarcopenia

One of the most noteworthy expressions of biological aging is vascular aging, and arterial stiffness (AS) is currently an established independent risk factor for cardiovascular disease (CVD), above and beyond conventional risk factors [60]. Several studies have documented a close relation between sarcopenia and AS [61], and an interplay between AS, sarcopenia, and cognitive impairment in the elderly has also been suggested [62]. The link between sarcopenia and vascular dysfunction may even be aggravated by the clustering of cardiovascular risk factors in old adults, which impair blood circulation and muscle supply, constituting an added factor for impaired muscle function and overall functionality in the elderly population [63].

The link between vascular dysfunction and sarcopenia can be examined at the micro and macrovascular levels, with intersecting contributions that add to significant muscle effects, and may share common denominators, e.g., endothelial dysfunction and vascular calcification [64].

생물학적 노화의 가장 주목할 만한 표현 중 하나는 혈관 노화이며, 동맥 경직(AS)은 현재 기존의 위험 요인을 넘어 심혈관 질환(CVD)의 독립적인 위험 요인으로 확립되어 있습니다[60]. 여러 연구에서 근감소증과 AS 사이의 밀접한 관계가 입증되었으며[61], 노인의 AS, 근감소증, 인지 장애 사이의 상호 작용도 제안되었습니다[62]. 근감소증과 혈관 기능 장애 사이의 연관성은 혈액 순환과 근육 공급을 저해하는 노인의 심혈관 위험 요인의 군집으로 인해 더욱 악화될 수 있으며, 이는 노인 인구의 근육 기능 및 전반적인 기능 장애의 추가 요인이 될 수 있습니다[63].

혈관 기능 장애와 근육감소증 사이의 연관성은 미세 혈관 및 대혈관 수준에서 검토할 수 있으며, 서로 교차하여 중요한 근육 효과에 기여하고 내피 기능 장애 및 혈관 석회화와 같은 공통 분모를 공유할 수 있습니다[64].

Vascular calcification follows aging as a result of the long-lasting stress that is imposed hemodynamically onto the arterial wall. Its distribution may include the inner layers of the arterial wall or even spread onto the outer layers, promoting changes in the arterial wall dynamics, which, in turn, produces downstream hemodynamic changes germane to inadequate muscle perfusion [65,66]. Several biological mechanisms have been implied in age-dependent vascular calcification. Oxidative stress is an all-mark in aging and has a well-established role in vascular dysfunction. Reactive oxygen species yields endothelial cell apoptosis, interferes with nitric oxide (NO), and unbalances monocyte dynamics, leading to endothelial dysfunction and impaired endothelial-dependent vasodilation [67,68]. Deposition of calcium in the arterial wall as a consequence of vascular smooth muscle cells senescence and osteochondrogenesis is also related to oxidative-stress-induced hyperphosphatemia through the promotion of p65 translocation [69,70]. Oxidative stress is also a cornerstone for a proinflammatory status in the circulatory system, activating the NF-κB, which, in turn, increases the release of proinflammatory cytokines, decisively contributing to atherosclerosis and calcification [71,72]. Circulating cytokines are known to promote calcification through TNF-α, which interferes with the MGP and induces mineral deposition in the atheroma plaque encompassed in the atherosclerotic continuum [73] vis-a-vis the stimulation of smooth muscle cell differentiation onto osteoblast-like configurations [74]. Increasing blood pressure further enhances these effects, combining a mechanical substrate in the arterial wall with neurohumoral paths that further damages and stiffens the arterial wall [60,65]. Aside from the shear-stress aggression promoted by high blood pressure, insulin resistance is also a crucial contributor to vascular dysfunction and calcification by reducing NO bioavailability [75].

혈관 석회화는 동맥벽에 혈역학적으로 오래 지속되는 스트레스의 결과로 노화에 따라 발생합니다. 석회화의 분포는 동맥벽의 내층을 포함하거나 심지어 외층으로 퍼져 동맥벽 역학의 변화를 촉진하여 부적절한 근육 관류와 관련된 하류 혈역학 변화를 일으킬 수 있습니다[65,66]. 연령에 따른 혈관 석회화에는 몇 가지 생물학적 메커니즘이 암시되어 있습니다. 산화 스트레스는 노화의 모든 징후이며 혈관 기능 장애에서 잘 알려진 역할입니다. 활성 산소 종은 내피 세포 사멸을 일으키고 산화질소(NO)를 방해하며 단핵구 역학의 불균형을 초래하여 내피 기능 장애와 내피 의존성 혈관 확장 장애를 일으킵니다[67,68]. 혈관 평활근 세포 노화 및 골 연골 형성의 결과로 동맥벽에 칼슘이 침착되는 것도 p65 전위의 촉진을 통한 산화 스트레스 유발 고인산혈증과 관련이 있습니다[69,70]. 산화 스트레스는 또한 순환계에서 염증성 상태의 초석이 되어 NF-κB를 활성화하고, 이는 다시 염증성 사이토카인의 방출을 증가시켜 죽상경화증과 석회화에 결정적으로 기여합니다[71,72]. 순환 사이토카인은 죽상경화 연속체에 포함된 죽종 플라크에 미네랄 침착을 유도하고 조골세포와 유사한 구성으로 평활근 세포 분화를 자극하는 TNF-α를 통해 석회화를 촉진하는 것으로 알려져 있습니다[73,74]. 혈압이 상승하면 동맥벽의 기계적 기질과 동맥벽을 더욱 손상시키고 경직시키는 신경 체액 경로가 결합하여 이러한 효과가 더욱 강화됩니다[60,65]. 고혈압에 의해 촉진되는 전단 스트레스 공격 외에도 인슐린 저항성은 NO 생체 이용률을 감소시켜 혈관 기능 장애와 석회화에 중요한 기여를 합니다[75].

An inverse relation between micro- and macrovascular dysfunction and skeletal muscle mass and function has been recently depicted in a systematic review including 33 clinical studies [63]. It is believed that this association between vascular dysfunction and muscle loss (mass and function) may be associated with impaired muscle perfusion through a reduction in peripheral blood flow, relying both on anatomic changes and hemodynamic features of the aging circulatory physiology. The blood flow restrictions to the muscles will limit the supply of important nutrients and hormones to the myocytes, from which muscle function and structure will be affected and progress in close connection with sarcopenia. In fact, it is suggested that this reduction in the nutritive supply may contribute to muscle dysfunction and loss through changes in anabolic resistance of the muscle (e.g., [76]).

The identification and implementation of strategies to prevent and treat these features are of the utmost importance. These may include aspects such as proper management of behavioral and environmental risk factors, such as nutrition, exercise, smoking habits, stress management, social support, pollution, and body composition. Physical exercise should play a major role, as it is the main component for the prevention and treatment of sarcopenia [77], and further evidence exists that additionally supports the positive modulation of physical exercise for vascular health [78,79] in old adults. Therefore, physical activity should contribute to a positive modulation of the aging trajectories, particularly if administered in a personalized approach, tailored to the individual needs and expectations.

미세 및 대혈관 기능 장애와 골격근 질량 및 기능 사이의 반비례 관계는 최근 33개의 임상 연구를 포함한 체계적인 검토에서 밝혀졌습니다[63]. 혈관 기능 장애와 근육 손실(질량 및 기능) 사이의 이러한 연관성은 노화 순환 생리학의 해부학적 변화와 혈역학적 특징에 의존하여 말초 혈류 감소를 통한 근육 관류 장애와 관련이 있을 수 있다고 믿어집니다. 근육으로의 혈류 제한은 근세포에 중요한 영양분과 호르몬의 공급을 제한하여 근육 기능과 구조에 영향을 미치고 근감소증과 밀접한 관련성을 가지고 진행됩니다. 실제로 이러한 영양 공급의 감소는 근육의 동화 작용 저항의 변화를 통해 근육 기능 장애 및 손실에 기여할 수 있다고 제안됩니다(예: [76]).

이러한 특징을 예방하고 치료하기 위한 전략을 파악하고 실행하는 것이 가장 중요합니다. 여기에는 영양, 운동, 흡연 습관, 스트레스 관리, 사회적 지원, 공해, 체성분과 같은 행동 및 환경적 위험 요인의 적절한 관리와 같은 측면이 포함될 수 있습니다. 신체 운동은 근감소증 예방 및 치료의 주요 구성 요소이므로 중요한 역할을 해야 하며[77], 노인의 혈관 건강을 위한 신체 운동의 긍정적 조절[78,79]을 추가로 뒷받침하는 추가 증거가 존재합니다. 따라서 신체 활동은 특히 개인의 필요와 기대에 맞춘 개인화된 접근 방식으로 관리할 경우 노화 궤적을 긍정적으로 조절하는 데 기여해야 합니다.

3. Impact of Exercise on Inflammatory Profile and Association with Clock Genes

Exercise, specifically aerobic and combined with resistance training, have been recognized as a potential intervention to modulate inflammatory profile in humans [80,81,82], with a particular emphasis in older adults, in reversing or attenuate immunosenescence in aging [83,84,85], as well as reducing the development of chronic diseases [86].

During exercise, skeletal muscle functions as an endocrine organ, secreting several myokines such as IL-6, IL-7, and IL-15. In addition to the pleotropic effects mentioned above, IL-6 can stimulate cortisol released by the adrenal glands, acting as a second anti-inflammatory signal and improving glucose uptake through the stimulation of AMPK signaling [87]. IL-6 is conventionally used as marker of inflammation and several studies eval‎uating the impact of exercise in their inflammatory profile report the significant reduction in IL-6 levels after different periods of intervention. A study on females with metabolic syndrome found that a 12 week-long aerobic exercise intervention promotes a decrease in IL-6 [88]. The role of IL-6 in the framework of exercise as an anti-inflammatory therapy for cancer cachexia is also very significant (reviewed in [86]).

운동, 특히 유산소 운동과 저항력 훈련과 결합된 운동은 인간의 염증 프로파일을 조절하는 잠재적 개입으로 인식되어 왔으며[80,81,82], 특히 노인의 경우 노화에 따른 면역 노화를 역전시키거나 약화시키고[83,84,85] 만성 질환의 발병을 감소시키는 데 중점을 두고 있습니다[86].

운동하는 동안 골격근은 내분비 기관으로 기능하여 IL-6, IL-7, IL-15와 같은 여러 마이오카인을 분비합니다. 위에서 언급한 플레오트로픽 효과 외에도 IL-6는 부신에서 분비되는 코르티솔을 자극하여 두 번째 항염증 신호로 작용하고 AMPK 신호의 자극을 통해 포도당 흡수를 개선할 수 있습니다[87]. IL-6는 일반적으로 염증의 마커로 사용되며, 운동이 염증 프로필에 미치는 영향을 평가하는 여러 연구에서 다양한 개입 기간 후에 IL-6 수치가 크게 감소한 것으로 보고되었습니다. 대사증후군이 있는 여성을 대상으로 한 연구에 따르면 12주간의 유산소 운동 중재가 IL-6의 감소를 촉진하는 것으로 나타났습니다[88]. 암 악액질에 대한 항염증 요법으로서 운동의 틀에서 IL-6의 역할도 매우 중요합니다 ([86]에서 검토 됨).

A study conducted by Chen et al. [89] performed an eval‎uation of the differentially expressed genes (DEGs) in a group of 24 sedentary middle-aged men with different basal levels of IL-6 that undertook a 24 week-long physical activity program. The analysis of DEGs, followed by functional enrichment analysis and protein–protein interactions, showed that C-C motif chemokine receptor 7 (CCR7) and hemoglobin subunit delta (HBD) genes were induced by myocyte enhancer factor 2A (MEF2A), arising as key regulatory factors modulated by exercise [89]. The authors conclude that inflammation-related genes such as CCR7, HBD, and interferon-gamma (IFN-γ) might serve vital roles in reducing inflammation by exercise and might prevent the risk of chronic diseases in sedentary individuals [89].

Chen 등[89]이 수행한 연구에서는 24주 동안 신체 활동 프로그램을 수행한 IL-6의 기저 수치가 다른 24명의 앉아서 생활하는 중년 남성 그룹에서 차등 발현 유전자(DEG)를 평가했습니다. DEG를 분석한 후 기능 강화 분석과 단백질 간 상호작용을 수행한 결과, C-C 모티브 케모카인 수용체 7(CCR7)과 헤모글로빈 서브유닛 델타(HBD) 유전자가 운동에 의해 조절되는 주요 조절 인자로서 근세포 강화 인자 2A(MEF2A)에 의해 유도되는 것으로 나타났습니다[89]. 저자들은 CCR7, HBD, 인터페론-감마(IFN-γ)와 같은 염증 관련 유전자가 운동으로 염증을 줄이는 데 중요한 역할을 할 수 있으며, 앉아서 생활하는 사람의 만성 질환 위험을 예방할 수 있다고 결론지었습니다[89].

IFN-γ is a cytokine with a relevant role in several aspects of both adaptive and innate immunity. Firstly, it is most recognized for its pro-inflammatory properties but has been also recognized for its pleiotropic functions such as induction and maintenance of regulatory T cells, induction of tolerogenic dendritic cell characteristics, and immunosuppressive tumor environment. These properties place IFN-γ among the major endogenous immune regulators, contributing to both immunity and tolerance in several stages of the immune response [90,91]. Svajger et al. (2021) demonstrated that IFN-γ can exert important tolerogenic effects on dendritic cells, in in vitro assays, through a strong upregulation of programmed death-ligand 1 (PD-L1), an inhibitory molecule [90].

IFN-γ는 적응성 면역과 선천성 면역의 여러 측면에서 관련성이 있는 사이토카인입니다. 첫째, 전 염증성 특성으로 가장 잘 알려져 있지만 조절 T 세포의 유도 및 유지, 관용성 수지상 세포 특성 유도 및 면역 억제 종양 환경과 같은 다능성 기능도 인정받고 있습니다. 이러한 특성으로 인해 IFN-γ는 면역 반응의 여러 단계에서 면역과 관용 모두에 기여하는 주요 내인성 면역 조절제 중 하나입니다 [90,91]. Svajger 등(2021)은 시험관 내 분석에서 IFN-γ가 억제 분자인 프로그램된 사멸 리간드 1(PD-L1)의 강력한 상향 조절을 통해 수지상 세포에 중요한 관용 효과를 발휘할 수 있음을 입증했습니다[90].

Shaw et al. (2020) observed that exercise in acute hyperketonemia appears to amplify the initiation of the pro-inflammatory T-cell-related IFN-γ response, with an increased IFN-γ mRNA expression‎ during and following prolonged, strenuous exercise [92]. Hasanli et al. (2020) eval‎uated the impact of physical or psychological stress on the IFN-γ levels in male Sprague Dawley rats submitted to exercise activity, psychological stress, or the combination of exercise and psychological stress. The study showed that the different interventions did not modulate significantly the levels of IFN-γ either immediately after exercise or after 72 h, despite fluctuations in cytokine values, with a tendency to decrease immediately after exercise and increase 72 h later [93]. Vijayaraghava (2017) conducted an experimental study with the application of different grades of exercise and eval‎uated the impact on IFN-γ plasma levels, in individuals of different ages and body mass index (BMI) values. The levels of plasma IFN-γ were significantly modulated by moderate exercise, with a significant increase in plasma levels after a bout of moderated exercise, and the highest values were found after 1 month of moderate exercise. On the contrary, after a bout of strenuous exercise, plasma levels reduced in comparison with baseline values. The study results also showed that regular physical activity confers protection against excessive inflammation in spite of higher age or BMI, with respect to IFN-γ levels [94]. Conversely, Farinha et al. eval‎uated the impact of 12 weeks of aerobic exercise and observed a decrease in IL-1β, TNF-α, IL-6, and IFN-γ in women with metabolic syndrome [88].

Shaw 등(2020)은 급성 고케톤혈증에서 운동은 장기간의 격렬한 운동 중과 운동 후에 IFN-γ mRNA 발현이 증가하여 염증성 T세포 관련 IFN-γ 반응의 시작을 증폭시키는 것으로 보인다고 관찰했습니다[92]. Hasanli 등(2020)은 운동 활동, 심리적 스트레스 또는 운동과 심리적 스트레스의 조합에 노출된 수컷 Sprague Dawley 쥐의 IFN-γ 수치에 대한 신체적 또는 심리적 스트레스의 영향을 평가했습니다. 이 연구에 따르면 사이토카인 수치의 변동에도 불구하고 운동 직후 또는 72시간 후에도 다양한 개입이 IFN-γ 수치를 크게 조절하지 않았으며, 운동 직후에는 감소하고 72시간 후에는 증가하는 경향을 보였습니다[93]. Vijayaraghava(2017)는 다양한 운동 등급을 적용한 실험 연구를 수행하여 연령과 체질량 지수(BMI) 값이 다른 개인에서 IFN-γ 혈장 수치에 미치는 영향을 평가했습니다. 혈장 IFN-γ 수치는 적당한 운동에 의해 유의하게 조절되었으며, 한 번의 적당한 운동 후 혈장 수치가 유의하게 증가했으며, 1개월 동안 적당한 운동을 한 후 가장 높은 수치가 나타났습니다. 반대로 격렬한 운동을 한 후에는 혈장 수치가 기준치에 비해 감소했습니다. 또한 연구 결과에 따르면 규칙적인 신체 활동은 IFN-γ 수치와 관련하여 높은 연령이나 BMI에도 불구하고 과도한 염증에 대한 보호 기능을 부여합니다 [94]. 반대로 Farinha 등은 12주간의 유산소 운동이 미치는 영향을 평가한 결과 대사증후군이 있는 여성에서 IL-1β, TNF-α, IL-6 및 IFN-γ가 감소하는 것을 관찰했습니다[88].

Therefore, exercise has an emerging potential to improve immune system performance and reduce the risk of low-grade inflammation from childhood to old age [88,95,96,97,98,99]. A systematic review conducted by Bautmans et al. (2021) revealed significant anti-inflammatory effects of exercise in the elderly—namely, in reducing circulating levels of CRP, IL-6, and TNF-alpha and also that the performed exercise interventions seem suitable to apply and safe for older patients, without inducing an exacerbation of inflammation following exercise [100].

따라서 운동은 면역 체계 성능을 개선하고 어린 시절부터 노년기까지 저급 염증의 위험을 줄일 수 있는 새로운 잠재력을 가지고 있습니다[88,95,96,97,98,99]. (2021)이 수행한 체계적 문헌고찰에 따르면 노인에서 운동의 중요한 항염증 효과, 즉 순환하는 CRP, IL-6 및 TNF-알파 수치를 감소시키는 것으로 나타났으며, 수행된 운동 중재는 운동 후 염증의 악화를 유발하지 않고 노인 환자에게 적용하기에 적합하고 안전한 것으로 보입니다[100].

Desynchronization of circadian clocks induced by modern lifestyle could predispose to inflammation and metabolic impairment and increase the risk of chronic diseases [101,102]. A relevant aspect is the connection of exercise with circadian rhythm physiology. Several studies point that exercise can modulate circadian rhythm, acting as a circadian time cue and changing the phase of a molecular clock in peripheral tissues. In addition to studies on animal models, studies on humans have revealed that endurance and resistance exercises stimulate the expression‎ of clock genes [103,104,105]. Several studies explain the effect of exercise on core molecular clock genes, through the influence in exercise-responsive genes—AMPK, HIF-1α, and PGC1α. Increased activity of AMPK changes Per and Cry stability, modulating clock genes expression‎ [103,105,106].

현대 생활 방식에 의해 유도 된 일주기 시계의 비동기화는 염증과 대사 장애를 유발하고 만성 질환의 위험을 증가시킬 수 있습니다 [101,102]. 이와 관련된 측면은 운동과 일주기 리듬 생리학의 연관성입니다. 여러 연구에 따르면 운동은 일주기 리듬을 조절하여 일주기 시간 신호로 작용하고 말초 조직의 분자 시계 위상을 변화시킬 수 있다고 합니다. 동물 모델에 대한 연구 외에도 인간에 대한 연구에 따르면 지구력 및 저항 운동이 시계 유전자의 발현을 자극하는 것으로 나타났습니다[103,104,105]. 여러 연구에서 운동이 핵심 분자 시계 유전자에 미치는 영향을 운동 반응성 유전자인 AMPK, HIF-1α, PGC1α의 영향을 통해 설명합니다. AMPK의 활성 증가는 퍼 및 크라이 안정성을 변화시켜 시계 유전자 발현을 조절합니다[103,105,106].

A recent study by Souza Teixeira et al. shows an improvement in the anti-inflammatory profile, with a lifelong physical exercise related to clock genes expression‎ in effector-memory CD4+ T cells in master athletes. Master athletes presented different peripheral and cellular inflammatory responses after acute exercise, compared with untrained individuals, with higher levels of IL-8, IL-10, IL-12p70, and IL-17A and augmented expression‎ of Cry1, REV-ERBα, and TBX21 [107].

Souza Teixeira 등의 최근 연구에 따르면, 평생 운동하는 숙련된 운동선수의 이펙터-기억 CD4+ T 세포에서 시계 유전자 발현과 관련된 항염증 프로필이 개선되는 것으로 나타났습니다. 숙련된 운동선수들은 훈련을 받지 않은 사람에 비해 급성 운동 후 말초 및 세포 염증 반응이 다르게 나타났는데, IL-8, IL-10, IL-12p70, IL-17A의 수치가 더 높았고 Cry1, REV-ERBα, TBX21의 발현이 증가했습니다[107].

Clock genes are involved in inflammatory response through the activation of NF-κB transcription and activation of pro-inflammatory cytokines [107,108]. CLOCK can upregulate NF-κB-mediated transcription in the absence of BMAL1; therefore, BMAL1 may have an anti-inflammatory role [54]. Tylutka et al. concluded that physical activity sustained throughout life could lead to rejuvenation of the immune system by increasing the percentage of naïve T lymphocytes or by decreasing the inverse CD4/CD8 ratio [108]. Taking into account the available data, growing evidence supports the vision that exercise may counteract immunosenescence and improve the immune system. Exercise-induced changes in immunosenescence-related markers of immune cells were reviewed by Mathot et al., supporting the effect of long-term exercise on senescent T-lymphocytes and the increase in dendritic cells after exercise in older adults. The data also suggest a significant influence of the type and intensity of exercise on immunosenescence-related markers, mainly in older adults, highlighting the greater impact of aerobic exercise and resistance exercise protocols with lower loads and a greater number of repetitions (2 sets of 30 consecutive repetitions at 40% of 1RM) [85,107].

클럭 유전자는 NF-κB 전사의 활성화와 전 염증성 사이토카인의 활성화를 통해 염증 반응에 관여합니다 [107,108]. CLOCK은 BMAL1이 없을 때 NF-κB 매개 전사를 상향 조절할 수 있으므로 BMAL1은 항염증 역할을 할 수 있습니다 [54]. Tylutka 등은 평생 동안 지속되는 신체 활동이 순진한 T 림프구의 비율을 증가시키거나 역 CD4/CD8 비율을 감소시킴으로써 면역 체계의 회춘으로 이어질 수 있다고 결론지었습니다[108]. 이용 가능한 데이터를 고려할 때, 운동이 면역 노화에 대응하고 면역 체계를 개선할 수 있다는 비전을 뒷받침하는 증거가 점점 더 많아지고 있습니다. Mathot 등은 운동으로 인한 면역 세포의 면역 노화 관련 마커의 변화를 검토하여 장기 운동이 노화 T 림프구에 미치는 영향과 고령자의 운동 후 수지상 세포의 증가를 뒷받침했습니다. 이 데이터는 또한 운동의 종류와 강도가 주로 노년층에서 면역 노화 관련 표지자에 상당한 영향을 미친다는 것을 시사하며, 유산소 운동과 저항 운동 프로토콜이 부하가 낮고 반복 횟수가 많은 운동(1RM의 40%에서 30회 연속 반복 2세트)에 더 큰 영향을 미친다는 점을 강조합니다[85,107].

4. Impact of Exercise on Circadian Skeletal Muscle Rhythm

The skeletal muscle system has its own clock gene expression‎ and can be stimulated by physical activity. Acute aerobic and resistance exercise increases the expression‎ of skeletal muscle clock genes in humans [109]. An acute session of aerobic exercise (70 min at 70% VO2max) increased the expression‎ of the BMAL1 gene by 1.6 times 4 h after exercise, and to 3.5 times 8 h after exercise, in trained men [109]. Likewise, an active session of isotonic knee extension resistance, including both concentric and eccentric phases (10 sets of 8 repetitions at 80% of 1RM) increased the expression‎ of the BMAL1 gene by approximately 1.2 times, assessed 6 h after exercise in untrained healthy men [110], as well as positively regulating the clock genes Cry1 and Per2 by exercise, compared with control without exercise.

골격근 시스템에는 자체 시계 유전자 발현이 있으며 신체 활동에 의해 자극을 받을 수 있습니다. 급성 유산소 운동과 저항 운동은 사람의 골격근 시계 유전자 발현을 증가시킵니다[109]. 훈련된 남성의 경우 급성 유산소 운동 세션(최대산소섭취량 70%에서 70분)을 하면 운동 4시간 후 BMAL1 유전자의 발현이 1.6배, 운동 8시간 후 3.5배까지 증가했습니다[109]. 마찬가지로, 동심 및 편심 단계를 모두 포함한 등장성 무릎 확장 저항(1RM의 80%에서 8회 반복 10세트)의 적극적인 세션은 훈련을 받지 않은 건강한 남성에서 운동 6시간 후 평가한 BMAL1 유전자의 발현을 약 1.2배 증가시켰으며[110], 운동을 하지 않은 대조군에 비해 운동으로 시계 유전자 Cry1 및 Per2를 긍정적으로 조절하는 것으로 나타났습니다.

Four weeks of low-intensity resistance exercises resulted in a significant change in the expression‎ of clock genes in the skeletal muscle of mice [111], supporting the fact that exercise can be an external stimulus for skeletal muscle rhythm. Skeletal muscle BMAL1 and Per2 gene expression‎ significantly increased after a 12-week exercise intervention in elderly with obesity and prediabetes [112] Furthermore, skeletal muscle BMAL1 gene expression‎ may improve insulin sensitivity. Interestingly, Clock- and BMAL1 gene mutant mice exhibit approximately 30% reductions in maximum muscle strength and 40% in mitochondrial volume [12]. Although with the absence of the CLOCK gene, the animals’ ability to adapt to 8 weeks of endurance exercise was not impaired [113].

Thus, the practice of physical exercise seems to modulate the interrupted skeletal muscle clock, contributing to improvements in the metabolic health of the entire body. These data have broad implications in the context of clinical practice, suggesting the importance of exercise, and, more specifically, the interaction of exercise and muscle, as a therapeutic strategy to help readjust body molecular clocks.

4주간의 저강도 저항 운동은 생쥐의 골격근에서 시계 유전자의 발현에 유의미한 변화를 가져왔으며[111], 이는 운동이 골격근 리듬에 대한 외부 자극이 될 수 있다는 사실을 뒷받침합니다. 비만 및 당뇨병 전단계 노인의 12주 운동 중재 후 골격근 BMAL1 및 Per2 유전자 발현이 유의하게 증가했습니다 [112] 또한 골격근 BMAL1 유전자 발현은 인슐린 감수성을 개선할 수 있습니다. 흥미롭게도 클락 및 BMAL1 유전자 돌연변이 마우스는 최대 근력이 약 30%, 미토콘드리아 용적이 40% 감소한 것으로 나타났습니다[12]. CLOCK 유전자가 없더라도 8주간의 지구력 운동에 적응하는 동물의 능력은 손상되지 않았습니다 [113].

따라서 신체 운동은 중단된 골격근 시계를 조절하여 전신의 대사 건강을 개선하는 데 기여하는 것으로 보입니다. 이러한 데이터는 신체 분자 시계를 재조정하는 데 도움이 되는 치료 전략으로서 운동의 중요성, 특히 운동과 근육의 상호 작용을 시사하는 임상 진료의 맥락에서 광범위한 의미를 갖습니다.

5. Impact of Exercise on Vascular Circadian Rhythm

The cardiovascular system is influenced to a great extent by chronobiologic rhythms that are determined by the CNS and peripheral clocks, determining short- (minutes and hours) and long-term (months and years) functional fluctuations. The peripheral clocks are within each cardiovascular cell and are crucial in the modulation of aspects such as endothelial function, vasodilation and resistance, blood pressure, hormone dynamics, body temperature, heart rate, etc. [114].

심혈관계는 중추신경계와 말초 시계에 의해 결정되는 생체리듬의 영향을 크게 받아 단기(분 및 시간) 및 장기(수개월 및 수년) 기능 변동을 결정합니다. 말초 시계는 각 심혈관 세포 내에 있으며 내피 기능, 혈관 확장 및 저항, 혈압, 호르몬 역학, 체온, 심박수 등과 같은 측면을 조절하는 데 매우 중요한 역할을 합니다. [114].

The effects of physical exercise on the cardiovascular system have been widely described, which include improvements in endothelial function, relaxation of the arterial wall and vasodilation, lower blood pressure and impedance, lower heart rate, improved heart-to-vascular coupling, and overall greater cardiovascular efficiency [115]. Even though acute exercise induces an increase in systolic blood pressure and heart rate, the intensification in shear stress that encompasses physical activity stimulates the release of NO by the endothelial cells, thus promoting vasodilation and improved blood supply to the working muscles [116,117,118]. The post-exercise phase depicts lower blood pressure and heart rate, in line with a positive modulation of the autonomic nervous system, with a change in the sympathetic/parasympathetic balance toward a higher influence of the parasympathetic axis [118]. The positive modulation of the cardiovascular system provided by physical exercise has also important long-term effects, mostly due to its beneficial impact on the endothelium and overall arterial structure, able to shift the trajectories of arterial aging toward a more beneficial one and therefore preventing the occurrence of early vascular aging [119,120]. Physical exercise thus provides a valuable tool to prevent biological aging and contribute to better cardiovascular health and lesser incidence of major cardiovascular events. Furthermore, physical exercise has been shown to modulate the circadian clocks to a similar extent as that produced by photic light cues [121], thus adding to its regulatory effect on the cardiovascular system. Physical exercise, particularly aerobic training, also produces important neuroendocrine changes, including, but not limited to, decreased cortisol and increased melatonin production during the night, contributing to a more effective sleep [122,123,124].

신체 운동이 심혈관계에 미치는 영향은 내피 기능 개선, 동맥벽 이완 및 혈관 확장, 혈압 및 임피던스 감소, 심박수 감소, 심장-혈관 결합 개선, 전반적인 심혈관계 효율성 향상 등 광범위하게 설명되어 있습니다[115]. 급성 운동은 수축기 혈압과 심박수의 증가를 유도하지만, 신체 활동을 포함하는 전단 응력의 강화는 내피 세포에 의한 NO의 방출을 자극하여 혈관 확장을 촉진하고 작업 근육으로의 혈액 공급을 개선합니다[116,117,118]. 운동 후 단계에서는 자율 신경계의 긍정적인 조절과 함께 교감/부교감 균형이 부교감 축의 영향력이 높아지는 방향으로 변화하면서 혈압과 심박수가 낮아지는 것을 볼 수 있습니다[118]. 신체 운동이 제공하는 심혈관계의 긍정적인 조절은 주로 내피와 전반적인 동맥 구조에 유익한 영향을 미쳐 동맥 노화의 궤적을 더 유익한 방향으로 전환하여 초기 혈관 노화의 발생을 예방할 수 있기 때문에 장기적으로도 중요한 영향을 미칩니다 [119,120]. 따라서 신체 운동은 생물학적 노화를 예방하고 심혈관 건강을 개선하고 주요 심혈관 질환의 발생률을 낮추는 데 기여하는 유용한 도구입니다. 또한, 신체 운동은 광신호[121]에 의해 생성되는 것과 유사한 정도로 일주기 시계를 조절하여 심혈관계에 대한 조절 효과를 더하는 것으로 나타났습니다. 신체 운동, 특히 유산소 운동은 또한 밤 동안 코르티솔 감소 및 멜라토닌 생성 증가를 포함하되 이에 국한되지 않는 중요한 신경 내분비 변화를 일으켜 보다 효과적인 수면에 기여합니다[122,123,124].

The adjustments of circadian rhythmicity produced by exercise have been shown to occur, even for low-intensity endurance exercise [111], and seem to be independent of the time of day the individual performs the exercise [125], although optimal diurnal exercise periods can be adjusted according to the individual chronotype [126]. According to previous research, individuals can be categorized into three distinct chronotype groups: early circadian chronotype, intermediate circadian chronotype, and late circadian chronotype [127]. Individuals in the early circadian chronotype group appear to have a greater disposition to early (morning) physical exercise, while those in the late circadian chronotype prefer to exercise during the late evening. The matching of exercise periodicity with individual chronotype could thus be an enhancement factor for skeletal muscle performance and circadian clock adjustments, producing better cardiovascular protection and improved sleep quality [128].

운동에 의해 생성되는 일주기 리듬의 조정은 저강도 지구력 운동에서도 발생하는 것으로 나타났으며[111], 개인이 운동을 수행하는 시간과는 무관한 것으로 보입니다[125], 최적의 일주기 운동 기간은 개인의 크로노타입에 따라 조정될 수 있습니다[126]. 이전 연구에 따르면 개인은 일주기 초기 크로노타입, 일주기 중간 크로노타입, 일주기 후기 크로노타입의 세 가지 크로노타입 그룹으로 분류할 수 있습니다[127]. 일주기 초기 크로노타입 그룹에 속하는 사람은 이른(아침) 운동을 선호하는 반면, 일주기 후기 크로노타입에 속하는 사람은 늦은 저녁에 운동하는 것을 더 선호하는 것으로 나타났습니다. 따라서 운동 주기성과 개인의 크로노타입이 일치하면 골격근 성능과 일주기 시계 조정이 향상되어 심혈관을 더 잘 보호하고 수면의 질을 개선할 수 있습니다[128].

6. Conclusions

Mainly due to the pro-inflammatory cytokines impact of aging, there is a deregulation of the circadian rhythm, and its relationship with skeletal muscle changes; vascular health may be a possible risk factor for the development of sarcopenia. Lifestyle interventions such as regular physical exercise are essential to promoting an anti-inflammatory status, reducing muscle loss and strength, and improving endothelial function usually affected by aging. In addition, the adoption of physical exercise can act as a potential resynchronizer of peripheral muscle and vascular clock misalignment, which could favor vascular health and indirectly also affect positively skeletal muscle function. However, the exercise modality, as well as the ideal intensity and frequency to promote better effects on senescence, should be better investigated in future experimental studies.

주로 노화로 인한 전 염증성 사이토카인의 영향으로 인해 일주기 리듬의 조절이 완화되고 골격근 변화와의 관계가 있으며, 혈관 건강이 근감소증 발병의 위험 요인이 될 수 있습니다. 규칙적인 운동과 같은 생활 습관 개입은 항염증 상태를 촉진하고 근육 손실과 근력을 줄이며 일반적으로 노화의 영향을 받는 내피 기능을 개선하는 데 필수적입니다. 또한, 운동을 하면 말초 근육과 혈관 시계의 부정렬을 잠재적으로 재동기화하여 혈관 건강에 도움이 되고 골격근 기능에도 간접적으로 긍정적인 영향을 미칠 수 있습니다. 그러나 운동 방식과 노화에 더 나은 효과를 촉진하는 이상적인 운동 강도 및 빈도는 향후 실험 연구를 통해 더 잘 조사되어야 합니다.

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Author Contributions

Conceptualization, B.S.d.A.S., F.S.L. and A.C.; writing—original draft preparation, B.S.d.A.S., F.S.L., J.S.U., T.P. and A.C.; writing—review and editing, B.S.d.A.S., F.S.L., A.C. and M.J.C.-E.-S. All authors have read and agreed to the published version of the manuscript.

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Funding

This research received no external funding.

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Conflicts of Interest

The authors declare no conflict of interest.

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Footnotes

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