Epigenetic Dysregulation and Osteocyte Senescence: Convergent Drivers of Osteosarcopenia in Aging Bone and Muscle.

IF 7 2区 医学 Q1 GERIATRICS & GERONTOLOGY
Shahneela Nusrat, Rahman Ud Din, Muhammad Akram Tariq, Haisheng Yang
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引用次数: 0

Abstract

Osteosarcopenia the concurrent deterioration of bone (osteoporosis) and muscle (sarcopenia) represents a critical yet understudied geriatric syndrome that synergistically amplifies frailty, fractures, and loss of independence in aging populations. This dual pathology imposes a staggering socioeconomic burden through increased disability, prolonged hospitalization, and elevated mortality. Despite its clinical urgency, therapeutic advances remain stagnant, as current interventions e.g., bisphosphonates, vitamin D supplementation are palliative and fail to address the shared molecular drivers of bone-muscle crosstalk. Emerging evidence implicates cellular senescence and epigenetic dysregulation as convergent mechanisms driving osteosarcopenia. Senescent osteocytes, burdened by oxidative stress and mitochondrial dysfunction, secrete pro-inflammatory cytokines e.g., IL-6, TNF-α and matrix-degrading enzymes (e.g., MMPs) via the senescence-associated secretory phenotype (SASP), which erodes bone integrity and propagates muscle atrophy. Simultaneously, epigenetic alterations DNA hypermethylation of osteogenic genes RUNX2, histone deacetylation repressing myogenesis MYOD1, and dysregulated non-coding RNAs (miR-133, miR-214) lock musculoskeletal tissues into a degenerative state. These processes are exacerbated by age-related inflammaging and metabolic disturbances e.g., NAD+ depletion, which amplify oxidative stress and chromatin instability. The synergy between senescence and epigenetics in perpetuating osteosarcopenia remains poorly defined. Most preclinical models overlook comorbidities (e.g., diabetes, chronic inflammation) that accelerate musculoskeletal decline. Current therapies senolytics, histone deacetylase (HDAC) inhibitors lack tissue specificity and exhibit pleiotropic effects. This review addresses these gaps by synthesizing cutting-edge insights into the senescence-epigenetics axis as a unifying driver of osteosarcopenia. By elucidating how SASP factors (e.g., myostatin) and epigenetic reprogramming e.g., sirtuin 1 (SIRT1) hypermethylation disrupt bone-muscle crosstalk, we propose novel strategies to break the self-sustaining cycle of tissue degeneration. We highlight the promise of precision geroscience leveraging CRISPR-engineered organoids, multi-omics profiling, and AI-driven biomarkers to decode tissue-specific vulnerabilities and design dual-target therapies e.g., senolytics ++ bromodomain and extra-terminal (BET) inhibitors.

表观遗传失调和骨细胞衰老:骨和肌肉老化中骨骼肌减少的趋同驱动因素。
骨骼肌减少症是骨骼(骨质疏松症)和肌肉(骨骼肌减少症)同时恶化的一种严重但尚未得到充分研究的老年综合征,它会在老年人中协同放大虚弱、骨折和丧失独立性。这种双重病理通过增加残疾、延长住院时间和提高死亡率,施加了惊人的社会经济负担。尽管其临床紧迫性,但治疗进展仍然停滞不前,因为目前的干预措施,如双膦酸盐,维生素D补充是姑息性的,未能解决骨肌串扰的共同分子驱动因素。新出现的证据暗示细胞衰老和表观遗传失调是驱动骨骨骼肌减少症的趋同机制。衰老的骨细胞受氧化应激和线粒体功能障碍的影响,通过衰老相关分泌表型(SASP)分泌促炎细胞因子,如IL-6、TNF-α和基质降解酶(如MMPs),从而侵蚀骨完整性并导致肌肉萎缩。同时,表观遗传改变成骨基因RUNX2的DNA高甲基化,抑制肌生成MYOD1的组蛋白去乙酰化,以及失调的非编码rna (miR-133, miR-214)将肌肉骨骼组织锁定到退行性状态。与年龄相关的炎症和代谢紊乱(如NAD+耗竭)会加剧这些过程,从而放大氧化应激和染色质不稳定性。衰老和表观遗传学之间的协同作用在使骨骼肌减少症永久化的过程中仍然不明确。大多数临床前模型忽略了加速肌肉骨骼衰退的合并症(如糖尿病、慢性炎症)。目前的治疗药物,组蛋白去乙酰化酶(HDAC)抑制剂缺乏组织特异性,并表现出多效性。本综述通过综合衰老-表观遗传学轴作为骨骼肌减少症的统一驱动因素的前沿见解来解决这些差距。通过阐明SASP因子(如肌肉生长抑制素)和表观遗传重编程(如sirtuin 1 (SIRT1)超甲基化)如何破坏骨骼肌串扰,我们提出了打破组织退化自我维持循环的新策略。我们强调了利用crispr工程类器官、多组学分析和人工智能驱动的生物标志物来解码组织特异性漏洞和设计双靶点疗法(如senolytics ++ bromodomain和extra- end (BET) inhibitors)的精确老年科学的前景。
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来源期刊
Aging and Disease
Aging and Disease GERIATRICS & GERONTOLOGY-
CiteScore
14.60
自引率
2.70%
发文量
138
审稿时长
10 weeks
期刊介绍: Aging & Disease (A&D) is an open-access online journal dedicated to publishing groundbreaking research on the biology of aging, the pathophysiology of age-related diseases, and innovative therapies for conditions affecting the elderly. The scope encompasses various diseases such as Stroke, Alzheimer's disease, Parkinson’s disease, Epilepsy, Dementia, Depression, Cardiovascular Disease, Cancer, Arthritis, Cataract, Osteoporosis, Diabetes, and Hypertension. The journal welcomes studies involving animal models as well as human tissues or cells.
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