衰老的分子机制与干预研究的最新进展

随着全球老龄化时代的到来,衰老和衰老相关疾病带来的健康问题日益突出。如何最大限度地维持老龄人口健康、干预衰老相关疾病并延缓衰老的发生对于医疗系统、科研机构乃至整个社会都是巨大的挑战。目前,对于衰老的分子机制研究已经有长足的进步,对于衰老进程的生物学和遗传学机制已有突破性的认识,对于衰老相关疾病的发病机制也有了深刻的理解。但这些研究成果还远远达不到能够延缓人类衰老并遏制衰老相关疾病的发生的要求。该文将从衰老的分子机制和干预手段这两个方面入手,综述衰老的理论研究和实际应用中的主要成果和最新进展。     

Obesity is a common soil for premature cardiac aging and heart diseases - Role of autophagy

The advance in medical technology and healthcare has dramatically improved the average human lifespan. One of the consequences for longevity is the high prevalence of aging-related chronic disorders such as cardiovascular diseases, cancer and metabolic abnormalities. As the composition of aging population is raising in western countries, heart failure remains the number one cause of death with a more severe impact in the elderly. Obesity and aging are the most critical risk factors for increased susceptibility to heart failure in developing and developed countries. Numerous population-based and experimental data have depicted a close relationship between the age-related diseases and obesity. There is an overall agreement that obesity is causally linked to the development of cardiovascular disorders and severe premature cardiac aging. Accumulating evidence indicates that autophagy plays an important role in obesity, cardiac aging and diseases. In this review, we will focus on the role of autophagy in obesity-related cardiac aging and diseases, and how it regulates age-dependent changes in the heart.     

Regulation of the lysosome by sphingolipids: Potential role in aging

Sphingolipids are a class of bioactive complex lipids that have been closely associated with aging and aging-related diseases. However, the mechanism through which sphingolipids control aging has long been a mystery. Emerging studies reveal that sphingolipids exert tight control over lysosomal homeostasis and function, as evidenced by sphingolipid-related diseases, including but not limited to lysosomal storage disorders. These diseases are defined by primary lysosomal defects and a few secondary defects such as mitochondrial dysfunction. Intriguingly, recent research indicates that the majority of these defects are also associated with aging, implying that sphingolipid-related diseases and aging may share common mechanisms. We propose that the lysosome is a pivotal hub for sphingolipid-mediated aging regulation. This review discusses the critical roles of sphingolipid metabolism in regulating various lysosomal functions, with an emphasis on how such regulation may contribute to aging and aging-related diseases.     

肠道微生物群在人类健康衰老中的作用机制研究进展北大核心

衰老的特征是组织器官的功能衰退以及衰老相关疾病风险的增加,这给维护和促进健康长寿带来一系列新的挑战。尽管进行了广泛的衰老相关研究,但进展有限。人们越来越意识到肠道微生物群的结构和功能积极参与了衰老过程。肠道微生物群紊乱表现为许多与年龄相关的肠外器官轴的衰老。肠道微生物群可以被调节,这暗示了通过肠道微生物群抗衰老是一个可以实现的重要目标。本综述总结了肠道微生物群在不同年龄段中的动态演替,这种动态的肠道微生物群从胎儿到出生和婴儿期开始迅速发展,从断奶期到幼儿期迅速变化,然后建立稳定的成年人菌群,直到随着年龄增长最后发生衰退;肠道微生物群与肠外器官轴(大脑、心脏、肝脏、胰腺、肌肉、皮肤和骨骼)衰老相关疾病,以及通过饮食、粪菌移植和微生态制剂调节肠道微生物群靶向抗衰老的研究进展,以期为调控肠道微生物群抗衰老研究提供参考。     

端粒生物学与胸主动脉瘤的研究进展

摘要：随着细胞生理性衰老,端粒（telomere）即染色体末端的重复性 DNA 序列会出现累积性损伤,而血管内皮细胞、平滑肌细胞衰老相关的端粒损伤和修复则被认为是退行性血管疾病发病的分子机制之一。胸主动脉瘤为老年人群中的重要致死性疾病之一,与衰老相关的退行性变在其中发挥着重要的作用。因此本文主要对端粒/端粒酶在胸主动脉瘤发病和进展中的作用做了概述,总结了血管病理学中端粒/端粒酶的调控机制。     

综述: 人类早衰症的发病机制及干预方法

衰老是一种在细胞和组织水平逐渐发生功能衰退的过程.早衰症是一类罕见的人类遗传性疾病,以加速衰老为特征.对早衰症的研究有助于理解人类衰老的生理过程,对衰老相关疾病的防治具有借鉴意义.成人早衰症和儿童早衰症是两种著名的人类早衰症,本文将综述这两种早衰症的发病机制及干预方法.     

The role of PGC-1 coactivators in aging skeletal muscle and heart

Aging is the progressive decline in cellular, tissue, and organ function. This complex process often manifests as loss of muscular strength, cardiovascular function, and cognitive ability. Mitochondrial dysfunction and decreased mitochondrial biogenesis are believed to participate in metabolic abnormalities and loss of organ function, which will eventually contribute to aging and decreased lifespan. In this review, we discuss what is currently known about mitochondrial dysfunction in the aging skeletal muscle and heart. We focused our discussion on the role of PGC-1 coactivators in the regulation of mitochondrial biogenesis and function and possible therapeutic benefits of increased mitochondrial biogenesis in compensating for mitochondrial dysfunction and circumventing aging and aging-related diseases.     

Whole-genome methylation analysis of aging human tissues identifies age-related changes in developmental and neurological pathways

Age-associated changes in the DNA methylation state can be used to assess the pace of aging. However, it is not understood what mechanisms drive these changes and whether these changes affect the development of aging phenotypes and the aging process in general. This study was aimed at gaining a more comprehensive understanding of aging-related methylation changes across the whole genome, and relating these changes to biological functions. It has been shown that skeletal muscle and blood monocytes undergo typical changes with aging. Using whole-genome bisulfite sequencing, we sought to characterize the genome-wide changes in methylation of DNA derived from both skeletal muscle and blood monocytes, and link these changes to specific genes and pathways through enrichment analysis. We found that methylation changes occur with aging at the locations enriched for developmental and neuronal pathways regulated in these two peripheral tissues. These results contribute to our understanding of changes in epigenome in human aging.     

Complement C1q activates canonical Wnt signaling and promotes aging-related phenotypes

Wnt signaling plays critical roles in development of various organs and pathogenesis of many diseases, and augmented Wnt signaling has recently been implicated in mammalian aging and aging-related phenotypes. We here report that complement C1q activates canonical Wnt signaling and promotes aging-associated decline in tissue regeneration. Serum C1q concentration is increased with aging, and Wnt signaling activity is augmented during aging in the serum and in multiple tissues of wild-type mice, but not in those of C1qa-deficient mice. C1q activates canonical Wnt signaling by binding to Frizzled receptors and subsequently inducing C1s-dependent cleavage of the ectodomain of Wnt coreceptor low-density lipoprotein receptor-related protein 6. Skeletal muscle regeneration in young mice is inhibited by exogenous C1q treatment, whereas aging-associated impairment of muscle regeneration is restored by C1s inhibition or C1qa gene disruption. Our findings therefore suggest the unexpected role of complement C1q in Wnt signal transduction and modulation of mammalian aging.     

Mitochondrial sirtuins,metabolism, and aging

Maintaining metabolic homeostasis is essential for cellular and organismal health throughout life. Multiple signaling pathways that regulate metabolism also play critical roles in aging, such as PI3K/AKT, mTOR, AMPK, and sirtuins (SIRTs). Among them, sirtuins are known as a protein family with versatile functions, such as metabolic control, epigenetic modification and lifespan extension. Therefore, by understanding how sirtuins regulate metabolic processes, we can start to understand how they slow down or accelerate biological aging from the perspectives of metabolic regulation. Here, we review the biology of SIRT3, SIRT4, and SIRT5, known as the mitochondrial sirtuins due to their localization in the mitochondrial matrix. First, we will discuss canonical pathways that regulate metabolism more broadly and how these are integrated with aging regulation. Then, we will summarize the current knowledge about functional differences between SIRT3, SIRT4, and SIRT5 in metabolic control and integration in signaling networks. Finally, we will discuss how mitochondrial sirtuins regulate processes associated with aging and aging-related diseases.     

Mechanical strain modulates age-related changes in the proliferation and differentiation of mouse adipose-derived stromal cells

Background  

Previous studies on the effects of aging in human and mouse mesenchymal stem cells suggest that a decline in the number and differentiation potential of stem cells may contribute to aging and aging-related diseases. In this report, we used stromal cells isolated from adipose tissue (ADSCs) of young (8-10 weeks), adult (5 months), and old (21 months) mice to test the hypothesis that mechanical loading modifies aging-related changes in the self-renewal and osteogenic and adipogenic differentiation potential of these cells.     

Aging selectively decreases oxidative capacity in rat heart interfibrillar mitochondria

Mitochondrial-derived oxidative injury contributes to cellular aging as well as to reperfusion-induced tissue damage. While the aging-heart suffers greater tissue damage following ischemia and reperfusion than the adult heart, the occurrence of aging-related alterations in mitochondrial oxidative metabolism in the elderly heart has remained uncertain. We determined if aging altered oxidative metabolism in either of the two populations of cardiac mitochondria, subsarcolemmal mitochondria (SSM) that reside beneath the plasma membrane or interfibrillar mitochondria (IFM) located between the myofibrils. SSM and IFM were isolated from 6-month adult and 24- and 28-month elderly Fischer 344 rat hearts. Aging-related alterations were limited to IFM, while SSM remained unaffected. Aging decreased the rate of oxidative phosphorylation in IFM, including when stimulated by electron donors specific for cytochrome oxidase. Cytochrome oxidase enzyme activity was decreased in IFM from aging hearts, while activity in SSM remained similar to adult controls. These findings allow future studies of aging-related decrements in oxidative function to focus upon IFM, while SSM provide an inherent control group of mitochondria that are free of aging-related alterations in oxidative function. The selective alteration of IFM during aging raises the possibility that the consequences of aging-induced mitochondrial dysfunction will be enhanced in specific subcellular regions of the senescent myocyte.     

G-MDSCs promote aging-related cardiac fibrosis by activating myofibroblasts and preventing senescence

Aging is one of the most prominent risk factors for heart failure. Myeloid-derived suppressor cells (MDSCs) accumulate in aged tissue and have been confirmed to be associated with various aging-related diseases. However, the role of MDSCs in the aging heart remains unknown. Through RNA-seq and biochemical approaches, we found that granulocytic MDSCs (G-MDSCs) accumulated significantly in the aging heart compared with monocytic MDSCs (M-MDSCs). Therefore, we explored the effects of G-MDSCs on the aging heart. We found that the adoptive transfer of G-MDSCs of aging mice to young hearts resulted in cardiac diastolic dysfunction by inducing cardiac fibrosis, similar to that in aging hearts. S100A8/A9 derived from G-MDSCs induced inflammatory phenotypes and increased the osteopontin (OPN) level in fibroblasts. The upregulation of fibroblast growth factor 2 (FGF2) expression in fibroblasts mediated by G-MDSCs promoted antisenescence and antiapoptotic phenotypes of fibroblasts. SOX9 is the downstream gene of FGF2 and is required for FGF2-mediated and G-MDSC-mediated profibrotic effects. Interestingly, both FGF2 levels and SOX9 levels were upregulated in fibroblasts but not in G-MDSCs and were independent of S100A8/9. Therefore, a novel FGF2-SOX9 signaling axis that regulates fibroblast self-renewal and antiapoptotic phenotypes was identified. Our study revealed the mechanism by which G-MDSCs promote cardiac fibrosis via the secretion of S100A8/A9 and the regulation of FGF2-SOX9 signaling in fibroblasts during aging.Subject terms: Senescence, Cardiovascular diseases     

Cellular and molecular mechanisms of muscle atrophy

Skeletal muscle is a plastic organ that is maintained by multiple pathways regulating cell and protein turnover. During muscle atrophy, proteolytic systems are activated, and contractile proteins and organelles are removed, resulting in the shrinkage of muscle fibers. Excessive loss of muscle mass is associated with poor prognosis in several diseases, including myopathies and muscular dystrophies, as well as in systemic disorders such as cancer, diabetes, sepsis and heart failure. Muscle loss also occurs during aging. In this paper, we review the key mechanisms that regulate the turnover of contractile proteins and organelles in muscle tissue, and discuss how impairments in these mechanisms can contribute to muscle atrophy. We also discuss how protein synthesis and degradation are coordinately regulated by signaling pathways that are influenced by mechanical stress, physical activity, and the availability of nutrients and growth factors. Understanding how these pathways regulate muscle mass will provide new therapeutic targets for the prevention and treatment of muscle atrophy in metabolic and neuromuscular diseases.     

JAK-STAT信号通路与衰老及衰老相关疾病

老龄化是许多慢性疾病的首要危险因素.如果老年人的疾病预防水平得不到大幅度的提高,不仅会影响老年人及家庭成员的生活质量,还会导致国家的经济以及医疗资源严重的匮乏.因此,如何延缓衰老已成为全世界关注的焦点.近些年,对衰老相关的机制也进行了广泛的研究,其中JAK-STAT信号通路吸引了大量学者的眼球.但是对JAK-STAT信...     

Deciphering RNA m6A regulation in aging: Perspectives on current advances and future directions

N⁶-methyladenosine (m⁶A) is a dynamic and reversible RNA modification that has emerged as a crucial player in the life cycle of RNA, thus playing a pivotal role in various biological processes. In recent years, the potential involvement of RNA m⁶A modification in aging and age-related diseases has gained increasing attention, making it a promising target for understanding the molecular mechanisms underlying aging and developing new therapeutic strategies. This Perspective article will summarize the current advances in aging-related m⁶A regulation, highlighting the most significant findings and their implications for our understanding of cellular senescence and aging, and the potential for targeting RNA m⁶A regulation as a therapeutic strategy. We will also discuss the limitations and challenges in this field and provide insights into future research directions. By providing a comprehensive overview of the current state of the field, this Perspective article aims to facilitate further advances in our understanding of the molecular mechanisms underlying aging and to identify new therapeutic targets for aging-related diseases.     

主要干性基因与衰老相关基因表达水平的相互拮抗关系

目前广泛地利用传统的体细胞衰老理论和方法对成体干细胞衰老进行研究,忽视了成体干细胞特有的自我更新功能和相应的干性基因的作用.干性基因的下调可能是导致间充质干细胞衰老的主要原因.通过查阅相关资料发现主要干性基因与衰老相关基因表达水平的相互拮抗关系,这体现在以下4个方面:a.干细胞衰老伴随着干性基因的下调;b.干性基因表达抑制细胞的衰老;c.干性基因抑制衰老相关基因的表达;d.抑制衰老相关基因促进干性基因的表达.干性基因与衰老相关基因的表达水平存在相互拮抗关系,这为成体干细胞衰老可能源于成体干细胞的干性降低的观点提供了坚实的分子基础.     

Accelerated aging phenotype in mice with conditional deficiency for mitochondrial superoxide dismutase in the connective tissue

The free radical theory of aging postulates that the production of mitochondrial reactive oxygen species is the major determinant of aging and lifespan. Its role in aging of the connective tissue has not yet been established, even though the incidence of aging-related disorders in connective tissue-rich organs is high, causing major disability in the elderly. We have now addressed this question experimentally by creating mice with conditional deficiency of the mitochondrial manganese superoxide dismutase in fibroblasts and other mesenchyme-derived cells of connective tissues in all organs. Here, we have shown for the first time that the connective tissue-specific lack of superoxide anion detoxification in the mitochondria results in reduced lifespan and premature onset of aging-related phenotypes such as weight loss, skin atrophy, kyphosis (curvature of the spine), osteoporosis and muscle degeneration in mutant mice. Increase in p16(INK4a) , a robust in vivo marker for fibroblast aging, may contribute to the observed phenotype. This novel model is particularly suited to decipher the underlying mechanisms and to develop hopefully novel connective tissue-specific anti-aging strategies.