随着人口老龄化问题的加剧,延长老年人的健康寿命和防治衰老相关性疾病已成为全球公共健康问题面临的重大挑战。组织中衰老细胞的大量积累是引起机体衰老和多种老年性疾病发生的重要原因。研究显示,衰老细胞向胞外分泌多种各类因子,包括多种细胞因子和趋化因子,生长因子以及蛋白酶等,衰老细胞的这种特性被称为衰老相关分泌表型(senescence-associated secretory phenotype, SASP)。目前人们普遍认为,SASP与老年性疾病的发生发展密切相关,因此成为国际衰老领域研究的热点。本专栏重点关注了SASP表达的调控机制及干预手段,衰老细胞的选择性清除以及CRISPR筛选工具在衰老研究中的应用等前沿领域,特邀长期从事相关研究领域的一线科研工作者,结合当前研究进展和他们自己的相关工作撰写了较为系统的综述文章,以期为相关领域的研究者提供参考。
本专栏3篇文章是由国内长期从事衰老研究的3个课题组结合各自研究组的工作积累和当前相关研究进展撰写完成的综述文章。中国科学院动物研究所刘光慧研究员课题组长期致力于细胞衰老分子机制研究以及机体衰老标志物的挖掘及其应用。“CRISPR筛选在衰老研究中的应用”一文对CRISPR基因筛选工具的研究进展及其在衰老研究中的应用进行了总结。阐释了CRISPR相关基因操纵工具有望成为延缓衰老和干预衰老相关疾病的重要手段。北京大学衰老研究中心陈军副教授和毛泽斌教授课题组长期从事衰老与肿瘤的相关性研究。“衰老相关分泌表型”一文总结了衰老相关分泌表型的组成,指出其组成具有高度的异质性和动态性。本文在转录、转录后、翻译、翻译后修饰、表观遗传等多种水平总结了其调控机制。之后总结了其多种生物学功能,包括其在抑制肿瘤、组织修复和胚胎发育中的有益作用,以及在诱导细胞衰老、促进肿瘤发生发展、衰老相关疾病和机体衰老中的有害作用。在应用上,本文概述了通过靶向清除衰老细胞和抑制衰老相关分泌表型来干预衰老和衰老相关疾病的治疗方法。清华大学王钊教授课题组长期从事药物的抗衰老作用研究。“衰老细胞清除策略与CAR细胞疗法在抗衰老治疗中的应用”一文从细胞衰老和免疫衰老的特征入手,进而总结了目前衰老的非靶向干预方法和靶向衰老细胞清除的干预方法及其优缺点,并重点综述了靶向衰老细胞的免疫治疗清除策略,相信对相关研究人员会有所裨益。
希望本专栏文章使读者更好地了解目前抗衰老研究领域的新方法新技术,以及所面临的新挑战,进而激发更多的读者,特别是青年学生对延缓人类寿命和防治老年性疾病研究的热情。

Skeletal muscle aging is a biological process that occurs as the body ages, characterized by mass loss and functional decline. The involvement of metallomics, particularly copper metallomics, is pivotal in understanding its functional roles. Copper metallomics manifests as copper overload with aging. It triggers toxic effects that activate apoptosis, pyroptosis, ferroptosis, cuproptosis and also promote α-synuclein aggregation. The related signaling cascades can eventually promote metabolic turbulence and the loss of proteins, mitochondria, satellite cells and other cell contents in senescent myofibers, while causing the degeneration and abnormality of neuromuscular junctions. This is a new physiopathgical mechanism of aging-related atrophy in skeletal muscles. Here we firstly review the molecular biological functions of copper in the regulatory networks of aging-related atrophy for skeletal muscles, the potential mechanisms of copper overload in senescent skeletal muscles, and the novel role of multiple signaling transduction pathways associated with copper overload-induced cell death modes comprising apoptosis, pyroptosis, ferroptosis and cuproptosis in aging-related atrophy for skeletal muscles. We aim to provide potential molecular targets and option choices for clinically applying copper chelation to improve and treat aging-related atrophy in skeletal muscles.

Ferroptosis is a novel programmed cell death pathway, which was first proposed by Dixon in 2012. It is characterized by intracellular iron overload and oxidative damage. Aging is an inevitable process characterized by the gradual deterioration of various physiological functions, which results from multiple factors. During the aging process,physiological functions of tissues and organs become dysregulated and deteriorated, leading to increase drisk of disease and death, such as neurodegenerative diseases, cancer and cardiovascular diseases. Recently, some studies have shown that there is an inextricable link between ferroptosis and aging. Aging processes of certain cell lines and age-related diseases exhibit some properties of ferroptosis. However, it remains unclear whether there is a causal relationship between ferroptosis and aging.In this review, we summarize the features of ferroptosis and aging, and point out the common characteristics in ferroptosis and aging, such as DNA damage, redox homeostasis imbalance, mitochondrial dysfunction and so on. In addition, this review discusses the relationship between ferroptosis and some age-related diseases, including Parkinson’s disease, Alzheimer’s disease, and some types of cancers. This review summarizes the potential link between ferroptosis and aging, provides a novel perspective on the fundamental research on ferroptosis and aging, aiming for valuable insights in the treatment of related diseases.

Recent studies have shown that miR-155-5p can induce senescence of bone marrow stem cells by affecting mitochondrial fission, but whether it can affect the senescence of umbilical cord mesenchymal stem cells and its mechanism are still unclear. To investigate its effect and mechanism, umbilical cord mesenchymal stem cells were obtained from the umbilical cord tissue and passed to the P10 generation. The expression of miR-155-5p was found to be significantly increased in the P10 generation by RT-qPCR (P < 0.001). The expression of forkhead box O3 (FOXO3)and autophagy-related genes LC3 and Beclin-1 were decreased in P2 generation umbilical cord mesenchymal stem cells when overexpressing miR-155-5p. Prediction by targetscan online database suggests that FOXO3’s 3′ UTR region has a specific binding site to miR-155-p. Dual luciferase reporter gene assays confirmed that FOXO3 is one of the target genes of miR-155-5p. Western blotting analysis showed that the expression of FOXO3, p-AMPK, LC3 II/I and Beclin-1 proteins were significantly increased (P<0.01 or 0.001) and the senescence-related proteins p16, p21 and p53 were significantly decreased (P<0.01 or 0.001) when the miR-155-5p inhibitor was transfected into P10 generation umbilical cord mesenchymal stem cells. After staining for β-galactosidase activity, we found that the expression of β-galactosidase was significantly decreased in P10 generation umbilical cord mesenchymal stem cells transfected with miR-155-5p inhibitors (P < 0.01). Gene expression and protein secretion levels of TGF-β, HGF and VEGF were significantly increased in P10 generation umbilical cord mesenchymal stem cells transfected with miR-155-5p inhibitors and their cultured supernatants by RT-qPCR and ELISA, respectively (P<0.05 or 0.01). The bronchopulmonary dysplasia model of neonatal rat was treated with intravenous injection of umbilical cord mesenchymal stem cells. We found that the P10 generation umbilical cord mesenchymal stem cells transfected with miR-155-5p inhibitors significantly enhanced the survival rate (P<0.05) and significantly improved the pathological lung injury in neonatal rats. In conclusion, miR-155-5p affects umbilical cord mesenchymal stem cell senescence through negative regulation of the FOXO3 gene, and miR-155-5p inhibitors reversed umbilical cord mesenchymal stem cell senescence by increasing cellular autophagy through the FOXO3/AMPK signaling pathway.

Multiple organs are physiologically and pathologically interconnected during aging, and the brain plays a central role in this process. There is a direct two-way communication between the brain and the gut called “brain-gut interaction”, which is of great significance for the study of aging, and the molecular mechanism remains to be further studied. The aim of this study is to explore the mechanism of aging in the context of brain-gut interaction. The results of general physical signs of mice showed that the amount of exercise decreased, body weight and food intake decreased significantly in aged mice (P<0.001, P<0.05). The thymus index of aged mice was significantly lower than that of normal mice (P<0.05), and the thymic pathological results showed that the thymic cortex of aging mice was thinner, the boundary between medulla and cortex was blurred, and the cells were loosely arranged. Metabolomics analysis revealed 317 differential metabolites in feces and 100 differential metabolites in hippocampus. The results of microbiome showed that Bacteroidetes and Firmicutes were the dominant phyla of gut microbiota. Bacteroidetes showed an upward trend and Firmicutes showed a downward trend after aging. KEGG pathway results showed that 26 metabolic pathways were related to the study of aging, among which galactose metabolism, ABC transporter and purine metabolism were of great significance for the brain-gut interaction. The results of Spearman correlation analysis of the three groups showed that the types of metabolites involved were mainly lipids and lipid-like molecules and organic acids and derivatives, and the gut microbiota involved were mainly Bacteroidetes and Firmicutes. In conclusion, the present study demonstrated that the synergistic changes between brain and gut in aging mice were related to the mechanism of aging, which provided new insights into the mechanism of aging process.

Aging contributes to age-related diseases such as cardiovascular diseases, diabetes, and Alzheimer’s disease, which are characterized by imbalance of protein homeostasis, accumulation of oxidative damage, stem cell failure, altered intercellular communication, chronic inflammation, and microecological disorders. It is well known that hydrogen sulfide(H₂S) is an endogenous gas signaling molecule that widely exists in all kinds of organisms from bacteria to plants and animals. In the human body, H₂S can regulate cell signal transduction through S-sulfhydration modification of proteins at physiological concentrations. Recent studies have found that aging is accompanied by a decrease in the production of endogenous H₂S and a general decline of protein S-sulfhydration. Exogenous H₂S can inhibit body aging. In some age-related diseases such as Alzheimer’s disease, senile myasthenia gravis and osteoporosis, anappropriate amount of exogenous H₂S plays anti-aging effect. This review summarizes the molecular mechanisms of H₂S in antagonizing aging, including inhibition of oxidative stress, inhibition of inflammation, protection of mitochondrial function, maintenance of protein homeostasis and up-regulation of autophagy. We also discuss the issues and frontiers in the anti-aging mechanism of H₂S, so as to provide new ideas for inhibiting aging and the treatment of aging-related diseases.

Along with the social structure of population aging, aging and age-related diseases have become an urgent issue In recent years, researchers have found that stem cells can inhibit inflammation, regulate immune responses, prevent apoptosis of target cells, replace and promote restoration of the damaged parts. Accumulating evidence suggests that the beneficial effects of stem cell therapy are predominantly stem cell-derived exosomes. Exosomes are nano-sized vesicles derived from endocytic membranes and contain biomolecules such as proteins, lipids, RNAs, and DNAs regulating cell-to-cell communications. Exosomes may transfer bioactive molecules to target cells, which in turn cause phenotypic changes and then modulate repair and regenerative programs of various organs. These phenotypic changes arise from several mechanisms, ranging from prevention of apoptosis in recipient cells, induction of target cell proliferation, stimulation of immunomodulatory responses, and reduction of oxidative stresses in target cells to the enhancement of oxygen supply. This review gives a brief introduction to biogenesis, release and signaling of exosomes, and focuses on analysis of the effects of exosomes from different stem cells on skin aging and aging-related diseases (such as cardiovascular diseases, osteoarthritis, osteoporosis, and Alzheimer's disease) in basic research and clinical applications. Although many problems with exosomes in the clinical setting exist, the prospects of basic research to clinical applications are worthy of exploration, which is of great significance for anti-ageing treatment.

Nicotinamide adenine dinucleotide (NAD⁺) is an important coenzyme for redox reactions, making it central to energy metabolism. NAD⁺ is also a cosubstrate for non-redox NAD⁺-dependent enzymes, including Sirtuins, poly-ADP-ribose polymerases (PARPs), and CD38/157 ectoenzymes. NAD⁺has also emerged as a key modulator of cell signaling and survival pathways. Recent works have revealed that Sirtuins catalyze a variety of NAD⁺-dependent reactions, including deacetylation, deacylation and ADP-ribosylation. The catalytic activity of Sirtuins depends on the level of NAD⁺. Therefore, Sirtuins are critical sensors of cell metabolic and redox states. Seven Sirtuins family members (SIRT1-7) have been identified and characterized in mammals, which are involved in various physiological processes such as inflammation, cell growth, circadian rhythm, energy metabolism, neuron function, and stress response. This review summarized the physiological concentration and state of NAD⁺, the biosynthesis pathway of NAD⁺, the biological functions of Sirtuins, especially the relationship between the expression and activity of SIRT1-7 and aging and disease. Furthermore, this review also delineated the mechanism of NAD⁺and Sirtuins-dependent aging. The level of NAD⁺ decreases with age, leading to the decline of Sirtuins activity, especially SIRT1, SIRT3, and SIRT6, causing defects in nuclear and mitochondrial functions, and the occurrence of aging and age-related diseases. The study showed that NAD⁺ precursor supplement can rapidly improve the NAD⁺ level and Sirtuins activity, which is an effective anti-aging intervention, providing hope to aging societies worldwide.

Osteoarthritis (OA) is one of the most common geriatric motor system diseases in the clinical practice. Aging, whose hallmark is cellular senescence, is an important factor leading to the occurrence and development of OA, but its exact role in the pathological development of OA is not completely clear. Studies have proved that targeting senescence can effectively treat aging-related diseases. In this study, the heterozygous mouse model of Cdkn2a-e (Luc-2A-tdTomato-2a-CreerT2-Wpre-PA)1 was established by the CRISPR/Cas9 technique. The expression of Cdkn2a (p16, p16INK4a), a classical marker of senescence, can be traced in vivo in mice. We then utilized anterior cruciate ligament transection (ACLT) to induce OA in Cdkn2a mice, and we hope to verify the relationship between aging and the occurrence and development of OA and visualize aging changes during OA development through the mice model. In this study, 10-12 weeks old Cdkn2a mice were randomly divided into no surgery control group, sham operation group and ACLT group. OA model was constructed in mice by ACLT operation. After surgery for 4 weeks, animals were collected for fluorescence imaging detection in vivo, which showed that local fluorescence expression of Cdkn2a increased in knee joints of mice in the ACLT group four weeks after surgery (P<0.05). The Safranin O-Fast Green Staining of mouse knee tissue sections showed degeneration of the knee cartilage in the ACLT group at 4 weeks after surgery (P<0.05). Immunohistochemical staining of Cdkn2a was performed on the knee tissue of mice. Compared with the other two groups, Cdkn2a staining on the cartilage surface of the knee tissue of mice in the ACLT group was deeper. The results showed that the OA model induced by surgery showed local aging, which further verified the relationship between aging and OA. At the same time, the Cdkn2a tracer mouse model can reflect the aging progress of mice in vivo, with combination of imaging examinations, so that the occurrence and progress of the relationship between aging and OA can be observed in real time. This heterozygous mouse model of Cdkn2a-e(Luc-2A-tdTomato-2a-CreerT2-Wpre-PA)1 is not only useful for mechanism research of aging and OA diseases, but also beneficial for finding more potential therapy targets to OA and aging.

Exosomes are small vesicles with double lipid membranes secreted by cells into the extracellular space and body fluids. Exosomes contain genetic materials, proteins, lipids and so on, and thus unveil a novel mechanism of intercellular communication. CircRNAs, which function as “microRNA sponges”, are emerging regulator for gene expression. CircRNAs exist in a variety of cells, thereby widely affect the life process of cells through different regulatory networks at the pre- and post-transcriptional levels. The critical role of exosomal circRNAs in the physiological and pathological processes has also attracted increasing attention. Aging process is driven by various contributing factors, which inevitably impairs tissue function and increases susceptibility to disease and death. It is demonstrated that the presence and progressive accumulation of senescent cells contributes to overall organism aging. Senescent cells aggregated in aging tissues have been considered as a causal factor for aging-related disorders. Recent studies have suggested that exosomal circRNAs might act as the senescence-associated secretory phenotype (SASP)of senescent cells and play an important role in the aging process and the occurrence of aging-related diseases. This review introduced the occurrence of exosomal circRNAs in detail, and summarized the research advances of exosomal circRNAs in aging and aging-related diseases. This study may provide references for the further research and clinical application of exosomal circRNAs.

p21-activated kinase 5 (PAK5), a kind of the PAK family of serine/threonine kinases, modulates various cellular processes, including cytoskeletal remodeling, cell proliferation, migration and metastasis. Although studies have suggested that PAK5 is a key regulator of breast cancer progression, the link of PAK5 to senescence has not been reported yet. In this study, the CRISPR/Cas9 lentivirus infection method was used to construct two PAK5 stably knockdown cell lines of human breast cancer (MDA-MB-231 and BT474). The effect of PAK5 knockdown on the proliferation of breast cancer cells was detected by CCK-8 and clone formation assays. The effect of PAK5 knockdown on cell cycle was detected by flow cytometry. The effect of PAK5 knockdown on cell senescence was observed by β-galactosidase staining. Western blotting was performed to detect the expression of senescence-related proteins including p53, p21 and p16 in breast cancer cells. Cells were treated by CHX and MG132 to explore the possible mechanism of PAK5 regulating p53 protein expression. The results showed that knockdown of PAK5 inhibited cell proliferation and blocked cells in the G₀/G₁ phase (P＜0.05); Moreover, knockdown of PAK5 promoted cell senescence by upregulating the expression of cellular senescence-related proteins p53, p21 and p16 (P<0.05). Further studies have proved that PAK5 may degrade p53 by ubiquitination. These findings suggest that knockdown of PAK5 can inhibit breast cancer cell proliferation and promote cell senescence, providing potential targets for the treatment of breast cancer.

Splicing factor Heterogeneous Nuclear Ribonucleoprotein A2/B1 (HNRNPA2B1) is associated with mouse lifespan and human longevity. It also plays a causal role in cancer development. However, whether it participates in cellular senescence, a biological process that contributes to individual aging and inhibits cancer, remains unknown. Here, we report that HNRNPA2B1 showed significantly increased expression in various cancer types while consistently decreased expression in multiple cellular senescence models. Knocking down HNRNPA2B1 in cancer cells leads to a series of senescence-associated phenotypes. In line with its function as a splicing factor, HNRNPA2B1 downregulation causes alternative splicing changes in over one thousand genes, including those known to have a causal role in senescence. Our results also suggests that the E2F transcription factor 1 (E2F1) could regulate the expression of HNRNPA2B1, and E2F1-HNRNPA2B1 may be a new regulatory axis functioning in both cancer and cellular senescence, which might also have potential medical implications for cancer therapies.

With the advent of aging society, the effects of aging on all aspects of the body are attracting more and more attention. Among them, the increasing incidence of chronic wounds in the elderly not only affects the quality of the elderly’s life significantly, but also brings a heavy medical burden on society. Delayed and poor wound healing increases the possibility of severe infections. To find out a solution for infection and chronic wounds, it is necessary to clarify the specific mechanisms of wound healing and possible intervention targets. Wound healing is a complex physiological process in the human body, which involves the coordinated activation of multiple cell types and signaling pathways. The role of senescent cells in wound healing is causing growing attention in recent years. It was thought that wound healing needs to take a longer time in elder people. In recent years, it has been found that senescent cells promote wound healing. So far, the effects of senescent cells on the efficiency and quality of wound healing and its specific mechanism have not been fully clarified. What is certain is that different types of senescent cells and even different subtypes of the same senescent cells play different roles in fast and chronic wound healing. It is not only the heterogeneity of the senescent cell itself, but also the difference in the surrounding microenvironment that determines the effect of senescent cells on wound healing. The study of its mechanism is helpful to find a way to promote the healing of wounds. It is worth noting that senescent cells themselves may also induce poor wound prognosis, such as chronic wounds, inflammation and decreased anti-infection ability. Therefore, the ideal treatment strategy to apply senescent cells will be a comprehensive plan that maximizes the efficiency and quality of wound healing, while minimizing the risk of senescent cells itself becoming an inducement for chronic wounds.

Cell senescence is a ubiquitous phenomenon in biology. Tumor cells are a kind of cells that can proliferate with impunity and break through the Hayflick limit, and cancer is also considered as a disease related to cell senescence. From an evolutionary perspective, senescence is beneficial to organisms and can lead to irreversible cell cycle arrest, which is considered to be an autonomous tumor suppression mechanism. In malignant proliferating cancer cells, the cell senescence can be triggered by a variety of cell-intrinsic and extrinsic stimuli, including telomere shortening, DNA damage, oxidative stress and exposure to chemotherapeutic agents. Senescent cells can secrete dozen of factors to maintain their own senescence phenotype and affect the growth of surrounding cells. This characteristic is called senescence-associated secretory phenotype (SASP). The induction of senescence in cancer cells is considered to be an emerging means for cancer therapy. This paper reviews the morphological features, molecular markers and detection methods of cell senescence, signal transduction pathways (p53-p21, p16-pRB and PTEN-p27), as well as the relationship between cell senescence and tumorigenesis. Meanwhile we offer an extensive description of current potential pharmacological interventions for pro-senescence therapy for cancer. This article lays a foundation for further elucidating new ideas and new directions for future research.