BACKGROUND: Senescent human skin primary fibroblast (FB) models have been established for studying aging-related, proliferative, and inflammatory skin diseases. The aim of this study was to compare the transcriptome characteristics of human primary dermal FBs from children and the elderly with four senescence models. METHODS: Human skin primary FBs were obtained from healthy children (FB-C) and elderly donors (FB-E). Senescence models were generated by ultraviolet B irradiation (FB-UVB), D-galactose stimulation (FB-D-gal), atazanavir treatment (FB-ATV), and replication exhaustion induction (FB-P30). Flow cytometry, immunofluorescence staining, real-time quantitative polymerase chain reaction, co-culturing with immune cells, and bulk RNA sequencing were used for systematic comparisons of the models. RESULTS: In comparison with FB-C, FB-E showed elevated expression of senescence-related genes related to the skin barrier and extracellular matrix, proinflammatory factors, chemokines, oxidative stress, and complement factors. In comparison with FB-E, FB-UVB and FB-ATV showed higher levels of senescence and expression of the genes related to the senescence-associated secretory phenotype (SASP), and their shaped immune microenvironment highly facilitated the activation of downstream immune cells, including T cells, macrophages, and natural killer cells. FB-P30 was most similar to FB-E in terms of general transcriptome features, such as FB migration and proliferation, and aging-related characteristics. FB-D-gal showed the lowest expression levels of senescence-related genes. In comparisons with the single-cell RNA sequencing results, FB-E showed almost complete simulation of the transcriptional spectrum of FBs in elderly patients with atopic dermatitis, followed by FB-P30 and FB-UVB. FB-E and FB-P30 showed higher similarity with the FBs in keloids. CONCLUSIONS Each senescent FB model exhibited different characteristics. In addition to showing upregulated expression of natural senescence features, FB-UVB and FB-ATV showed high expression levels of senescence-related genes, including those involved in the SASP, and FB-P30 showed the greatest similarity with FB-E. However, D-galactose-stimulated FBs did not clearly present aging characteristics.
Humans ; Fibroblasts/drug effects* ; Cellular Senescence/physiology* ; Skin/metabolism* ; Child ; Transcriptome/genetics* ; Aged ; Ultraviolet Rays ; Cells, Cultured ; Galactose/pharmacology*

Acute kidney injury (AKI) affects more than 20% of hospitalized patients and is a significant contributor to morbidity and mortality, primarily due to ischemia-reperfusion injury (IRI), which is one of the leading causes of AKI. IRI not only exacerbates the immediate impact of AKI but also facilitates its progression to chronic kidney disease (CKD) and, in cases of preexisting CKD, to end-stage renal disease (ESRD). One of the critical pathological processes associated with IRI-AKI is cellular senescence, characterized by an irreversible arrest in the cell cycle, morphological and chromatin organization changes, altered transcriptional and metabolic profiles, and the development of a hypersecretory phenotype known as the senescence-associated secretory phenotype (SASP). The SASP amplifies senescence signals in surrounding normal cells through senescence-related pathways, contributing to tissue damage, fibrosis, and chronic inflammation. This review provides an overview of the defining features of senescent cells and explores the fundamental mechanisms underlying senescent cell generation following IRI. We elucidate the pivotal roles of cellular senescence in the transition from IRI-AKI to chronic kidney injury. Furthermore, we discuss emerging therapies targeting cellular senescence, including senolytics and senomorphics, which have shown promising results in both preclinical and clinical settings. These therapies position cellular senescence as a crucial target for the treatment of IRI in the kidneys. Additionally, advancements in single-cell sequencing technology and artificial intelligence-assisted drug screening are expected to accelerate the discovery of novel senescent biomarkers and synotherapeutics, paving the way for optimized and personalized therapeutic interventions.
Humans ; Cellular Senescence/physiology* ; Reperfusion Injury/pathology* ; Acute Kidney Injury/pathology* ; Animals ; Kidney/metabolism* ; Senescence-Associated Secretory Phenotype/physiology*

Cellular senescence, stable cell cycle arrest that can be triggered in normal cells in response to various intrinsic and extrinsic stressors, has been highlighted as one of the most important mechanisms involved in kidney diseases. It not only serves as a fundamental biological process promoting normal organogenesis and successful wound repair but also contributes to organ dysfunction, tissue fibrosis, and the generalized aging phenotype. Moreover, senescent cells exhibit reduced regenerative capacity, which impairs renal function recovery from injuries. Importantly, senescent cells are involved in immune regulation via secreting a diverse array of proinflammatory and profibrotic factors known as senescence-associated secretory phenotype (SASP) with autocrine, paracrine, and endocrine activities. Thus, eliminating detrimental senescent cells or inhibiting SASP production holds great promise for developing innovative therapeutic strategies for kidney diseases. In this review, we summarize the current knowledge of the intricate mechanisms and hallmarks of cellular senescence in kidney diseases and emphasize novel therapeutic targets, including epigenetic regulators, G protein-coupled receptors, and lysosome-related proteins. Particularly, we highlight the recently identified senotherapeutics, which provide new therapeutic strategies for treating kidney diseases.
Humans ; Cellular Senescence/genetics* ; Kidney Diseases/pathology* ; Senescence-Associated Secretory Phenotype/physiology* ; Animals ; Epigenesis, Genetic/physiology*

Virus-induced senescence (VIS) is a significant biological phenomenon, which is associated with declining immune function, accelerating aging process and causing aging-related diseases. A variety of common viruses, including RNA viruses (such as SARS-CoV-2), DNA viruses (such as herpesviruses and hepatitis B virus), and prions can cause VIS in host cells. The primary mechanisms include abnormal activation of the cGAS-STING signaling pathway, DNA damage response, and potential correlations with the integrated stress response due to intracellular phase separation. Viral infection and cellular senescence influence each other: cellular senescence serves as a defense to restrict viral replication and transmission, while some viruses exploit cellular senescence to enhance their infectivity and replication. Understanding the mechanisms of VIS is conducive to the development of therapeutic strategies for viral infections and promotion of healthy aging. However, there is lack of research on therapeutic targets and drug development in this field so far. Although senolytics may be effective for anti-senescent cells therapy, their efficacy for VIS needs evidence from further clinical trials. This article reviews the research progress on the connection between viral infection and cellular senescence, to provide insights for the prevention and treatment of aging related diseases.
Humans ; Cellular Senescence/physiology* ; Virus Diseases/physiopathology* ; Signal Transduction ; Nucleotidyltransferases/metabolism* ; DNA Damage ; Virus Replication ; COVID-19 ; Membrane Proteins/metabolism* ; SARS-CoV-2

Kidney fibrosis is the final common pathway of virtually all chronic kidney disease (CKD). However, despite great progress in recent years, no targeted antifibrotic therapies have been approved. Epidemiologic, clinical, and molecular evidence suggest that aging is a major contributor to the increasing incidence of CKD. Senescent renal tubular cells, fibroblasts, endothelial cells, and podocytes have been detected in the kidneys of patients with CKD and animal models. Nonetheless, although accumulated evidence supports the essential role of cellular senescence in CKD, the mechanisms that promote cell senescence and how senescent cells contribute to CKD remain largely unknown. In this review, we summarize the features of the cellular senescence of the kidney and discuss the possible functions of senescent cells in the pathogenesis of kidney fibrosis. We also address whether pharmacological approaches targeting senescent cells can be used to retard the the progression of kidney fibrosis.
Humans ; Cellular Senescence/physiology* ; Fibrosis ; Renal Insufficiency, Chronic/pathology* ; Kidney/pathology* ; Animals

Aging is typically associated with decreased musculoskeletal function, leading to reduced mobility and increased frailty. As a hallmark of aging, cellular senescence plays a crucial role in various age-related musculoskeletal diseases, including osteoporosis, osteoarthritis, intervertebral disc degeneration, and sarcopenia. The detrimental effects of senescence are primarily due to impaired regenerative capacity of stem cells and the pro-inflammatory environment created by accumulated senescent cells. The secreted senescence-associated secretory phenotype (SASP) can induce senescence in neighboring cells, further amplifying senescent signals. Although the removal of senescent cells and the suppression of SASP factors have shown promise in alleviating disease progression and restoring musculoskeletal health in mouse models, clinical trials have yet to demonstrate significant efficacy. This review summarizes the mechanisms of cellular senescence in age-related musculoskeletal diseases and discusses potential therapeutic strategies targeting cellular senescence.
Humans ; Cellular Senescence/physiology* ; Musculoskeletal Diseases/pathology* ; Aging/pathology* ; Animals ; Senescence-Associated Secretory Phenotype/physiology* ; Sarcopenia ; Osteoporosis

In recent years, aging and cellular senescence have triggered an increased interest in corresponding research fields. Evidence shows that the complex aging process is involved in the development of many chronic liver diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). In fact, aging has a tremendous effect on the liver, leading to a gradual decline in the metabolism, detoxification and immune functions of the liver, which in turn increases the risk of liver disease. These changes can be based on the aging of liver cells (hepatocytes, liver sinusoidal endothelial cells, hepatic stellate cells, and Kupffer cells). Similarly, patients with liver diseases exhibit increases in the aging phenotype and aging cells, often manifesting as faster physical functional decline, which is closely related to the promoting effect of liver disease on aging. This review summarizes the interplay between MASLD/MASH development and aging, aiming to reveal the complex relationships that exacerbate one another. Moreover, the corresponding schemes for delaying aging or treating diseases are discussed to provide a basis for the development of effective prevention and treatment strategies in the future.
Humans ; Aging/physiology* ; Fatty Liver/metabolism* ; Liver/pathology* ; Cellular Senescence ; Animals

Cellular senescence, an irreversible state of cell cycle arrest characterized by phenotypic changes and a specific secretory profile, plays a dual role in liver health and disease. Under physiological conditions, senescence aids organ repair and regeneration, but its accumulation due to aging or pathological stress significantly contributes to chronic liver diseases, including alcoholic liver disease, metabolic dysfunction-associated steatohepatitis, liver fibrosis, and hepatocellular carcinoma. Senescence is identified by a range of cellular and molecular changes, such as morphological alterations, expression of cell cycle inhibitors, senescence-associated β-galactosidase activity, and nuclear membrane changes. The onset of senescence in organ cells can affect the entire organism, primarily through the senescence-associated secretory phenotype, which has autocrine, paracrine, and endocrine effects on tissue microenvironments. The objective of this review is to offer a contemporary overview of the pathophysiological events involving hepatic senescent cells and to elucidate their role in the onset and progression of liver diseases, particularly through mechanisms like telomere shortening, genomic and mitochondrial DNA damage, and inflammation. Additionally, this review discusses the emerging senolytic therapies aimed at targeting senescent cells to delay or mitigate liver disease progression. The therapeutic potential of these interventions, alongside their safety and effectiveness, highlights the need for further research to refine these approaches and address unresolved problems in the field of hepatic cellular senescence.
Humans ; Cellular Senescence/physiology* ; Liver Diseases ; Animals ; DNA Damage ; Telomere Shortening/physiology*

Chronological aging is the leading risk factor for human diseases, while aging at the cellular level, namely cellular senescence, is the fundamental driving force of organismal aging. The impact of cellular senescence on various life processes, including normal physiology, organismal aging and the progress of various age-related pathologies, has been largely ignored for a long time. However, with recent advancement in relevant fields, cellular senescence has become the core of aging biology and geriatric medicine. Although senescent cells play important roles in physiological processes including tissue repair, wound healing, and embryonic development, they can also contribute to tissue dysfunction, organ degeneration and various pathological conditions during adulthood. Senescent cells exert paracrine effects on neighboring cells in tissue microenvironments by developing a senescence-associated secretory phenotype, thus maintaining long-term and active intercellular communications that ultimately results in multiple pathophysiological effects. This is regarded as one of the most important discoveries in life science of this century. Notably, selective elimination of senescent cells through inducing their apoptosis or specifically inhibiting the senescence-associated secretory phenotype has shown remarkable potential in preclinical and clinical interventions of aging and age-related diseases. This reinforces the belief that senescent cells are the key drug target to alleviate various aging syndromes. However, senescent cells exhibit heterogeneity in terms of form, function and tissue distribution, and even differ among species, which presents a challenge for the translation of significant research achievements to clinical practice in future. This article reviews and discusses the characteristics of senescent cells, current targeting strategies and future trends, providing useful and valuable references for the rapidly blooming aging biology and geriatric medicine.
Humans ; Adult ; Aged ; Cellular Senescence/genetics* ; Aging ; Apoptosis ; Cell Communication ; Wound Healing/physiology*

Although the mTOR-4E-BP1 signaling pathway is implicated in aging and aging-related disorders, the role of 4E-BP1 in regulating human stem cell homeostasis remains largely unknown. Here, we report that the expression of 4E-BP1 decreases along with the senescence of human mesenchymal stem cells (hMSCs). Genetic inactivation of 4E-BP1 in hMSCs compromises mitochondrial respiration, increases mitochondrial reactive oxygen species (ROS) production, and accelerates cellular senescence. Mechanistically, the absence of 4E-BP1 destabilizes proteins in mitochondrial respiration complexes, especially several key subunits of complex III including UQCRC2. Ectopic expression of 4E-BP1 attenuates mitochondrial abnormalities and alleviates cellular senescence in 4E-BP1-deficient hMSCs as well as in physiologically aged hMSCs. These f indings together demonstrate that 4E-BP1 functions as a geroprotector to mitigate human stem cell senescence and maintain mitochondrial homeostasis, particularly for the mitochondrial respiration complex III, thus providing a new potential target to counteract human stem cell senescence.
Mesenchymal Stem Cells/physiology* ; Cellular Senescence ; Homeostasis ; Cell Cycle Proteins/metabolism* ; Adaptor Proteins, Signal Transducing/metabolism* ; Mitochondria/metabolism* ; Electron Transport Complex III/metabolism* ; Humans ; Cells, Cultured