Aging profoundly impacts mesenchymal and hematopoietic lineage cells, including their progenitors-the skeletal stem cells (SSCs) and hematopoietic stem cells (HSCs), respectively. SSCs are crucial for skeletal development, homeostasis, and regeneration, maintaining bone integrity by differentiating into osteoblasts, adipocytes, and other lineages that contribute to the bone marrow (BM) microenvironment. Meanwhile, HSCs sustain hematopoiesis and immune function. With aging, SSCs and HSCs undergo significant functional decline, partly driven by cellular senescence-a hallmark of aging characterized by irreversible growth arrest, secretion of pro-inflammatory factors (senescence associated secretory phenotype, SASP), and impaired regenerative potential. In SSCs, senescence skews lineage commitment toward adipogenesis at the expense of osteogenesis, contributing to increased bone marrow adiposity , reduced bone quality, and osteoporosis. Similarly, aged HSCs exhibit diminished self-renewal, biased differentiation, and heightened inflammation, compromising hematopoietic output and immune function. In this review, we examine the age-related cellular and molecular changes in SSCs and HSCs, their lineage decisions in the aging microenvironment, and the interplay between skeletal and hematopoietic compartments. We also discuss the role of senescence-driven alterations in BM homeostasis and how targeting cellular aging mechanisms may offer therapeutic strategies for mitigating age-related skeletal and hematopoietic decline.

Diacetylmorphine abuse is a major social problem that jeopardizes the world, and abuse can cause serious neurological disorders. Apoptosis plays an important role in neurological diseases. A previous study by our group found that the brain tissue of diacetylmorphine-addicted rats showed severe vacuole-like degeneration and increased apoptosis, but the exact mechanism has not yet been reported. We used TMT technology to sequence the diseased brain tissue of rats, and selected neurofilament light chain (NEFL) and neuritin (NRN1) as the focus of our research. We explore the possible roles and mechanisms played by both. Based on the construction of apoptotic cell model, we used overexpression/silencing lentiviral vectors to interfere with the expression of NEFL in PC12 cells, and the results suggested that NEFL could regulate NRN1 to affect the apoptosis level. To further understand the specific mechanism, we used transmission electron microscopy to observe the ultrastructure of apoptotic cells, and the results showed that compared with the control group, mitochondria in the model group showed obvious vacuolation as well as expansion, a significant increase in the accumulation of ROS, and a significant decrease in the mitochondrial membrane potential; after overexpression/silencing of NEFL, these changes were found to occur along with the alteration of NEFL expression. In summary, we conclude that diacetylmorphine induces neuronal apoptosis, and the specific mechanism is that NEFL regulates the NRN1-mediated mitochondrial pathway to promote apoptosis.

Hepatocellular carcinoma (HCC) is a malignant tumor of the digestive system, influenced by various factors. Due to its subtle clinical symptoms, it delayed results in poor prognosis and limited treatment options. Cellular senescence, characterized by stable growth arrest, is closely linked to tumor proliferation inhibition, making it a promising therapeutic strategy for HCC. However, the role of Dual Specificity Phosphatase 3 (DUSP3) in HCC-induced senescence and its underlying mechanisms remain poorly understood. Our preliminary data show a marked upregulation of DUSP3 in HCC tissues compared to adjacent group. Additionally, DUSP3 knockdown induced senescence in HCC cells in vitro. Further investigation revealed that inhibiting Notch1 reversed the senescence induced by DUSP3 knockdown in these cells. Thus, targeting DUSP3 to activate the Notch1 pathway and induction of senescence as a promising anti-tumor strategy.

The impaired function of periodontal ligament stem cells (PDLSCs) impedes restoration of periodontal tissues. The cGAS-cGAMP-STING pathway is an innate immune pathway that sensing cytosolic double-stranded DNA (dsDNA), but its role in regulating the function of PDLSCs is still unclear. In this study, we found that mitochondrial DNA (mtDNA) was released into the cytoplasm through the mitochondrial permeability transition pore (mPTP) in PDLSCs upon inflammation, which binds to cGAS and activated the STING pathway by promoting the production of cGAMP, and ultimately impaired the osteogenic differentiation of PDLSCs. Additionally, it is first found that inflammation can down-regulate the level of the ATP-binding cassette membrane subfamily member C1 (ABCC1, a cGAMP exocellular transporter) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1, a cGAMP hydrolase), which further aggravated the accumulation of intracellular cGAMP, leading to the persistent activation of the cGAS-STING pathway and thus the impaired the differentiation capacity of PDLSCs. Furthermore, we designed a hydrogel system loaded with a mPTP blocker, an ABCC1 agonist and ENPP1 to promote periodontal tissue regeneration by modulating the production, exocytosis, and clearance of cGAMP. In conclusion, our results highlight the profound effects, and specific mechanisms, of the cGAS-STING pathway on the function of stem cells and propose a new strategy to promote periodontal tissue restoration based on the reestablishment of cGAMP homeostasis.

In-situ tumor vaccination remains challenging due to difficulties in the exposure and presentation of tumor-associated neoantigens (TANs). In view of the central role of lipid metabolism in cell fate determination and tumor-immune cell communication, here we report a photo-controlled lipid metabolism nanoregulator (PLMN) to achieve robust in-situ adjuvant-free vaccination, which is constructed through hierarchically integrating photothermal-inducible arachidonate 15-lipoxygenase (ALOX15)-expressing plasmids, cypate and FIN56 into cationic liposomes. Near-infrared light (NIR) stimulation triggers on-demand ALOX15 editing and causes excessive accumulation of downstream pro-ferroptosis lipid metabolites. PLMN treatment enables efficient TAN release through ferroptosis-dependent membrane perturbation and facilitates their capture and processing by antigen-presenting cells via cationic lipid-mediated TAN enrichment. Meanwhile, upregulation of ALOX15-associated lipid metabolites also enhances M2-to-M1 phenotypic transition of tumor-associated macrophages through regulating tumor-macrophage metabolic crosstalk. PLMN treatment significantly enhance the robustness and durability of adaptive antitumor immunity in vivo, offering an approach for in-situ tumor vaccination in the clinic.

Mitochondria are essential organelles in the life and death of a cell. During apoptosis, mitochondrial outer membrane permeabilisation (MOMP) engages caspase activation and cell death. Under nonlethal apoptotic stress, some mitochondria undergo permeabilisation, termed minority MOMP. Nonlethal apoptotic signalling impacts processes including genome stability, senescence and innate immunity. Recent studies have shown that upon MOMP, mitochondria and consequent signalling can trigger inflammation. We discuss how this occurs, and how mitochondrial inflammation might be targeted to increase tumour immunogenicity. Finally, we highlight how mitochondria contribute to other types of cell death including pyroptosis and ferroptosis. Collectively, these studies reveal critical new insights into how mitochondria regulate cell death, highlighting that mitochondrial signals engaged under nonlethal apoptotic stress have wide-ranging biological functions.

Cancer remains one of the most devastating diseases, severely affecting public health and contributing to economic instability. Researchers worldwide are dedicated to developing effective therapeutics to target cancer cells. One promising strategy involves inducing cellular senescence, a complex state in which cells exit the cell cycle. Senescence has profound effects on both physiological and pathological processes, influencing cellular systems through secreted factors that affect surrounding and distant cells. Among these factors are exosomes, small extracellular vesicles that play crucial roles in cellular communication, development, and defense, and can contribute to pathological conditions. Recently, there has been increasing interest in engineering exosomes as precise drug delivery vehicles, capable of targeting specific cells or intracellular components. Studies have emphasized the significant role of exosomes from senescent cells in cancer progression and therapy. Notably, chemotherapeutic agents can alter the tumor microenvironment, induce senescence, and trigger immune responses through exosome-mediated cargo transfer. This review explores the intricate relationship between cellular senescence, exosomes, and cancer, examining how different therapeutics can eliminate cancer cells or promote drug resistance. It also investigates the molecular mechanisms and signaling pathways driving these processes, highlighting current challenges and proposing future perspectives to uncover new therapeutic strategies for cancer treatment.

Type I interferon (IFN-I) signalling is intricately involved in the pathogenesis of multiple infectious diseases, autoimmune diseases, and neurological diseases. Acute ischemic stroke provokes overactivation of IFN-I signalling within the injured brain, particularly in microglia. Following cerebral ischemia, damage-associated molecular patterns (DAMPs) released from injured neural cells elicit marked proinflammatory episodes within minutes. Among these, self-nucleic acids, including nuclear DNA and mitochondrial DNA (mtDNA), have been recognized as a critical alarm signal to fan the flames of neuroinflammation, predominantly via inducing IFN-I signalling activation in microglia. The concept of interferon-responsive microglia (IRM), marked by upregulation of a plethora of IFN-stimulated genes, has been emergingly elucidated in ischemic mouse brains, particularly in aged ones. Among the pattern recognition receptors responsible for IFN-I induction, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) plays integral roles in potentiating microglia-driven neuroinflammation and secondary brain injury after cerebral ischemia. Here, we aim to provide an up-to-date review on the multifaceted roles of IFN-I signalling, the detailed molecular and cellular mechanisms leading to and resulting from aberrant IFN-I signalling activation after cerebral ischemia, and the therapeutic potentials. A thorough exploration of these above points will inform our quest for IFN-based therapies as effective immunomodulatory therapeutics to complement the limited repertoire of thrombolytic agents, thereby facilitating the translation from bench to bedside.

Hippocampal sclerosis, characterized by significant hippocampal neuronal loss, oxidative stress, glial cell proliferation, and inflammatory responses, constitutes a pivotal component in the pathogenesis of temporal lobe epilepsy (TLE). Traditional treatment strategies, mainly involving anti-epileptic drugs, face challenges including ineffectiveness, drug tolerance, and adverse reactions, complicating management of the condition. Herein, we design and engineer ultrasmall potassium calcium hexacyanoferrate (III) nanoparticles, designated as KCaHNPs, which feature a broad spectrum of enzymatic activities analogous to superoxide dismutase, catalase, peroxidase, and glutathione peroxidase. KCaHNPs efficiently neutralize excessive reactive oxygen species, mitigate mitochondrial dysfunction, maintain neuronal integrity, and prevent apoptosis. Importantly, KCaHNPs significantly reduce neuronal damage, apoptosis, ferroptosis, and glial cells activation in TLE-afflicted rats, thereby improving spatial and short-term memory, and diminishing epileptic hyperexcitability. Prophylactic deployment of KCaHNPs markedly decreases the frequency and duration of seizures, extends the latency period before the onset of initial seizures, and enhances neural functions within the hippocampal CA3 area. Collectively, these findings underscore the potent therapeutic and prophylactic efficacy of KCaHNPs in mitigating TLE by bolstering cellular defense mechanisms against oxidative stress and inflammation. This innovative approach holds promise as a comprehensive and efficacious strategy for managing temporal lobe epilepsy and potentially other complex neurological disorders.

Autoimmune diseases (AIDs) are a group of disorders in which the immune system mistakenly attacks the body's own tissues, characterized by the loss of tolerance to self-antigens and destruction of tissues. Aging is a natural process of physiological decline that also alters the immune system, a condition known as immunosenescence. During immunosenescence, the immune system undergoes various changes, including modifications and antigenicity of self-antigens, abnormalities in the quantity, phenotype, and function of lymphocytes and antibodies, as well as a narrowing of the B and T cell receptor repertoire, changes that may increase susceptibility to AIDs. Additionally, senescent immune cells and the senescence-associated secretory phenotype (SASP) contribute to target organ involvement in AIDs, exacerbating chronic inflammation and tissue damage. Mitochondrial dysfunction and metabolic imbalances in AIDs lead to the accumulation of senescent cells, which act as upstream drivers of immunosenescence. In this review, we summarize the bidirectional relationship between AIDs and immunosenescence, as well as its potential mechanisms. Therapeutic approaches targeting immunosenescence in AIDs remain at an early stage. Strategies aimed at resetting or reversing the aging immune system are expected to become a novel direction in the future.

Radiation-induced brain injury (RIBI) is caused by exposure to high doses of ionizing radiation and characterized by severe cognitive dysfunction and brain necrosis. However, the pathogenesis of RIBI is not fully understood, and no effective intervention is available. This work describes a blood-brain barrier (BBB) microphysiological system (MPS), that allowed to explore the responses of BBB and distinct brain cells to radiation exposure. Following acute exposure to radiation of X-ray or γ-ray, characteristic RIBI-associated pathological responses are observed, including BBB compromise, DNA breaks, inhibited cell proliferation, cell hypertrophy, and proinflammatory cytokine release. Among the distinctive types of cells, brain endothelial cells show the highest radiosensitivity as compared to other cells in the MPS. Intriguingly, X-ray and γ-ray radiation consistently induce prominent sterile inflammation responses, especially type I interferon response, in the BBB MPS. These responses are mediated by radiation-induced mitochondrial DNA release and subsequent activation of cGAS-STING signaling pathway. Furthermore, it is found abrocitinib (JAK1 inhibitor) and idebenone (mitochondrial protectant) can attenuate radiation-induced inflammation and ameliorate injuries in the BBB MPS. These findings reveal the involvement of mitochondria-mediated sterile inflammation in RIBI pathogenesis, identifying mitochondria as a potential target for new radioprotective measures.

Neurodegenerative diseases (NDDs) represent a rapidly escalating global health challenge, contributing significantly to the worldwide disease burden and posing substantial threats to public health systems across nations. Among the many risk factors for neurodegeneration, aging is the major risk factor. In the context of aging, multiple factors lead to the release of endogenous DNA (especially mitochondrial DNA, mtDNA), which is an important trigger for the activation of the cGAS-STING innate immune pathway. Recent studies have identified an increasing role for activation of the cGAS-STING signaling pathway as a driver of senescence-associated secretory phenotypes (SASPs) in aging and NDDs. The cGAS-STING pathway mediates the immune sensing of DNA and is a key driver of chronic inflammation and functional decline during the aging process. Blocking cGAS-STING signaling may reduce the inflammatory response by preventing mtDNA release and enhancing mitophagy. Targeted inhibition of the cGAS-STING pathway by biological macromolecules such as natural products shows promise in therapeutic strategies for age-related NDDs. This review aims to systematically and comprehensively introduces the role of the cGAS-STING pathway in age-related NDDs in the context of aging while revealing the molecular mechanisms of the cGAS-STING pathway and its downstream signaling pathways and to develop more targeted and effective therapeutic strategies for NDDs.

Cellular senescence is a complex biological process with a dual role in tissue homeostasis and aging-related pathologies. Accumulation of senescent cells promotes chronic inflammation, tissue dysfunction, age-related diseases, and tumor suppression. Recent advancements in immunotherapy have positioned T cell-based approaches as precision tools for the targeted clearance of senescent cells, offering a novel avenue for anti-aging interventions. This review explores the molecular mechanisms underlying cellular senescence, focusing on its immunogenic features and interactions with T cells, including T-cell activation, antigen recognition, modulation of tumor microenvironment (TME), and immune evasion strategies. Innovations such as chimeric antigen receptor (CAR)-T cells, immune checkpoint therapies, and SASP-neutralizing approaches are highlighted as breakthrough strategies for enhancing senescent cell eradication. The integration of multi-omics and artificial intelligence is further catalyzing the development of personalized therapies to amplify immune surveillance and tissue rejuvenation. Clinically, T cell-based interventions hold promise for mitigating age-related pathologies and extending healthspan, yet challenges remain in optimizing target specificity, countering immunosuppressive niches, and overcoming immune senescence in aging populations. This review synthesizes current advances and challenges, highlighting the potential of T cell immunotherapy as a cornerstone of anti-aging medicine and emphasizing the need for interdisciplinary innovation to translate preclinical findings into transformative therapies for aging and age-related diseases.

To evaluate the value of mtDNA copy number measurement in spent culture medium of blastocysts for predicting the chance of implantation following single blastocyst transfer (SBT).

Copy numbers of mtDNA and genomic DNA (gDNA) were determined using multiplex PCR and NGS and modeled to predict implantation following SBT using a generalized linear model (GLM), generalized additive model (GAM), and extreme gradient boosting (XGBoost). The predictive power of the models was demonstrated and compared with the area under the receiver operating characteristic curve (AUC-ROC).

Neither the mtDNA copy number nor the mtDNA/gDNA provided meaningful discriminatory power for prediction in GLM and GAM models. However, higher gDNA quartiles were associated with a negative correlation with pregnancy (OR 0.92, 95% CI 0.85, 1) and an interaction with mtDNA, suggesting that gDNA should not be used to normalize mtDNA copy number. An XGBoost model, which considered both mtDNA and gDNA values, demonstrated an AUC of 0.837 (95% CI 0.800, 0.874).

The mtDNA copy number in spent medium alone may not be a reliable predictor of pregnancy, and dividing mtDNA by gDNA could distort the outcome. Alternatively, a model that makes full use of the interaction of the values may improve the prediction power.

Lung adenocarcinoma (LUAD) is a leading cause of cancer-related mortality. Poor prognostic results in LUAD are frequently associated with KRAS mutations and drug resistance. KRAS mutations can induce STING activation by triggering DNA damage response (DDR) activation. This persistently activated STING signaling gives rise to an immunosuppressive microenvironment, thereby complicating treatment efforts. In this study, we identified that the low-toxicity pro-apoptotic drug Berbamine (BBM) as a potential therapeutic agent for LUAD cells with KRAS mutations. BBM exhibits anti-tumor effects by triggering cell cycle arrest, enhancing senescence, and activating apoptosis. BBM also targets STING, leading to the downregulation of p-STING (Ser366) and CCL2. This in turn reduced the infiltration of M-MDSCs into the tumor microenvironment. These combined mechanisms not only suppress STING-dependent tumor growth but also remodel the immunosuppressive tumor microenvironment, thereby enhancing anti-tumor immunity. Collectively, our findings position BBM as a promising therapeutic agent for LUAD with KRAS mutations, offering a strategy to target STING-associated pathways, overcome immune suppression, and ultimately improve patient outcomes.

Targeting metabolic disorders has emerged as a promising therapeutic strategy in the treatment of chronic kidney disease (CKD). 18β-glycyrrhetinic acid (18β-GA) is known for its metabolic regulatory and antioxidant effects in various diseases. However, the precise effects and underlying mechanisms of 18β-GA on CKD remain unclear.

This study aims to evaluate the therapeutic efficacy of 18β-GA on CKD and to identify the molecular targets of 18β-GA with a particular emphasis on its role in metabolic regulation.

A high-fat diet-induced CKD model was established to investigate the influence of 18β-GA on lipid metabolic disorders, cellular senescence and fibrosis in the kidneys. Co-immunoprecipitation was performed to investigate the impact of 18β-GA on the interaction between transcription factor EB (TFEB) and sirtuin 1 (SIRT1). Additionally, network pharmacology and molecular docking analyses were conducted to identify the specific target proteins of 18β-GA.

18β-GA alleviated renal lipid accumulation, tubular cell senescence and renal interstitial fibrosis in CKD mice. Treatment with 18β-GA largely restored mitochondrial function and attenuated intracellular lipotoxicity and associated cellular senescence by promoting lipophagy in renal tubular cells. Mechanistically, 18β-GA acting as a partial antagonist of peroxisome proliferator-activated receptor gamma (PPARγ) enhanced lipophagy through SIRT1-mediated nuclear translocation of TFEB which induced the expression of microtubule-associated protein light chain 3 (LC3).

Our findings demonstrate that 18β-GA, functioning as a partial antagonist of PPARγ, counteracts CKD progression by activating the SIRT1-TFEB-LC3 signaling axis-mediated lipophagy and thus uncover a novel mechanism by which 18β-GA improves renal lipid metabolism disorders and exerts renoprotective effects. These results highlight the potential of 18β-GA as a promising therapeutic agent for the treatment and prevention of CKD.

Meniscus degeneration contributes to knee arthritis progression, but the cellular and molecular mechanisms of meniscus aging remain poorly understood. We aimed to characterize age-related changes in the rat meniscus using single-cell RNA sequencing (scRNA-seq) and identify key pathogenic cell populations and pathways.

Meniscal tissues from young (12 weeks) and aged (24 months) rats were processed for histology, flow cytometry, and scRNA-seq. Bioinformatics tools, including Seurat, Monocle 2, and CellChat, were used to analyze cellular composition, pseudotime trajectories, and intercellular communication. Senescence-related features and signaling pathways were evaluated.

Knee joint of aged rats exhibited higher Osteoarthritis Research Society International (OARSI) scores and synovial inflammation. scRNA-seq revealed three major chondrocyte subpopulations: Sox9 + stable chondrocytes, Fndc1 + fibrochondrocytes, and Atf3 + senescent chondrocytes. Aging caused a significant increase in Atf3 + senescent chondrocytes, characterized by the expression of senescence markers (Cdkn1a/Cdkn2a) and activation of inflammatory pathways such as tumor necrosis factor (TNF) and nuclear factor-κB (NF-κB). These cells were predominantly located at the endpoint of differentiation trajectories. CellChat analysis identified the ANGPTL4-SDC4 axis as a key signaling pathway mediated by Atf3 + cells. Immunostaining confirmed elevated Angiopoietin-Like Protein 4 (ANGPTL4) expression in aged menisci.

We identified Atf3 + senescent chondrocytes as a key pathogenic population in the aging meniscus, driving degeneration via the ANGPTL4 pathway. Targeting Atf3 + cells or ANGPTL4 signaling may offer new therapeutic strategies for age-related meniscus degeneration and arthritis.

Mitochondrial dysfunction is one of the important signs of cellular and even individual aging. Ganoderma lucidum is a common edible and medicinal mushroom, widely used as a functional food in Asia. This study investigated the potential anti-aging effects of Ganoderma lucidum extract (GLE). Our results demonstrated that GLE alleviated cellular oxidative stress, reduced the abnormal increase of mitochondrial ROS in aging cells, and maintained mitochondrial membrane integrity and inner membrane potential. Additionally, GLE affected mitochondrial biogenesis in aging cells. In a murine photoaging model, GLE treatment mitigated UVA-induced mitochondrial dysfunction while markedly attenuating UVA-triggered epidermal thickening and dermal protein depletion. These properties may be interrelated with the presence of abundant triterpenoids identified by LC-MS analysis.

Sepsis involves endothelial cell dysfunction leading to the development of lung injury. Fatty acid synthesis contributes to the development of inflammatory injury in sepsis. However, the regulatory mechanisms of fatty acid synthesis-related endothelial activation remain unclear. In this study, we found that fatty acid synthesis in patients with sepsis was greatly disordered. Inhibition of fatty acid synthesis significantly alleviated sepsis-induced endothelial damage and lung injury both in vitro and in vivo. We further found that the release of mtDNA participated in fatty acid synthesis-related regulation of endothelial inflammatory and coagulation activation. Mechanistically, fatty acid synthesis promoted the oligomerization of voltage-dependent anion channel 1 (VDAC1) via ETS proto-oncogene 1 (ETS1)-mediated inhibition of VDAC1 ubiquitination, thereby leading to the increased release of mtDNA and subsequent activation of cGAS-STING signaling and pyroptosis in endothelial cells. Our findings revealed that fatty acid synthesis promoted endothelial dysfunction through mtDNA release, providing new insight into the therapeutic strategies for treating sepsis-associated lung injury.

Testicular aging results in degeneration in testicular function, including decreased testosterone production and quality of sperm. Decreased testosterone level is associated with a range of systemic diseases and comorbidities, including cardiovascular disease, cognitive decline, depression, osteoporosis, frailty, increased body fat, and metabolic syndrome. In addition, with the rapid development of industrialization and increasing environmental pollution, the quality of male semen continues to decline globally. Currently, the average age of first marriage and childbirth for men is delayed, and the birth rate has been declining year by year. At present, the therapies for testosterone level decline in clinical practice are relatively limited. Therefore, studying the triggering and delaying mechanisms of testicular aging is significant for improving male health and protecting male fertility. This review summarizes the mechanisms and treatment strategies for male reproductive aging.

Aging is a process in which organisms or cells undergo a decline in their functions. Epigenetic modification changes have been recognized as a senescence hallmark in both natural aging and stimulation-induced senescence. An acetylation modification is a dynamic process, which plays a crucial role in the senescence process through DNA stability, metabolism, and signaling pathways. We summarized the role and regulatory pathways of acetylation modifications in senescence. Various cell fate-determining proteins regulate multiple cellular processes through acetylation modifications. These processes interact and coordinate with each other, forming an integrated regulatory network framework that collectively drives cellular senescence via multiple systemic mechanisms. Based on these findings, we proposed the "acetylation-network regulation-cellular senescence" model, to elaborate how acetylation contributes to senescence. We believe this insight could provide new directions and intervention strategies for senescence and aging-related diseases.

Photoaging, the premature aging of skin due to chronic ultraviolet (UV) exposure, is a growing concern in dermatology and cosmetic science. While UV radiation is known to induce DNA damage, oxidative stress, and inflammation in skin cells, recent research unveils a promising countermeasure: autophagy. This review explores the intricate relationship between autophagy and photoaging, highlighting how this cellular recycling process can mitigate UV-induced damage. We begin by examining the differential impacts of UVA and UVB radiation on skin cells and the role of oxidative stress in accelerating photoaging. Next, we delve into the molecular mechanisms of autophagy, including its various forms and regulatory pathways. Central to this review is the discussion of autophagy's protective functions, such as the clearance of damaged organelles and proteins, and its role in maintaining genomic integrity. Furthermore, we address the current challenges in harnessing autophagy for therapeutic purposes, including the need for selective autophagy inducers and a deeper understanding of its context-dependent effects. By synthesizing recent advancements and proposing future research directions, this review underscores the potential of autophagy modulation as a novel strategy to prevent and treat photoaging. This comprehensive analysis aims to inspire further investigation into autophagy-based interventions, offering new hope for preserving skin health in the face of environmental stressors.

Aging of hematopoietic and immune system (HIS) leads to cellular senescence and immune dysregulation, contributing to age-related diseases. Here, we show that Procyanidin C1 (PCC1), a compound with both senolytic and senomorphic properties, can counteract aging-related changes in HIS. Using single-cell RNA sequencing and validation experiments, we found that aging induced cellular senescence, inflammation, and immune dysregulation in the bone marrow and spleen tissues of mice. Long-term PCC1 treatment improved key physiological parameters especially the grip strength of aged mice. Further single-cell analysis revealed PCC1's broad geroprotective effects on HIS, including an increase in the proportion of B cells (BCs) and hematopoietic stem cells (HSCs), suppression of senescence-associated markers, and restoration of normal immune processes. Specifically, PCC1 mitigated inflammation and restored immune homeostasis in BCs by suppressing Cebpb expression and age-associated BCs. Moreover, PCC1 reversed aging-induced alterations in HSCs through upregulating Nedd4 and CD62L-Ca2+ axis expression. Finally, we identified senescent cells (SnCs) using machine learning and gene set enrichment analysis, revealing that PCC1 induced apoptosis of SnCs and regulated their metabolic processes, particularly in granulocytes and myeloid cells. The experimental validation further confirmed the senolytic and senomorphic effects of PCC1 both in vivo and in vitro. Overall, PCC1 holds potential as a therapeutic agent for alleviating immune dysfunction and promoting healthy aging via senolytic and senomorphic effects.

The build-up of senescent cells in tissues is a key indicator of aging, associated with negative prognosis and therapy resistance. Despite immune dysfunction related to aging, also known as immunosenescence, is recognized as a factor in this process, the exact mechanisms are still unclear. In this study, we reported that melatonin deficiency accelerated macrophage senescence in triple-negative breast cancer, whereas melatonin could defend macrophages against senescence through the Nfatc1-Trim26-cgas-Sting pathway. Mechanistically, melatonin enhanced the nuclear translocation of Nfatc1 and elevated Trim26 transcription levels. Trim26, functioning as an E3 ligase, ubiquitinates cgas, thereby inhibiting the activation of the cgas-Sing pathway and consequently preventing cell senescence. Conversely, melatonin deficiency induced cgas-Sting pathway activation to promote macrophage aging. Our results show that melatonin inhibited macrophage senescence and improved chemotherapy responsiveness, with further enhancement when combined with the cgas inhibitor (G150). Overall, our findings indicated that melatonin protects macrophages from immunosenescence, suggesting its therapeutic potential for enhancing chemotherapy response.

The pervasive utilization of plastic products has led to a significant escalation in plastic waste accumulation. Concurrently, the implications of emerging pollutants such as microplastics (MPs) and nanoplastics (NPs) on human health are increasingly being acknowledged. Recent research has demonstrated that MPs/NPs may contribute to the onset of human aging and age-related diseases. Additionally, MPs/NPs have the potential to induce mitochondrial damage, resulting in mitochondrial dysfunction. Mitochondrial dysfunction is widely recognized as a hallmark of aging; thus, it is necessary to elucidate the relationship between them. In this article, we first elucidate the distribution of MPs/NPs in various environmental media, their pathways into the human body, and their subsequent distribution within human tissues and organs. Subsequently, we examine the interplay between MPs/NPs, mitochondrial dysfunction, and the aging process. We aspire that this article will enhance awareness regarding the toxicity of MPs/NPs while also offering a theoretical framework to support the development of improved regulatory policies in the future.

Cellular senescence is characterized by proliferation arrest and a senescence-associated secretory phenotype (SASP), that plays a role in aging and the progression of various age-related diseases. Although various metabolic alterations have been reported, no consensus exists regarding mitochondrial bioenergetics. Here we compared mitochondrial metabolism of human fibroblasts after inducing senescence with different stimuli: the oxidant hydrogen peroxide (H2O2), the genotoxic doxorubicin, serial passage, or expression of the H-RASG12V oncogene (RAS). In senescence induced by H2O2, doxorubicin or serial passage a decrease in respiratory control ratio (RCR) and coupling efficiency was noted, in relation to control cells. On the contrary, oncogene-induced senescent cells had an overall increase in respiration rates, RCR, spare respiratory capacity and coupling efficiency. In oncogene-induced senescence (OIS) the increase in respiration rates was accompanied by an increase in fatty acid catabolism, AMPK activation, and a persistent DNA damage response (DDR), that were not present in senescent cells induced by either H2O2 or doxorubicin. Inhibition of AMPK reduced mitochondrial oxygen consumption and secretion of proinflammatory cytokines in OIS. Assessment of enzymes involved in acetyl-CoA metabolism in OIS showed a 3- to 7.5-fold increase in pyruvate dehydrogenase complex (PDH), a 40% inhibition of mitochondrial aconitase, increased phosphorylation and activation of ATP-citrate lyase (ACLY), and inhibition of acetyl-CoA carboxylase (ACC). There was also a significant increase in expression and nuclear levels of the deacetylase sirtuin 6 (SIRT6). These changes can influence the sub-cellular distribution of acetyl-CoA and modulate protein acetylation reactions in the cytoplasm and nuclei. In fact, ACLY inhibition reduced histone 3 acetylation (H3K9Ac) in OIS and secretion of SASP components. In summary, our data show marked heterogeneity in mitochondrial energy metabolism of senescent cells, depending on the inducing stimulus, reveal new metabolic features of oncogene-induced senescent cells and identify AMPK and ACLY as potential targets for SASP modulation.

As we have learned more about mitochondria over the past decades, including about their essential cellular roles and how altered mitochondrial biology results in disease, it has become apparent that they are not just powerplants pumping out ATP at the whim of the cell. Rather, mitochondria are dynamic information and energy processors that play crucial roles in directing dozens of cellular processes and behaviors. They provide instructions to enact programs that regulate various cellular operations, such as complex metabolic networks, signaling and innate immunity, and even control cell fate, dictating when cells should divide, differentiate or die. To help current and future generations of cell biologists incorporate the dynamic, multifaceted nature of mitochondria and assimilate modern discoveries into their scientific framework, mitochondria need a 21st century 'rebranding'. In this Opinion article, we argue that mitochondria should be considered as the 'Chief Executive Organelle' - the CEO - of the cell.

Senescent and cancer cells share common inflammatory characteristics, including factors of the senescence-associated secretory phenotype (SASP) and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Inflammation in the tumor microenvironment not only provides an opportunity for immune cells to attack cancer cells, but also promotes cancer invasion and metastasis. Immune checkpoint molecule PD-L1 is transcriptionally induced by inflammation, and the immunological state of PD-L1-positive tumors influences the efficacy of Immune checkpoint inhibitors (ICIs). ICIs are effective against the PD-L1-positive "hot" tumors; however, the non-immunoactive "cold" tumors that express PD-L1 rarely respond to ICIs, suggesting that converting PD-L1-positive "cold" tumors into "hot" tumors would improve the efficacy of ICIs. To eliminate cancer via the innate immune system, a therapeutic strategy for manipulating inflammatory responses must be established. To date, the molecular mechanisms of inflammation-induced tumorigenesis are not yet fully understood. However, it is becoming clear that the regulatory mechanisms of inflammation in cancer via the cGAS-STING pathway play an important role in both cancer and sensescent cells. In this review, we focus on inflammation and immune escape triggered by DNA damage in cancer and senescent cells.

Cellular senescence contributes to a variety of pathologies associated with aging and is implicated as a cellular state in which cancer cells can survive treatment. Reported senolytic drug treatments act through varying molecular mechanisms, but heterogeneous efficacy across the diverse contexts of cellular senescence indicates a need for predictive biomarkers of senolytic activity. Using multi-parametric analyses of commonly reported molecular features of the senescent phenotype, we assayed a variety of models, including malignant and nonmalignant cells, using several triggers of senescence induction and found little univariate predictive power of these traditional senescence markers to identify senolytic drug sensitivity. We sought to identify novel drug targets in senescent cells that were insensitive to frequently implemented senolytic therapies, such as Navitoclax (ABT-263), using quantitative mass spectrometry to measure changes in the senescent proteome, compared to cells which acquire an acute sensitivity to ABT-263 with senescence induction. Inhibition of the antioxidant GPX4 or the Bcl-2 family member MCL-1 using small molecule compounds in combination with ABT-263 significantly increased the induction of apoptosis in some, but not all, previously insensitive senescent cells. We then asked if we could use BH3 profiling to measure differences in mitochondrial apoptotic priming in these models of cellular senescence and predict sensitivity to the senolytics ABT-263 or the combination of dasatinib and quercetin (D + Q). We found, despite being significantly less primed for apoptosis overall, the dependence of senescent mitochondria on BCL-XL was significantly correlated to senescent cell killing by both ABT-263 and D + Q, despite no significant changes in the gene or protein expression of BCL-XL. However, our data caution against broad classification of drugs as globally senolytic and instead provide impetus for context-specific senolytic targets and propose BH3 profiling as an effective predictive biomarker.

Granulosa cell-produced inflammatory factors may be key contributors to ovarian dysfunction, and Immp2l deficiency accelerates ovarian aging via granulosa cell senescence; however, the role of inflammation in granulosa cell senescence is largely unknown. Therefore, in this study, cGAS-STING-mediated inflammation was explored in Immp2l deficiency-induced granulosa cell senescence. Immp2l deficiency led to senescence-associated secretory phenotype (SASP) and granulosa cell senescence. Immp2l knockout caused mitochondrial dysfunction and mitochondrial DNA (mtDNA) leakage into the cytoplasm. The cytoplasmic mtDNA was recognized by the DNA-sensing molecule cGAS-STING, which activates cGAS-STING and key downstream interferon-stimulated genes (ISGs) and then promotes the secretion of proinflammatory factors, leading to SASP in senescent granulosa cells. Interestingly, the mitochondrial inner membrane pore protein (Cyclophilin D40) CyPD40 and the outer membrane pore protein voltage-dependent-anion channel 1 (VDAC1) were markedly increased in senescent granulosa cells, accompanied by significantly increased expression of the mtDNA stability protein mitochondrial transcription factor A (TFAM). Downregulation of TFAM with siRNA in senescent granulosa cells improved mitochondrial function, significantly decreased mtDNA in the cytoplasm, inhibited the cGAS-STING pathway and markedly decreased CyPD40 and VDAC1 protein levels in TFAM-treated senescent granulosa cells. The SASP phenotype was also alleviated. In addition, senescent granulosa cells were treated with procyanidin B2 (PCB2), which has anti-inflammatory effects, and the TFAM-mediated mtDNA-cGAS-STING pathway was inhibited, accompanied by a markedly reduced SASP phenotype and granulosa cell senescence. In conclusion, Immp2l gene knockout induced granulosa cell senescence by activation of the cGAS-STING pathway via TFAM-mediated mtDNA leakage into the cytoplasm through the CyPD40 and the VDAC1.

Age-related macular degeneration (AMD) is a disease that affects the vision of elderly individuals worldwide. Although current therapeutics have shown effectiveness against AMD, some patients may remain unresponsive and continue to experience disease progression. Therefore, in-depth knowledge of the mechanism underlying AMD pathogenesis is urgently required to identify potential drug targets for AMD treatment. Recently, studies have suggested that dysfunction of mitochondria can lead to the aggregation of reactive oxygen species (ROS) and activation of the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) innate immunity pathways, ultimately resulting in sterile inflammation and cell death in various cells, such as cardiomyocytes and macrophages. Therefore, combining strategies targeting mitochondrial dysfunction and inflammatory mediators may hold great potential in facilitating AMD management. Notably, emerging evidence indicates that natural products targeting mitochondrial quality control (MQC) and the cGAS/STING innate immunity pathways exhibit promise in treating AMD. Here, we summarize phytochemicals that could directly or indirectly influence the MQC and the cGAS/STING innate immunity pathways, as well as their interconnected mediators, which have the potential to mitigate oxidative stress and suppress excessive inflammatory responses, thereby hoping to offer new insights into therapeutic interventions for AMD treatment.

The aging microenvironment promotes persistent inflammation and loss of intrinsic regenerative capacity. These are major obstacles to effective bone tissue repair in older adults. This study aims to explore how physical thermal stimulation can effectively delay the bone marrow mesenchymal stem cells (BMSCs) aging process. Based on this, an implantable physical signal-converter platform is designed as a therapeutic system that enables stable heat signals at the bone injury site under ultrasound stimulation (US). It is found that the therapeutic platform controllably reduces the mitochondrial outer membrane permeabilization of aging BMSCs, bidirectionally inhibiting mitochondrial reactive oxygen species and mitochondrial DNA (mtDNA) leakage. The leakage ratio of mtDNA decreases by 22.7%. This effectively mitigates the activation of the cGAS-STING pathway and its downstream NF-κB signaling induced by oxidative stress in aging BMSCs, thereby attenuating the pathological advancement of chronic inflammation. Thus, it effectively restores the metabolism and osteogenic differentiation of aging BMSCs in vitro, which is further confirmed in a rat model. In the GMPG/US group, the bone mineral density increases 2-3 times at 4 weeks in the rats femoral defect model. Therefore, this ultrasound-based signal-conversion platform provides a promising strategy for aging bone defect repair.

Cellular senescence, a hallmark of aging, reveals context-dependent phenotypes across multiple biological length scales. Despite its mechanistic importance, identifying and characterizing senescence across cell populations is challenging. Using primary dermal fibroblasts, we combined single-cell imaging, machine learning, several induced senescence conditions, and multiple protein biomarkers to define functional senescence subtypes. Single-cell morphology analysis revealed 11 distinct morphology clusters. Among these, we identified three as bona fide senescence subtypes (C7, C10, and C11), with C10 exhibiting the strongest age dependence within an aging cohort. In addition, we observed that a donor's senescence burden and subtype composition were indicative of susceptibility to doxorubicin-induced senescence. Functional analysis revealed subtype-dependent responses to senotherapies, with C7 being most responsive to the combination of dasatinib and quercetin. Our single-cell analysis framework, SenSCOUT, enables robust identification and classification of senescence subtypes, offering applications in next-generation senotherapy screens, with potential toward explaining heterogeneous senescence phenotypes based on the presence of senescence subtypes.

There has been a recent expansion in our understanding of DNA-sensing mechanisms. Mitochondrial dysfunction, oxidative and proteostatic stresses, instability and impaired disposal of nucleoids cause the release of mitochondrial DNA (mtDNA) from the mitochondria in several human diseases, as well as in cell culture and animal models. Mitochondrial DNA mislocalized to the cytosol and/or the extracellular compartments can trigger innate immune and inflammation responses by binding DNA-sensing receptors (DSRs). Here, we define the features that make mtDNA highly immunogenic and the mechanisms of its release from the mitochondria into the cytosol and the extracellular compartments. We describe the major DSRs that bind mtDNA such as cyclic guanosine-monophosphate-adenosine-monophosphate synthase (cGAS), Z-DNA-binding protein 1 (ZBP1), NOD-, LRR-, and PYD- domain-containing protein 3 receptor (NLRP3), absent in melanoma 2 (AIM2) and toll-like receptor 9 (TLR9), and their downstream signaling cascades. We summarize the key findings, novelties, and gaps of mislocalized mtDNA as a driving signal of immune responses in vascular, metabolic, kidney, lung, and neurodegenerative diseases, as well as viral and bacterial infections. Finally, we define common strategies to induce or inhibit mtDNA release and propose challenges to advance the field.

The accumulation of dysfunctional giant mitochondria is a hallmark of aged cardiomyocytes. This study investigated the core mechanism underlying this phenomenon, focusing on the disruption of mitochondrial lipid metabolism and its effects on mitochondrial dynamics and autophagy, using both naturally aging mouse models and etoposide-induced cellular senescence models. In aged cardiomyocytes, a reduction in endoplasmic reticulum-mitochondrial (ER-Mito) contacts impairs lipid transport and leads to insufficient synthesis of mitochondrial phosphatidylethanolamine (PE). A deficiency in phosphatidylserine decarboxylase (PISD) further hinders the conversion of phosphatidylserine to PE within mitochondria, exacerbating the deficit of PE production. This PE shortage disrupts autophagosomal membrane formation, leading to impaired autophagic flux and the accumulation of damaged mitochondria. Modulating LACTB expression to enhance PISD activity and PE production helps maintain mitochondrial homeostasis and the integrity of aging cardiomyocytes. These findings highlight the disruption of mitochondrial lipid metabolism as a central mechanism driving the accumulation of dysfunctional giant mitochondria in aged cardiomyocytes and suggest that inhibiting LACTB expression could serve as a potential therapeutic strategy for mitigating cardiac aging and preserving mitochondrial function.

Apoptosis controls cell fate, ensuring tissue homeostasis and promoting disease when dysregulated. The rate-limiting step in apoptosis is mitochondrial poration by the effector B cell lymphoma 2 (BCL-2) family proteins BAK and BAX, which are activated by initiator BCL-2 homology 3 (BH3)-only proteins (e.g., BIM) and inhibited by guardian BCL-2 family proteins (e.g., MCL-1). We integrated structural, biochemical, and pharmacological approaches to characterize the human prosurvival MCL-1:BAK complex assembled from their BCL-2 globular core domains. We reveal a canonical interaction with BAK BH3 bound to the hydrophobic groove of MCL-1 and disordered and highly dynamic BAK regions outside the complex interface. We predict similar conformations of activated effectors in complex with other guardians or effectors. The MCL-1:BAK complex is a major cancer drug target. We show that MCL-1 inhibitors are inefficient in neutralizing the MCL-1:BAK complex, requiring high doses to initiate apoptosis. Our study underscores the need to design superior clinical candidate MCL-1 inhibitors.

This study aimed to explore the efficacy and mechanisms of raspberry (Rubus idaeus L. fruit) aqueous extract (RE) in alleviating high-fat diet (HFD)-induced metabolic-associated fatty liver disease (MAFLD). The MAFLD mouse model was established to examine the effects of RE through liver transcriptome and metabolomics analysis. In this study, RE supplementation significantly alleviated HFD-induced liver injury, hepatosteatosis, inflammation, and insulin resistance. Liver transcriptome analysis demonstrated that RE supplementation favorably regulated signaling pathways involved in fatty acid metabolism and inflammation, including the AMPK signaling pathway, PPAR signaling pathway, apoptosis, etc. Furthermore, the injection of compound C, an antagonist of AMPK, notably reversed the hepatoprotective effects of RE, evidenced by increased lipid profile levels, accelerated fatty acid-related gene disorder, and increased positive tunnel staining area. Furthermore, liver metabolomics analysis demonstrated that RE treatment led to substantial enrichment of the liver tissue metabolite umbelliferone (UMB), which has the potential to ameliorate lipid accumulation and hepatocyte injury through the AMPK signaling pathway. In summary, RE intervention mitigated HFD-induced liver dysfunction in mice, with UMB likely being the primary component responsible for its therapeutic efficacy in the liver. In addition, this study provided new insights, suggesting that RE could be used as a promising therapeutic approach for modulating MAFLD via apoptosis and the AMPK/PPARα signaling pathway.