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Schematic diagram illustrating the senolytic role of D+Q in lumbar facet joint degeneration [Display omitted] Low back pain (LBP) is a pervasive issue, causing substantial economic burden and physical distress worldwide. Facet joint osteoarthritis (FJ OA) is believed to be a significant contributor to this problem. However, the precise role of chondrocyte senescence in FJ OA remains unclear, as does whether the clearance of chondrocyte senescence can alleviate the progression of FJ OA. The goal of this study was to understand the potential of Dasatinib (D) and Quercetin (Q) as a treatment to clear chondrocyte senescence during the progression of FJ OA. We used a preclinical bipedal standing mice model with the administration of Dasatinib (D) (5 mg/kg) and Quercetin (Q) (50 mg/kg) after 10 weeks of bipedal standing. Human degenerative lumbar facet joint (LFJ) samples were obtained to investigate the relationship between chondrocyte cellular senescence and LFJ osteoarthritis (OA). Subsequently, we established an in vitro model of excessive mechanical stress on chondrocytes and an in vivo bipedal standing mice model to induce LFJ OA. IHC (immunohistochemistry) staining in vivo and SA-β-gal staining, qRT-PCR and Western blot analysis were applied to test the senolytic effect of the combination of Dasatinib (D) and Quercetin (Q). IHC staining and X-ray microscope were also performed to examine the contribution of D+Q to the anabolism in cartilage and subchondral bone recoupling. Immunofluorescence and Western blot analysis in vitro and IHC staining in vivo were conducted to assess the impact of D+Q on the regulation of the NF-κB pathway activation during chondrocyte senescence. We observed that facet joint cartilage degeneration is associated with chondrocyte cellular senescence in both human and mouse degenerative samples. Following treatment with D+Q in vitro, cellular senescence was significantly reduced. Upon oral gavage administration of D+Q in the bipedal standing mice model, decreased cellular senescence and reversed chondrocyte anabolism were observed. Furthermore, administration of D+Q maintained subchondral bone remodeling homeostasis and potentially reversed the activation of the NF-κB pathway in chondrocytes of the lumbar facet joint. In summary, our investigation unveiled a significant correlation between chondrocyte senescence and LFJOA. Treatment with the senolytic combination of D+Q in FJ OA yielded a notable reduction in chondrocyte senescence, along with a decrease in the release of SASP factors. Additionally, it facilitated the promotion of cartilage anabolism, maintenance of subchondral bone coupling, and amelioration of NF-κB pathway activation. Our outcomes revealed that D+Q, the renowned combination used for senolytic treatment, alleviate the progression of LFJ OA. The utilization of D+Q as a senolytic demonstrates a novel and promising alternative for LFJ OA treatment. [ABSTRACT FROM AUTHOR]

Psoriasis is an inflammatory skin disease with unclear pathogenesis and unmet therapeutic needs. To investigate the role of senescent CD4+ T cells in psoriatic lesion formation and explore the application of senolytics in treating psoriasis. We explored the expression levels of p16INK4a and p21, classical markers of cellular senescence, in CD4+ T cells from human psoriatic lesions and imiquimod (IMQ)-induced psoriatic lesions. We prepared a senolytic gel using B-cell lymphoma 2 (BCL-2) inhibitor ABT-737 and evaluated its therapeutic efficacy in treating psoriasis. Using multispectrum immunohistochemistry (mIHC) staining, we detected increased expression levels of p16INK4a and p21 in CD4+ T cells from psoriatic lesions. After topical application of ABT-737 gel, significant alleviation of IMQ-induced psoriatic lesions was observed, with milder pathological alterations. Mechanistically, ABT-737 gel significantly decreased the percentage of senescent cells, expression of T cell receptor (TCR) α and β chains, and expression of Tet methylcytosine dioxygenase 2 (Tet2) in IMQ-induced psoriatic lesions, as determined by mIHC, high-throughput sequencing of the TCR repertoire, and RT-qPCR, respectively. Furthermore, the severity of psoriatic lesions in CD4creTet2f/f mice was milder than that in Tet2f/f mice in the IMQ-induced psoriasis model. We revealed the roles of senescent CD4+ T cells in developing psoriasis and highlighted the therapeutic potential of topical ABT-737 gel in treating psoriasis through the elimination of senescent cells, modulation of the TCR αβ repertoire, and regulation of the TET2-Th17 cell pathway. • We highlight the crucial role of senescent CD4+ T cells in pathogenesis of psoriasis. • The TET2 emerges as an important regulator of senescent CD4+ T cells in psoriasis. • Topical ABT-737 gel shows potential as a therapy for psoriasis by eliminating senescent cells. [ABSTRACT FROM AUTHOR]

B cell leukemia/lymphoma 2 (BCL2) homology domain 3 (BH3) mimetics were reported to selectively kill senescent cells and improve age-related diseases. Defining why these cells show increased sensitivity to these molecules will help to identify new pharmacological compounds with senolytic activity. Here, we discuss how recent research findings provide new clues to understand this vulnerability. [ABSTRACT FROM AUTHOR]

Cellular senescence is a stress response associated with aging and disease, including cancer. Senescent cells undergo a stable cell cycle arrest, undergo a change in morphology and metabolic reprogramming, and produce a bioactive secretome termed the senescence-associated secretory phenotype (SASP). In cancer, senescence is an important barrier to tumor progression. Induction of senescence in preneoplastic cells limits cancer initiation, and many cancer therapies act in part by inducing senescence in cancer cells. Paradoxically, senescent cells lingering in the tumor microenvironment (TME) can contribute to tumor progression, metastasis, and therapy resistance. In this review, we discuss the different types of senescent cells present in the TME and how these senescent cells and their SASP reshape the TME, affect immune responses, and influence cancer progression. Furthermore, we will highlight the importance of senotherapies, including senolytic drugs that eliminate senescent cells and impede tumor progression and metastasis by restoring anti-tumor immune responses and influencing the TME. [Display omitted] Senescence can affect cancer cells and different components of the tumor microenvironment (TME). In this review, D'Ambrosio and Gil describe the anti- and pro-tumorigenic roles of senescent cells inside the TME and discuss different therapeutic approaches to kill senescent cells to benefit cancer patients. [ABSTRACT FROM AUTHOR]

Senescent cells are highly associated with aging and pathological conditions and could be targeted to slow the aging process. One commonly used marker to examine senescent cells in vivo is p16, which has led to important discoveries. Recent studies have also described new senescence markers beyond p16 and have highlighted the importance of investigating senescence heterogeneity in cell types and tissues. With the development of high-throughput technologies, such as single-cell RNA-seq and single-nucleus RNA-seq, we can examine senescent cells at the single-cell level and potentially uncover new markers. This review emphasizes that there is an urgent need to investigate senescence heterogeneity and discuss how this could be accomplished by using advanced technologies and sequencing datasets. Currently, senescent cells do not have a known gold standard genetic marker. Single cell RNA-seq and single-nucleus RNA-seq have emerged as powerful methods for investigating senescence heterogeneity. It is unknown what cell populations are being targeted by senolytics in vivo. Gaining a greater understanding of senescent cell heterogeneity can have large clinical implications and improve patient treatment. [ABSTRACT FROM AUTHOR]

Neuroinflammatory diseases remain a therapeutic challenge, notably when progressing towards neurodegeneration. In this context, multiple sclerosis represents a central nervous system (CNS) disorder that combines pathogenic inflammatory and degenerative processes. Immunosuppression is effective for managing inflammatory activity, but neurodegenerative processes secondary to chronic inflammation are often refractory to contemporary treatments. Recent evidence indicates that pathways involved in chronic neuroinflammation demonstrate features of cellular senescence. These features could provide a framework that could serve as a target for senotherapeutics. In this review, we discuss the unmet need for strategies capable of overcoming the treatment resistance of neuroinflammatory diseases, and we discuss the potential of cellular senescence towards developing these strategies. There is an unmet need for novel therapeutic strategies that can halt neuroinflammatory disorders progressing towards a degenerative phenotype. Accumulating evidence links cellular senescence to a plethora of human diseases. Initial data indicate the presence of cellular senescence in neuroinflammatory disorders, suggesting it as a potential driver of pathogenesis. Senotherapeutics were able to reduce the senescent burden in animal models and, more recently, in humans. Incorporating senotherapeutics in the field of neuroinflammation could improve treatment outcomes. [ABSTRACT FROM AUTHOR]

Senescent cells are characterized by a persistent cessation of their cell cycle, rendering them valuable targets for anti-tumor strategies in cancer treatment. Numerous studies have explored induced senescence as a promising approach in tumor therapy. Nevertheless, these treatments often come with drawbacks, including adverse side effects and weaker senescence-inducing effects. To address these challenges, we synthesized 223Ra/Ba single-atom nanozyme (SAzyme), wherein Ba SAzyme acts concurrently as a carrier for 223RaCl 2 , facilitating targeted delivery and minimizing side effects. The 223Ra/Ba SAzyme complex enhances various enzyme-mimicking functions, including catalase (CAT) and peroxidase (POD) activities. Importantly, 223Ra/Ba SAzyme induces cellular senescence and boost anti-tumor immunity. The persistent presence of a senescence-associated secretory phenotype (SASP) in the tumor microenvironment presents risks of immune suppression and tumor recurrence, which can be effectively mitigated by senolytics. As a result, 223Ra/Ba SAzyme were combined with anti-PD-L1 checkpoint blockade to achieve a one-two punch therapy, wherein 223Ra/Ba SAzyme exploits senescence followed by anti-PD-L1 therapy to eradicate senescent cells. This one‐two punch strategy approach presents a straightforward and potent intervention for both primary tumors and distant tumor. The developed 223Ra/Ba SAE demonstrates optimized catalytic efficiency, showcasing robust dual peroxidase (POD) and catalase (CAT) mimetic activities. This catalytic capability leads to pronounced reactive oxygen species (ROS) generation, which in turn initiates cellular senescence (first punch) and enhances anti-tumor immunity. Furthermore, the integration of this approach with anti-PD-L1 therapy effectively mitigates the potential drawbacks associated with prolonged presence of senescent cells (second punch). The one-two punch therapy leads to significant inhibition of primary and distant tumors. [Display omitted] [ABSTRACT FROM AUTHOR]

Targeting senescent cells has recently emerged as a promising strategy for treating age-related diseases, such as atherosclerosis, which significantly contributes to global cardiovascular morbidity and mortality. This review elucidates the role of senescent cells in the development of atherosclerosis, including persistently damaging DNA, inducing oxidative stress and secreting pro-inflammatory factors known as the senescence-associated secretory phenotype. Therapeutic approaches targeting senescent cells to mitigate atherosclerosis are summarized in this review, which include the development of senotherapeutics and immunotherapies. These therapies are designed to either remove these cells or suppress their deleterious effects. These emerging therapies hold potential to decelerate or even alleviate the progression of AS, paving the way for new avenues in cardiovascular research and treatment. • In-depth Mechanistic Study : Reveal the mechanisms by which senescent cells contribute to the progression of AS. • Evaluation of Multiple therapeutic Strategies : Senolytic and senomorphic drugs in the treatment of AS. • Innovative Immunotherapy Prospects : Summarize the application of anti-senescence drugs and the prospects of immunotherapy. • Interdisciplinary Approaches : Bioinformatics and AI methods can identify potential targets and optimize strategies. [ABSTRACT FROM AUTHOR]

[Display omitted] Human immunodeficiency virus (HIV) is known to cause cellular senescence and inflammation among infected individuals. While the traditional antiretroviral therapies (ART) have allowed the once fatal infection to be managed effectively, the quality of life of HIV patients on prolonged ART use is still inferior. Most of these individuals suffer from life-threatening comorbidities like chronic obstructive pulmonary disease (COPD), pulmonary arterial hypertension (PAH), and diabetes, to name a few. Interestingly, cellular senescence is known to play a critical role in the pathophysiology of these comorbidities as well. It is therefore important to understand the role of cellular senescence in the disease progression and co-morbidity development in HIV-infected individuals. In this respect, use of senolytic/senomorphic drugs as combination therapy with ART would be beneficial for HIV patients. This review provides a critical analysis of the current literature to determine the potential and efficacy of using senolytics/senotherapeutics in managing HIV infection, latency, and associated co-morbidities in humans. The various classes of senolytics have been studied in detail to focus on their potential to combat against HIV infections and associated pathologies with advancing age. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a common degenerative joint disease that disproportionately impacts the elderly population on a global scale. As aging is a significant risk factor for OA, there is a growing urgency to develop specific therapies that target the underlying mechanisms of aging associated with this condition. This summary seeks to offer a thorough introduction of ongoing research efforts aimed at developing therapies to combat senescence in the context of OA. Cellular senescence plays a pivotal role in both the deterioration of cartilage integrity and the perpetuation of chronic inflammation and tissue remodeling. Consequently, targeting SnCs has emerged as a promising therapeutic approach to alleviate symptoms and hinder the progression of OA. This review examines a range of approaches, including senolytic drugs targeting SnCs, senomorphics that modulate the senescence-associated secretory phenotype (SASP), and interventions that enhance immune system clearance of SnCs. Novel methodologies, such as utilizing novel materials for exosome delivery and administering anti-aging medications with precision, offer promising avenues for the precise treatment of OA. Accumulating evidence underscores the potential of targeting senescence in OA management, potentially facilitating the development of more effective and personalized therapeutic interventions. [Display omitted] • Therapies like senolytics and senomorphics may alleviate symptoms and slow OA progression. • Using advanced materials for exosome delivery and precise anti-aging medication. • Targeted therapy with the senescence of autophagy related to osteoarthritis. • Preclinical studies show promise for senolytic and senomorphic drugs in delaying OA. [ABSTRACT FROM AUTHOR]

The underlying mechanisms of diseases affecting the central nervous system (CNS) remain unclear, limiting the development of effective therapeutic strategies. Remarkably, cellular senescence, a biological phenomenon observed in cultured fibroblasts in vitro , is a crucial intrinsic mechanism that influences homeostasis of the brain microenvironment and contributes to the onset and progression of CNS diseases. Cellular senescence has been observed in disease models established in vitro and in vivo and in bodily fluids or tissue components from patients with CNS diseases. These findings highlight cellular senescence as a promising target for preventing and treating CNS diseases. Consequently, emerging novel therapies targeting senescent cells have exhibited promising therapeutic effects in preclinical and clinical studies on aging-related diseases. These innovative therapies can potentially delay brain cell loss and functional changes, improve the prognosis of CNS diseases, and provide alternative treatments for patients. In this study, we examined the relevant advancements in this field, particularly focusing on the targeting of senescent cells in the brain for the treatment of chronic neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, and multiple sclerosis) and acute neurotraumatic insults (e.g., ischemic stroke, spinal cord injury, and traumatic brain injury). [Display omitted] • Cellular senescence (CS) is intricately linked with central nervous system (CNS) diseases. • CS is a novel therapeutic target for treating CNS diseases. • Senomorphics and senolytics bring new hope for patients with CNS diseases. • Further exploration of CS-centered research is essential for advancing the treatment of aging-related diseases. [ABSTRACT FROM AUTHOR]

The skin is the largest organ and has a key protective role. Similar to any other tissue, the skin is influenced not only by intrinsic/chronological aging, but also by extrinsic aging, triggered by environmental factors that contribute to accelerating the skin aging process. Aged skin shows structural, cellular, and molecular changes and accumulation of senescent cells. These senescent cells can induce or accelerate the age-related dysfunction of other nearby cells from the skin, or from different origins. However, the extent and underlying mechanisms remain unknown. In this opinion, we discuss the possible relevant role of skin senescence in the induction of aging phenotypes to other organs/tissues, contributing to whole-body aging. Moreover, we suggest that topical administration of senolytics/senotherapeutics could counteract the overall whole-body aging phenotype. With age, senescent cells accumulate in the skin and spread the aging phenotype to neighboring cells, resulting in decreased thickness, regenerative capacity, and a barrier effect in the skin. Aging and cellular senescence phenotypes in the skin were found to correlate with immunosenescence, longevity, or cardiovascular disease risk. Skin aging, induced by ultraviolet radiation, has an impact in the brain, by decreasing hippocampal neurogenesis and activating the central hypothalamic–pituitary–adrenal axis. Senolytics, such as dasatinib and fisetin, are drugs that selectively eliminate senescent cells and are already topically administered to the skin, showing potential antiaging effects. [ABSTRACT FROM AUTHOR]

This year in review on osteoarthritis biology summarizes a series of research articles published between the 2020 and 2021 Osteoarthritis Research Society International (OARSI) World Congress. Research hightlights were selected and discussed based on the new discoveries of OA's cellular molecular mechanism, anatomical signatures, potential therapeutic targets, and regenerative therapy. The recently developed potential therapeutic targets are summarized, and the research focuses on TGFβ and WNT signaling in joint tissue homeostasis, joint aging and the dynamic of synolytics in OA joint, and the roles of TRP2, LDHA, OSCAR in cartilage homeostasis and OA joints are highlighted. Subsquencially, new anatomical structures and OA features are introduced, such as synovitis-induced venous portal circulation, horiozontal fissures between cartilage and subchondral bone, the cellular derivation of osteophytes formation, OA subtypes, and subchondral remodeling and pain biology. Then, research on the possibility of tissue regeneration in OA joints are discussed; skeletal stem cells in OA cartilage regeneration, and preclinical results of regenerative therapy for meniscus tear and osteochondral tissue morphoghesis are included. At last, the clinical evidence of the importance of delivery site of bone marrow stem cells for OA treatment is discussed. These findings represent advances in our understanding of OA pathophysiology. [ABSTRACT FROM AUTHOR]

• Cytotoxic therapy increases the risk for therapy-related myeloid neoplasms (t-MN). • While HSC-intrinsic effects are crucial, t-MN is also dependent on extrinsic factors. • Cytotoxic therapy drives senescence in the bone marrow microenvironment (BMME). • Current studies support a role for BMME senescence in the development of t-MN. • Targeting of senescent BMSCs may alleviate BM dysfunction and mitigate t-MN. Therapy-related myeloid neoplasms (t-MN) are a growing concern due to the continued use of cytotoxic therapies to treat malignancies. Cytotoxic therapies have been shown to drive therapy-induced senescence in normal tissues, including in the bone marrow microenvironment (BMME), which plays a crucial role in supporting normal hematopoiesis. This review examines recent work that focuses on the contribution of BMME senescence to t-MN pathogenesis, as well as offers a perspective on potential opportunities for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Dasatinib and quercetin (D & Q) have demonstrated promise in improving aged-related pathophysiological dysfunctions in humans and mice. Herein we aimed to ascertain whether the heat stress (HS)-induced cognitive deficits in aged or even young adult male mice can be reduced by D & Q therapy. Before the onset of HS, animals were pre-treated with D & Q or placebo for 3 consecutive days every 2 weeks over a 10-week period. Cognitive function, intestinal barrier permeability, and blood-brain barrier permeability were assessed. Compared to the non-HS young adult male mice, the HS young adult male mice or the aged male mice had significantly lesser extents of the exacerbated stress reactions, intestinal barrier disruption, endotoxemia, systemic inflammation and oxidative stress, blood-brain barrier disruption, hippocampal inflammation and oxidative stress, and cognitive deficits evaluated at 7 days post-HS. All the cognitive deficits and other syndromes that occurred in young adult HS mice or in aged HS mice were significantly attenuated by D & Q therapy (P < 0.01). Compared to the young adult HS mice, the aged HS mice had significantly (P < 0.01) higher severity of cognitive deficits and other related syndromes. First, our data show that aged male mice are more vulnerable to HS-induced cognitive deficits than those of the young adult male mice. Second, we demonstrate that a combination of D and Q therapy attenuates cognitive deficits in heat stressed aged or young adult male mice via broad normalization of the brain-gut-endotoxin axis function. [ABSTRACT FROM AUTHOR]

Stress-induced premature senescent (SIPS) cells induced by various stresses deteriorate cell functions. Dasatinib and quercetin senolytics (DQ) can alleviate several diseases by eliminating senescent cells. α-tricalcium phosphate (α-TCP) is a widely used therapeutic approach for bone restoration but induces bone formation for a comparatively long time. Furthermore, bone infection exacerbates the detrimental prognosis of bone formation during material implant surgery due to oral cavity bacteria and unintentional contamination. It is essential to mitigate the inhibitory effects on bone formation during surgical procedures. Little is known that DQ improves bone formation in Lipopolysaccharide (LPS)-contaminated implants and its intrinsic mechanisms in the study of maxillofacial bone defects. This study aims to investigate whether the administration of DQ ameliorates the impairments on bone repair inflammation and contamination by eliminating SIPS cells. α-TCP and LPS-contaminated α-TCP were implanted into Sprague-Dawley rat calvaria bone defects. Simultaneously, bone formation in the bone defects was investigated with or without the oral administration of DQ. Micro-computed tomography and hematoxylin-eosin staining showed that senolytics significantly enhanced bone formation at the defect site. Histology and immunofluorescence staining revealed that the levels of p21- and p16-positive senescent cells, inflammation, macrophages, reactive oxygen species, and tartrate-resistant acid phosphatase-positive cells declined after administering DQ. DQ could partially alleviate the production of senescent markers and senescence-associated secretory phenotypes in vitro. This study indicates that LPS-contaminated α-TCP-based biomaterials can induce cellular senescence and hamper bone regeneration. Senolytics have significant therapeutic potential in reducing the adverse osteogenic effects of biomaterial-related infections and improving bone formation capacity. [Display omitted] • LPS-contaminated biomaterials induce cellular senescence and impede bone regeneration. • Senolytics reduce senescent cells and adverse osteogenic effects. • Senolytics may enhance bone formation in infections associated with biomaterial implantation. [ABSTRACT FROM AUTHOR]

Despite the increasing number of treatment options available for liver cancer, only a small proportion of patients achieve long-term clinical benefits. Here, we aim to develop new therapeutic approaches for liver cancer. A compound screen was conducted to identify inhibitors that could synergistically induce senescence when combined with cyclin-dependent kinase (CDK) 4/6 inhibitor. The combination effects of CDK4/6 inhibitor and exportin 1 (XPO1) inhibitor on cellular senescence were investigated in a panel of human liver cancer cell lines and multiple liver cancer models. A senolytic drug screen was performed to identify drugs that selectively killed senescent liver cancer cells. The combination of CDK4/6 inhibitor and XPO1 inhibitor synergistically induces senescence of liver cancer cells in vitro and in vivo. The XPO1 inhibitor acts by causing accumulation of RB1 in the nucleus, leading to decreased E2F signaling and promoting senescence induction by the CDK4/6 inhibitor. Through a senolytic drug screen, cereblon (CRBN)–based proteolysis targeting chimera (PROTAC) ARV-825 was identified as an agent that can selectively kill senescent liver cancer cells. Up-regulation of CRBN was a vulnerability of senescent liver cancer cells, making them sensitive to CRBN-based PROTAC drugs. Mechanistically, we find that ubiquitin specific peptidase 2 (USP2) directly interacts with CRBN, leading to the deubiquitination and stabilization of CRBN in senescent liver cancer cells. Our study demonstrates a striking synergy in senescence induction of liver cancer cells through the combination of CDK4/6 inhibitor and XPO1 inhibitor. These findings also shed light on the molecular processes underlying the vulnerability of senescent liver cancer cells to CRBN-based PROTAC therapy. [Display omitted] Our study demonstrates that simultaneous inhibition of CDK4/6 and XPO1 induces senescence in liver cancer cells, making them susceptible to CRBN-based PROTAC drugs. [ABSTRACT FROM AUTHOR]

The accumulation of senescent cells induces age-related dysfunction in various organs, and the selective clearance of senescent cells is a potential approach for treating age-related diseases. Hence, identifying natural foods that provide senolytic benefits is important because they may serve as a preventative measure and an alternative to pharmaceutical interventions for aging that mitigates the potential side effects associated with drug-based approaches. In this study, we investigated the senolytic activity of ethanol extracts derived from Agrimonia pilosa Ledeb (APL-E) and agrimol B, an active component of the plant, in doxorubicin-induced senescent WI38 cells. APL-E and agrimol B decreased senescence-associated-β-galactosidase (SA-β-gal)-positive senescent WI38 cells in a concentration-dependent manner. Annexin V staining revealed that APL-E and agrimol B caused apoptosis in senescent cells. To investigate the effect of APL-E on senolytic activity in vivo , aged male C57BL/6J mice were fed APL-E for 3 months. SA-β-gal staining revealed significantly decreased senescent cells in the liver and kidney of APL-E-fed aged mice. The expression levels of senescence-associated secretory phenotype factors Il1β , Ccl2 , and Cxcl9 were also decreased in the livers and kidneys of APE-fed mice. The number of senescent CD8+T cells in the blood decreased in APL-E-fed aged mice. Furthermore, APL-E-fed mice showed improvement in aging-induced immune senescence, marked by increased naïve CD8+T cells and decreased memory CD8+T cells. This study provides evidence of the novel senolytic activity of APL-E and agrimol B and suggests their application as preventatives against various age-related disorders. [ABSTRACT FROM AUTHOR]

Cellular senescence is a heterogeneous process guided by genetic, epigenetic and environmental factors, characterizing many types of somatic cells. It has been suggested as an aging hallmark that is believed to contribute to aging and chronic diseases. Senescent cells (SC) exhibit a specific senescence-associated secretory phenotype (SASP), mainly characterized by the production of proinflammatory and matrix-degrading molecules. When SC accumulate, a chronic, systemic, low-grade inflammation, known as inflammaging, is induced. In turn, this chronic immune system activation results in reduced SC clearance thus establishing a vicious circle that fuels inflammaging. SC accumulation represents a causal factor for various age-related pathologies. Targeting of several aging hallmarks has been suggested as a strategy to ameliorate healthspan and possibly lifespan. Consequently, SC and SASP are viewed as potential therapeutic targets either through the selective killing of SC or the selective SASP blockage, through natural or synthetic compounds. These compounds are members of a family of agents called senotherapeutics divided into senolytics and senomorphics. Few of them are already in clinical trials, possibly representing a future treatment of age-related pathologies including diseases such as atherosclerosis, osteoarthritis, osteoporosis, cancer, diabetes, neurodegenerative diseases such as Alzheimer's disease, cardiovascular diseases, hepatic steatosis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and age-related macular degeneration. In this review, we present the already identified senolytics and senomorphics focusing on their redox-sensitive properties. We describe the studies that revealed their effects on cellular senescence and enabled their nomination as novel anti-aging agents. We refer to the senolytics that are already in clinical trials and we present various adverse effects exhibited by senotherapeutics so far. Finally, we discuss aspects of the senotherapeutics that need improvement and we suggest the design of future senotherapeutics to target specific redox-regulated signaling pathways implicated either in the regulation of SASP or in the elimination of SC. [Display omitted] • Senescent cells exhibit a senescence-associated secretory phenotype (SASP). • Senomorphics are small molecules that can suppress SASP. • Senolytics are agents that selectively eliminate senescent cells. • Various natural compounds and drugs are potential senolytics and/or senomorphics. • Future senotherapeutics to target specific redox-regulated signaling pathways. [ABSTRACT FROM AUTHOR]

Cellular senescence has a critical role in many physiopathological contexts. Recent studies highlight the beneficial and adverse effects that eliminating senescent endothelial cells can have on health span, questioning the current development of drugs that induce the death of senescent cells, named senolytics, as a therapeutic strategy. [ABSTRACT FROM AUTHOR]

Much of the population is now faced with an enormous burden of age-associated chronic diseases. Recent discoveries in geroscience indicate that healthspan in model organisms such as mice can be manipulated by targeting cellular senescence, a hallmark mechanism of aging, defined as an irreversible proliferative arrest that occurs when cells experience oncogenic or other diverse forms of damage. Senescent cells and their proinflammatory secretome have emerged as contributors to age-related tissue dysfunction and morbidity. Cellular senescence has causal roles in mediating osteoporosis, frailty, cardiovascular diseases, osteoarthritis, pulmonary fibrosis, renal diseases, neurodegenerative diseases, hepatic steatosis, and metabolic dysfunction. Therapeutically targeting senescent cells in mice can prevent, delay, or alleviate each of these conditions. Therefore, senotherapeutic approaches, including senolytics and senomorphics, that either selectively eliminate senescent cells or interfere with their ability to promote tissue dysfunction, are gaining momentum as potential realistic strategies to abrogate human senescence to thereby compress morbidity and extend healthspan. [ABSTRACT FROM AUTHOR]

Hsp90 chaperone is an encouraging target for the development of novel anticancer agents. The failure of Hsp90 inhibitors to get regulatory approval for the treatment of cancer is hindered due to toxicity, cost involved in their development and formulation issues. The inhibitors against this chaperone are also being evaluated in pre-clinical models for the treatment of diseases other than cancer (Alzheimer, malaria, AIDS, etc.). Recently, Hsp90 inhibitors have shown promising senolytic effect that is helpful in increasing the health and life span of mice. The senolytic property of Hsp90 inhibitors will make them less toxic for use in humans. The review focuses on Hsp90 inhibitors discovered till date as senolytic agents along with their future prospects. Further, the various models used for the evaluation of senolytic effect are also discussed. [ABSTRACT FROM AUTHOR]

Aging is a major risk factor for numerous human pathologies, including cardiovascular, metabolic, musculoskeletal, and neurodegenerative conditions and various malignancies. While our understanding of aging is far from complete, recent advances suggest that targeting fundamental aging processes can delay, prevent, or alleviate age-related disorders. Cellular senescence is physiologically beneficial in several contexts, but it has causal roles in multiple chronic diseases. New studies have illustrated the promising feasibility and safety to selectively ablate senescent cells from tissues, a therapeutic modality that holds potential for treating multiple chronic pathologies and extending human healthspan. Here, we review molecular links between cellular senescence and age-associated complications and highlight novel therapeutic avenues that may be exploited to target senescent cells in future geriatric medicine. Aging is the largest risk factor for most pathologies, ranging from cancer to neurodegenerative disorders. Senescent cells accumulate in organs during aging, promote tissue dysfunction, and cause pathological manifestations, with senescence as a defining feature of myriad aging-related diseases. Senescent cells display hallmark features, including the senescence-associated secretory phenotype (SASP), a major driver of pathologies, and alterations to the structure and function of organelles. Targeted elimination of senescent cells has emerged as a promising therapeutic solution to ameliorate tissue damage and promote repair and regeneration. In the scope of clinical medicine, advances that identify key biochemical pathways, specifically those differentiating senescent cells from their proliferating counterparts, would positively affect pathological and aging processes. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA), a chronic joint disease affecting millions of people aged over 65 years, is the main musculoskeletal cause of diminished joint mobility in the elderly. It is characterized by lingering pain and increasing deterioration of articular cartilage. Aging and accumulation of senescent cells (SCs) in the joints are frequently associated with OA. Apoptosis resistance; irreversible cell cycle arrest; increased p16INK4a expression, secretion of senescence-associated secretory phenotype factors, senescence-associated β-galactosidase levels, secretion of extracellular vesicles, and levels of reactive oxygen and reactive nitrogen species; and mitochondrial dysregulation are some common changes in cellular senescence in joint tissues. Development of OA correlates with an increase in the density of SCs in joint tissues. Senescence-associated secretory phenotype has been linked to OA and cartilage breakdown. Senolytics and therapeutic pharmaceuticals are being focused upon for OA management. SCs can be selectively eliminated or killed by senolytics to halt the pathogenesis and progression of OA. Comprehensive understanding of how aging affects joint dysfunction will benefit OA patients. Here, we discuss age-related mechanisms associated with OA pathogenesis and senolytics as an emerging modality in the management of age-related SCs and pathogenesis of OA in preclinical and clinical studies. [Display omitted] • Senescence in joint tissue accelerates osteoarthritis. • Senescent cells (SCs) exhibit increased SA-β-gal activity and p16 upregulation. • Increase in SCs and SASP factors can promote osteoarthritis development. • Senolytics can eliminate SCs by targeting signaling pathways active in these cells. • Targeted removal of SCs offers a promising avenue for osteoarthritis treatment. [ABSTRACT FROM AUTHOR]

Many cancers respond to initial treatment but most of them relapse due to the persistence of dormant tumor cells. Determining the exact nature of the dormant state is crucial to develop therapies aiming to eradicate the dormant cells. Here, we argue that therapy-induced senescence of cancer cells could be an alternative form of dormancy. [ABSTRACT FROM AUTHOR]

Abstract Radiotherapy is still a treatment of choice for many malignancies, often in combination with other strategies. However, its efficacy is limited by the dose that can be safely administered without eliciting serious side-effects, as well as the fact that recurrence is common, particularly in large tumours. Combining radiotherapy with drugs that could sensitise cells to radiation and/or reduce the factors that promote the recovery of the surviving cancer cells is a promising approach. Ionising radiation has been shown to induce senescence and the accumulation of senescent cells creates a microenvironment that facilitates neoplastic growth. This provides a rationale to test the addition of anti-senescent drugs, some of which are already available in the clinic, to radiotherapy protocols. Here, we discuss the relevance of radiotherapy-induced senescent cell accumulation and the potential interventions to minimise its negative effects. [ABSTRACT FROM AUTHOR]

Oxidative stress has long been considered a key component contributing to pathologies associated with brain aging and age-related neurodegenerative diseases. The proposed mechanisms involved are varied, but recently have been suggested to include induction of cellular senescence, a cellular growth arrest state characterized by the secretion of pre-inflammatory senescence-associated secretory phenotype (SASP) factors. The post-mitotic status of neurons has been traditionally considered to prohibit cellular senescence, however recent studies have provided compelling evidence that neurons may be capable of undergoing senescence in response to oxidative stress and other factors. Development of senolytics, small molecules that selectively induce senescent cell death, could represent a paradigm change for the treatment of neurodegenerative diseases including Alzheimer's and Parkinson's disease (AD, PD). However, their use depends on unequivocal validation that neurons can senesce and that they do not have detrimental off-target effects in other cell types in the brain and elsewhere. fx1 • Cellular senescence, a growth arrest state in replication-competent cells, has been implicated in brain aging and disease. • Recent studies suggest that post-mitotic neurons can undergo senescence in response to oxidative stress and other factors. • Senescent cell-eliminating drugs called senolytics may constitute a novel therapeutic for neurodegenerative diseases. • Their use will be however dependent on both validation of neuronal senescence and lack of detrimental off-target effects. [ABSTRACT FROM AUTHOR]

[Display omitted] • 6-shogaol improved motor and memory deficits in the aged mice. • 6-shogaol attenuated neurodegeneration and neuroinflammation in the aged mice. • 6-shogaol inhibited p75 neurotrophin receptor expression in the brain of aged mice. The present study aimed to investigate the effect of 6-shogaol (6S) treatment on brain senescence. Mice were naturally aged until 25-month-old and treated with 10 mg/kg of 6S for a month. Behavioral tests were performed to measure locomotion and cognitive function. Neuronal damage, synaptic plasticity, neuroinflammation, neurogenesis and p75 neurotrophin receptor (p75NTR) expression were examined by immunohistochemistry or immunofluorescence. 6S treatment improved locomotion during open field test in the aged mice and spontaneous alternation in Y-maze. These data are in line with that 6S administration improved dopaminergic neuronal loss and dopamine signaling and attenuated hippocampal synaptic plasticity in the aged brain. Additionally, 6S treatment reduced striatal and hippocampal microgliosis and astrocytosis but promoted neurogenesis in subventricular zone. Furthermore, 6S treatment reversed the p75NTR expression in the senescent brain. The current findings suggest that 6S can be a functional food for successful aging through brain rejuvenation at the molecular level. [ABSTRACT FROM AUTHOR]

[Display omitted] Selective removal of senescent cells (SnCs) offers a promising therapeutic strategy to treat chronic and age-related diseases. Our prior investigations led to the discovery of piperlongumine (PL) and its derivatives as senolytic agents. In this study, our medicinal chemistry campaign on both the α,β-unsaturated δ-valerolactam ring and the phenyl ring of PL culminated in the identification of compound 24 , which exhibited an impressive 50-fold enhancement in senolytic activity against senescent WI-38 fibroblasts compared to PL. [ABSTRACT FROM AUTHOR]

Cellular senescence is a state of terminal cell cycle arrest associated with various macromolecular changes and a hypersecretory phenotype. In the brain, senescent cells naturally accumulate during aging and at sites of age-related pathologies. Here, we discuss the recent advances in understanding the accumulation of senescent cells in brain aging and disorders. Here we highlight the phenotypical heterogeneity of different senescent brain cell types, highlighting the potential importance of subtype-specific features for physiology and pathology. We provide a comprehensive overview of various senescent cell types in naturally occurring aging and the most common neurodegenerative disorders. Finally, we critically discuss the potential of adapting senotherapeutics to improve brain health and reduce pathological progression, addressing limitations and future directions for application and development. • Accumulation of senescent cells is common in aging brains and classical neurodegenerative diseases in humans. • Preclinical models have demonstrated that the elimination of senescent cells alleviates neurodegeneration. • Anti-senescence therapies are a promising approach for alleviating neurodegenerative disorders in humans. • Enhanced technologies are facilitating the identification of senescent subtypes present at sites of age-related brain disorders. • The anti-senescence approach urges for targeting specific cellular senescence subtypes. [ABSTRACT FROM AUTHOR]

The identification of senolytics, compounds that eliminate senescent cells, is presently a key priority given their therapeutic promise in cancer and aging-associated diseases. Two recent papers by Triana-Martínez et al. and Guerrero et al. report the senolytic activity of cardiac glycosides (CGs) and their efficacy in these pathophysiological contexts. [ABSTRACT FROM AUTHOR]

Abstract Musculoskeletal ageing and its associated diseases are major contributors to the loss of independence and reduced quality of life in older people. Several recent studies indicate that cellular senescence is a contributor to age-related loss of function in various organs including muscle, bones and joints. Importantly, these studies indicate that therapies targeting specifically senescent cells have great therapeutic potential in improving musculoskeletal health during ageing. Senescent cells are characterised by dramatic changes in mitochondrial function, metabolism and homeostasis. Mitochondrial dysfunction has been shown to contribute to senescence and the SASP. Here we review the role of cellular senescence in musculoskeletal ageing as well as the potential mechanisms by which mitochondrial dysfunction may impact on the induction and development of the senescent phenotype. Graphical abstract fx1 Highlights • Cellular senescence is a contributor to age-related loss of musculoskeletal health. • Senotherapies improve musculoskeletal function during ageing in mice. • Mitochondrial dysfunction drives senescence and the SASP. • Targeting mitochondrial dysfunction may counteract the negative impact of senescence. [ABSTRACT FROM AUTHOR]

Cellular senescence is a process that results in irreversible cell-cycle arrest, and is thought to be an autonomous tumor-suppressor mechanism. During senescence, cells develop distinctive metabolic and signaling features, together referred to as the senescence-associated secretory phenotype (SASP). The SASP is implicated in several aging-related pathologies, including various malignancies. Accumulating evidence argues that cellular senescence acts as a double-edged sword in human cancer, and new agents and innovative strategies to tackle senescent cells are in development pipelines to counter the adverse effects of cellular senescence in the clinic. We focus on recent discoveries in senescence research and SASP biology, and highlight the potential of SASP suppression and senescent cell clearance in advancing precision medicine. Highlights Cellular senescence is a highly conserved stress response that restrains the proliferation of cells at risk of oncogenic transformation. Senescent cells spatially occupy tissue environmental niches and elaborate numerous extracellular factors encoded by the SASP, contributing to aging-related disorders, notably cancer. In the tumor microenvironment, senescent cells can drive events that support malignant progression, including but not limited to therapeutic resistance, disease relapse, and distant metastasis. In cancer clinics, the abundance of senescent cells can serve as a 'molecular' marker that predicts adverse outcomes, while senescent cell clearance significantly mitigates pathological exacerbation. A new class of agents, termed senolytics, has been shown to be effective in extending healthspan, reducing frailty and improving stem cell function in animal models of aging. [ABSTRACT FROM AUTHOR]

Selectively ablating damaged cells is an evolving therapeutic approach for age-related disease. Current methods for genome-wide screens to identify genes whose deletion might promote the death of damaged or senescent cells are generally underpowered because of the short timescales of cell death as well as the difficulty of scaling non-dividing cells. Here, we establish "Death-seq," a positive-selection CRISPR screen optimized to identify enhancers and mechanisms of cell death. Our screens identified synergistic enhancers of cell death induced by the known senolytic ABT-263. The screen also identified inducers of cell death and senescent cell clearance in models of age-related diseases by a related compound, ABT-199, which alone is not senolytic but exhibits less toxicity than ABT-263. Death-seq enables the systematic screening of cell death pathways to uncover molecular mechanisms of regulated cell death subroutines and identifies drug targets for the treatment of diverse pathological states such as senescence, cancer, and fibrosis. [Display omitted] • Death-seq is a screening method that enables the systematic study of cell death • Death-seq enables the identification of enhancers and inhibitors of cell death • CRISPR screens with Death-seq identify senolytics for age-related disease Colville et al. present a genetic screening method called Death-seq to compare positively selected dying cells directly against living cells to improve the ability to systematically identify enhancers and mechanisms of cell death. They then applied this method to identify enhancers of selective cell death in senescent cells in age-related disease. [ABSTRACT FROM AUTHOR]

Since Hayflick’s discovery of cellular senescence (CS), a great volume of knowledge in the field has been accumulated and intensively discussed. Here, we attempted to organize the evidence “for” and “against” the hypothesized causal role of CS in aging. For that purpose, we utilized robust Koch-like logical criteria, based on the assumption that some quantitative relationships between the accumulation of senescent cells and aging rate should exist. If so, it could be expected that (i) the “CS load” would be greater in the premature aging phenotype and lesser in longevity phenotype; (ii) CS would promote age-related diseases, and (iii) the interventions that modulate the levels of senescent cells should also modulate health/lifespan. The analysis shows that CS can be considered a causal factor of aging and an important player in various age-related diseases, though its contribution may greatly vary across species. While the relative impact of senescent cells to aging could overall be rather limited and their elimination is hardly expected to be the “fountain of youth”, the potential benefits of the senolytic strategy seems a promising option in combating age-related diseases and extending healthspan. [ABSTRACT FROM AUTHOR]

The growing burden of obesity- and aging-related diseases has hastened the search for governing biological processes. Cellular senescence is a stress-induced state of stable growth arrest strongly associated with aging that is aberrantly activated by obesity. The transition of a cell to a senescent state is demarcated by an array of phenotypic markers, and leveraging their context-dependent presentation is essential for determining the influence of senescent cells on tissue pathogenesis. Biomarkers of senescent cells have been identified in tissues that contribute to metabolic disease, including fat, liver, skeletal muscle, pancreata, and cardiovascular tissue, suggesting that pharmacological and behavioral interventions that alter their abundance and/or behavior may be a novel therapeutic strategy. However, contradictory findings with regard to a protective versus deleterious role of senescent cells in certain contexts emphasize the need for additional studies to uncover the complex interplay that defines multi-organ disease processes associated with obesity and aging. [ABSTRACT FROM AUTHOR]

• Parkinson's Disease (PD) affects motor functions of individual. • Accumulation of senescent cells (SC) deteriorate the pathological cascade of PD. • SC secrete components that make up the senescence-associated secretory phenotype (SASP). • Senolytics are reported to selectively kill SC via apoptosis. • Dasatinib, Quercetin, Fisetin and Navitoclax have ability to kill SC. Aging is one of the major risk factors for most neurodegenerative disorders including Parkinson's disease (PD). More than 10 million people are affected with PD worldwide. One of the predominant factors accountable for progression of PD pathology could be enhanced accumulation of senescent cells in the brain with the progress of age. Recent investigations have highlighted that senescent cells can ignite PD pathology via increased oxidative stress and neuroinflammation. Senolytics are agents that kill senescent cells. This review mainly focuses on understanding the pathological connection between senescence and PD, with emphasis on some of the recent advances made in the area of senolytics and their evolution to potential clinical candidates for future pharmaceuticals against PD. [ABSTRACT FROM AUTHOR]

Cardiac fibroblasts are a cell population that controls the homeostasis of the extracellular matrix and orchestrates a damage response to maintain cardiac architecture and performance. Due to these functions, fibroblasts play a central role in cardiac fibrosis development, and there are large differences in matrix protein secretion profiles between fibroblasts from aged versus young animals. Senescence is a multifactorial and complex process that has been associated with inflammatory and fibrotic responses. After damage, transient cellular senescence is usually beneficial, as these cells promote tissue repair. However, the persistent presence of senescent cells within a tissue is linked with fibrosis development and organ dysfunction, leading to aging-related diseases such as cardiovascular pathologies. In the heart, early cardiac fibroblast senescence after myocardial infarction seems to be protective to avoid excessive fibrosis; however, in non-infarcted models of cardiac fibrosis, cardiac fibroblast senescence has been shown to be deleterious. Today, two new classes of drugs, termed senolytics and senostatics, which eliminate senescent cells or modify senescence-associated secretory phenotype, respectively, arise as novel therapeutical strategies to treat aging-related pathologies. However, further studies will be needed to evaluate the extent of the utility of senotherapeutic drugs in cardiac diseases, in which pathological context and temporality of the intervention must be considered. • Cardiac fibroblast senescence play an important role in cardiac fibrosis • Cardiac fibroblasts senescence could limit the excessive fibrotic response after MI. • In a chronic setting, SASP contributes to chronic inflammation, collagen deposition, and cardiac fibrosis. • Senotherapeutics drugs could be new therapies to reduce the burden of fibrotic diseases. [ABSTRACT FROM AUTHOR]

Aging is one of the world's greatest concerns, requiring urgent, effective, large-scale interventions to decrease the number of late-life chronic diseases and improve human healthspan. Anti-aging drug therapy is one of the most promising strategies to combat the effects of aging. However, most geroprotective compounds are known to successfully affect only a few aging-related targets. Given this, there is a great biological rationale for the use of combinations of anti-aging interventions. In this review, we characterize the various types of compound combinations used to modulate lifespan, discuss the existing evidence on their role in life extension, and present some key points about current challenges and future prospects for the development of combination drug anti-aging therapy. • Using combinations of compounds for anti-aging therapy is a promising strategy. • The effects of combinations with metformin, rapamycin, rifampicin are best studied. • Synergistic combinations multiply life extension and alleviate adverse effects. • Combinations of compounds causing synergistic anti-aging effects are of most interest. • For now, resveratrol combined with plant extracts shows the best synergistic effects. [ABSTRACT FROM AUTHOR]

Several behavioral and pharmacological strategies improve longevity, which is indicative of delayed organismal aging, with the most effective interventions extending both life- and healthspan. In free living creatures, maintaining health and function into old age requires resilience against a multitude of stressors. Conversely, in experimental settings, conventional housing of rodents limits exposure to such challenges, thereby obscuring an accurate assessment of resilience. Caloric restriction (CR) and exercise, as well as pharmacologic strategies (resveratrol, rapamycin, metformin, senolytics), are well established to improve indices of health and aging, but some paradoxical effects have been observed on resilience. For instance, CR potently retards the onset of age-related diseases, and improves lifespan to a greater extent than exercise in a variety of models. However, exercise has proven more consistently beneficial to organismal resilience against a broad array of stressors, including infections, surgery, wound healing and frailty. CR can improve cellular stress defenses and protect from frailty, but also impairs the response to infections, bed rest and healing. How an intervention will impact not only longevity, health and function, but also resiliency, is critical to better understanding translational implications. Thus, organismal robustness represents a critical, albeit understudied aspect of aging, which needs more careful attention in order to better inform on how putative age-delaying strategies will impact preservation of health and function in response to stressors with aging in humans. [ABSTRACT FROM AUTHOR]

• MSC senescence poses a major challenge in regenerative application. • Senotherapeutics could overcome MSC senescence during in vitro expansion. • Senotherapeutics could foster efficient tissue rejuvenation and transplantation. • Repurposing approved drugs can accelerate the clinical applications of senotherapeutics. Mesenchymal stem cells (MSCs) are susceptible to replicative senescence and senescence-associated functional decline, which hampers their use in regenerative medicine. Senotherapeutics are drugs that target cellular senescence through senolytic and senomorphic functions to induce apoptosis and suppress chronic inflammation caused by the senescence-associated secreted phenotype (SASP), respectively. Therefore, senotherapeutics could delay aging-associated degeneration. They could also be used to eliminate senescent MSCs during in vitro expansion or bioprocessing for transplantation. In this review, we discuss the role of senotherapeutics in MSC senescence, rejuvenation, and transplantation, with examples of some tested compounds in vitro. The prospects, challenges, and the way forward in clinical applications of senotherapeutics in cell-based therapeutics are also discussed. [ABSTRACT FROM AUTHOR]

Cellular senescence is a cell fate involving cell cycle arrest, resistance against apoptosis, and the development of a secretome that can be pro-inflammatory. In aging and obesity, senescent cells accumulate in many tissues, including adipose tissue, brain, kidney, pancreas, and liver. These senescent cells and their downstream effects appear to perpetuate inflammation and have been implicated in the pathogenesis of metabolic dysfunction. Senescent cells are cleared in part by the immune system, a process that is diminished in obesity and aging, likely due in part to senescence of immune cells themselves. Targeting senescent cells or their products improves metabolic function in both aging and in animal models of obesity. Novel therapeutics to target senescent cells are on the horizon and are currently being investigated in clinical trials in humans for multiple diseases. Early evidence suggests that senolytic drugs, which transiently disarm the anti-apoptotic defenses of pro-inflammatory senescent cells, are effective in causing depletion of senescent cells in humans. Senescence-targeting therapeutics, including senolytic drugs and strategies to increase immune clearance of senescent cells, hold significant promise for treating metabolic dysfunction in multiple tissues and disease states. [ABSTRACT FROM AUTHOR]

• Senescent astrocytes lose neuron-supportive function. • Senescent astrocytes and other CNS cell types increase in Alzheimer's disease (AD). • Targeting senescence in these cell types has reversed pathology in AD mouse models. • Many drugs that modulate or clear senescence have been tested in clinical trials. • Senescence clearing compounds (senolytics) are now being tested in AD patients. [ABSTRACT FROM AUTHOR]

Osteoporosis, is the most common bone disorder worldwide characterized by low bone mineral density, leaving affected bones vulnerable to fracture. Bone homeostasis depends on the precise balance between bone resorption by osteoclasts and bone matrix formation by mesenchymal lineage osteoblasts, and involves a series of complex and highly regulated steps. Bone homeostasis will be disrupted when the speed of bone resorption is faster than bone formation. Based on various regulatory mechanisms of bone homeostasis, a series of drugs targeting osteoporosis have emerged in clinical practice, including bisphosphonates, selective estrogen receptor modulators, calcitonin, molecular-targeted drugs and so on. However, many drugs have major adverse effects or are unsuitable for long-term use. Therefore, it is very urgent to find more effective therapeutic drugs based on the new pathogenesis of osteoporosis. In this review, we summarize novel mechanisms involved in the pathological process of osteoporosis, including the roles of gut microbiome, autophagy, iron balance and cellular senescence. Based on the above pathological mechanism, we found promising drugs for osteoporosis treatment, such as: probiotics, alpha-ketoglutarate, senolytics and hydrogen sulfide. This new finding may provide an important basis for elucidating the complex pathological mechanisms of osteoporosis and provide promising drugs for clinical osteoporosis treatment. [ABSTRACT FROM AUTHOR]

• Let-7f is the most stable miRNA in bone in aging mice and humans. • Let-7f is stable in bone cells following induction or elimination of senescence. • Let-7f is a more highly stable reference gene than the commonly used U6 gene. MicroRNAs (miRNAs) are promising tools as biomarkers and therapeutic agents in various chronic diseases such as osteoporosis, cancers, type I and II diabetes, and cardiovascular diseases. Considering the rising interest in the regulatory role of miRNAs in bone metabolism, aging, and cellular senescence, accurate normalization of qPCR-based miRNA expression data using an optimal endogenous control becomes crucial. We used a systematic approach to select candidate endogenous control miRNAs that exhibit high stability with aging from our miRNA sequence data and literature search. Validation of miRNA expression was performed using qPCR and their comprehensive stability was assessed using the RefFinder tool which is based on four statistical algorithms: GeNorm, NormFinder, BestKeeper, and comparative delta CT. The selected endogenous control was then validated for its stability in mice and human bone tissues, and in bone marrow stromal cells (BMSCs) following induction of senescence and senolytic treatment. Finally, the utility of selected endogenous control versus U6 was tested by using each as a normalizer to measure the expression of miR-34a , a miRNA known to increase with age and senescence. Our results show that Let-7f did not change across the groups with aging, senescence or senolytic treatment, and was the most stable miRNA, whereas U6 was the least stable. Moreover, using Let-7f as a normalizer resulted in significantly increased expression of miR-34a with aging and senescence and decreased expression following senolytic treatment. However, the expression pattern for miR-34a reversed for each of these conditions when U6 was used as a normalizer. We show that optimal endogenous control miRNAs, such as Let-7f , are essential for accurate normalization of miRNA expression data to increase the reliability of results and prevent misinterpretation. Moreover, we present a systematic strategy that is transferrable and can easily be used to identify endogenous control miRNAs in other biological systems and conditions. [ABSTRACT FROM AUTHOR]

[Display omitted] Senescence is a special state of tumor suppression induced by cell cycle arrest. However, releasing senescence-associated secretory phenotypes by senescent cells could provide tumorigenic conditions and epigenetic changes in neighboring cells. The conventional anticancer drugs activate therapy-induced senescence by several mechanisms which include an increase in mitochondrial biogenesis and reactive oxygen species, up-regulation of tumor suppressor proteins (e.g., p53, p21, p38, and p16) and modulation of dysregulated signaling mediators, including senescence-associated β-galactosidase, ataxia-telangiectasia mutated/ATM and Rad3-related, checkpoint kinase1/2, phosphatidylinositol 3-kinases/Akt, Ras/Raf pathway, and extracellular signal-regulated kinase/mitogen-activated protein kinase. On the other hand, conventional anticancer agents induce the secretion of procarcinogenic molecules, including inflammatory mediators, such as nuclear factor-κB, tumor necrosis factor-α, and interleukins, and angiogenic mediators, namely vascular endothelial growth factor, in the tumor microenvironment. This condition urges the need for finding novel alternative therapies, novel senolytics, senescence inducers and combination therapies in the regulation of senescence towards the regulation of multiple tumorigenic conditions. This comprehensive review highlights the therapeutic targets and signaling pathways in the senescence of tumor cells. The critical roles of anticancer drug-induced senescence, senolytics, and associated combined administrations are evaluated in the attenuation of cellular senescence pathways to achieve cancer prevention and efficient treatment. Current challenges/pitfalls, limitations, and future research are also discussed. [ABSTRACT FROM AUTHOR]

Cell death by apoptosis and permanent cell cycle arrest by senescence serve as barriers to the development of cancer. Chemotherapeutic agents not only induce apoptosis, they can also induce senescence known as therapy-induced senescence (TIS). There are, however, controversies whether TIS improves or worsens therapeutic outcome. Unlike apoptosis, which permanently removes cancer cells, senescent cells are metabolically active, and can contribute to tumor progression and relapse. If senescent cells are not cleared by the immune system or if cancer cells escape senescence, they may acquire resistance to apoptotic stimuli and become highly aggressive. Thus, there have been significant efforts in developing senolytics, drugs that target these pro-survival molecules to eliminate senescent cells. The anti-apoptotic Bcl-2 family proteins not only protect against cell death by apoptosis, but they also allow senescent cells to survive. While combining senolytics with chemotherapeutic drugs is an attractive approach, there are also limitations. Moreover, members of the Bcl-2 family have distinct effects on apoptosis and senescence. The purpose of this review article is to discuss recent literatures on how members of the Bcl-2 family orchestrate the interplay between apoptosis and senescence, and the challenges and progress in targeting these Bcl-2 family proteins for cancer therapy. [ABSTRACT FROM AUTHOR]

Insulin resistance is a pathological state often associated with obesity, representing a major risk factor for type 2 diabetes. Limited mechanism-based strategies exist to alleviate insulin resistance. Here, using single-cell transcriptomics, we identify a small, critically important, but previously unexamined cell population, p21 Cip1 highly expressing (p21 high) cells, which accumulate in adipose tissue with obesity. By leveraging a p21 -Cre mouse model, we demonstrate that intermittent clearance of p21 high cells can both prevent and alleviate insulin resistance in obese mice. Exclusive inactivation of the NF-κB pathway within p21 high cells, without killing them, attenuates insulin resistance. Moreover, fat transplantation experiments establish that p21 high cells within fat are sufficient to cause insulin resistance in vivo. Importantly, a senolytic cocktail, dasatinib plus quercetin, eliminates p21 high cells in human fat ex vivo and mitigates insulin resistance following xenotransplantation into immuno-deficient mice. Our findings lay the foundation for pursuing the targeting of p21 high cells as a new therapy to alleviate insulin resistance. [Display omitted] • p21 high cells, distinct from p16 high cells, accumulate in fat with obesity • Intermittent p21 high cell clearance both prevents and alleviates insulin resistance • Exclusive inactivation of NF-κB in p21 high cells improves insulin sensitivity • A senolytic reduces p21 high cells in human fat and alleviates its metabolic harm in vivo Wang et al. identify a previously unexamined senescent cell population (p21 high cells) in fat and demonstrate their causal role in metabolic dysfunction with obesity, as well as the underlying mechanism involved. Treatment with a senolytic cocktail, dasatinib plus quercetin, reduces p21 high cells in human fat and alleviates their harmful metabolic effects following transplantation into immunodeficient mice in vivo. [ABSTRACT FROM AUTHOR]