Mini-encyclopedia of mitochondria-relevant nutraceuticals protecting health in primary and secondary care-clinically relevant 3PM innovation.

Despite their subordination in humans, to a great extent, mitochondria maintain their independent status but tightly cooperate with the "host" on protecting the joint life quality and minimizing health risks. Under oxidative stress conditions, healthy mitochondria promptly increase mitophagy level to remove damaged "fellows" rejuvenating the mitochondrial population and sending fragments of mtDNA as SOS signals to all systems in the human body. As long as metabolic pathways are under systemic control and well-concerted together, adaptive mechanisms become triggered increasing systemic protection, activating antioxidant defense and repair machinery. Contextually, all attributes of mitochondrial patho-/physiology are instrumental for predictive medical approach and cost-effective treatments tailored to individualized patient profiles in primary (to protect vulnerable individuals again the health-to-disease transition) and secondary (to protect affected individuals again disease progression) care. Nutraceuticals are naturally occurring bioactive compounds demonstrating health-promoting, illness-preventing, and other health-related benefits. Keeping in mind health-promoting properties of nutraceuticals along with their great therapeutic potential and safety profile, there is a permanently growing demand on the application of mitochondria-relevant nutraceuticals. Application of nutraceuticals is beneficial only if meeting needs at individual level. Therefore, health risk assessment and creation of individualized patient profiles are of pivotal importance followed by adapted nutraceutical sets meeting individual needs. Based on the scientific evidence available for mitochondria-relevant nutraceuticals, this article presents examples of frequent medical conditions, which require protective measures targeted on mitochondria as a holistic approach following advanced concepts of predictive, preventive, and personalized medicine (PPPM/3PM) in primary and secondary care.

Nanocarriers for natural polyphenol senotherapeutics.

Senescence is a heterogenous and dynamic process in which various cell types undergo cell-cycle arrest due to cellular stressors. While senescence has been implicated in aging and many human pathologies, therapeutic interventions remain inadequate due to the absence of a comprehensive set of biomarkers in a context-dependent manner. Polyphenols have been investigated as senotherapeutics in both preclinical and clinical settings. However, their use is hindered by limited stability, toxicity, modest bioavailability, and often inadequate concentration at target sites. To address these limitations, nanocarriers such as polymer nanoparticles and lipid vesicles can be utilized to enhance the efficacy of senolytic polyphenols. Focusing on widely studied senolytic agents-specifically fisetin, quercetin, and resveratrol-we provide concise summaries of their physical and chemical properties, along with an overview of preclinical and clinical findings. We also highlight common signaling pathways and potential toxicities associated with these agents. Addressing challenges linked to nanocarriers, we present examples of senotherapeutic delivery to various cell types, both with and without nanocarriers. Finally, continued research and development of senolytic agents and nanocarriers are encouraged to reduce the undesirable effects of senescence on different cell types and organs. This review underscores the need for establishing reliable sets of senescence biomarkers that could assist in evaluating the effectiveness of current and future senotherapeutic candidates and nanocarriers.

Emerging roles of senolytics/senomorphics in HIV-related co-morbidities.

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.

Targeting Cell Senescence and Senolytics: Novel Interventions for Age-Related Endocrine Dysfunction.

Multiple changes occur in hormonal regulation with aging and across various endocrine organs. These changes are associated with multiple age-related disorders and diseases. A better understanding of responsible underling biological mechanisms could help in the management of multiple endocrine disorders over and above hormone replacement therapy (HRT). Cellular senescence is involved in multiple biological aging processes and pathologies common in elderly individuals. Cellular senescence, which occurs in many older individuals but also across the lifespan in association with tissue damage, acute and chronic diseases, certain drugs, and genetic syndromes, may contribute to such endocrine disorders as osteoporosis, metabolic syndrome, and type II diabetes mellitus (T2DM). Drugs that selectively induce senescent cell removal, "senolytics", and drugs that attenuate the tissue-destructive secretory state of certain senescent cells, "senomorphics", appear to delay the onset or alleviate multiple diseases, including but not limited to endocrine disorders such as diabetes, complications of obesity, age-related osteoporosis, and cancers as well as atherosclerosis, chronic kidney disease, neurodegenerative disorders, and many others. Over thirty clinical trials of senolytic and senomorphic agents have already been completed, are underway, or are planned for a variety of indications. Targeting senescent cells is a novel strategy that is distinct from conventional therapies such as HRT, and thus might address unmet medical needs and can potentially amplify effects of established endocrine drug regimens, perhaps allowing for dose decreases and reducing side effects.

Plant-Derived Senotherapeutics for the Prevention and Treatment of Intervertebral Disc Degeneration and Aging.

Chronic low back pain, a major cause of disability with a great global socioeconomic impact, has been inextricably associated with intervertebral disc degeneration. On the other hand, an enhanced number of senescent cells has been identified in aged and degenerated intervertebral discs and their senescence-associated secretory phenotype (SASP) has been connected with qualitative/quantitative alterations in the extracellular matrix and ultimately with the disturbance of tissue homeostasis. Given that selective elimination of senescent cells (by the so-called senolytics) or amendment of their secretome towards a less catabolic/inflammatory phenotype (by molecules known as senomorphics) has been reported to alleviate symptoms of several age-associated diseases and to improve tissue quality during aging, here we will review the emerging role of senolytic and senomorphic agents derived from plants and natural products against intervertebral disc degeneration. The mode of action of these senotherapeutics, as well as the challenges in their practical application, will also be explicitly discussed in an attempt to direct their more targeted and effective use in exclusive or combinatorial therapeutic schemes for the prevention and/or treatment of disc degenerative disorders.

Senotherapeutics to Counteract Senescent Cells Are Prominent Topics in the Context of Anti-Ageing Strategies.

Cellular senescence is implicated in ageing and associated with a broad spectrum of age-related diseases. Importantly, a cell can initiate the senescence program irrespective of the organism's age. Various stress signals, including those defined as ageing hallmarks and alterations leading to cancer development, oncogene activation, or loss of cancer-suppressive functions, can trigger cellular senescence. The primary outcome of these alterations is the activation of nuclear factor (NF)-κB, thereby inducing the senescence-associated secretory phenotype (SASP). Proinflammatory cytokines and chemokines, components of this phenotype, contribute to chronic systemic sterile inflammation, commonly referred to as inflamm-ageing. This inflammation is linked to age-related diseases (ARDs), frailty, and increased mortality in older individuals. Additionally, senescent cells (SCs) accumulate in multiple tissues with age and are believed to underlie the organism functional decline, as demonstrated by models. An escalating effort has been dedicated to identify senotherapeutics that selectively target SCs by inducing apoptosis; these drugs are termed senolytics. Concurrently, small molecules that suppress senescent phenotypes without causing cell death are known as senomorphics. Both natural and synthetic senotherapeutics, along with immunotherapies employing immune cell-mediated clearance of SCs, currently represent the most promising strategies to combat ageing and ARDs. Indeed, it is fascinating to observe that information regarding the immune reaction to SCs indicates that regulation by specific lymphocyte subsets, elevated in the oldest centenarians, plays a role in attaining extreme longevity. Regardless, the application of methods already utilized in cancer treatment, such as CAR cells and monoclonal antibodies, broadens the spectrum of potential approaches to be utilized.

Rutin is a potent senomorphic agent to target senescent cells and can improve chemotherapeutic efficacy.

Aging is a major risk factor for most chronic disorders, for which cellular senescence is one of the central hallmarks. Senescent cells develop the pro-inflammatory senescence-associated secretory phenotype (SASP), which significantly contributes to organismal aging and age-related disorders. Development of senotherapeutics, an emerging class of therapeutic agents to target senescent cells, allows to effectively delay aging and alleviate chronic pathologies. Here we report preliminary outputs from screening of a natural medicinal agent (NMA) library for senotherapeutic candidates and validated several agents with prominent potential as senomorphics. Rutin, a phytochemical constituent found in a number of plants, showed remarkable capacity in targeting senescent cells by dampening expression of the full spectrum SASP. Further analysis indicated that rutin restrains the acute stress-associated phenotype (ASAP) by specifically interfering with the interactions of ATM with HIF1α, a master regulator of cellular and systemic homeostasis activated during senescence, and of ATM with TRAF6, part of a key signaling axis supporting the ASAP development toward the SASP. Conditioned media produced by senescent stromal cells enhanced the malignant phenotypes of prostate cancer cells, including in vitro proliferation, migration, invasion, and more importantly, chemoresistance, while rutin remarkably downregulated these gain-of-functions. Although classic chemotherapy reduced tumor progression, the treatment outcome was substantially improved upon combination of a chemotherapeutic agent with rutin. Our study provides a proof of concept for rutin as an emerging natural senomorphic agent, and presents an effective therapeutic avenue for alleviating age-related pathologies including cancer.

Translating Senotherapeutic Interventions into the Clinic with Emerging Proteomic Technologies.

Cellular senescence is a state of irreversible growth arrest with profound phenotypic changes, including the senescence-associated secretory phenotype (SASP). Senescent cell accumulation contributes to aging and many pathologies including chronic inflammation, type 2 diabetes, cancer, and neurodegeneration. Targeted removal of senescent cells in preclinical models promotes health and longevity, suggesting that the selective elimination of senescent cells is a promising therapeutic approach for mitigating a myriad of age-related pathologies in humans. However, moving senescence-targeting drugs (senotherapeutics) into the clinic will require therapeutic targets and biomarkers, fueled by an improved understanding of the complex and dynamic biology of senescent cell populations and their molecular profiles, as well as the mechanisms underlying the emergence and maintenance of senescence cells and the SASP. Advances in mass spectrometry-based proteomic technologies and workflows have the potential to address these needs. Here, we review the state of translational senescence research and how proteomic approaches have added to our knowledge of senescence biology to date. Further, we lay out a roadmap from fundamental biological discovery to the clinical translation of senotherapeutic approaches through the development and application of emerging proteomic technologies, including targeted and untargeted proteomic approaches, bottom-up and top-down methods, stability proteomics, and surfaceomics. These technologies are integral for probing the cellular composition and dynamics of senescent cells and, ultimately, the development of senotype-specific biomarkers and senotherapeutics (senolytics and senomorphics). This review aims to highlight emerging areas and applications of proteomics that will aid in exploring new senescent cell biology and the future translation of senotherapeutics.

Cellular Senescence in Cardiovascular Diseases: From Pathogenesis to Therapeutic Challenges.

Cellular senescence (CS), classically considered a stable cell cycle withdrawal, is hallmarked by a progressive decrease in cell growth, differentiation, and biological activities. Senescent cells (SNCs) display a complicated senescence-associated secretory phenotype (SASP), encompassing a variety of pro-inflammatory factors that exert influence on the biology of both the cell and surrounding tissue. Among global mortality causes, cardiovascular diseases (CVDs) stand out, significantly impacting the living quality and functional abilities of patients. Recent data suggest the accumulation of SNCs in aged or diseased cardiovascular systems, suggesting their potential role in impairing cardiovascular function. CS operates as a double-edged sword: while it can stimulate the restoration of organs under physiological conditions, it can also participate in organ and tissue dysfunction and pave the way for multiple chronic diseases under pathological states. This review explores the mechanisms that underlie CS and delves into the distinctive features that characterize SNCs. Furthermore, we describe the involvement of SNCs in the progression of CVDs. Finally, the study provides a summary of emerging interventions that either promote or suppress senescence and discusses their therapeutic potential in CVDs.

Reversing and modulating cellular senescence in beta cells, a new field of opportunities to treat diabetes.

Diabetes constitutes a world-wide pandemic that requires searching for new treatments to halt its progression. Cellular senescence of pancreatic beta cells has been described as a major contributor to development and worsening of diabetes. The concept of reversibility of cellular senescence is critical as is the timing to take actions against this "dormant" senescent state. The reversal of cellular senescence can be considered as rejuvenation of the specific cell if it returns to the original "healthy state" and doesn't behave aberrantly as seen in some cancer cells. In rodents, treatment with senolytics and senomorphics blunted or prevented disease progression, however their use carry drawbacks. Modulators of cellular senescence is a new area of research that seeks to reverse the senescence. More research in each of these modalities should lead to new treatments to stop diabetes development and progression.

Las células senescentes como factores patogénicos y posibles dianas terapéuticas en osteoporosis / Cellular senescence as a pathogenic factor and potential therapeutic target in osteoporosis

La senescencia celular es un proceso inducido por varios tipos de estrés que causan una detención irreversible del ciclo celular y un cambio en las características y la funcionalidad de las células, además de la adquisición de un fenotipo secretor que genera un ambiente proinflamatorio. Si bien en determinados contextos es beneficiosa para los tejidos y promueve el desarrollo del organismo, la senescencia es un destino celular implicado en el proceso de envejecimiento y en las patologías degenerativas relacionadas con la edad. Los senolíticos son fármacos que eliminan específicamente a las células senescentes y los senomórficos son fármacos que suprimen su fenotipo secretor asociado a senescencia (SASP) sin inducir la muerte celular. Así, las estrategias terapéuticas enfocadas en las células senescentes (senolíticos y senomórficos) como mecanismo subyacente al envejecimiento, se erigen en una alternativa con gran potencial para luchar contra las enfermedades relacionadas con la edad en su conjunto, y no de forma individual. Una de estas patologías es la osteoporosis, donde además se han descrito, a nivel experimental, que fármacos como el ácido zoledrónico tiene efecto sobre los preosteoblastos y actúa sobre las células senescentes, prolongando la supervivencia y abriendo la puerta a la posibilidad de tratar las enfermedades relacionadas con la edad con fármacos que ya se empleen en la práctica, y que puedan tener un efecto más allá del propio hueso y aumentar la supervivencia. En este trabajo se va a realizar una revisión en este campo de vertiginoso crecimiento en los últimos años y con indudable interés traslacional.(AU)

Cellular senescence is a process induced by various types of stress that irreversibly cause cell cycle arrest and changes tothe characteristics and functionality of cells, as well as the acquisition of a secretory phenotype that generates a pro-in-flammatory environment. While, in certain contexts, it is beneficial for tissues and promotes organism development, senes-cence is a cellular fate implicated in the process of aging and age-related degenerative conditions. Senolytics are drugs thatspecifically eliminate senescent cells, and senomorphics are drugs that suppress their senescence-associated secretoryphenotype (SASP) without inducing cell death. Therefore, therapeutic strategies targeting senescent cells (senolytics andsenomorphics) as an underlying mechanism of aging emerge as an alternative with great potential to fight age-relateddiseases as a whole rather than individually. One of these conditions is osteoporosis where it has been experimentallydescribed that drugs such as zoledronic acid have effects on preosteoblasts and act on senescent cells extending survivaland opening up the possibility of treating age-related diseases with drugs already used in practice, which may have effectsbeyond the bone itself and increase overall survival. In this study, a review will be conducted in this rapidly growing fieldin recent years of undeniable translational interest.(AU)

[Skin aging-cellular senescence : What is the future?] / Hautalterung ­ zelluläre Seneszenz : Wohin geht die Reise?

BACKGROUND: Cellular senescence is the main cause of skin and organ aging and is associated with a wide range of aging-related diseases. OBJECTIVES: To understand which senolytics, senomorphics, and cell-based therapies have been developed to alleviate and even rejuvenate skin aging and reduce cellular senescence. METHODS: Basic literature for the mode of action of senolytics and senomorphics and their clinical perspectives in daily routine are discussed. RESULTS: Various causes lead to mitochondrial dysfunction and the activation of pro-aging signaling pathways, which eventually lead to cellular senescence with degradation of structural proteins of the dermal connective tissue and severe suppression of regenerative stem cell niches of the skin. CONCLUSIONS: Depletion of senescent cells suppress skin aging and enforce rejuvenation of skin and other organs and their function. The removal of senescent cells by cells of the native immune system is severely disturbed during aging. Selected senolytics and senomorphics are approved and are already on the market.

Challenges in anti-aging medicine-trends in biomarker discovery and therapeutic interventions for a healthy lifespan.

We are facing a growing aging population, along with increasing pressure on health systems, caused by the impact of chronic co-morbidities (i.e. cancer, cardiovascular and neurodegenerative diseases) and functional disabilities as people age. Relatively simple preventive lifestyle interventions, such as dietary restriction and physical exercise, are important contributors to active and healthy aging in the general population. However, as shown in model organisms or in 'in vitro' conditions, lifestyle-independent interventions may have additional health benefits and can even be conceived as possible reversers of the aging process. Thus, pharmaceutical laboratories, research institutes, and universities are putting more and more effort into finding new molecular pathways and druggable targets to develop gerotherapeutics. One approach is to target the driving mechanisms of aging, some of which, like cellular senescence and impaired autophagy, we discussed in an update on the biology of aging at AgingFit 2023 in Lille, France. We underline the importance of carefully and extensively testing senotherapeutics, given the pleiotropism and heterogeneity of targeted senescent cells within different organs, at different time frames. Other druggable targets emerging from new putative mechanisms, like those based on transcriptome imbalance, nucleophagy, protein phosphatase depletion, glutamine metabolism, or seno-antigenicity, have been evidenced by recent preclinical studies in classical models of aging but need to be validated in humans. Finally, we highlight several approaches in the discovery of biomarkers of healthy aging, as well as for the prediction of neurodegenerative diseases and the evaluation of rejuvenation strategies.

Vascular Ageing: Mechanisms, Risk Factors, and Treatment Strategies.

Ageing constitutes the biggest risk factor for poor health and adversely affects the integrity and function of all the cells, tissues, and organs in the human body. Vascular ageing, characterised by vascular stiffness, endothelial dysfunction, increased oxidative stress, chronic low-grade inflammation, and early-stage atherosclerosis, may trigger or exacerbate the development of age-related vascular diseases, which each year contribute to more than 3.8 million deaths in Europe alone and necessitate a better understanding of the mechanisms involved. To this end, a large number of recent preclinical and clinical studies have focused on the exponential accumulation of senescent cells in the vascular system and paid particular attention to the specific roles of senescence-associated secretory phenotype, proteostasis dysfunction, age-mediated modulation of certain microRNA (miRNAs), and the contribution of other major vascular risk factors, notably diabetes, hypertension, or smoking, to vascular ageing in the elderly. The data generated paved the way for the development of various senotherapeutic interventions, ranging from the application of synthetic or natural senolytics and senomorphics to attempt to modify lifestyle, control diet, and restrict calorie intake. However, specific guidelines, considering the severity and characteristics of vascular ageing, need to be established before widespread use of these agents. This review briefly discusses the molecular and cellular mechanisms of vascular ageing and summarises the efficacy of widely studied senotherapeutics in the context of vascular ageing.

Sex-Specific Protection of Endothelial Function after Vascular Ischemia/Reperfusion Injury by the Senomorphic Agent Ruxolitinib.

Ischemia/reperfusion (I/R)-induced endothelial dysfunction occurs in various cardiovascular disorders. I/R injury is partially driven by the release of cytokines. Known for its use in senotherapy, the JAK inhibitor ruxolitinib is able to block the release of cytokines. We investigated the effect of ruxolitinib on the cytokine release and endothelial-dependent vasorelaxation in an in vitro model of I/R. Aortic segments of C57BL/6J mice (N = 12/group) were divided into three groups: control, in vitro I/R (I/R group), and in vitro I/R with ruxolitinib during ischemic incubation (I/R+Ruxo group). We determined cytokine expression. In organ bath chambers, we investigated the maximal endothelial-dependent relaxation to acetylcholine (RmaxACh) and maximal endothelial-independent relaxation to sodium-nitroprusside (RmaxSNP). RmaxACh was decreased in I/R compared to the control (83.6 ± 2.4 vs. 48.6 ± 3.4%; p < 0.05) and I/R+Ruxo (74.4 ± 2.6 vs. 48.6 ± 3.4%; p < 0.05). RmaxSNP was comparable between all groups. IL-10 was detectable only in I/R+Ruxo. CXCL5, CCL2, CCL3, CCL8, CCL11, ICAM-1, IL-1α, IL-7, TNF-α, and G-CSF were decreased or not detectable in I/R+Ruxo. In I/R+Ruxo, ICAM-1 was reduced in rings only from male mice. Treatment of the aorta from mice during in vitro ischemia with the senomorphic agent ruxolitinib reduces cytokine release and protects the endothelium from I/R-mediated dysfunction.

Exploring the Communication of the SASP: Dynamic, Interactive, and Adaptive Effects on the Microenvironment.

Cellular senescence is a complex cell state that can occur during physiological ageing or after exposure to stress signals, regardless of age. It is a dynamic process that continuously evolves in a context-dependent manner. Senescent cells interact with their microenvironment by producing a heterogenous and plastic secretome referred to as the senescence-associated secretory phenotype (SASP). Hence, understanding the cross-talk between SASP and the microenvironment can be challenging due to the complexity of signal exchanges. In this review, we first aim to update the definition of senescence and its associated biomarkers from its discovery to the present day. We detail the regulatory mechanisms involved in the expression of SASP at multiple levels and develop how SASP can orchestrate microenvironment modifications, by focusing on extracellular matrix modifications, neighboring cells' fate, and intercellular communications. We present hypotheses on how these microenvironmental events may affect dynamic changes in SASP composition in return. Finally, we discuss the various existing approaches to targeting SASP and clarify what is currently known about the biological effects of these modified SASPs on the cellular environment.

Cellular senescence in asthma: from pathogenesis to therapeutic challenges.

Asthma is a heterogeneous chronic respiratory disease that impacts nearly 10% of the population worldwide. While cellular senescence is a normal physiological process, the accumulation of senescent cells is considered a trigger that transforms physiology into the pathophysiology of a tissue/organ. Recent advances have suggested the significance of cellular senescence in asthma. With this review, we focus on the literature regarding the physiology and pathophysiology of cellular senescence and cellular stress responses that link the triggers of asthma to cellular senescence, including telomere shortening, DNA damage, oncogene activation, oxidative-related senescence, and senescence-associated secretory phenotype (SASP). The association of cellular senescence to asthma phenotypes, airway inflammation and remodeling, was also reviewed. Importantly, several approaches targeting cellular senescence, such as senolytics and senomorphics, have emerged as promising strategies for asthma treatment. Therefore, cellular senescence might represent a mechanism in asthma, and the senescence-related molecules and pathways could be targeted for therapeutic benefit.

Senolytic and senomorphic interventions to defy senescence-associated mitochondrial dysfunction.

The accumulation of senescent cells in the aging individual is associated with an increase in the occurrence of age-associated pathologies that contribute to poor health, frailty, and mortality. The number and type of senescent cells is viewed as a contributor to the body's senescence burden. Cellular models of senescence are based on induction of senescence in cultured cells in the laboratory. One type of senescence is triggered by mitochondrial dysfunction. There are several indications that mitochondria defects contribute to body aging. Senotherapeutics, targeting senescent cells, have been shown to induce their lysis by means of senolytics, or repress expression of their secretome, by means of senomorphics, senostatics or gerosuppressors. An outline of the mechanism of action of various senotherapeutics targeting mitochondria and senescence-associated mitochondria dysfunction will be here addressed. The combination of geroprotective interventions together with senotherapeutics will help to strengthen mitochondrial energy metabolism, biogenesis and turnover, and lengthen the mitochondria healthspan, minimizing one of several molecular pathways contributing to the aging phenotype.

Senotherapeutic Effect of Retinaldehyde and Hyaluronate Fragments in Dermatoporosis.

Cellular senescence is one of the important mechanisms of skin aging. In a recent study, we have shown that in patients with dermatoporosis, an extreme senescence condition of the skin, cells positive for p16Ink4a, a biomarker of senescence, were significantly increased in the epidermis. Senescent cells can develop a senescence-associated secretory phenotype (SASP) comprising pro-inflammatory cytokines, chemokines, and other soluble factors, leading to chronic inflammation and tissue dysfunction. These senescent cells and SASP pathways represent therapeutic targets for the development of senotherapeutics either by inducing selective cell death of senescent cells called senolytics, or suppressing markers of the SASP, called senomorphics. In this study where we conducted a retrospective immunohistochemical analysis of p16Ink4a expression in the skin samples of dermatoporosis patients included in a previous clinical study, we describe the senotherapeutic effect of retinaldehyde (RAL) and intermediate-size hyaluronate fragments (HAFi). Topical application of RAL and HAFi significantly reduced the number of p16Ink4a-positive cells in the epidermis and dermis in dermatoporosis patients which also showed a significant clinical improvement.

Metformin mitigates SASP secretion and LPS-triggered hyper-inflammation in Doxorubicin-induced senescent endothelial cells.

Introduction: Doxorubicin (DOX), a chemotherapeutic drug, induces senescence and increases the secretion of senescence-associated secretory phenotype (SASP) in endothelial cells (ECs), which contributes to DOX-induced inflammaging. Metformin, an anti-diabetic drug, demonstrates senomorphic effects on different models of senescence. However, the effects of metformin on DOX-induced endothelial senescence have not been reported before. Senescent ECs exhibit a hyper-inflammatory response to lipopolysachharide (LPS). Therefore, in our current work, we identified the effects of metformin on DOX-induced endothelial senescence and LPS-induced hyper-inflammation in senescent ECs. Methods: ECs were treated with DOX ± metformin for 24 h followed by 72 h incubation without DOX to establish senescence. Effects of metformin on senescence markers expression, SA-ß-gal activity, and SASP secretion were assessed. To delineate the molecular mechanisms, the effects of metformin on major signaling pathways were determined. The effect of LPS ± metformin was determined by stimulating both senescent and non-senescent ECs with LPS for an additional 24 h. Results: Metformin corrected DOX-induced upregulation of senescence markers and decreased the secretion of SASP factors and adhesion molecules. These effects were associated with a significant inhibition of the JNK and NF-κB pathway. A significant hyper-inflammatory response to LPS was observed in DOX-induced senescent ECs compared to non-senescent ECs. Metformin blunted LPS-induced upregulation of pro-inflammatory SASP factors. Conclusion: Our study demonstrates that metformin mitigates DOX-induced endothelial senescence phenotype and ameliorates the hyper-inflammatory response to LPS. These findings suggest that metformin may protect against DOX-induced vascular aging and endothelial dysfunction and ameliorate infection-induced hyper-inflammation in DOX-treated cancer survivors.