The connection between aging, cellular senescence and gut microbiome alterations: A comprehensive review.

The intricate interplay between cellular senescence and alterations in the gut microbiome emerges as a pivotal axis in the aging process, increasingly recognized for its contribution to systemic inflammation, physiological decline, and predisposition to age-associated diseases. Cellular senescence, characterized by a cessation of cell division in response to various stressors, induces morphological and functional changes within tissues. The complexity and heterogeneity of senescent cells, alongside the secretion of senescence-associated secretory phenotype, exacerbate the aging process through pro-inflammatory pathways and influence the microenvironment and immune system. Concurrently, aging-associated changes in gut microbiome diversity and composition contribute to dysbiosis, further exacerbating systemic inflammation and undermining the integrity of various bodily functions. This review encapsulates the burgeoning research on the reciprocal relationship between cellular senescence and gut dysbiosis, highlighting their collective impact on age-related musculoskeletal diseases, including osteoporosis, sarcopenia, and osteoarthritis. It also explores the potential of modulating the gut microbiome and targeting cellular senescence as innovative strategies for healthy aging and mitigating the progression of aging-related conditions. By exploring targeted interventions, including the development of senotherapeutic drugs and probiotic therapies, this review aims to shed light on novel therapeutic avenues. These strategies leverage the connection between cellular senescence and gut microbiome alterations to advance aging research and development of interventions aimed at extending health span and improving the quality of life in the older population.

Cellular Senescence and Inflammaging in the Bone: Pathways, Genetics, Anti-Aging Strategies and Interventions.

Advancing age is associated with several age-related diseases (ARDs), with musculoskeletal conditions impacting millions of elderly people worldwide. With orthopedic conditions contributing towards considerable number of patients, a deeper understanding of bone aging is the need of the hour. One of the underlying factors of bone aging is cellular senescence and its associated senescence associated secretory phenotype (SASP). SASP comprises of pro-inflammatory markers, cytokines and chemokines that arrest cell growth and development. The accumulation of SASP over several years leads to chronic low-grade inflammation with advancing age, also known as inflammaging. The pathways and molecular mechanisms focused on bone senescence and inflammaging are currently limited but are increasingly being explored. Most of the genes, pathways and mechanisms involved in senescence and inflammaging coincide with those associated with cancer and other ARDs like osteoarthritis (OA). Thus, exploring these pathways using techniques like sequencing, identifying these factors and combatting them with the most suitable approach are crucial for healthy aging and the early detection of ARDs. Several approaches can be used to aid regeneration and reduce senescence in the bone. These may be pharmacological, non-pharmacological and lifestyle interventions. With increasing evidence towards the intricate relationship between aging, senescence, inflammation and ARDs, these approaches may also be used as anti-aging strategies for the aging bone marrow (BM).

Biomarkers of Cellular Senescence and Aging: Current State-of-the-Art, Challenges and Future Perspectives.

Population aging has increased the global prevalence of aging-related diseases, including cancer, sarcopenia, neurological disease, arthritis, and heart disease. Understanding aging, a fundamental biological process, has led to breakthroughs in several fields. Cellular senescence, evinced by flattened cell bodies, vacuole formation, and cytoplasmic granules, ubiquitously plays crucial roles in tissue remodeling, embryogenesis, and wound repair as well as in cancer therapy and aging. The lack of universal biomarkers for detecting and quantifying senescent cells, in vitro and in vivo, constitutes a major limitation. The applications and limitations of major senescence biomarkers, including senescence-associated ß-galactosidase staining, telomere shortening, cell-cycle arrest, DNA methylation, and senescence-associated secreted phenotypes are discussed. Furthermore, explore senotherapeutic approaches for aging-associated diseases and cancer. In addition to the conventional biomarkers, this review highlighted the in vitro, in vivo, and disease models used for aging studies. Further, technologies from the current decade including multi-omics and computational methods used in the fields of senescence and aging are also discussed in this review. Understanding aging-associated biological processes by using cellular senescence biomarkers can enable therapeutic innovation and interventions to improve the quality of life of older adults.

Polyphenols and Diets as Current and Potential Nutrition Senotherapeutics in Alzheimer's Disease: Findings from Clinical Trials.

Cellular senescence, a hallmark of aging, plays an important role in age-related conditions among older adults. Targeting senescent cells and its phenotype may provide a promising strategy to delay the onset or progression of Alzheimer's disease (AD). In this review article, we investigated efficacy and safety of nutrition senotherapy in AD, with a focus on the role of polyphenols as current and potential nutrition senotherapeutic agents, as well as relevant dietary patterns. Promising results with neuroprotective effects of senotherapeutic agents such as quercetin, resveratrol, Epigallocatechin-gallate, curcumin and fisetin were reported from preclinical studies. However, in-human trials remain limited, and findings were inconclusive. In future, nutrition senotherapeutic agents should be studied both individually and within dietary patterns, through the perspective of cellular senescence and AD. Further studies are warranted to investigate bioavailability, dosing regimen, long term effects of nutrition senotherapy and provide better understanding of the underlying mechanisms. Collaboration between researchers needs to be established, and methodological limitations of current studies should be addressed.

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.

Novel Insights into Psychosis and Antipsychotic Interventions: From Managing Symptoms to Improving Outcomes.

For the past 70 years, the dopamine hypothesis has been the key working model in schizophrenia. This has contributed to the development of numerous inhibitors of dopaminergic signaling and antipsychotic drugs, which led to rapid symptom resolution but only marginal outcome improvement. Over the past decades, there has been limited research on the quantifiable pathological changes in schizophrenia, including premature cellular/neuronal senescence, brain volume loss, the attenuation of gamma oscillations in electroencephalograms, and the oxidation of lipids in the plasma and mitochondrial membranes. We surmise that the aberrant activation of the aryl hydrocarbon receptor by toxins derived from gut microbes or the environment drives premature cellular and neuronal senescence, a hallmark of schizophrenia. Early brain aging promotes secondary changes, including the impairment and loss of mitochondria, gray matter depletion, decreased gamma oscillations, and a compensatory metabolic shift to lactate and lactylation. The aim of this narrative review is twofold: (1) to summarize what is known about premature cellular/neuronal senescence in schizophrenia or schizophrenia-like disorders, and (2) to discuss novel strategies for improving long-term outcomes in severe mental illness with natural senotherapeutics, membrane lipid replacement, mitochondrial transplantation, microbial phenazines, novel antioxidant phenothiazines, inhibitors of glycogen synthase kinase-3 beta, and aryl hydrocarbon receptor antagonists.

The potential for senotherapy as a novel approach to extend life quality in veterinary medicine.

Cellular senescence, a condition where cells undergo arrest and can assume an inflammatory phenotype, has been associated with initiation and perpetuation of inflammation driving multiple disease processes in rodent models and humans. Senescent cells secrete inflammatory cytokines, proteins, and matrix metalloproteinases, termed the senescence associated secretory phenotype (SASP), which accelerates the aging processes. In preclinical models, drug interventions termed "senotherapeutics" selectively clear senescent cells and represent a promising strategy to prevent or treat multiple age-related conditions in humans and veterinary species. In this review, we summarize the current available literature describing in vitro evidence for senotheraputic activity, preclinical models of disease, ongoing human clinical trials, and potential clinical applications in veterinary medicine. These promising data to date provide further justification for future studies identifying the most active senotherapeutic combinations, dosages, and routes of administration for use in veterinary medicine.

Cell Senescence in Heterotopic Ossification.

The formation of bone outside the normal skeleton, or heterotopic ossification (HO), occurs through genetic and acquired mechanisms. Fibrodysplasia ossificans progressiva (FOP), the most devastating genetic condition of HO, is due to mutations in the ACVR1/ALK2 gene and is relentlessly progressive. Acquired HO is mostly precipitated by injury or orthopedic surgical procedures but can also be associated with certain conditions related to aging. Cellular senescence is a hallmark of aging and thought to be a tumor-suppressive mechanism with characteristic features such as irreversible growth arrest, apoptosis resistance, and an inflammatory senescence-associated secretory phenotype (SASP). Here, we review possible roles for cellular senescence in HO and how targeting senescent cells may provide new therapeutic approaches to both FOP and acquired forms of HO.

Cellular senescence in cancer: molecular mechanisms and therapeutic targets.

Aging exhibits several hallmarks in common with cancer, such as cellular senescence, dysbiosis, inflammation, genomic instability, and epigenetic changes. In recent decades, research into the role of cellular senescence on tumor progression has received widespread attention. While how senescence limits the course of cancer is well established, senescence has also been found to promote certain malignant phenotypes. The tumor-promoting effect of senescence is mainly elicited by a senescence-associated secretory phenotype, which facilitates the interaction of senescent tumor cells with their surroundings. Targeting senescent cells therefore offers a promising technique for cancer therapy. Drugs that pharmacologically restore the normal function of senescent cells or eliminate them would assist in reestablishing homeostasis of cell signaling. Here, we describe cell senescence, its occurrence, phenotype, and impact on tumor biology. A "one-two-punch" therapeutic strategy in which cancer cell senescence is first induced, followed by the use of senotherapeutics for eliminating the senescent cells is introduced. The advances in the application of senotherapeutics for targeting senescent cells to assist cancer treatment are outlined, with an emphasis on drug categories, and the strategies for their screening, design, and efficient targeting. This work will foster a thorough comprehension and encourage additional research within this field.

Mechanisms and therapeutic strategies for senescence-associated secretory phenotype in the intervertebral disc degeneration microenvironment.

As a permanent state of cell cycle arrest, cellular senescence has become an important factor in aging and age-related diseases. As a central regulator of physiology and pathology associated with cellular senescence, the senescence associated secretory phenotype can create an inflammatory and catabolic environment through autocrine and paracrine ways, ultimately affecting tissue microstructure. As an age-related disease, the correlation between intervertebral disc degeneration and cellular senescence has been confirmed by many studies. Various pathological factors in the microenvironment of intervertebral disc degeneration promote senescent cells to produce and accumulate and express excessive senescence associated secretory phenotype. In this case, senescence associated secretory phenotype has received considerable attention as a potential target for delaying or treating disc degeneration. Therefore, we reviewed the latest research progress of senescence associated secretory phenotype, related regulatory mechanisms and intervertebral disc cell senescence treatment strategies. It is expected that further understanding of the underlying mechanism between cellular senescence pathology and intervertebral disc degeneration will help to formulate reasonable senescence regulation strategies, so as to achieve ideal therapeutic effects. The translational potential of this article: Existing treatment strategies often fall short in addressing the challenge of repairing intervertebral disc Intervertebral disc degeneration（IVD） degeneration. The accumulation of senescent cells and the continuous release of senescence-associated secretory phenotype (SASP) perpetually impede disc homeostasis and hinder tissue regeneration. This impairment in repair capability presents a significant obstacle to the practical clinical implementation of strategies for intervertebral disc degeneration. As a result, we present a comprehensive overview of the latest advancements in research, the associated regulatory mechanisms, and strategies for treating SASP in IVD cells. This article aims to investigate effective interventions for delaying the onset and progression of age-related intervertebral disc degeneration. In an era where the aging population is becoming increasingly prominent, this endeavor holds paramount practical and translational significance.

Focus on senescence: Clinical significance and practical applications.

The older population is increasing worldwide, and life expectancy is continuously rising, predominantly thanks to medical and technological progress. Healthspan refers to the number of years an individual can live in good health. From a gerontological viewpoint, the mission is to extend the life spent in good health, promoting well-being and minimizing the impact of aging-related diseases to slow the aging process. Biologically, aging is a malleable process characterized by an intra- and inter-individual heterogeneous and dynamic balance between accumulating damage and repair mechanisms. Cellular senescence is a key component of this process, with senescent cells accumulating in different tissues and organs, leading to aging and age-related disease susceptibility over time. Removing senescent cells from the body or slowing down the burden rate has been proposed as an efficient way to reduce age-dependent deterioration. In animal models, senotherapeutic molecules can extend life expectancy and lifespan by either senolytic or senomorphic activity. Much research shows that dietary and physical activity-driven lifestyle interventions protect against senescence. This narrative review aims to summarize the current knowledge on targeting senescent cells to reduce the risk of age-related disease in animal models and their translational potential for humans. We focused on studies that have examined the potential role of senotherapeutics in slowing the aging process and modifying age-related disease burdens. The review concludes with a general discussion of the mechanisms underlying this unique trajectory and its implications for future research.

Cellular senescence in reproduction: a two-edged sword†.

Cellular senescence (CS) is the state when cells are no longer capable to divide even after stimulation with grown factors. Cells that begin to undergo CS stop in the cell cycle and enter a suspended state without committing to programmed cell death. These cells assume a specific phenotype and influence their microenvironment by secreting molecules and extracellular vesicles that are part of the so-called senescent cell-associated secretory phenotype (SASP). Cellular senescence is intertwined with physiological and pathological conditions in the human organism. In terms of reproduction, senescent cells are present from reproductive tissues and germ cells to gestational tissues, and participate from fertilization to delivery, going through adverse reproductive outcomes such as pregnancy losses. Furthermore, various SASP molecules are enriched in gestational tissues throughout pregnancy. Thus, the aim of this review is to provide a basis about the features and potential roles played by CS throughout the reproductive process, encompassing its implication in each step of it and proposing a way to manage it in adverse reproductive contexts.

Cellular senescence in chronic lung diseases from newborns to the elderly: An update literature review.

The role of cellular senescence in age-related diseases has been fully recognized. In various age-related-chronic lung diseases, the function of alveolar epithelial cells (AECs) is impaired and alveolar regeneration disorders, especially in bronchopulmonary dysplasia，pulmonary fibrosis (PF), chronic obstructive pulmonary disease (COPD), cancer, etc. Except for age-related-chronic lung diseases, an increasing number of studies are exploring the role of cellular senescence in developmental chronic lung diseases, which typically originate in childhood and even in the neonatal period. This review provides an overview of cellular senescence and lung diseases from newborns to the elderly, attempting to draw attention to the relationship between cellular senescence and developmental lung diseases.

Activation of senescence in critically ill patients: mechanisms, consequences and therapeutic opportunities.

Whereas aging is a whole-organism process, senescence is a cell mechanism that can be triggered by several stimuli. There is increasing evidence that critical conditions activate cell senescence programs irrespective of patient's age. In this review, we briefly describe the basic senescence pathways and the consequences of their activation in critically ill patients. The available evidence suggests a paradigm in which activation of senescence can be beneficial in the short term by rendering cells resistant to apoptosis, but also detrimental in a late phase by inducing a pro-inflammatory and pro-fibrotic state. Senescence can be a therapeutic target. The use of drugs that eliminate senescent cells (senolytics) or the senescence-associated phenotype (senomorphics) will require monitoring of these cell responses and identification of therapeutic windows to improve the outcome of critically ill patients.

Cells in Atherosclerosis: Focus on Cellular Senescence from Basic Science to Clinical Practice.

Aging is a major risk factor of atherosclerosis through different complex pathways including replicative cellular senescence and age-related clonal hematopoiesis. In addition to aging, extracellular stress factors, such as mechanical and oxidative stress, can induce cellular senescence, defined as premature cellular senescence. Senescent cells can accumulate within atherosclerotic plaques over time and contribute to plaque instability. This review summarizes the role of cellular senescence in the complex pathophysiology of atherosclerosis and highlights the most important senotherapeutics tested in cardiovascular studies targeting senescence. Continued bench-to-bedside research in cellular senescence might allow the future implementation of new effective anti-atherosclerotic preventive and treatment strategies in clinical practice.

The Role of Cellular Senescence in Cyclophosphamide-Induced Primary Ovarian Insufficiency.

Young female cancer patients can develop chemotherapy-induced primary ovarian insufficiency (POI). Cyclophosphamide (Cy) is one of the most widely used chemotherapies and has the highest risk of damaging the ovaries. Recent studies elucidated the pivotal roles of cellular senescence, which is characterized by permanent cell growth arrest, in the pathologies of various diseases. Moreover, several promising senolytics, including dasatinib and quercetin (DQ), which remove senescent cells, are being developed. In the present study, we investigated whether cellular senescence is involved in Cy-induced POI and whether DQ treatment rescues Cy-induced ovarian damage. Expression of the cellular senescence markers p16, p21, p53, and γH2AX was upregulated in granulosa cells of POI mice and in human granulosa cells treated with Cy, which was abrogated by DQ treatment. The administration of Cy decreased the numbers of primordial and primary follicles, with a concomitant increase in the ratio of growing to dormant follicles, which was partially rescued by DQ. Moreover, DQ treatment significantly improved the response to ovulation induction and fertility in POI mice by extending reproductive life. Thus, cellular senescence plays critical roles in Cy-induced POI, and targeting senescent cells with senolytics, such as DQ, might be a promising strategy to protect against Cy-induced ovarian damage.

Senescent and disease-associated microglia are modifiable features of aged brain white matter.

Brain white matter tracts undergo structural and functional changes linked to late-life cognitive decline, but the cellular and molecular contributions to their selective vulnerability are not well defined. In naturally aged mice, we demonstrate that senescent and disease-associated microglia (DAM) phenotypes converge in hippocampus-adjacent white matter. Through gold-standard gene expression and immunolabeling combined with high-dimensional spatial mapping, we identified microglial cell fates in aged white matter characterized by aberrant morphology, microenvironment reorganization, and expression of senescence and DAM markers, including galectin 3 (GAL3/Lgals3), B-cell lymphoma 2 (Bcl2), and cyclin dependent kinase inhibitors, including Cdkn2a/p16ink4a. Pharmacogenetic or pharmacological targeting of p16ink4a or BCL2 reduced white matter GAL3+ DAM abundance and rejuvenated microglial fimbria organization. Our results demonstrate dynamic changes in microglial identity in aged white matter that can be reverted by senotherapeutic intervention to promote homeostatic maintenance in the aged brain.

Piperlongumine mediates amelioration of osteoarthritis via inhibition of chondrocyte senescence and inflammation in a goat ex vivo model.

In osteoarthritis (OA), chondrocytes manifest senescence, which results in a vicious signaling loop that aids the progression of the disease. More specifically, inflammation-associated senescence is one of the major regulators of the initiation and progression of OA. Therefore, we targeted senescence through inflammation with a pharmacological approach for OA amelioration. In this study, we first confirmed the suitability of the IL1ß-induced goat ex vivo OA model (emphasizing 3R's principle) for the screening of senotherapeutics, namely, ABT-263, ABT-737, and Piperlongumine (PL), wherein PL showed a positive outcome in the preliminary studies. Thereafter, we determined the cytocompatible concentrations of PL using live/dead staining. Further, treatment of ex vivo OA cartilage with PL exhibited a concentration-dependent increase in the retention of key cartilage matrix components. We then examined the effect of PL on chondrocyte senescence and observed a decreased expression of major senescence markers in the PL-treated groups. Interestingly, PL treatment reduced the expression of major downstream effectors of the chondrocyte senescence pathway in a concentration-dependent manner at both gene and protein levels. Moreover, IL1ß-induced elevated levels of oxidative stress and DNA damage in cartilage explants were rescued by all the tested concentrations of PL. In addition, PL also reduced the expression of major inflammatory markers of OA in the goat ex vivo OA model. Finally, we proposed a model for the mechanism of action of PL in the treatment of OA. Overall, PL showed a promising outcome as a senotherapeutic for the amelioration of OA in the goat ex vivo OA model.

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.