Developing transcriptomic signatures as a biomarker of cellular senescence.

Cellular senescence is a cell fate driven by different types of stress, where damaged cells exit from the cell cycle and, in many cases, develop an inflammatory senescence-associated secretory phenotype (SASP). Senescence has often been linked to driving aging and the onset of multiple diseases conferred by the harmful SASP, which disrupts tissue homeostasis and impairs the regular function of many tissues. This phenomenon was first observed in vitro when fibroblasts halted replication after approximately 50 population doublings. In addition to replication-induced senescence, factors such as DNA damage and oncogene activation can induce cellular senescence both in culture and in vivo. Despite their contribution to aging and disease, identifying senescent cells in vivo has been challenging due to their heterogeneity. Although senescent cells can express the cell cycle inhibitors p16Ink4a and/or p21Cip1 and exhibit SA-ß-gal activity and evidence of a DNA damage response, there is no universal biomarker for these cells, regardless of inducer or cell type. Recent studies have analyzed the transcriptomic characteristics of these cells, leading to the identification of signature gene sets like CellAge, SeneQuest, and SenMayo. Advancements in single-cell and spatial RNA sequencing now allow for analyzing senescent cell heterogeneity within the same tissue and the development of machine learning algorithms, e.g., SenPred, SenSig, and SenCID, to discover cellular senescence using RNA sequencing data. Such insights not only deepen our understanding of the genetic pathways driving cellular senescence, but also promote the development of its quantifiable biomarkers. This review summarizes the current knowledge of transcriptomic signatures of cellular senescence and their potential as in vivo biomarkers.

Targeting cellular senescence with senotherapeutics: senolytics and senomorphics.

The concept of geroscience is that since ageing is the greatest risk factor for many diseases and conditions, targeting the ageing process itself will have the greatest impact on human health. Of the hallmarks of ageing, cellular senescence has emerged as a druggable therapeutic target for extending healthspan in model organisms. Cellular senescence is a cell state of irreversible proliferative arrest driven by different types of stress, including oncogene-induced stress. Many senescent cells (SnCs) develop a senescent-associated secretory phenotype (SASP) comprising pro-inflammatory cytokines, chemokines, proteases, bioactive lipids, inhibitory molecules, extracellular vesicles, metabolites, lipids and other factors, able to promote chronic inflammation and tissue dysfunction. SnCs up-regulate senescent cell anti-apoptotic pathways (SCAPs) that prevent them from dying despite the accumulation of damage to DNA and other organelles. These SCAPs and other pathways altered in SnCs represent therapeutic targets for the development of senotherapeutic drugs that induce selective cell death of SnCs, specifically termed senolytics or suppress markers of senescence, in particular the SASP, termed senomorphics. Here, we review the current state of the development of senolytics and senomorphics for the treatment of age-related diseases and disorders and extension of healthy longevity. In addition, the challenges of documenting senolytic and senomorphic activity in pre-clinical models and the current state of the clinical application of the different senotherapeutics will be discussed.

Challenges and considerations for treating PTSD with medicinal cannabis: the Australian clinician's perspective.

INTRODUCTION: Preclinical and experimental research have provided promising evidence that medicinal cannabis may be efficacious in the treatment of posttraumatic stress disorder (PTSD). However, implementation of medicinal cannabis into routine clinical therapies may not be straightforward. AREAS COVERED: In this review, we describe some of the clinical, practical, and safety challenges that must be addressed for cannabis-based treatment of PTSD to be feasible in a real-world setting. These issues are especially prevalent if medicinal cannabis is to be combined with trauma-focused psychotherapy. EXPERT OPINION: Future consideration of the clinical and practical considerations of cannabis use in PTSD therapy will be essential to both the efficacy and safety of the treatment protocols that are being developed. These issues include dose timing and titration, potential for addiction, product formulation, windows of intervention, and route of administration. In particular, exposure therapy for PTSD involves recall of intense emotions, and the interaction between cannabis use and reliving of trauma memories must be explored in terms of patient safety and impact on therapeutic outcomes.

Cellular senescence: a key therapeutic target in aging and diseases.

Cellular senescence is a hallmark of aging defined by stable exit from the cell cycle in response to cellular damage and stress. Senescent cells (SnCs) can develop a characteristic pathogenic senescence-associated secretory phenotype (SASP) that drives secondary senescence and disrupts tissue homeostasis, resulting in loss of tissue repair and regeneration. The use of transgenic mouse models in which SnCs can be genetically ablated has established a key role for SnCs in driving aging and age-related disease. Importantly, senotherapeutics have been developed to pharmacologically eliminate SnCs, termed senolytics, or suppress the SASP and other markers of senescence, termed senomorphics. Based on extensive preclinical studies as well as small clinical trials demonstrating the benefits of senotherapeutics, multiple clinical trials are under way. This Review discusses the role of SnCs in aging and age-related diseases, strategies to target SnCs, approaches to discover and develop senotherapeutics, and preclinical and clinical advances of senolytics.

Targeting Cellular Senescence with Senotherapeutics: Development of New Approaches for Skin Care.

SUMMARY: Aging of the skin is evidenced by increased wrinkles, age spots, dryness, and thinning with decreased elasticity. Extrinsic and intrinsic factors including UV, pollution, and inflammation lead to an increase in senescent cells (SnCs) in skin with age that contribute to these observed pathological changes. Cellular senescence is induced by multiple types of damage and stress and is characterized by the irreversible exit from the cell cycle with upregulation of cell cycle-dependent kinase inhibitors p16INK4a and p21CIP1. Most SnCs also developed an inflammatory senescence-associated secretory phenotype (SASP) that drives further pathology through paracrine effects on neighboring cells and endocrine effects on cells at a distance. Recently, compounds able to kill senescent cells specifically, termed senolytics, or suppress the SASP, termed senomorphics, have been developed that have the potential to improve skin aging as well as systemic aging in general. Here, we provide a summary of the evidence for a key role in cellular senescence in driving skin aging. In addition, the evidence for the potential application of senotherapeutics for skin treatments is presented. Overall, topical, and possibly oral senotherapeutic treatments have tremendous potential to eventually become a standard of care for skin aging and related skin disorders.

Recent advances in the discovery of senolytics.

The demonstration in model organisms that cellular senescence drives aging and age-related diseases has led to widespread efforts to identify compounds able to selectively kill senescent cells, termed senolytics. Approaches used to identify senolytics include bioinformatic analysis of senescent cell anti-apoptotic pathways (SCAPs) for drug development and screening of drugs libraries on different senescent cell types in culture. Alternatively, cytotoxic compounds can be made specific to senescent cells through a prodrug strategy such as linking the compound to a galactose moiety where toxicity is activated by lysosomal ß-galactosidase. Identified senolytics can then be optimized through medicinal chemistry or linking to E3 targeting moieties to facilitate proteolysis of their targets. This review will provide an overview of approaches to identify senolytics and an update of the classes of senolytics identified to date.