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Senescent Cells

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• Exercise Counters the Age-related Accumulation of Senescent Cells - Medscape, 1/20/23 - "Exercise is, arguably, the most effective means to extend human healthspan. New insights into the mechanisms through which exercise optimizes function and counters disease have the potential to guide public health initiatives to promote physical activity and, concurrently, reveal biology that may be targeted through pharmacological intervention. The literature summarized herein suggests exercise both counters diverse forms of molecular damage that cause cellular senescence and potentially promotes immune-mediated senescent cell clearance. This evidence supports the hypothesis that exercise prevents the age-associated accumulation of senescent cells. Although more comprehensive and confirmatory studies are needed, the senotherapeutic effects of exercise have been demonstrated in multiple tissues in both preclinical models and humans"
• Resveratrol induces DNA damage-mediated cancer cell senescence through the DLC1-DYRK1A-EGFR axis - Food Funct 2023 Jan 18 - "Inducing cell senescence is widely regarded as a potent tumor suppression mechanism. Resveratrol has attracted increasing attention for its capacity to prevent and suppress cancer. However, the mechanism of resveratrol on the induction of cancer cell senescence has not been well clarified. Our results showed that resveratrol inhibited cell viability and colony formation and promoted cell senescence along with augmentation of SA-β-gal activity and modulation of senescence-associated molecular markers p53, p21 and LaminB protein in breast and liver cancer cells ... This is the first report to investigate whether resveratrol induces DNA damage-mediated cancer cell senescence through the DLC1-DYRK1A-EGFR axis, which could provide a solid base for resveratrol's application in cancer prevention and clinical treatment as a food additive or adjuvant therapies." - See resveratrol products at Amazon.com.
• NMN Shown To Remove Senescent Cells In Aging Eyes - YouTube, Modern Healthspan  - See NMN at Amazon.com.
• Combined use of dasatinib and quercetin alleviates overtraining-induced deficits in learning and memory through eliminating senescent cells and reducing apoptotic cells in rat hippocampus - Behav Brain Res 2022 Dec 16 - "Excessive physical exercise (overtraining, OT) charactered by long-term and excessive training results in the damage of multiple vital tissues including hippocampus which plays a critical role in learning and memory. A combination of dasatinib (D) plus quercetin (Q) (D+Q) belongs to senolytic drugs which selectively kill senescent cells in vitro and vivo ... These results indicated that D+Q alleviates overtraining-induced deficits in learning and memory through elimination of senescent cells and reduction of apoptotic cell number" - See quercetin at Amazon.com.
• Downregulation of Sirt6 by CD38 promotes cell senescence and aging - Aging (Albany NY) 2022 Dec 6 - "Decreased nicotinamide adenine dinucleotide (NAD+) levels accompany aging. CD38 is the main cellular NADase. Cyanidin-3-O-glucoside (C3G), a natural inhibitor of CD38, is a well-known drug that extends the human lifespan ... We suggest that CD38 downregulates Sirt6 expression to promote cell senescence and C3G exerts an antiaging effect through CD38-Sirt6 signaling" - See cyanidin 3-glucoside supplements at Amazon.com.
  • Showing Compound Cyanidin 3-glucoside - foodb - "Outside of the human body, Cyanidin 3-glucoside is found, on average, in the highest concentration within a few different foods, such as black elderberries, rubus (blackberry, raspberry), and bilberries and in a lower concentration in redcurrants, strawberries, and sweet oranges"
• Nicotinamide mononucleotide alleviates osteoblast senescence induction and promotes bone healing in osteoporotic mice - J Gerontol A Biol Sci Med Sci 2022 Aug 29 - "Combating the accumulated senescent cells and the healing of osteoporotic bone fracture in the elderly remains a significant challenge. Nicotinamide mononucleotide (NMN), a precursor of NAD +, is an excellent candidate for mitigating aging-related disorders. However, it is unknown if NMN can alleviate senescent cell induction and enhance osteoporotic bone fracture healing. Here we show that NMN treatment partially reverses the effects of tumor necrosis factor-alpha (TNF-α) on human primary osteoblasts (HOBs): senescent cell induction, diminished osteogenic differentiation ability and intracellular NAD + and NADH levels. Mechanistically, NMN restores the mitochondrial dysfunction in HOBs induced by TNF-α evidenced by increased mitochondrial membrane potential and reduced reactive oxidative species and mitochondrial mass. NMN also increases mitophagy activity by down-regulating P62 expression and up-regulating light chain 3B-II (LC3B-II) protein expression. In addition, the cell senescence protective effects of NMN on HOBs are mitigated by a mitophagy inhibitor (Bafilomycin A1). In vivo, NMN supplementation attenuates senescent cell induction in growth plates, partially prevents osteoporosis in an ovariectomized mouse model and accelerates bone healing in osteoporotic mice. We conclude that NMN can be a novel and promising therapeutic candidate to enhance bone fracture healing capacity in the elderly." - See NMN at Amazon.com.
• Artemisia argyi exhibits anti-aging effects through decreasing the senescence in aging stem cells - Aging (Albany NY) 2022 Aug 9 - "Aging is accompanied by functional loss of many cellular pathways, creating an increased risk of many age-related complications (ARC). Aging causes stem cell exhaustion with a concomitant increase in cellular dysfunction. Recently, interest in senotherapeutics has been growing rapidly to promote healthy aging and as an intervention for ARCs. This research focused on screening the senomorphic properties of Artemisia argyi, as an emerging strategy for longevity, and prevention or treatment of ARCs. In this study, we aimed to find the clinical efficacy of daily consumption of Artemisia argyi water extract (AAW) on aging ... In vitro study showed the protective effect of AAW in telomere shortening and helps in maintaining a balance in the expression of anti-aging protein Klotho and TERT. AAW effectively reduced mitochondrial superoxide and also provided a protective shield against senescence markers like over-expression of p21 and formation of double strand breaks, which is known to cause premature aging. Moreover, animal studies indicated that AAW promoted the expression of Klotho in naturally aging rats. In addition, AAW successfully restored the decline cardiac function and improved the grip strength and memory of aging rat. These findings showed that therapeutic targeting of senescent stem cells by AAW restored stem cell homeostasis and improves overall health" - See Artemisia argyi at Amazon.com.
• Nicotinamide Mononucleotide Ameliorates Cellular Senescence and Inflammation Caused by Sodium Iodate in RPE - Oxid Med Cell Longev 2022 Jul 18 - "retinal pigment epithelium (RPE) ... The protective effects of NMN were demonstrated to rely on undisturbed Sirt1 signaling. Moreover, both the expression of senescence markers of RPE and subretinal inflammatory cell infiltration were decreased by NMN treatment in vivo. Our results indicate that RPE senescence induced by NaIO3 acquired several key features of AMD. More importantly, NMN may potentially be used to treat RPE senescence and senescence-associated pre-AMD changes by restoring the NAD+ levels in cells and tissues." - See NMN at Amazon.com.
• Curcumin Alleviates D-Galactose-Induced Cardiomyocyte Senescence by Promoting Autophagy via the SIRT1/AMPK/mTOR Pathway - Evid Based Complement Alternat Med 2022 Jul 16 - "Oxidative stress and impaired autophagy are the hallmarks of cardiac aging. However, there are no specific drugs available to prevent cardiac aging. Curcumin is a natural polyphenolic drug with antioxidant, antiaging, and autophagy-promoting effects. Here, we describe the preventive role of Curcumin in cardiac aging through the induction of autophagy and the restoration of autophagy via the SIRT1/AMPK/mTOR pathway. The number of cells positive for senescence-associated β-galactosidase, P53, P16, and intracellular ROS increased significantly in senescent cardiomyocytes, stimulated using D-galactose. Curcumin reversed this effect in a dose-dependent manner. Curcumin-induced autophagy increased the expression of SIRT1and phosphorylated AMPK and decreased phosphorylated mTOR in a dose-dependent manner. SIRT1-siRNA-mediated knockdown inhibited the antioxidation, antiaging, the promotion of autophagy, and the SIRT1/AMPK/mTOR pathway activation effect of curcumin. Therefore, curcumin could be an effective anticardiac aging drug" - See curcumin at Amazon.com.
• Metformin mitigates stress-induced premature senescence by upregulating AMPKα at Ser485 phosphorylation induced SIRT3 expression and inactivating mitochondrial oxidants - Mech Ageing Dev 2022 Jul 18 - "The senescence of vascular smooth muscle cells (VSMCs) is an important cause of cardiovascular disease such as atherosclerosis and hypertension. These senescence may be triggered by many factors, such as oxidative stress, inflammation, DNA damage, and senescence-associated secretory phenotypes (SASPs). Mitochondrial oxidative stress induces cellular senescence, but the mechanisms by which mitochondrial reactive oxygen species (mtROS) regulates cellular senescence are still largely unknown ... This study provides mechanistic evidence that metformin acts as an anti-aging agent and alleviates VSMC senescence by upregulating mitochondrial antioxidant induced p-AMPK (Ser485)-dependent SIRT3 expression, which suggests metformin has therapeutic potential for the treatment of age-associated vascular disease" - See metformin at ReliableRX.
• New Horizons in the Treatment of Age-Associated Obesity, Sarcopenia and Osteoporosis - Drugs Aging 2022 Jul 4 - "The rapid increase in both the lifespan and proportion of older adults in developed countries is accompanied by the dramatic growth of age-associated chronic diseases, including obesity, sarcopenia, and osteoporosis. Hence, prevention and treatment of age-associated chronic diseases has become increasingly urgent. The key to achieving this goal is a better understanding of the mechanisms underlying their pathophysiology, some aspects of which, despite extensive investigation, are still not fully understood. Aging, obesity, sarcopenia, and osteoporosis are characterized by the creation of a systemic, chronic, low-grade inflammation (SCLGI). The common mechanisms that govern the development of these chronic conditions include a failed resolution of inflammation. Physiologically, the process of inflammation resolution is provided mainly by specialized pro-resolving mediators (SPMs) acting via cognate G protein-coupled receptors (GPCRs). Noteworthy, SPM levels and the expression of their receptors are significantly reduced in aging and the associated chronic disorders. In preclinical studies, supplementation of SPMs or their stable, small-molecule SPM mimetics and receptor agonists reveals clear beneficial effects in inflammation-related obesity and sarcopenic and osteoporotic conditions, suggesting a translational potential. Age-associated chronic disorders are also characterized by gut dysbiosis and the accumulation of senescent cells in the adipose tissue, skeletal muscle, and bones. Based on these findings, we propose SCLGI resolution as a novel strategy for the prevention/treatment of age-associated obesity, sarcopenia, and osteoporosis. Our approach entails the enhancement of inflammation resolution by SPM mimetics and receptor agonists in concert with probiotics/prebiotics and compounds that eliminate senescent cells and their pro-inflammatory activity" - See probiotic supplements at Amazon.com and prebiotic supplements at Amazon.com.
• Doxorubicin-induced senescence in normal fibroblasts promotes in vitro tumour cell growth and invasiveness: the role of Quercetin in modulating these processes - Mech Ageing Dev 2022 Jun 18 - "Ageing is a complex biological phenomenon representing the major risk factor for developing age-related diseases, such as cardiovascular pathologies, neurodegenerative diseases, and cancer. Geroscience, the new vision of gerontology, identifies cellular senescence as an interconnected biological process that characterises ageing and age-related diseases. Therefore, many strategies have been employed in the last years to reduce the harmful effects of senescence, and among these, the most intriguing ones use nutraceutical compounds. Here we show that a pre-treatment with Quercetin, a bioactive flavonoid present in many fruits and vegetables, increasing cellular antioxidant defence, can alleviate Doxorubicin (Doxo)-induced cellular senescence in human normal WI-38 fibroblasts. Furthermore, our work demonstrates that Quercetin pre-treatment, reducing the number of senescent cells and the production of the senescence-associated secretory phenotype (SASP) factors, can decrease the pro-tumour effects of conditioned medium from Doxo-induced senescent fibroblasts on osteosarcoma cells. Overall, our findings are consistent with the hypothesis that targeting senescent cells can be an emerging strategy for cancer treatment, especially in elderly patients, in which senescent cells are already abundant in several tissues and organs" - See quercetin at Amazon.com.
• Resveratrol drives cancer cell senescence via enhancing p38MAPK and DLC1 expressions - Food Funct 2022 Mar 2 - "Pro-senescence therapy is a recently proposed anti-cancer strategy and has been shown to effectively inhibit cancer. Resveratrol is gaining attention for its cancer preventive and suppressive properties ... resveratrol induced cell senescence along with an increase of SA-β-Gal activity and inhibition of colony formation in breast and lung cancer cells. The underlying mechanisms were that resveratrol induced ER-stress by increasing SIRT1 to promote p38MAPK expression and by reducing NO level to up-regulate DLC1 expression, and ER-stress further resulted in DNA damage and mitochondrial dysfunction, eventually leading to cancer cell senescence. Our findings on resveratrol's induction of cancer cell senescence via activating ER-stress through the SIRT1/p38MAPK and NO/DLC1 pathways provide a solid base for its clinical application and its preventive application as a food additive" - See resveratrol products at Amazon.com.
• Enhanced co-culture and enrichment of human natural killer cells for the selective clearance of senescent cells - Aging (Albany NY) 2022 Mar 4 - "In the context of aging and age-associated diseases, Natural Killer (NK) cells have been revealed as a key cell type responsible for the immune clearance of senescent cells. Subsequently, NK cell-based therapies have emerged as promising alternatives to drug-based therapeutic interventions for the prevention and treatment of age-related disease and debility. Given the promise of NK cell-mediated immunotherapies as a safe and effective treatment strategy, we outline an improved method by which primary NK cells can be efficiently enriched from human peripheral blood across multiple donors (ages 20-42 years old), with a practical protocol that reliably enhances both CD56dim and CD56bright NK cells by 15-fold and 3-fold, respectively. Importantly, we show that our co-culture protocol can be used as an easily adaptable tool to assess highly efficient and selective killing of senescent cells by primary NK cells enriched via our method using longer co-culture durations and a low target to effector ratio, which may be more physiological than has been achieved in previous literature"
• Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice - Aging Cell 2021 Feb - "Cellular senescence is characterized by an irreversible cell cycle arrest and a pro-inflammatory senescence-associated secretory phenotype (SASP), which is a major contributor to aging and age-related diseases. Clearance of senescent cells has been shown to improve brain function in mouse models of neurodegenerative diseases. However, it is still unknown whether senescent cell clearance alleviates cognitive dysfunction during the aging process. To investigate this, we first conducted single-nuclei and single-cell RNA-seq in the hippocampus from young and aged mice. We observed an age-dependent increase in p16Ink4a senescent cells, which was more pronounced in microglia and oligodendrocyte progenitor cells and characterized by a SASP. We then aged INK-ATTAC mice, in which p16Ink4a -positive senescent cells can be genetically eliminated upon treatment with the drug AP20187 and treated them either with AP20187 or with the senolytic cocktail Dasatinib and Quercetin. We observed that both strategies resulted in a decrease in p16Ink4a exclusively in the microglial population, resulting in reduced microglial activation and reduced expression of SASP factors. Importantly, both approaches significantly improved cognitive function in aged mice. Our data provide proof-of-concept for senolytic interventions' being a potential therapeutic avenue for alleviating age-associated cognitive impairment" - See quercetin at Amazon.com.
  • Dasatinib - Medline Plus - "Dasatinib is used to treat a certain type of chronic myeloid leukemia (CML; a type of cancer of the white blood cells) as a first treatment and in people who can no longer benefit from other leukemia medications including imatinib (Gleevec) or in those who cannot take these medications because of side effects"
• Fisetin Longevity Benefits | Mayo Clinic Trials - Dr Brad Stanfield, YouTube
  • What Are Senescent Cells - Dr James Kirkland Interview Series Ep 2, YouTube
  • Senescent Cells Effect & Benefits of Removing - Dr James Kirkland Interview Series Ep 3, YouTube
• Cellular senescence - Wiki - "Cellular senescence is a phenomenon characterized by the cessation of cell division. In their experiments during the early 1960s, Leonard Hayflick and Paul Moorhead found that normal human fetal fibroblasts in culture reach a maximum of approximately 50 cell population doublings before becoming senescent.[1][2][3] This process is known as "replicative senescence", or the Hayflick limit. Hayflick's discovery of mortal cells paved the path for the discovery and understanding of cellular aging molecular pathways.[4] Cellular senescence can be initiated by a wide variety of stress inducing factors. These stress factors include both environmental and internal damaging events, abnormal cellular growth, oxidative stress, autophagy factors, among many other things ... The physiological importance for cell senescence has been attributed to prevention of carcinogenesis, and more recently, aging, development, and tissue repair.[6] Senescent cells contribute to the aging phenotype, including frailty syndrome, sarcopenia, and aging-associated diseases.[7] Senescent astrocytes and microglia contribute to neurodegeneration."
• Overview of Cell Senescence - SENS Foundation, YouTube
• Fisetin Longevity Benefits | Mayo Clinic Trials - Dr Brad Stanfield, YouTube
• Fisetin, Quercetin & Dasatinib in Clinical Trials - Dr. James Kirkland Interview Series Ep 4, YouTube - Note: The consensus seems to be that you should take supplements that eliminate senescent cells in a hit and run fashion, i.e., take them in large quantities then stop them for a period of time. This doctor says the half-life of quercetin is 11 hours and it’s totally illuminated in three half-life’s or 36 hours. Fisetin’s half-life is three hours so it’s eliminated in 9 hours. As far as dasatinib, it’s a chemo medication for leukemia so I doubt if you’ll find a doctor to prescribe it. Overseas pharmacies sell it for $8.50 per pill. Most chemotherapy drugs increase senescent cells but dasatinib works on a different pathway.
• Combination of dasatinib and quercetin improves cognitive abilities in aged male Wistar rats, alleviates inflammation and changes hippocampal synaptic plasticity and histone H3 methylation profile
• What Are Senescent Cells - Dr James Kirkland Interview Series Ep 2, YouTube
• Senescent Cells Effect & Benefits of Removing - Dr James Kirkland Interview Series Ep 3, YouTube
• The Role of Senescence in Driving the Pathology of Aging-Related Diseases - Nicolas Musi, MD, YouTube
• Reversal of cell senescence by resveralogues- from mechanisms to therapies? - Richard Faragher, YouTube - He claims resveratrol will reverse senescence (around 20 minutes into the video).

Other News:

• Cellular senescence and cardiovascular diseases: moving to the "heart" of the problem - Physiol Rev 2022 Sep 1 - "Cardiovascular diseases (CVDs) constitute the prime cause of global mortality with an immense impact on patient quality of life and disability. Clinical evidence has revealed a strong connection between cellular senescence and worse cardiac outcomes in the majority of CVDs concerning both ischemic and non-ischemic cardiomyopathies. Cellular senescence is characterized by cell cycle arrest accompanied by alterations in several metabolic pathways, resulting in morphological and functional changes. Metabolic rewiring of senescent cells results in marked paracrine activity, through a unique secretome, often exerting deleterious effects on neighboring cells. Here, we recapitulate the hallmarks and key molecular pathways involved in cellular senescence in the cardiac context and summarize the different roles of senescence in the majority of CVDs. In the last few years, the possibility of eliminating senescent cells in various pathological conditions is being increasingly explored, giving rise to the field of senotherapeutics"
• Transformed cells after senescence give rise to more severe tumor phenotypes than transformed non-senescent cells - Cancer Lett 2022 Aug 1 - "Oncogenic stress-induced senescence initially inhibits tumor initiation by blocking proliferation and by attracting immune cells to clear potentially harmful cells. If these cells are not eliminated they may resume proliferation upon loss-of-tumor suppressors, and be at risk of transformation. During tumor formation, depending on the sequence of events of gain-of-oncogenes and/or loss-of-tumor suppressors, cancer cells may emerge from senescent cells. Here, we show that these transformed cells after senescence (TS) display more aggressive tumorigenic features, with a greater capacity to migrate and a higher resistance to anti-tumoral drugs than cells having undergone transformation without senescence. Bulk transcriptomic analysis and single cell RNA sequencing revealed a signature unique to TS cells. A score of this signature was then generated and a high score was correlated with decreased survival of patients with lung adenocarcinoma, head-neck squamous cell carcinoma, adrenocortical carcinoma, liver hepatocellular carcinoma, skin cutaneous melanoma and low-grade glioma. Together, these findings strongly support that cancer cells arising from senescent cells are more dangerous, and that a molecular signature of these cells may be of prognostic value for some human cancers"
• Cellular senescence: a key therapeutic target in aging and diseases - J Clin Invest 2022 Aug 1 - "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"