bims-caglex 2024-11-17 papers

bims-caglex

Biomed News

on Cellular aging and life extension

Issue of 2024–11–17
35 papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño

Novel Approach to Skin Anti-Aging: Boosting Pharmacological Effects of Exogenous Nicotinamide Adenine Dinucleotide (NAD+) by Synergistic Inhibition of CD38 Expression.
The Anti-Elixir Triad: Non-Synced Circadian Rhythm, Gut Dysbiosis and Telomeric Damage.
Senescence as a therapeutic target in cancer and age-related diseases.
HSF-1 promotes longevity through ubiquilin-1-dependent mitochondrial network remodelling.
Agar oligosaccharides improve the intestinal health of induced-aging mice by maintaining intestinal homeostasis via balancing the ISCs proliferation and differentiation.
Rapid DNA Repair in Mesenchymal Stem Cells and Bone Regeneration by Nanoparticle-Based Codelivery of Nrf2-mRNA and Dexamethasone.
Delivery of Stem Cell-Rejuvenating Compounds via Subcutaneous Osmotic Pumps.
Genetics and dietary restriction impact lifespan.
Reactive oxygen species in age-related musculoskeletal decline: implications for nutritional intervention.
Editorial: Genetic and molecular mechanisms of healthy aging and age-related diseases.
Aging, ROS, and cellular senescence: a trilogy in the progression of liver fibrosis.
Targeted CRISPR regulation of ZNF865 enhances stem cell cartilage deposition, tissue maturation rates, and mechanical properties in engineered intervertebral discs.
Aging with rejuvenation or morbidity and disability expansion?
Nicotinamide and pyridoxine stimulate muscle stem cell expansion and enhance regenerative capacity during aging.
The Senolytic Effect of Indole-3-Carbinol (I3C) on Mouse Embryonic (MEF) and Human Fibroblast Cell Lines.
Metformin restores autophagic flux and mitochondrial function in late passage myoblast to impede age-related muscle loss.
iTRAQ-Based Proteomic Profiling of Skin Aging Protective Effects of Tremella fuciformis-Derived Polysaccharides on D-Galactose-Induced Aging Mice.
Exercise, exerkines and exercise mimetic drugs: Molecular mechanisms and therapeutics.
Injectable "Skin Boosters" in Aging Skin Rejuvenation: A Current Overview.
Crosstalk between adipogenesis and aging: role of polyphenols in combating adipogenic-associated aging.
Body Composition and Senescence: Impact of Polyphenols on Aging-Associated Events.
Molecular and Cellular Effects of Microplastics and Nanoplastics: Focus on Inflammation and Senescence.
Various Strategies of Tendon Stem/Progenitor Cell Reprogramming for Tendon Regeneration.
Bioactive fraction of Musa balbisiana seed mitigates D-galactose-induced brain aging via SIRT1/PGC-1α/FoxO3a activation and intestinal barrier dysfunction by modulating gut microbiota and core metabolites.
Exploring the Role of Herbal Compounds in Skin Aging: A Systematic Review of Topical Approaches.
Dawn-to-dusk intermittent fasting is associated with overexpression of autophagy genes: A prospective study on overweight and obese cohort.
Lipid sensing by PPARα: Role in controlling hepatocyte gene regulatory networks and the metabolic response to fasting.
The immune landscape of murine skeletal muscle regeneration and aging.
Ginsenoside compound K alleviates brain aging by inhibiting ferroptosis through modulation of the ASK1-MKK7-JNK signaling pathway.
Argonaute-Based Nucleic Acid Detection Technology: Advantages, Current Status, Challenges, and Perspectives.
p63 affects distinct metabolic pathways during keratinocyte senescence, evaluated by metabolomic profile and gene expression analysis.
Can hypoxic exercise retard cellular senescence? A narrative review.
Chronic social stress induces p16-mediated senescent cell accumulation in mice.
Metabolic Regulation of Inflammation: Exploring the Potential Benefits of Itaconate in Autoimmune Disorders.
Digital Doppelgängers and Lifespan Extension: What Matters?

Cells. 2024 Oct 30. pii: 1799. [Epub ahead of print]13(21):

Novel Approach to Skin Anti-Aging: Boosting Pharmacological Effects of Exogenous Nicotinamide Adenine Dinucleotide (NAD+) by Synergistic Inhibition of CD38 Expression.

Seongsu Kang, Jiwon Park, Zhihong Cheng, Sanghyun Ye, Seung-Hyun Jun, Nae-Gyu Kang.

  Nicotinamide adenine dinucleotide (NAD+) is indispensable for the regulation of biological metabolism. Previous studies have revealed its role in aging and degenerative diseases, while crucially showing that supplementation with NAD+ or its precursors could ameliorate or reverse the progression of aging. Despite extensive evidence for the role and action of NAD+ in aging, its pharmacological activity on the skin, or even its mechanism, has not been elucidated. In this study, we established a novel approach to effectively utilize NAD+ for skin anti-aging by enhancing the pharmacological efficacy of exogenous NAD+ using a phytochemical complex consisting of quercetin, and enoxolone through inhibition of CD38. Through the comprehensive in vitro experiments based on human fibroblasts, we observed that exogenous NAD+ could exert protective effects against both extrinsic aging induced by ultraviolet light exposure and intrinsic aging. Additionally, we found that its effects were significantly boosted by quercetin and enoxolone. In this in-depth study, we demonstrated that these beneficial effects are mediated by improved sirtuin activation, autophagy, and mitochondrial functionality. Our approach is expected to verify the applicability of the topical application of NAD+ and offer more effective solutions for the unmet needs of patients and consumers who demand more effective anti-aging effects.

Keywords:  CD38; anti-aging; enoxolone; nicotinamide adenine dinucleotide (NAD+); quercetin; topical application

DOI:  https://doi.org/10.3390/cells13211799
Med Princ Pract. 2024 Nov 13. 1-21

The Anti-Elixir Triad: Non-Synced Circadian Rhythm, Gut Dysbiosis and Telomeric Damage.

Anup Kumar Mani, V Deepa Parvathi, Sumitha Ravindran.

Aging is an inevitable life process which is accelerated by lifestyle and environmental factors. It is an irreversible accretion of molecular and cellular damage associated with changes in the body composition and deterioration in physiological functions. Each cell (other than stem cells), reaches the limit of its ability to replicate, known as cellular or replicative senescence and consequently, the organs lose their physiological functions resulting in overall impairment. Other factors that promote aging include smoking, alcohol, UV rays, sleep habits, food, stress, sedentary life style and genetic abnormalities. These stress factors, can alter our endogenous clock (the circadian rhythm) and the microbial commensals. As a result of effect of these stressors, the microorganisms that generally support human physiological processes become baleful. The disturbance of natural physiology instigates many age-related pathologies, such as cardiovascular diseases, chronic obstructive pulmonary disorder, cerebrovascular diseases, opportunistic infections, high blood pressure, cancer, diabetes, kidney diseases, dementia, and Alzheimer's disease. The present review covers the three most essential processes of the circadian clock; the circadian gene mechanism and regulation, the mitotic clock (which plays a vital role in the telomere's attrition) and gut microbiota and their metabolome that drive aging and lead to age-related pathologies. In conclusion, maintaining a synchronized circadian rhythm, a healthy gut microbiome and telomere integrity is essential for mitigating the effects of aging and promoting longevity. The interplay among these factors underscores the importance of lifestyle choices in enhancing overall health and lifespan.

DOI: https://doi.org/10.1159/000542557
Nat Rev Drug Discov. 2024 Nov 15.

Senescence as a therapeutic target in cancer and age-related diseases.

Domhnall McHugh, Imanol Durán, Jesús Gil.

Cellular senescence is a stress response that restrains the growth of aged, damaged or abnormal cells. Thus, senescence has a crucial role in development, tissue maintenance and cancer prevention. However, lingering senescent cells fuel chronic inflammation through the acquisition of a senescence-associated secretory phenotype (SASP), which contributes to cancer and age-related tissue dysfunction. Recent progress in understanding senescence has spurred interest in the development of approaches to target senescent cells, known as senotherapies. In this Review, we evaluate the status of various types of senotherapies, including senolytics that eliminate senescent cells, senomorphics that suppress the SASP, interventions that mitigate senescence and strategies that harness the immune system to clear senescent cells. We also summarize how these approaches can be combined with cancer therapies, and we discuss the challenges and opportunities in moving senotherapies into clinical practice. Such therapies have the potential to address root causes of age-related diseases and thus open new avenues for preventive therapies and treating multimorbidities.

DOI: https://doi.org/10.1038/s41573-024-01074-4
Nat Commun. 2024 Nov 12. 15(1): 9797

HSF-1 promotes longevity through ubiquilin-1-dependent mitochondrial network remodelling.

Annmary Paul Erinjeri, Xunyan Wang, Rhianna Williams, Riccardo Zenezini Chiozzi, Konstantinos Thalassinos, Johnathan Labbadia.

Increased activity of the heat shock factor, HSF-1, suppresses proteotoxicity and enhances longevity. However, the precise mechanisms by which HSF-1 promotes lifespan are unclear. Using an RNAi screen, we identify ubiquilin-1 (ubql-1) as an essential mediator of lifespan extension in worms overexpressing hsf-1. We find that hsf-1 overexpression leads to transcriptional downregulation of all components of the CDC-48-UFD-1-NPL-4 complex, which is central to both endoplasmic reticulum and mitochondria associated protein degradation, and that this is complemented by UBQL-1-dependent turnover of NPL-4.1. As a consequence, mitochondrial network dynamics are altered, leading to increased lifespan. Together, our data establish that HSF-1 mediates lifespan extension through mitochondrial network adaptations that occur in response to down-tuning of components associated with organellar protein degradation pathways.

DOI: https://doi.org/10.1038/s41467-024-54136-x
Eur J Nutr. 2024 Nov 15. 64(1): 9

Agar oligosaccharides improve the intestinal health of induced-aging mice by maintaining intestinal homeostasis via balancing the ISCs proliferation and differentiation.

Shuhang Fan, Qianyi Zhang, Jianyi She, Xianjun Dai.

   PURPOSE: Aging is a process that accompanies a decline in the function of various tissues and organs, especially affecting intestinal health. Agarose oligosaccharide (AOS) can prolong the lifespan of organisms and protect the intestine in the previous study. It was examined to evaluate the effects of AOS on intestinal health, and the potential associations between intestinal homeostasis and health status were further validated.
METHODS: D-galactose-induced aging mice were used to investigate the role of AOS in promoting intestinal health by determining intestinal physiology, microbiota and stem cells.
RESULTS: AOS supplementation decreased the clinical frailty index of aging mice with increasing intestinal length and crypt depth; moreover, it decreased the average flatulence index and PCNA protein content in the intestine. Besides, AOS contributed to the diversity of the gut microbiota by increasing the relative abundance of Bacteroidetes and other bacteria that could produce short-chain fatty acids. Furthermore, AOS affected the expression of proinflammatory factors in aging mice, promoting the proliferative equilibrium of intestinal stem cells.
CONCLUSION: These findings confirmed that AOS could improve intestinal health in aging mice by maintaining intestinal homeostasis, which provides new insights into the potential application of AOS as a prebiotic.

Keywords:  Agarose oligosaccharide; Aging mouse; Intestinal homeostasis; Intestinal microbiota; Intestinal stem cell

DOI:  https://doi.org/10.1007/s00394-024-03512-w
ACS Nano. 2024 Nov 09.

Rapid DNA Repair in Mesenchymal Stem Cells and Bone Regeneration by Nanoparticle-Based Codelivery of Nrf2-mRNA and Dexamethasone.

Ji Sun Park, Hayoung Jeon, Yeeun Lee, Seo Young Cheon, Donghyun Lee, Seong Gi Lim, Heebeom Koo.

  Directional differentiation is a key factor determining the result of stem cell therapy. Herein, we developed a polyethylenimine (PEI)-coated poly(lactic-co-glycolic) acid (PLGA) nanoparticle (mPDN) carrying both nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA and dexamethasone (Dex) to human mesenchymal stem cells (hMSCs). The combination of Dex and Nrf2-mRNA delivered by mPDN promoted the osteogenic differentiation of hMSCs. In particular, Nrf2-mRNA rapidly reduced the DNA damage caused by ROS due to early and efficient gene expression at 3 h after treatment, which was not achieved in traditional pDNA systems. High and rapid transfection, effective ROS-scavenging effect, and protection of mitochondrial dynamics were observed in hMSCs after treatment with the resulting Nrf2-mPDN. Osteogenic differentiation was also observed in 3D pellets for up to 5 weeks. Finally, the effects of rapid DNA repair in hMSCs by Nrf2-mPDN and on in vivo bone regeneration were evaluated in a rat femoral bone defect model using CT. This study demonstrated the potential of an NP-based codelivery system and efficient transfection of mRNA at early stages in hMSCs for bone regeneration and stem cell therapy.

Keywords:  bone regeneration; mRNA; mesenchymal stem cell; mitochondrial dynamics; nanoparticle; nuclear factor erythroid 2-related factor 2 (Nrf2)

DOI:  https://doi.org/10.1021/acsnano.4c08939
Methods Mol Biol. 2024 Nov 10.

Delivery of Stem Cell-Rejuvenating Compounds via Subcutaneous Osmotic Pumps.

Sen Zhang, Sandra Pinho.

  Aging is widely regarded as an irreversible physiological process throughout the mammalian lifespan, characterized by functional tissue deterioration and increased disease incidence. One hallmark of mammalian aging is reduced tissue regeneration, primarily attributed to the declining function of tissue-specific stem cells. In recent years, various strategies aimed at rejuvenating stem cells through drug-delivery systems have been extensively explored. Here we describe a method for the long-term, controlled, systemic delivery of drugs using subcutaneous implantations of osmotic pumps.

Keywords:  Controlled release method; Long-term administration; Osmotic pump; Rejuvenation; Systemic

DOI:  https://doi.org/10.1007/7651_2024_573
Nat Genet. 2024 Nov;56(11): 2295

Genetics and dietary restriction impact lifespan.

Wei Li.

DOI: https://doi.org/10.1038/s41588-024-02005-0
Proc Nutr Soc. 2024 Nov 08. 1-9

Reactive oxygen species in age-related musculoskeletal decline: implications for nutritional intervention.

Malcolm J Jackson.

  Musculoskeletal disorders and age-related musculoskeletal decline are major contributors to the burden of ill health seen in older subjects. Despite this increased burden, these chronic disorders of old age receive a relatively small proportion of national research funds. Much has been learned about fundamental processes involved in ageing from basic science research and this is leading to identification of key pathways that mediate ageing which may help the search for interventions to reduce age-related musculoskeletal decline. This short review will focus on the role of reactive oxygen species in age-related skeletal muscle decline and on the implications of this work for potential nutritional interventions in sarcopenia. The key physiological role of reactive oxygen species is now known to be in mediating redox signalling in muscle and other tissues and ageing leads to disruption of such pathways. In muscle, this is reflected in an age-related attenuation of specific adaptations and responses to contractile activity that impacts the ability of skeletal muscle from ageing individuals to respond to exercise. These pathways provides potential targets for identification of logical interventions that may help maintain muscle mass and function during ageing.

Keywords:  Ageing; Redox; Skeletal muscle

DOI:  https://doi.org/10.1017/S0029665124004877
Front Genet. 2024 ;15 1509961

Editorial: Genetic and molecular mechanisms of healthy aging and age-related diseases.

Yunpeng Xu, Jiang-An Yin, Zhiyong Shao.



Keywords:  age-related diseases; aging; genetic; lifespan; molecular

DOI:  https://doi.org/10.3389/fgene.2024.1509961
Biogerontology. 2024 Nov 15. 26(1): 10

Aging, ROS, and cellular senescence: a trilogy in the progression of liver fibrosis.

Waleed Hassan Almalki, Salem Salman Almujri.

  Ageing is an inevitable and multifaceted biological process that impacts a wide range of cellular and molecular mechanisms, leading to the development of various diseases, such as liver fibrosis. Liver fibrosis progresses to cirrhosis, which is an advanced form due to high amounts of extracellular matrix and restoration of normal liver structure with failure to repair damaged tissue and cells, marking the end of liver function and total liver failure, ultimately death. The most important factors are reactive oxygen species (ROS) and cellular senescence. Oxidative stress is defined as an impairment by ROS, which are by-products of the mitochondrial electron transport chain and other key molecular pathways that induce cell damage and can activate cellular senescence pathways. Cellular senescence is characterized by pro-inflammatory cytokines, growth factors, and proteases secreted by senescent cells, collectively known as the senescence-associated secretory phenotype (SASP). The presence of senescent cells, which disrupt tissue architecture and function and increase senescent cell production in liver tissues, contributes to fibrogenesis. Hepatic stellate cells (HSCs) are activated in response to chronic liver injury, oxidative stress, and senescence signals that drive excessive production and deposition of extracellular matrix. This review article aims to provide a comprehensive overview of the pathogenic role of ROS and cellular senescence in the aging liver and their contribution to fibrosis.

Keywords:  Aging; Cellular senescence; Liver fibrosis; Oxidative stress; Reactive oxygen species; Senescence-associated secretory phenotype

DOI:  https://doi.org/10.1007/s10522-024-10153-3
Acta Biomater. 2024 Nov 08. pii: S1742-7061(24)00661-5. [Epub ahead of print]

Targeted CRISPR regulation of ZNF865 enhances stem cell cartilage deposition, tissue maturation rates, and mechanical properties in engineered intervertebral discs.

Hunter Levis, Christian Lewis, Matthew Fainor, Ameerah Lawal, Elise Stockham, Jacob Weston, Niloofar Farhang, Sarah E Gullbrand, Robby D Bowles.

  Cell and tissue engineering based approaches have garnered significant interest for treating intervertebral disc degeneration and associated low back pain due to the substantial limitations of currently available clinical treatments. Herein we present a clustered regularly interspaced short palindromic repeats (CRISPR)-guided gene modulation strategy to improve the therapeutic potential of cell and tissue engineering therapies for treating intervertebral disc disease. Recently, we discovered a zinc finger (ZNF) protein, ZNF865 (BLST), which is associated with no in-depth publications and has not been functionally characterized. Utilizing CRISPR-guided gene modulation, we show that ZNF865 regulates cell cycle progression and protein processing. As a result, regulating this gene acts as a primary titratable regulator of cell activity. We also demonstrate that targeted ZNF865 regulation can enhance protein production and fibrocartilage-like matrix deposition in human adipose-derived stem cells (hASCs). Furthermore, we demonstrate CRISPR-engineered hASCs ability to increase GAG and collagen II matrix deposition in human-size tissue-engineered discs by 8.5-fold and 88.6-fold, respectively, while not increasing collagen X expression compared to naive hASCs dosed with growth factors. With this increased tissue deposition, we observe significant improvements in compressive mechanical properties, generating a stiffer and more robust tissue. Overall, we present novel biology on ZNF865 and display the power of CRISPR-cell engineering to enhance strategies treating musculoskeletal disease. STATEMENT OF SIGNIFICANCE: This work reports on a novel gene, ZNF865 (also known as BLST), that when regulated with CRISPRa, improves cartilagenous tissue deposition in human sized tissue engineering constructs. Producing tissue engineering constructs at human scale has proven difficult, and this strategy presents a broadly applicable tool to enhance a cells ability to produce tissue at these scales, as we saw an ∼8-88 fold increase in tissue deposition and significantly improved biomechanics in large tissue engineered intervertebral disc compared to traditional growth factor differentiation methods. Additionally, this work begins to elucidate the biology of this novel zinc finger protein, which appears to be critical in regulating cell function and activity.

Keywords:  BLST; CRISPR-activation; Cell and tissue engineering; Degenerative disc disease; Intervertebral disc

DOI:  https://doi.org/10.1016/j.actbio.2024.11.007
Arch Gerontol Geriatr. 2024 Nov 06. pii: S0167-4943(24)00362-5. [Epub ahead of print] 105686

Aging with rejuvenation or morbidity and disability expansion?

Liang-Kung Chen.



Keywords:  Healthy aging; Healthy life expectancy; Healthy longevity; Population aging

DOI:  https://doi.org/10.1016/j.archger.2024.105686
J Clin Invest. 2024 Nov 12. pii: e163648. [Epub ahead of print]

Nicotinamide and pyridoxine stimulate muscle stem cell expansion and enhance regenerative capacity during aging.

Sara Ancel, Joris Michaud, Eugenia Migliavacca, Charline Jomard, Aurélie Fessard, Pauline Garcia, Sonia Karaz, Sruthi Raja, Guillaume E Jacot, Thibaut Desgeorges, José-Luis Sánchez-García, Loic Tauzin, Yann Ratinaud, Benjamin Brinon, Sylviane Métairon, Lucas Pinero, Denis Barron, Stephanie Blum, Leonidas G Karagounis, Ramin Heshmat, Afshin Ostovar, Farshad Farzadfar, Isabella Scionti, Rémi Mounier, Julien Gondin, Pascal Stuelsatz, Jerome N Feige.

  Skeletal muscle relies on resident muscle stem cells (MuSCs) for growth and repair. Aging and muscle diseases impair MuSC function, leading to stem cell exhaustion and regenerative decline that contribute to the progressive loss of skeletal muscle mass and strength. In the absence of clinically available nutritional solutions specifically targeting MuSCs, we used a human myogenic progenitor (hMP) high-content imaging screen of natural molecules from food to identify nicotinamide (NAM) and pyridoxine (PN) as bioactive nutrients that stimulate MuSCs and have history of safe human use. NAM and PN synergize via CK1-mediated cytoplasmic β-catenin activation and AKT signaling to promote amplification and differentiation of MuSCs. Oral treatment with a combination of NAM/PN accelerates muscle regeneration in vivo by stimulating MuSCs, increases muscle strength during recovery, and overcomes MuSC dysfunction and regenerative failure during aging. Levels of NAM and bioactive PN spontaneously decline during aging in model organisms and inter-independently associate with muscle mass and walking speed in a human cohort of 186 aged people. Collectively, our results establish NAM/PN as a new nutritional intervention that stimulates MuSCs, enhances muscle regeneration, and alleviates age-related muscle decline with a direct opportunity for clinical translation.

Keywords:  Adult stem cells; Epidemiology; Muscle biology; Skeletal muscle; Stem cells

DOI:  https://doi.org/10.1172/JCI163648
Int J Mol Sci. 2024 Oct 30. pii: 11652. [Epub ahead of print]25(21):

The Senolytic Effect of Indole-3-Carbinol (I3C) on Mouse Embryonic (MEF) and Human Fibroblast Cell Lines.

Scott L Sax, Maria Laura Centomo, Federica Centofanti, Barbara Rizzacasa, Sierra Cox, Chelsea Cox, Andrea Latini, Maria Rosaria D'Apice, Liliana Mannucci, Giuseppe Novelli, Pier Paolo Pandolfi.

  Senescence and apoptosis are two fundamental cellular processes that play crucial roles in various physiological and pathological conditions. Senescence refers to the irreversible growth arrest that cells undergo in response to various stimuli, including telomeric alterations, stress, and oncogenic signaling. Pharmacological and/or genetic removal of senescent cells, also referred to as senolysis, triggers organ rejuvenation and tissue regeneration. Indole-3-carbinol (I3C) is a natural compound contained in Brassicaceae plants and identified in multiple in vitro and in vivo studies as a well-tolerated and effective compound in cancer prevention and therapy. Its anti-cancer properties have been attributed at least in part to its inhibitory activity of proto-oncogenic HECT E3-ubiquitin ligases such as NEDD4 and WWP1. While the tumor suppressive effects of I3C in cancer cell lines have been reported in multiple studies, little is known regarding the biological effects of I3C in primary normal cells, which attain spontaneous cellular senesce over serial passaging. To this end, we used two model systems: mouse embryonic fibroblasts (MEFs) and human primary dermal fibroblasts. Here, we surprisingly show that I3C does increase cellular senescence at early passages, while dramatically reducing the number of senescent cells through the induction of apoptosis in both mouse and human primary cells. Thus, our findings support the notion that I3C acts as a senolytic compound with important therapeutic implications for the prevention and treatment of aging manifestations. The notion can be readily tested in future clinical trials in humans also in view of the high tolerability and safety previously displayed by I3C in preclinical and clinical studies.

Keywords:  Indole-3-carbinol; apoptosis; senescence; senolytic

DOI:  https://doi.org/10.3390/ijms252111652
Biomed Pharmacother. 2024 Nov;pii: S0753-3322(24)00865-5. [Epub ahead of print]180 116981

Metformin restores autophagic flux and mitochondrial function in late passage myoblast to impede age-related muscle loss.

Sooyoon Bang, Dong-Eun Kim, Hee-Taik Kang, Jong Hun Lee.

  Sarcopenia, which refers to age-related muscle loss, presents a significant challenge for the aging population. Age-related changes that contribute to sarcopenia include cellular senescence, decreased muscle stem cell number and regenerative capacity, impaired autophagy, and mitochondrial dysfunction. Metformin, an anti-diabetic agent, activates AMP-activated protein kinase (AMPK) and affects various cellular processes in addition to reducing hepatic gluconeogenesis, lowering blood glucose levels, and improving insulin resistance. However, its effect on skeletal muscle cells remains unclear. This study aimed to investigate the effects of metformin on age-related muscle loss using a late passage C2C12 cell model. The results demonstrated that metformin alleviated hallmarks of cellular senescence, including SA-β-gal activity and p21 overexpression. Moreover, treatment with pharmacological concentrations of metformin restored the reduced differentiation capacity in late passage cells, evident through increased myotube formation ability and enhanced expression of myogenic differentiation markers such as MyoD, MyoG, and MHC. These effects of metformin were attributed to enhanced autophagic activity, normalization of mitochondrial membrane potential, and improved mitochondrial respiratory capacity. These results suggest that pharmacological concentrations of metformin alleviate the hallmarks of cellular senescence, restore differentiation capacity, and improve autophagic flux and mitochondrial function. These findings support the potential use of metformin for the treatment of sarcopenia.

Keywords:  Autophagy; Cellular senescence; Metformin; Mitochondrial dysfunction; Myogenic differentiation; Sarcopenia

DOI:  https://doi.org/10.1016/j.biopha.2024.116981
Molecules. 2024 Nov 02. pii: 5191. [Epub ahead of print]29(21):

iTRAQ-Based Proteomic Profiling of Skin Aging Protective Effects of Tremella fuciformis-Derived Polysaccharides on D-Galactose-Induced Aging Mice.

Yuanyuan Xu, Xiaofei Liu, Jingjing Guan, Jin Chen, Xiaofei Xu.

  In the present study, a heteromannan primarily composed of mannose, fucose, xylose, glucose, and arabinose at a molar ratio of 4.78:1.18:1:0.82:0.11 containing a low proportion of glucuronic acid with weight-average molecular weights of 3.6 × 106 Da, named NTP, was prepared from the fruiting body of Tremella fuciformis. The anti-skin-aging effects of NTP on d-Galactose-induced aging mice and the biological mechanisms were investigated by an iTRAQ-based proteomics approach. NTP substantially mitigated skin aging characterized by a decreased loss of hydroxyproline and hyaluronic acid and reduced oxidative stress in the skin. Moreover, 43 differentially expressed proteins (DEPs) were identified in response to NTP, of which 23 were up-regulated and 20 were down-regulated. Bioinformatics analysis revealed that these DEPs were mainly involved in the biological functions of cellular and metabolic regulations, immune system responses, and structural components. The findings provided new insights into the biological mechanisms underlying the anti-skin-aging actions of T. fuciformis-derived polysaccharides and facilitated NTP applications in naturally functional foods.

Keywords:  anti-skin aging; differentially expressed protein; inflammation; mushroom polysaccharides; oxidative stress

DOI:  https://doi.org/10.3390/molecules29215191
Life Sci. 2024 Nov 09. pii: S0024-3205(24)00815-4. [Epub ahead of print]359 123225

Exercise, exerkines and exercise mimetic drugs: Molecular mechanisms and therapeutics.

Vedant Samant, Arati Prabhu.

  Chronic diseases linked with sedentary lifestyles and poor dietary habits are increasingly common in modern society. Exercise is widely acknowledged to have a plethora of health benefits, including its role in primary prevention of various chronic conditions like type 2 diabetes mellitus, obesity, cardiovascular disease, and several musculoskeletal as well as degenerative disorders. Regular physical activity induces numerous physiological adaptations that contribute to these positive effects, primarily observed in skeletal muscle but also impacting other tissues. There is a growing interest among researchers in developing pharmaceutical interventions that mimic the beneficial effects of exercise for therapeutic applications. Exercise mimetic medications have the potential to be helpful aids in enhancing functional outcomes for patients with metabolic dysfunction, neuromuscular and musculoskeletal disorders. Some of the potential targets for exercise mimetics include pathways involved in metabolism, mitochondrial function, inflammation, and tissue regeneration. The present review aims to provide an exhaustive overview of the current understanding of exercise physiology, the role of exerkines and biomolecular pathways, and the potential applications of exercise mimetic drugs for the treatment of several diseases.

Keywords:  Exercise; Exercise mimetic drugs; Exerkines; Metabolic dysfunction; Musculoskeletal disorders; Tissue regeneration

DOI:  https://doi.org/10.1016/j.lfs.2024.123225
Arch Plast Surg. 2024 Nov;51(6): 528-541

Injectable "Skin Boosters" in Aging Skin Rejuvenation: A Current Overview.

Nark-Kyoung Rho, Hyun-Seok Kim, Soo-Young Kim, Won Lee.

  Aging-related changes in the skin, such as dullness, dehydration, and loss of elasticity, significantly affect its appearance and integrity. Injectable "skin boosters," comprising various biological materials, have become increasingly prominent in addressing these issues, offering rejuvenation and revitalization. This review offers a comprehensive examination of these injectables, detailing their types, mechanisms of action, and clinical uses. It also evaluates the evidence for their effectiveness and safety in treating age-related skin alterations and other conditions. The goal is to provide an insightful understanding of injectable skin boosters in contemporary dermatological practice, summarizing the current state of knowledge.

Keywords:  amino acid; botulinum neurotoxin; collagen; hyaluronic acid; intradermal injection; needle-free jet injector; poly-(lactic acid); polycaprolactone; polydeoxyribonucleotide; skin booster

DOI:  https://doi.org/10.1055/a-2366-3436
Immun Ageing. 2024 Nov 07. 21(1): 76

Crosstalk between adipogenesis and aging: role of polyphenols in combating adipogenic-associated aging.

Khalid Al-Regaiey.

  In the last forty years, the number of people over 60 years of age has increased significantly owing to better nutrition and lower rates of infectious diseases in developing countries. Aging significantly impacts adipose tissue, which plays crucial role in hormone regulation and energy storage. This can lead to imbalances in glucose, and overall energy homeostasis within the body. Aging is irreversible phenomena and potentially causing lipid infiltration in other organs, leading to systemic inflammation, metabolic disorders. This review investigates various pathways contributing to aging-related defects in adipogenesis, such as changes in adipose tissue function and distribution. Polyphenols, a diverse group of natural compounds, can mitigate aging effects via free radicals, oxidative stress, inflammation, senescence, and age-related diseases. Polyphenols like resveratrol, quercetin and EGCG exhibit distinct mechanisms and regulate crucial pathways, such as the TGF-β, AMPK, Wnt, PPAR-γ, and C/EBP transcription factors, and influence epigenetic modifications, such as DNA methylation and histone modification. This review highlights the critical importance of understanding the intricate relationship between aging and adipogenesis for optimizing well-being with increasing age. These findings highlight the therapeutic potential of polyphenols like quercetin and resveratrol in enhancing adipose tissue function and promoting healthy aging.

Keywords:  AMPK; Adipogenesis; Adipose tissue redistribution; Aging; C/EBP; Endocrine changes; Epigenetic changes; PPAR-γ; Polyphenols; TGF-β; Wnt

DOI:  https://doi.org/10.1186/s12979-024-00481-w
Nutrients. 2024 Oct 25. pii: 3621. [Epub ahead of print]16(21):

Body Composition and Senescence: Impact of Polyphenols on Aging-Associated Events.

Tanila Wood Dos Santos, Quélita Cristina Pereira, Isabela Monique Fortunato, Fabrício de Sousa Oliveira, Marisa Claudia Alvarez, Marcelo Lima Ribeiro.

  Aging is a dynamic and progressive process characterized by the gradual accumulation of cellular damage. The continuous functional decline in the intrinsic capacity of living organisms to precisely regulate homeostasis leads to an increased susceptibility and vulnerability to diseases. Among the factors contributing to these changes, body composition-comprised of fat mass and lean mass deposits-plays a crucial role in the trajectory of a disability. Particularly, visceral and intermuscular fat deposits increase with aging and are associated with adverse health outcomes, having been linked to the pathogenesis of sarcopenia. Adipose tissue is involved in the secretion of bioactive factors that can ultimately mediate inter-organ pathology, including skeletal muscle pathology, through the induction of a pro-inflammatory profile such as a SASP, cellular senescence, and immunosenescence, among other events. Extensive research has shown that natural compounds have the ability to modulate the mechanisms associated with cellular senescence, in addition to exhibiting anti-inflammatory, antioxidant, and immunomodulatory potential, making them interesting strategies for promoting healthy aging. In this review, we will discuss how factors such as cellular senescence and the presence of a pro-inflammatory phenotype can negatively impact body composition and lead to the development of age-related diseases, as well as how the use of polyphenols can be a functional measure for restoring balance, maintaining tissue quality and composition, and promoting health.

Keywords:  adipose tissue; body composition; polyphenols; senescence; skeletal muscle

DOI:  https://doi.org/10.3390/nu16213621
Cells. 2024 Oct 29. pii: 1788. [Epub ahead of print]13(21):

Molecular and Cellular Effects of Microplastics and Nanoplastics: Focus on Inflammation and Senescence.

Faiza Mahmud, Drishty B Sarker, Jonathan A Jocelyn, Qing-Xiang Amy Sang.

  Microplastics and nanoplastics (MNPs) are ubiquitous environmental contaminants. Their prevalence, persistence, and increasing industrial production have led to questions about their long-term impact on human and animal health. This narrative review describes the effects of MNPs on oxidative stress, inflammation, and aging. Exposure to MNPs leads to increased production of reactive oxygen species (ROS) across multiple experimental models, including cell lines, organoids, and animal systems. ROS can cause damage to cellular macromolecules such as DNA, proteins, and lipids. Direct interaction between MNPs and immune cells or an indirect result of oxidative stress-mediated cellular damage may lead to increased production of pro-inflammatory cytokines throughout different MNP-exposure conditions. This inflammatory response is a common feature in the pathogenesis of neurodegenerative, cardiovascular, and other age-related diseases. MNPs also act as cell senescence inducers by promoting mitochondrial dysfunction, impairing autophagy, and activating DNA damage responses, exacerbating cellular aging altogether. Increased senescence of reproductive cells and transfer of MNPs/induced damages from parents to offspring in animals further corroborates the transgenerational health risks of the tiny particles. This review aims to provoke a deeper investigation into the notorious effects these pervasive particles may have on human well-being and longevity.

Keywords:  DNA damage; cellular aging; cytotoxicity; environmental pollutants; human health; inflammation; microplastics; nanoplastics; reactive oxygen species; senescence

DOI:  https://doi.org/10.3390/cells13211788
Int J Mol Sci. 2024 Nov 01. pii: 11745. [Epub ahead of print]25(21):

Various Strategies of Tendon Stem/Progenitor Cell Reprogramming for Tendon Regeneration.

Sung Yong Ahn.

  Rotator cuff tears (RCT) are the most common cause of shoulder pain among adults. "Rotator cuff" refers to the four muscles that cover the shoulder joint: supraspinatus, infraspinatus, subscapularis, and teres minor. These muscles help maintain the rotational movement and stability of the shoulder joint. RCT is a condition in which one or more of these four muscles become ruptured or damaged, causing pain in the arms and shoulders. RCT results from degenerative changes caused by chronic inflammation of the tendons and consequent tendon tissue defects. This phenomenon occurs because of the exhaustion of endogenous tendon stem cells. Tendon regeneration requires rejuvenation of these endogenous tendon stem/progenitor cells (TSPCs) prior to their growth phase. TSPCs exhibit clonogenicity, multipotency, and self-renewal properties; they express classical stem cell markers and genes associated with the tendon lineage. However, specific markers for TSPC are yet to be identified. In this review, we introduce novel TSPC markers and discuss various strategies for TSPC reprogramming. With further research, TSPC reprogramming technology could be adapted to treat age-related degenerative diseases, providing a new strategy for regenerative medicine.

Keywords:  cell reprogramming; extracellular vesicles; regeneration; rotator cuff disease; small molecules; tendon stem/progenitor cell

DOI:  https://doi.org/10.3390/ijms252111745
Free Radic Biol Med. 2024 Nov 12. pii: S0891-5849(24)01050-5. [Epub ahead of print]

Bioactive fraction of Musa balbisiana seed mitigates D-galactose-induced brain aging via SIRT1/PGC-1α/FoxO3a activation and intestinal barrier dysfunction by modulating gut microbiota and core metabolites.

Nonibala Gurumayum, M Bidyarani Devi, Puspanjali Khound, Anupam Bhattacharya, Himangshu Sarma, Mojibur R Khan, Rajlakshmi Devi.

  Aging is an inevitable biological process, and emerging research has highlighted the potential of dietary and pharmacological interventions to decelerate the trajectory of age-related diseases and prolong the health span. This study evaluates the protective effects of Musa balbisiana seed on healthy aging using D-galactose-induced accelerated aging rats. The results suggested that the bioactive ethyl acetate fraction of Musa balbisiana seed extract (BF) exhibited protective effects against aging-induced oxidative stress by reducing oxidative DNA damage, advanced glycation end-product formation, and malondialdehyde levels while restoring antioxidant and glyoxalase enzyme activities. BF also ameliorated neurodegeneration by decreasing acetylcholinesterase enzyme activity and amyloid beta plaque formation. Histopathological analysis demonstrated the protective effects of BF against brain aging, liver disruption, renal damage, and intestinal barrier dysfunction. BF further restored intestinal permeability by upregulating the tight junctions (zonula occludens 1 and 2, claudin 1,2,3 and 4, and occludin) and mucin (mucin 2 and mucin 5ac) gene expression while downregulating the expression of inflammatory cytokines (IL-1β, IL-6, and TNF-α). BF significantly induced the phosphorylation of FoxO3a proteins and upregulated the gene expression of SIRT1, PGC-1α, and TFAM in the hippocampus. Next-generation sequencing (NGS) of 16s rRNA amplicons of fecal metagenomics DNA and metabolites profiling showed that BF intervention restructured the gut microbiota and altered core metabolites related to cholesterol metabolism. Overall, our findings demonstrated the multifaceted protective effects of Musa balbisiana seed against D-galactose-induced aging.

Keywords:  D-galactose; Musa balbisiana; age-related diseases; aging; gut microbes; next-generation sequencing

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.11.016
Phytother Res. 2024 Nov 14.

Exploring the Role of Herbal Compounds in Skin Aging: A Systematic Review of Topical Approaches.

Asly Poh-Tze Goh, She-May Goh, Wai-Kit Tow, Kar-Men Toh, Uma Devi Palanisamy, Usha Sundralingam.

  Recently, dermatology has increasingly focused on understanding skin aging and exploring novel therapeutic approaches. Despite progress in cosmetic and pharmaceutical research, a significant gap remains in comprehensively understanding the effects and mechanisms of herbal extracts on skin aging. While many studies have examined the bioactivities of herbal compounds in preclinical models, comprehensive human trials have been scarce over the past decade. This review aims to address this gap by synthesizing human trials from the past decade, focusing on the therapeutic effects of herbal extracts on skin aging. The objective is to unravel the mechanisms contributing to skin aging and assess the therapeutic potential of herbal compounds. Following the PRISMA 2020 guideline, a systematic review was performed across OvidMEDLINE, Cochrane Central Register of Controlled Trials, and Embase via Ovid. A meticulous search strategy identified relevant clinical trials. The review highlights the essential role of herbal compounds in skin aging, particularly their antioxidant activity in suppressing the aging process. Analysis of 51 clinical trials offers valuable insights into their diverse effects on skin aging parameters. Herbal compounds are promising alternatives to synthetic products for treating skin aging. Their demonstrated efficacy in mitigating wrinkles, enhancing elasticity, maintaining hydration, and controlling pigmentation underscores their potential in developing antiaging therapeutics. However, further studies are needed to identify specific compounds responsible for these effects and understand their mechanisms. Future directions include conducting large-scale trials, exploring synergies with other ingredients, and optimizing delivery systems for sustainable, effective antiaging therapies.

Keywords:  elasticity; herbal compound; hydration; pigmentation; topical; wrinkle

DOI:  https://doi.org/10.1002/ptr.8375
Clin Nutr ESPEN. 2024 Nov 12. pii: S2405-4577(24)01510-9. [Epub ahead of print]

Dawn-to-dusk intermittent fasting is associated with overexpression of autophagy genes: A prospective study on overweight and obese cohort.

Lara J Bou Malhab, Mohamed I Madkour, Dana N Abdelrahim, Leen Eldohaji, Maha Saber-Ayad, Nabil Eid, Wael M Abdel-Rahman, MoezAlIslam E Faris.

   AIM AND BACKGROUND: A growing body of evidence supports the impact of intermittent fasting (IF) on longevity and healthy aging via the modulation of autophagy genes. The activation of the catabolic autophagic machinery (LAMP2, LC3B, ATG5, and ATG4D) has protective effects against degenerative aging and chronic diseases. This research examined the changes in the expression of the aforementioned genes upon the observance of dawn-to-dusk IF among metabolically healthy participants with overweight and obesity.
METHODS: Fifty-one (51) participants (36 males and 15 females, 38.84 ± 11.73 years) with overweight and obesity (BMI = 29.75 ± 5.04 kg/m2) were recruited and monitored before and at the end of the commencement of the four-week IF. Six healthy subjects with normal BMI (21.4±2.20 kg/m2) were recruited only to standardize the reference for normal levels of gene expressions. At the two time points, anthropometric, biochemical, and dietary assessments were performed, and LAMP2, LC3B, ATG5, and ATG4D gene expressions were assessed using qRT-PCR on RNA extracted from whole blood samples.
RESULTS: At the end of IF, and compared to the pre-fasting levels, the relative gene expressions among participants with overweight/obesity were significantly increased for the three autophagy genes LAMP2, LC3B, and ATG5, with increments of about 4.2 folds, 1.9-fold, and 1.4-fold, respectively. In contrast, the increase in the ATG4D gene was not significant. Concomitantly, significant decreases were found in body weight, BMI, fat mass, body fat percent, hip and waist circumferences, LDL, IL-6, and TNF-a (P <0.05), While HDL, IL-10, and CD163 significantly increased (P <0.05). Binary logistic regression analysis for genetic expressions showed no significant association between high-energy intake, waist circumference, or obesity and the four gene expressions.
CONCLUSIONS: Four consecutive weeks of dawn-to-dusk IF of Ramadan is associated with the upregulation of autophagy gene expressions in participants with overweight/obesity, and this may explain, at least in part, its favorable short-term temporal metabolic and health-improving effects on early aging-related markers. Hence, IF presumably may entail a protective impact against early markers of aging and metabolic diseases in participants with overweight/obesity.

Keywords:  Aging; Autophagy; Calorie restriction; Intermittent fasting; Longevity; Nutrigenomics; Personalized nutrition

DOI:  https://doi.org/10.1016/j.clnesp.2024.11.002
Prog Lipid Res. 2024 Nov 07. pii: S0163-7827(24)00036-5. [Epub ahead of print] 101303

Lipid sensing by PPARα: Role in controlling hepatocyte gene regulatory networks and the metabolic response to fasting.

Anne Fougerat, Justine Bruse, Arnaud Polizzi, Alexandra Montagner, Hervé Guillou, Walter Wahli.

  Peroxisome proliferator-activated receptors (PPARs) constitute a small family of three nuclear receptors that act as lipid sensors, and thereby regulate the transcription of genes having key roles in hepatic and whole-body energy homeostasis, and in other processes (e.g., inflammation), which have far-reaching health consequences. Peroxisome proliferator-activated receptor isotype α (PPARα) is expressed in oxidative tissues, particularly in the liver, carrying out critical functions during the adaptive fasting response. Advanced omics technologies have provided insight into the vast complexity of the regulation of PPAR expression and activity, as well as their downstream effects on the physiology of the liver and its associated metabolic organs. Here, we provide an overview of the gene regulatory networks controlled by PPARα in the liver in response to fasting. We discuss impacts on liver metabolism, the systemic repercussions and benefits of PPARα-regulated ketogenesis and fibroblast growth factor 21 (FGF21) production, a fasting- and stress-inducible metabolic hormone. We also highlight current challenges in using novel methods to further improve our knowledge of PPARα in health and disease.

Keywords:  fasting; fibroblast growth factor 21 (FGF21); gene expression; ketogenesis; peroxisome proliferator-activated receptors (PPARs)

DOI:  https://doi.org/10.1016/j.plipres.2024.101303
Cell Rep. 2024 Nov 13. pii: S2211-1247(24)01326-3. [Epub ahead of print]43(11): 114975

The immune landscape of murine skeletal muscle regeneration and aging.

Neuza S Sousa, Marta Bica, Margarida F Brás, Ana C Sousa, Inês B Antunes, Isabel A Encarnação, Tiago M Costa, Inês B Martins, Nuno L Barbosa-Morais, Pedro Sousa-Victor, Joana Neves.

  Age-related alterations in the immune system are starting to emerge as key contributors to impairments found in aged organs. A decline in regenerative capacity is a hallmark of tissue aging; however, the contribution of immune aging to regenerative failure is just starting to be explored. Here, we apply a strategy combining single-cell RNA sequencing with flow cytometry, histological analysis, and functional assays to perform a complete analysis of the immune environment of the aged regenerating skeletal muscle on a time course following injury with single-cell resolution. Our results reveal an unanticipated complexity and functional heterogeneity in immune populations within the skeletal muscle that have been regarded as homogeneous. Furthermore, we uncover a profound remodeling of both myeloid and lymphoid compartments in aging. These discoveries challenge established notions on immune regulation of skeletal muscle regeneration, providing a set of potential targets to improve skeletal muscle health and regenerative capacity in aging.

Keywords:  CP: Immunology

DOI:  https://doi.org/10.1016/j.celrep.2024.114975
Phytomedicine. 2024 Nov 10. pii: S0944-7113(24)00896-1. [Epub ahead of print]135 156239

Ginsenoside compound K alleviates brain aging by inhibiting ferroptosis through modulation of the ASK1-MKK7-JNK signaling pathway.

Xiaojun Yan, Xue Bai, Guanghui Sun, Zhiguang Duan, Rongzhan Fu, Wen Zeng, Chenhui Zhu, Daidi Fan.

   BACKGROUND: Aging of the brain is a major contributor to the onset and progression of neurodegenerative diseases. Conventional treatments for these diseases are often limited by significant side effects and a lack of efficacy in halting disease progression. Ginsenoside compound K (CK), a bioactive secondary metabolite derived from ginseng, has shown promise because of its potent antioxidant properties.
PURPOSE: This study aimed to elucidate the molecular mechanisms underlying the impact of CK on brain senescence, with a particular focus on its role in modulating oxidative stress and related signaling pathways.
METHODS: We employed a d-galactose (D-gal)-induced PC-12 senescent cell model and a mouse brain aging model to explore the antioxidant properties of CK in the context of brain aging. The effects of CK on mitochondrial dysfunction associated with brain aging were assessed using immunofluorescence and western blotting techniques. The potential molecular mechanisms by CK influences brain aging were investigated using transcriptomic analysis and western blotting. Additionally, CK's regulatory effect on apoptosis signal-regulating kinase 1 (ASK1) was validated by molecular docking, microscale thermophoresis, and small interfering RNA transfection.
RESULTS: Our findings demonstrate that CK effectively alleviates cognitive decline associated with brain aging. CK reduces the number of senescent cells, alleviates neuronal damage, and enhances the activity of key antioxidant enzymes, including catalase, superoxide dismutase, and glutathione peroxidase. Additionally, CK restores mitochondrial function and upregulated the expression of solute carrier family 7 member 11 and glutathione peroxidase 4, thereby inhibiting ferroptosis. Furthermore, CK targets ASK1 and suppresses the hyperphosphorylation of MAPK kinase 7 (MKK7) and c-Jun N-terminal kinase (JNK). This suppression promotes the nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2), effectively reducing ferroptosis and oxidative damage linked to brain aging.
CONCLUSION: In summary, our research demonstrates that CK effectively delays brain aging by inhibiting the ASK1-MKK7-JNK signaling pathway, enhancing nuclear Nrf2 expression, and suppressing the ferroptosis response. These findings highlight CK as a promising therapeutic agent for slowing brain aging and alleviating neurodegenerative diseases.

Keywords:  ASK1-MKK7-JNK signaling pathway; Brain aging; Ferroptosis; Ginsenoside compound k; Mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.phymed.2024.156239
ACS Sens. 2024 Nov 11.

Argonaute-Based Nucleic Acid Detection Technology: Advantages, Current Status, Challenges, and Perspectives.

Yaru Li, Lu Zhao, Jiali Wang, Long Ma, Yunfeng Bai, Feng Feng.

  Rapid and accurate detection is a prerequisite for precise clinical diagnostics, ensuring food safety, and facilitating biotechnological applications. The Argonaute system, as a cutting-edge technique, has been successfully repurposed in biosensing beyond the CRISPR/Cas system (clustered regularly interspaced short palindromic repeats and CRISPR-associated proteins), which has been extensively researched, but recognition of PAM sequences remains restricted. Argonaute, as a programmable and target-activated nuclease, is repurposed for fabricating novel detection methods due to its unparalleled biological features. In this comprehensive review, we initially elaborate on the current methods for nucleic acid testing and programmable nucleases, followed by delving into the structure and nuclease activity of the Argonaute system. The advantages of Argonaute compared with the CRISPR/Cas system in nucleic acid detection are highlighted and discussed. Furthermore, we summarize the applications of Argonaute-based nucleic acid detection and provide an in-depth analysis of future perspectives and challenges. Recent research has demonstrated that Argonaute-based biosensing is an innovative and rapidly advancing technology that can overcome the limitations of existing methods and potentially replace them. In summary, the implementation of Argonaute and its integration with other technologies hold promise in developing customized and intelligent detection methods for nucleic acid testing across various aspects.

Keywords:  Argonaute; CRISPR/Cas; detection methods; multiplexed detection; nucleic acid detection; programmable nucleases; sensitivity; specificity

DOI:  https://doi.org/10.1021/acssensors.4c01631
Cell Death Dis. 2024 Nov 14. 15(11): 830

p63 affects distinct metabolic pathways during keratinocyte senescence, evaluated by metabolomic profile and gene expression analysis.

Maria Cristina Piro, Rosalba Pecorari, Artem Smirnov, Angela Cappello, Erica Foffi, Anna Maria Lena, Yufang Shi, Gerry Melino, Eleonora Candi.

Unraveling the molecular nature of skin aging and keratinocyte senescence represents a challenging research project in epithelial biology. In this regard, depletion of p63, a p53 family transcription factor prominently expressed in human and mouse epidermis, accelerates both aging and the onset of senescence markers in vivo animal models as well as in ex vivo keratinocytes. Nonetheless, the biochemical link between p63 action and senescence phenotype remains largely unexplored. In the present study, through ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) and gas chromatography/mass spectrometry (GC/MS) metabolomic analysis, we uncover interesting pathways linking replicative senescence to metabolic alterations during p63 silencing in human keratinocytes. Integration of our metabolomic profiling data with targeted transcriptomic investigation empowered us to demonstrate that absence of p63 and senescence share similar modulation profiles of oxidative stress markers, pentose phosphate pathway metabolites and lyso-glycerophospholipids, the latter due to enhanced phospholipases gene expression profile often under p63 direct/indirect gene control. Additional biochemical features identified in deranged keratinocytes include a relevant increase in lipids production, glucose and pyruvate levels as confirmed by upregulation of gene expression of key lipid synthesis and glycolytic enzymes, which, together with improved vitamins uptake, characterize senescence phenotype. Silencing of p63 in keratinocytes instead, translates into a blunted flux of metabolites through both glycolysis and the Krebs cycle, likely due to a p63-dependent reduction of hexokinase 2 and citrate synthase gene expression. Our findings highlight the potential role of p63 in counteracting keratinocyte senescence also through fine regulation of metabolite levels and relevant biochemical pathways. We believe that our research might contribute significantly to the discovery of new implications of p63 in keratinocyte senescence and related diseases.

DOI: https://doi.org/10.1038/s41419-024-07159-7
Eur Rev Aging Phys Act. 2024 Nov 13. 21(1): 31

Can hypoxic exercise retard cellular senescence? A narrative review.

Tinghuai Huang, Charlotte Tsang, Jianwei Huang.

   BACKGROUND: Senescent cells are defined as normal cells that have undergone irreversible division arrest due to various factors. These cells have been found to play a pivotal role in aging and the development of chronic diseases. Numerous studies demonstrated that physical exercise is effective in anti-aging and anti-chronic diseases. Furthermore, the combination of exercise and hypoxia has been shown to optimize the stimulus of oxygen deprivation and extend cellular lifespan.
OBJECTIVE: This narrative review offers an exhaustive analysis of existing literature studying the effect of hypoxic exercise on cellular senescence under various conditions.
METHODS: Four electronic databases underwent title and abstract screening to summarize the effect of hypoxic exercise on cellular senescence under various conditions. Papers were deemed eligible if they examined the effect of hypoxic exercise on cellular senescence in full-text, peer-reviewed journals and published in English. The final search was carried out on May 4, 2024. Studied were excluded if they: (a) did not involve the utilization of hypoxic exercise as a sole intervention or a contributing factor; (b) did not investigate cellular senescence; (c) lacked sufficient information regarding the study design and findings. A total of 2033 articles were obtained from four databases. However, only 11 articles were deemed to meet eligibility criteria after thoroughly examining titles, abstracts, and full-text content. Authorship, publication year, details of the experimental subject, types of exercise, training protocols, organ, tissue or cell, markers of senescent cells examined, and their responses elicited by exercise were diligently recorded.
RESULTS: This review identified 11 articles for data extraction. The sample sizes varied across a spectrum of complexity, ranging from 4 to 60 (Median=20). The studied population encompassed different healthy cohorts, which comprised sedentary males (n=6), trained males (n=2), mountain climbers (n=1), and older adults (n=2). Included studies preferred using bicycle ergometers (72.7%, n=8) as the exercise modality and 10 studies (90.9%) utilized hypoxia chambers to mimic a normobaric hypoxia environment. Four studies (36.4%) opted to utilize hypoxia chambers to mimic an altitude of 2733 and 4460 m. Additionally, 54.5% of studies (n=6) specifically investigated the effect of hypoxic exercise on lymphocytes, commonly utilizing CD28 (n=3) and CD57 (n=3) as markers of cellular senescence. Four studies (33.3%) examined the impact of hypoxic exercise on erythrocytes using CD47 as the marker for detecting senescent cells.
CONCLUSION: These data support the notion that hypoxic exercise can retard cellular senescence of specific cells. In the future, standardization on the type of hypoxic exercise and markers of cellular senescence will be essential. Additionally, greater attention should be given to female populations and patients with different disease states. Lastly, further studies of the optimal form and dosage of exercise and the underlying cellular mechanisms are warranted.
TRIAL REGISTRATION: PROSPERO, identifier CRD42023431601.

Keywords:  Altitude; Hypoxia; Physical exercise; Senescence

DOI:  https://doi.org/10.1186/s11556-024-00352-9
Nat Aging. 2024 Nov 11.

Chronic social stress induces p16-mediated senescent cell accumulation in mice.

Carey E Lyons, Jean Pierre Pallais, Seth McGonigle, Rachel P Mansk, Charles W Collinge, Matthew J Yousefzadeh, Darren J Baker, Patricia R Schrank, Jesse W Williams, Laura J Niedernhofer, Jan M van Deursen, Maria Razzoli, Alessandro Bartolomucci.

Life stress can shorten lifespan and increase risk for aging-related diseases, but the biology underlying this phenomenon remains unclear. Here we assessed the effect of chronic stress on cellular senescence-a hallmark of aging. Exposure to restraint stress, a psychological non-social stress model, increased p21Cip1 exclusively in the brains of male, but not female mice, and in a p16Ink4a-independent manner. Conversely, exposure to chronic subordination stress (only males were tested) increased key senescent cell markers in peripheral blood mononuclear cells, adipose tissue and brain, in a p16Ink4a-dependent manner. p16Ink4a-positive cells in the brain of chronic subordination stress-exposed mice were primarily hippocampal and cortical neurons with evidence of DNA damage that could be reduced by p16Ink4a cell clearance. Clearance of p16Ink4a-positive cells was not sufficient to ameliorate the adverse effects of social stress on measured metrics of healthspan. Overall, our findings indicate that social stress induces an organ-specific and p16Ink4a-dependent accumulation of senescent cells, illuminating a fundamental way by which the social environment can contribute to aging.

DOI: https://doi.org/10.1038/s43587-024-00743-8
Immunology. 2024 Nov 14.

Metabolic Regulation of Inflammation: Exploring the Potential Benefits of Itaconate in Autoimmune Disorders.

Yin Luo, Li-Yan Jiang, Zhe-Zhen Liao, Yuan-Yuan Wang, Ya-Di Wang, Xin-Hua Xiao.

  Itaconic acid and its metabolites have demonstrated significant therapeutic potential in various immune diseases. Originating from the tricarboxylic acid cycle in immune cells, itaconic acid can modulate immune responses, diminish inflammation, and combat oxidative stress. Recent research has uncovered multiple mechanisms through which itaconic acid exerts its effects, including the inhibition of inflammatory cytokine production, activation of anti-inflammatory pathways, and modulation of immune cell function by regulating cellular metabolism. Cellular actions are influenced by the modulation of metabolic pathways, such as inhibiting succinate dehydrogenase (SDH) activity or glycolysis, activation of nuclear-factor-E2-related factor 2 (Nrf2), boosting cellular defences against oxidative stress, and suppression of immune cell inflammation through the NF-κB pathway. This comprehensive review discusses the initiation, progression, and mechanisms of action of itaconic acid and its metabolites, highlighting their modulatory effects on various immune cell types. Additionally, it examines their involvement in immune disease like rheumatoid arthritis, multiple sclerosis, type 1 diabetes mellitus, and autoimmune hepatitis, offering greater understanding for creating new therapies for these ailments.

Keywords:  autoimmune disease; itaconic acid; metabolic pathways

DOI:  https://doi.org/10.1111/imm.13875
Am J Bioeth. 2024 Nov 14. 1-16

Digital Doppelgängers and Lifespan Extension: What Matters?

Samuel Iglesias, Brian D Earp, Cristina Voinea, Sebastian Porsdam Mann, Anda Zahiu, Nancy S Jecker, Julian Savulescu.

  There is an ongoing debate about the ethics of research on lifespan extension: roughly, using medical technologies to extend biological human lives beyond the current "natural" limit of about 120 years. At the same time, there is an exploding interest in the use of artificial intelligence (AI) to create "digital twins" of persons, for example by fine-tuning large language models on data specific to particular individuals. In this paper, we consider whether digital twins (or digital doppelgängers, as we refer to them) could be a path toward a kind of life extension-or more precisely, a kind of person extension-that does not rely on biological continuity. We discuss relevant accounts of consciousness and personal identity and argue that digital doppelgängers may at least help us achieve some of the aims or ostensible goods of person-span extension, even if they may not count as literal extensions of our personhood on dominant philosophical accounts. We also consider relational accounts of personhood and discuss how digital doppelgängers may be able to extend personhood in a relational sense, or at least secure some of the goods associated with relevant relationships. We conclude by suggesting that a research program to investigate such issues is relevant to ongoing debates about the ethics of extending the human lifespan.

Keywords:  Aging; artificial intelligence; digital duplicates; digital twins; life extension; longevity research

DOI:  https://doi.org/10.1080/15265161.2024.2416133