bims-caglex 2024-01-14 papers

bims-caglex

Biomed News

on Cellular aging and life extension

Issue of 2024–01–14
twenty papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño

Ligustilide, A Novel Senolytic Compound Isolated from the Roots of Angelica Acutiloba.
Eternal Youth: A Comprehensive Exploration of Gene, Cellular, and Pharmacological Anti-Aging Strategies.
Icariin Improves Stress Resistance and Extends Lifespan in Caenorhabditis elegans through hsf-1 and daf-2-Driven Hormesis.
OXR1 maintains the retromer to delay brain aging under dietary restriction.
Emerging epigenetic insights into aging mechanisms and interventions.
Oroxylin A ameliorates ultraviolet radiation-induced premature skin aging by regulating oxidative stress via the Sirt1 pathway.
Age-related decline in melatonin contributes to enhanced osteoclastogenesis via disruption of redox homeostasis.
Novel 18-Norspirostane Steroidal Saponins: Extending Lifespan and Mitigating Neurodegeneration through Promotion of Mitophagy and Mitochondrial Biogenesis in Caenorhabditis elegans.
Cholesterol biosynthetic pathway induces cellular senescence through ERRα.
DMHPpp1r17 neurons regulate aging and lifespan in mice through hypothalamic-adipose inter-tissue communication.
Klotho: a potential therapeutic target in aging and neurodegeneration beyond chronic kidney disease-a comprehensive review from the ERA CKD-MBD working group.
Yo-yo Dieting Delays Male Drosophila melanogaster Aging Through Enhanced Mitochondrial Function, Relative to Sustained High-Calorie Diet Feeding.
A navitoclax-loaded nanodevice targeting matrix metalloproteinase-3 for the selective elimination of senescent cells.
Antiaging Strategies and Remedies: A Landscape of Research Progress and Promise.
Inhibitor PF-04691502 works as a senolytic to regulate cellular senescence.
Skin-protective biological activities of bio-fermented Aframomum angustifolium extract by a consortium of microorganisms.
Targeting COPIng liabilities of senescent cells.
Effects of resveratrol on in vitro circadian clock gene expression in young and older human adipose-derived progenitor cells.
Discovery of a 4-Hydroxy-3'-Trifluoromethoxy-Substituted Resveratrol Derivative as an Anti-Aging Agent.
Alginate oligosaccharide alleviates vascular aging by upregulating glutathione peroxidase 7.

Adv Biol (Weinh). 2024 Jan 06. e2300434

Ligustilide, A Novel Senolytic Compound Isolated from the Roots of Angelica Acutiloba.

Kento Takaya, Kazuo Kishi.

  Senescent cells accumulate with age and contribute to age-related diseases and organ dysfunctions. Early evidence suggests that removal of senescent cells using senolytic drugs improves the aging phenotype in mice and may improve the health of individuals with chronic diseases. Signs of skin aging, including wrinkles, and sagging, occur largely due to the accumulation of senescent fibroblasts within the dermis; However, there is currently no skin treatment that eliminates senescent cells. In this study, human fibroblasts subjected to replicative aging and ionizing radiation exposure are used to screen plant extracts for potential senescent cell-destructive and/or senescent cell-forming activities. Angelica acutiloba-a traditional Chinese herbal medicine-selectively kills senescent cells without affecting the proliferating cells. Among the major components of this herb, ligustilide shows promising senescent cell-destructive properties, and selectively eliminates senescent cells by inducing an apoptosis. Moreover, ligustilide markedly inhibits senescence-associated secretory phenotypes. Administration of ligustilide to mouse skin eliminates senescent cells and increases dermal collagen density and subcutaneous adipose tissue content; it selectively promotes death of senescent cells without affecting non-senescent cells. These results provide evidence that a natural compound-ligustilide-may exhibit therapeutic effects on the skin aging phenotype by specifically inducing apoptosis in senescent cells.

Keywords:  fibroblasts; ligustilide; senolysis; skin aging

DOI:  https://doi.org/10.1002/adbi.202300434
Int J Mol Sci. 2024 Jan 04. pii: 643. [Epub ahead of print]25(1):

Eternal Youth: A Comprehensive Exploration of Gene, Cellular, and Pharmacological Anti-Aging Strategies.

Kristina V Kitaeva, Valeriya V Solovyeva, Nataliya L Blatt, Albert A Rizvanov.

  The improvement of human living conditions has led to an increase in average life expectancy, creating a new social and medical problem-aging, which diminishes the overall quality of human life. The aging process of the body begins with the activation of effector signaling pathways of aging in cells, resulting in the loss of their normal functions and deleterious effects on the microenvironment. This, in turn, leads to chronic inflammation and similar transformations in neighboring cells. The cumulative retention of these senescent cells over a prolonged period results in the deterioration of tissues and organs, ultimately leading to a reduced quality of life and an elevated risk of mortality. Among the most promising methods for addressing aging and age-related illnesses are pharmacological, genetic, and cellular therapies. Elevating the activity of aging-suppressing genes, employing specific groups of native and genetically modified cells, and utilizing senolytic medications may offer the potential to delay aging and age-related ailments over the long term. This review explores strategies and advancements in the field of anti-aging therapies currently under investigation, with a particular emphasis on gene therapy involving adeno-associated vectors and cell-based therapeutic approaches.

Keywords:  AAV; aging; anti-aging therapy; cell therapy; gene therapy; senescent cells; senolytic

DOI:  https://doi.org/10.3390/ijms25010643
Int J Mol Sci. 2023 Dec 26. pii: 352. [Epub ahead of print]25(1):

Icariin Improves Stress Resistance and Extends Lifespan in Caenorhabditis elegans through hsf-1 and daf-2-Driven Hormesis.

Monika N Todorova, Martina S Savova, Liliya V Mihaylova, Milen I Georgiev.

  Aging presents an increasingly significant challenge globally, driven by the growing proportion of individuals aged 60 and older. Currently, there is substantial research interest in pro-longevity interventions that target pivotal signaling pathways, aiming not only to extend lifespan but also to enhance healthspan. One particularly promising approach involves inducing a hormetic response through the utilization of natural compounds defined as hormetins. Various studies have introduced the flavonoid icariin as beneficial for age-related diseases such as cardiovascular and neurodegenerative conditions. To validate its potential pro-longevity properties, we employed Caenorhabditis elegans as an experimental platform. The accumulated results suggest that icariin extends the lifespan of C. elegans through modulation of the DAF-2, corresponding to the insulin/IGF-1 signaling pathway in humans. Additionally, we identified increased resistance to heat and oxidative stress, modulation of lipid metabolism, improved late-life healthspan, and an extended lifespan upon icariin treatment. Consequently, a model mechanism of action was provided for icariin that involves the modulation of various players within the stress-response network. Collectively, the obtained data reveal that icariin is a potential hormetic agent with geroprotective properties that merits future developments.

Keywords:  Caenorhabditis elegans; aging; healthspan; icariin; lifespan; longevity

DOI:  https://doi.org/10.3390/ijms25010352
Nat Commun. 2024 Jan 11. 15(1): 467

OXR1 maintains the retromer to delay brain aging under dietary restriction.

Kenneth A Wilson, Sudipta Bar, Eric B Dammer, Enrique M Carrera, Brian A Hodge, Tyler A U Hilsabeck, Joanna Bons, George W Brownridge, Jennifer N Beck, Jacob Rose, Melia Granath-Panelo, Christopher S Nelson, Grace Qi, Akos A Gerencser, Jianfeng Lan, Alexandra Afenjar, Geetanjali Chawla, Rachel B Brem, Philippe M Campeau, Hugo J Bellen, Birgit Schilling, Nicholas T Seyfried, Lisa M Ellerby, Pankaj Kapahi.

Dietary restriction (DR) delays aging, but the mechanism remains unclear. We identified polymorphisms in mtd, the fly homolog of OXR1, which influenced lifespan and mtd expression in response to DR. Knockdown in adulthood inhibited DR-mediated lifespan extension in female flies. We found that mtd/OXR1 expression declines with age and it interacts with the retromer, which regulates trafficking of proteins and lipids. Loss of mtd/OXR1 destabilized the retromer, causing improper protein trafficking and endolysosomal defects. Overexpression of retromer genes or pharmacological restabilization with R55 rescued lifespan and neurodegeneration in mtd-deficient flies and endolysosomal defects in fibroblasts from patients with lethal loss-of-function of OXR1 variants. Multi-omic analyses in flies and humans showed that decreased Mtd/OXR1 is associated with aging and neurological diseases. mtd/OXR1 overexpression rescued age-related visual decline and tauopathy in a fly model. Hence, OXR1 plays a conserved role in preserving retromer function and is critical for neuronal health and longevity.

DOI: https://doi.org/10.1038/s41467-023-44343-3
Trends Pharmacol Sci. 2024 Jan 11. pii: S0165-6147(23)00260-2. [Epub ahead of print]

Emerging epigenetic insights into aging mechanisms and interventions.

Zeming Wu, Weiqi Zhang, Jing Qu, Guang-Hui Liu.

  Epigenetic dysregulation emerges as a critical hallmark and driving force of aging. Although still an evolving field with much to explore, it has rapidly gained significance by providing valuable insights into the mechanisms of aging and potential therapeutic opportunities for age-related diseases. Recent years have witnessed remarkable strides in our understanding of the epigenetic landscape of aging, encompassing pivotal elements, such as DNA methylation, histone modifications, RNA modifications, and noncoding (nc) RNAs. Here, we review the latest discoveries that shed light on new epigenetic mechanisms and critical targets for predicting and intervening in aging and related disorders. Furthermore, we explore burgeoning interventions and exemplary clinical trials explicitly designed to foster healthy aging, while contemplating the potential ramifications of epigenetic influences.

Keywords:  age-related diseases; aging; clinical trials; epigenetic; intervention

DOI:  https://doi.org/10.1016/j.tips.2023.12.002
Biomed Pharmacother. 2024 Jan 09. pii: S0753-3322(23)01908-X. [Epub ahead of print]171 116110

Oroxylin A ameliorates ultraviolet radiation-induced premature skin aging by regulating oxidative stress via the Sirt1 pathway.

Tao Liu, Shan Zhu, Yi Yang, Wenxiao Qin, Zijing Wang, Zhiyue Zhao, Tao Liu, Xiang Wang, Tian Duan, Yang Liu, Yan Liu, Qingmei Xia, Han Zhang, Nan Li.

  Skin is susceptible to premature aging in response to ultraviolet (UV) radiation-induced oxidative stress, which can ultimately result in aberrant aging or age-related disorders. Accordingly, strategies that can be adopted to mitigate oxidative stress may contribute to protecting skin from induced aging-related damage, thereby offering promising approaches for the treatment of skin diseases and disorders. In this regard, oroxylin A (OA), a natural flavonoid isolated from certain plants used in traditional Chinese medicine, is considered to have notable antioxidant, anti-inflammatory, and anti-apoptotic properties, and is often used to treat certain inflammatory diseases. To date, however, there has been comparatively little research on the effects of OA with respect skin aging. In this study, we utilized UV radiation-induced mouse and cellular models of aging to assess the efficacy of OA in protecting against skin aging. Subsequently, to elucidate the potential mechanisms underlying the protective effect of OA on skin aging, we performed molecular docking analysis to investigate the involvement of the anti-aging gene Sirt1, which was further confirmed on the basis of Sirt1 gene silencing. We accordingly demonstrated that by promoting an increase in the expression of Sirt1, OA can contribute to suppressing UV-induced skin photo-aging in cells/mice by reducing oxidative stress. Furthermore, we established that by activating Sirt1, OA can also promote the dissociation of Nrf2 from Keap1 and its subsequent nuclear translocation. Collectively, our findings in this study reveal OA to be an effective natural compound that can be administered to delay the aging of skin triggered by UV, both in vivo and in vitro, by binding to Sirt1 to promote the deacetylation and nuclear translocation of Nrf2, thereby contributing to a reduction in oxidative stress. These findings may this provide a therapeutic target for the prevention of skin aging or aging-induced skin diseases.

Keywords:  Acetylation; Natural compound; Nrf2; Oroxylin A; Oxidative stress; Sirt1

DOI:  https://doi.org/10.1016/j.biopha.2023.116110
Mol Med. 2024 Jan 12. 30(1): 10

Age-related decline in melatonin contributes to enhanced osteoclastogenesis via disruption of redox homeostasis.

Di-Zheng Wu, Guo-Zheng Zhu, Kai Zhao, Jia-Wen Gao, Gui-Xing Cai, Hong-Zhou Li, Yu-Sheng Huang, Chen Tu, Jing-Shen Zhuang, Zhi-Wei Huang, Zhao-Ming Zhong.

   BACKGROUND: Increased oxidative stress contributes to enhanced osteoclastogenesis and age-related bone loss. Melatonin (MT) is an endogenous antioxidant and declines with aging. However, it was unclear whether the decline of MT was involved in the enhanced osteoclastogenesis during the aging process.
METHODS: The plasma level of MT, oxidative stress status, bone mass, the number of bone marrow-derived monocytes (BMMs) and its osteoclastogenesis were analyzed in young (3-month old) and old (18-month old) mice (n = 6 per group). In vitro, BMMs isolated from aged mice were treated with or without MT, followed by detecting the change of osteoclastogenesis and intracellular reactive oxygen species (ROS) level. Furthermore, old mice were treated with MT for 2 months to investigate the therapeutic effect.
RESULTS: The plasma level of MT was markedly lower in aged mice compared with young mice. Age-related decline in MT was accompanied by enhanced oxidative stress, osteoclastogenic potential and bone loss. MT intervention significantly suppressed the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis, decreased intracellular ROS and enhanced antioxidant capacity of BMMs from aged mice. MT supplementation significantly attenuated oxidative stress, osteoclastogenesis, bone loss and deterioration of bone microstructure in aged mice.
CONCLUSIONS: These results suggest that age-related decline of MT enhanced osteoclastogenesis via disruption of redox homeostasis. MT may serve as a key regulator in osteoclastogenesis and bone homeostasis, thereby highlighting its potential as a preventive agent for age-related bone loss.

Keywords:  Aging; Bone loss; Melatonin; Osteoclastogenesis; Osteoporosis; Oxidative stress

DOI:  https://doi.org/10.1186/s10020-024-00779-x
Mech Ageing Dev. 2024 Jan 10. pii: S0047-6374(24)00001-0. [Epub ahead of print] 111901

Novel 18-Norspirostane Steroidal Saponins: Extending Lifespan and Mitigating Neurodegeneration through Promotion of Mitophagy and Mitochondrial Biogenesis in Caenorhabditis elegans.

An-Guo Wu, Yuan-Yuan Yong, Chang-Long He, Ya-Ping Li, Xing-Yue Zhou, Lu Yu, Qi Chen, Cai Lan, Jian Liu, Chong-Lin Yu, Da-Lian Qin, Jian-Ming Wu, Xiao-Gang Zhou.

  Pharmacological strategies to delay aging and combat age-related diseases are increasingly promising. This study explores the anti-aging and therapeutic effects of two novel 18-norspirostane steroidal saponins from Trillium tschonoskii Maxim, namely deoxytrillenoside CA (DTCA) and epitrillenoside CA (ETCA), using Caenorhabditis elegans (C. elegans). Both DTCA and ETCA significantly extended the lifespan of wild-type N2 worms and improved various age-related phenotypes, including muscle health, motility, pumping rate, and lipofuscin accumulation. Furthermore, these compounds exhibited notable alleviation of pathology associated with Parkinson's disease (PD) and Huntington's disease (HD), such as the reduction of α-synuclein and poly40 aggregates, improvement in motor deficits, and mitigation of neuronal damage. Meanwhile, DTCA and ETCA improved the lifespan and healthspan of PD- and HD-like C. elegans models. Additionally, DTCA and ETCA enhanced the resilience of C. elegans against heat and oxidative stress challenges. Mechanistic studies elucidated that DTCA and ETCA induced mitophagy and promoted mitochondrial biogenesis in C. elegans, while genetic mutations or RNAi knockdown affecting mitophagy and mitochondrial biogenesis effectively eliminated their capacity to extend lifespan and reduce pathological protein aggregates. Together, these compelling findings highlight the potential of DTCA and ETCA as promising therapeutic interventions for delaying aging and preventing age-related diseases.

Keywords:  anti-aging; deoxytrillenoside CA; epitrillenoside CA; mitochondrial biogenesis; mitophagy

DOI:  https://doi.org/10.1016/j.mad.2024.111901
NPJ Aging. 2024 Jan 12. 10(1): 5

Cholesterol biosynthetic pathway induces cellular senescence through ERRα.

Dorian V Ziegler, Joanna Czarnecka-Herok, Mathieu Vernier, Charlotte Scholtes, Clara Camprubi, Anda Huna, Amélie Massemin, Audrey Griveau, Christelle Machon, Jérôme Guitton, Jennifer Rieusset, Arnaud M Vigneron, Vincent Giguère, Nadine Martin, David Bernard.

Cellular senescence is a cell program induced by various stresses that leads to a stable proliferation arrest and to a senescence-associated secretory phenotype. Accumulation of senescent cells during age-related diseases participates in these pathologies and regulates healthy lifespan. Recent evidences point out a global dysregulated intracellular metabolism associated to senescence phenotype. Nonetheless, the functional contribution of metabolic homeostasis in regulating senescence is barely understood. In this work, we describe how the mevalonate pathway, an anabolic pathway leading to the endogenous biosynthesis of poly-isoprenoids, such as cholesterol, acts as a positive regulator of cellular senescence in normal human cells. Mechanistically, this mevalonate pathway-induced senescence is partly mediated by the downstream cholesterol biosynthetic pathway. This pathway promotes the transcriptional activity of ERRα that could lead to dysfunctional mitochondria, ROS production, DNA damage and a p53-dependent senescence. Supporting the relevance of these observations, increase of senescence in liver due to a high-fat diet regimen is abrogated in ERRα knockout mouse. Overall, this work unravels the role of cholesterol biosynthesis or level in the induction of an ERRα-dependent mitochondrial program leading to cellular senescence and related pathological alterations.

DOI: https://doi.org/10.1038/s41514-023-00128-y
Cell Metab. 2024 Jan 01. pii: S1550-4131(23)00462-X. [Epub ahead of print]

DMHPpp1r17 neurons regulate aging and lifespan in mice through hypothalamic-adipose inter-tissue communication.

Kyohei Tokizane, Cynthia S Brace, Shin-Ichiro Imai.

  Recent studies have shown that the hypothalamus functions as a control center of aging in mammals that counteracts age-associated physiological decline through inter-tissue communications. We have identified a key neuronal subpopulation in the dorsomedial hypothalamus (DMH), marked by Ppp1r17 expression (DMHPpp1r17 neurons), that regulates aging and longevity in mice. DMHPpp1r17 neurons regulate physical activity and WAT function, including the secretion of extracellular nicotinamide phosphoribosyltransferase (eNAMPT), through sympathetic nervous stimulation. Within DMHPpp1r17 neurons, the phosphorylation and subsequent nuclear-cytoplasmic translocation of Ppp1r17, regulated by cGMP-dependent protein kinase G (PKG; Prkg1), affect gene expression regulating synaptic function, causing synaptic transmission dysfunction and impaired WAT function. Both DMH-specific Prkg1 knockdown, which suppresses age-associated Ppp1r17 translocation, and the chemogenetic activation of DMHPpp1r17 neurons significantly ameliorate age-associated dysfunction in WAT, increase physical activity, and extend lifespan. Thus, these findings clearly demonstrate the importance of the inter-tissue communication between the hypothalamus and WAT in mammalian aging and longevity control.

Keywords:  DMH; PKG; Ppp1r17; aging; dorsomedial hypothalamus; eNAMPT; longevity; protein kinase G; sympathetic nervous system; white adipose tissue

DOI:  https://doi.org/10.1016/j.cmet.2023.12.011
Clin Kidney J. 2024 Jan;17(1): sfad276

Klotho: a potential therapeutic target in aging and neurodegeneration beyond chronic kidney disease-a comprehensive review from the ERA CKD-MBD working group.

Mehmet Kanbay, Sidar Copur, Lasin Ozbek, Ali Mutlu, Daniel Cejka, Paola Ciceri, Mario Cozzolino, Mathias Loberg Haarhaus.

  Klotho, a multifunctional protein, acts as a co-receptor in fibroblast growth factor 23 and exerts its impact through various molecular pathways, including Wnt, hypoxia-inducible factor and insulin-like growth factor 1 pathways. The physiological significance of Klotho is the regulation of vitamin D and phosphate metabolism as well as serving as a vital component in aging and neurodegeneration. The role of Klotho in aging and neurodegeneration in particular has gained considerable attention. In this narrative review we highlight several key insights into the molecular basis and physiological function of Klotho and synthesize current research on the role of Klotho in neurodegeneration and aging. Klotho deficiency was associated with cognitive impairment, reduced growth, diminished longevity and the development of age-related diseases in vivo. Serum Klotho levels showed a decline in individuals with advanced age and those affected by chronic kidney disease, establishing its potential diagnostic significance. Additionally, multiple medications have been demonstrated to influence Klotho levels. Therefore, this comprehensive review suggests that Klotho could open the door to novel interventions aimed at addressing the challenges of aging and neurodegenerative disorders.

Keywords:  Klotho; aging; chronic kidney disease; neurodegeneration

DOI:  https://doi.org/10.1093/ckj/sfad276
J Gerontol A Biol Sci Med Sci. 2024 Jan 10. pii: glae014. [Epub ahead of print]

Yo-yo Dieting Delays Male Drosophila melanogaster Aging Through Enhanced Mitochondrial Function, Relative to Sustained High-Calorie Diet Feeding.

Mengliu Luo, Qianhua Yuan, Yutong Xie, Meiqing Mai, Wanhan Song, Ya Wang, Haimei Shi, Enqin Xia, Honghui Guo.

  Weight regain subsequent to weight reduction resulting from dietary interventions represents a prevalent phenomenon recognized as "Yo-yo dieting." However, the impact of prolonged Yo-yo dieting on health, especially in relation to the aging process, remains poorly understood. This study aimed to investigate the influence of Yo-yo dieting on the aging process in male Drosophila melanogaster that have been exposed to a high-calorie (HC) diet. Fruit flies were fed with either a consistent HC diet or an alternating regimen of HC and low-calorie diets every three days (referred to as "Yo-yo dieting") for a total of 24 days. Biochemical assays were utilized to quantify levels of oxidative stress and activities of the mitochondrial respiratory chain complexes. The frozen section staining method was employed to assess the presence of lipid droplets, reactive oxygen species, cellular viability, and mitochondrial abundance in tissues. Additionally, we examined the expression of key regulators involved in mitochondrial dynamics and biogenic signaling pathways. Yo-yo dieting resulted in an extension of the fruit flies' lifespan, concomitant with reduced body weight, decreased body protein content, and lower triglyceride levels compared to continuous a HC diet feeding. Furthermore, Yo-yo dieting ameliorated impairments in motility and intestinal barrier function. Importantly, it improved mitochondrial function and upregulated the expression of essential mitochondrial fusion proteins, namely mitofusin 1 and mitofusin 2, optic atrophy 1 (Opa1), and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). Therefore, the practice of Yo-yo dieting extends the lifespan of fruit flies by modulating mitochondrial dynamics and the associated biogenic signaling pathways.

Keywords:  Low-calorie diet; Mitochondrial biogenesis; Mitochondrial dynamics; Oxidative stress; Weight cycling

DOI:  https://doi.org/10.1093/gerona/glae014
Acta Biomater. 2024 Jan 05. pii: S1742-7061(24)00002-3. [Epub ahead of print]

A navitoclax-loaded nanodevice targeting matrix metalloproteinase-3 for the selective elimination of senescent cells.

Blanca Escriche-Navarro, Eva Garrido, Félix Sancenón, Alba García-Fernández, Ramón Martínez-Máñez.

  Cellular senescence is implicated in the occurrence and progression of multiple age-related disorders. In this context, the selective elimination of senescent cells, senolysis, has emerged as an effective therapeutic strategy. However, the heterogeneous senescent phenotype hinders the discovery of a universal and robust senescence biomarker that limits the effective of senolytic with off-target toxic effects. Therefore, the development of more selective strategies represents a promising approach to increase the specificity of senolytic therapy. In this study, we have developed an innovative nanodevice for the selective elimination of senescent cells (SCs) based on the specific enzymatic activity of the senescent secretome. The results revealed that when senescence is induced in proliferating WI-38 by ionizing radiation (IR), the cells secrete high levels of matrix metalloproteinase-3 (MMP-3). Based on this result, mesoporous silica nanoparticles (MSNs) were loaded with the senolytic navitoclax (Nav) and coated with a specific peptide which is substrate of MMP-3 (NPs(Nav)@MMP-3). Studies in cells confirmed the preferential release of cargo in IR-induced senescent cells compared to proliferating cells, depending on MMP-3 levels. Moreover, treatment with NPs(Nav)@MMP-3 induced a selective decrease in the viability of SCs as well as a protective effect on non-proliferating cells. These results demonstrate the potential use of NPs to develop enhanced senolytic therapies based on specific enzymatic activity in the senescent microenvironment, with potential clinical relevance. STATEMENT OF SIGNIFICANCE: The common β-galactosidase activity has been exploited to develop nanoparticles for the selective elimination of senescent cells. However, the identification of new senescent biomarkers is a key factor for the development of improved strategies. In this scenario, we report for the first time the development of NPs targeting senescent cells based on specific enzymatic activity of the senescent secretome. We report a navitoclax-loaded nanodevice responsive to the matrix metalloproteinase-3 (MMP-3) associated with the senescent phenotype. Our nanosystem achieves the selective release of navitoclax in an MMP-3-dependent manner while limiting off-target effects on non-senescent cells. This opens the possibility of using nanoparticles able to detect an altered senescent environment and selectively release its content, thus enhancing the efficacy of senolytic therapies.

Keywords:  Matrix metalloproteinase-3; Mesoporous silica nanoparticles; Navitoclax; Senescence

DOI:  https://doi.org/10.1016/j.actbio.2024.01.002
ACS Chem Neurosci. 2024 Jan 12.

Antiaging Strategies and Remedies: A Landscape of Research Progress and Promise.

Rumiana Tenchov, Janet M Sasso, Xinmei Wang, Qiongqiong Angela Zhou.

  Aging is typified by a gradual loss of physiological fitness and accumulation of cellular damage, leading to deteriorated functions and enhanced vulnerability to diseases. Antiaging research has a long history throughout civilization, with many efforts put forth to understand and prevent the effects of aging. Multiple strategies aiming to promote healthy aging and extend the lifespan have been developed including lifestyle adjustments, medical treatments, and social programs. A multitude of antiaging medicines and remedies have also been explored. Here, we use data from the CAS Content Collection to analyze the publication landscape of recent research related to antiaging strategies and treatments. We review the recent advances and delineate trends in research headway of antiaging knowledge and practice across time, geography, and development pipelines. We further assess the state-of-the-art antiaging approaches and explore their correlations with age-related diseases. The landscape of antiaging drugs has been outlined and explored. Well-recognized and novel, currently evaluated antiaging agents have also been summarized. Finally, we review clinical applications of antiaging products with their development pipelines. The objective of this review is to summarize current knowledge on preventive strategies and treatment remedies in the field of aging, to outline challenges and evaluate growth opportunities, in order to further efforts to solve the problems that remain.

Keywords:  Antiaging strategy; antioxidant; caloric restriction; diet; hormesis; parabiosis; physical exercise; senotherapy

DOI:  https://doi.org/10.1021/acschemneuro.3c00532
Exp Gerontol. 2024 Jan 06. pii: S0531-5565(24)00001-9. [Epub ahead of print]186 112359

Inhibitor PF-04691502 works as a senolytic to regulate cellular senescence.

Ziqiang Fan, Yingdong Tong, Ziyue Yang, Shuai Wang, Tiantian Huang, Deying Yang, Qingyong Ni, Mingwang Zhang, Diyan Li, Mingyao Yang, Xiaolan Fan.

  Aging is a gradual process of natural change that occurs after reaching sexual maturity. It is also a known risk factor for many chronic diseases. Recent research has shown that senolytics can extend the lifespans and health spans of model organisms, and they have also been demonstrated effective in treating age-related diseases. In this study, we conducted a high-throughput screening of 156 drugs that targeted the PI3K/AKT/mTOR pathway to identify potential senolytic medications. Among these drugs, PF-04691502 was selected for further investigation to understand its molecular mechanism of action. Our findings indicate that PF-04691502, a dual inhibitor of PI3K/AKT and mTOR, specifically eliminates senescent cells. It reduces the expression levels of key markers of cellular senescence, such as SA-β-Gal, senescence-associated secretory phenotypes (SASPs) and p16INK4a. Additionally, PF-04691502 inhibits the phosphorylation of S6K and AKT, leading to the apoptosis of senescent cells. These results suggest that PF-04691502 holds promise as a new senolytic drug. This paper provides important insights into the potential application of PF-04691502 in the study of cell senescence.

Keywords:  AKT; PF-04691502; Senescent cells; Senolytic; mTOR

DOI:  https://doi.org/10.1016/j.exger.2024.112359
Front Pharmacol. 2023 ;14 1303198

Skin-protective biological activities of bio-fermented Aframomum angustifolium extract by a consortium of microorganisms.

Marion Albouy, Simon Aubailly, Olivier Jeanneton, Clarisse Marteau, Lauren Sobilo, Rachid Boulgana, Gerard Bru, Marine Bellanger, Emmanuelle Leblanc, Morgan Dos Santos, Karl Pays, Patrick Choisy, Elodie Bossard, Carine Nizard, Amelie Thepot, Lorene Gourguillon, Anne-Laure Bulteau.

  Background:Aframomum sp. is a genus of plants in the Zingiberaceae family. It includes several species, some of which are used in cosmetics for their various properties, making them useful in skincare products, particularly for anti-aging, moisturizing, and brightening the skin. However, to date, there is no experimental evidence on its natural extracts obtained or modified using microorganisms (bio-fermentation) as an anti-aging agent. Objective: The present study aimed to evaluate the antiaging effect of a Bio-fermented Aframomum angustifolium (BAA) extract on 3D bioprinted skin equivalent. Methods: The consortium of microorganisms contained Komagataeibacter, Gluconobacter, Acetobacter, Saccharomyces, Torulaspora, Brettanomyces, Hanseniaspora, Leuconostoc, Lactobacillus, Schizosaccharomyces. It was developed on a media containing water, sugar, and infused black tea leaves. The seeds of Aframomum angustifolium previously grounded were mixed with the culture medium, and the ferments in growth; this fermentation step lasted 10 days. Then, the medium was collected and filtered (0.22 µm) to obtain the BAA extract. To enhance our comprehension of the impact of BAA extract on skin aging, we developed skin equivalents using bio-printing methods with the presence or absence of keratinocyte stem cells (KSC). These skin equivalents were derived from keratinocytes obtained from both a middle-aged donor, with and without KSC. Moreover, we examined the effects of treating the KSC-depleted skin equivalents with Bio-fermented Aframomum angustifolium (BAA) extract for 5 days. Skin equivalents containing KSC-depleted keratinocytes exhibited histological characteristics typical of aged skin and were compared to skin equivalents derived from young donors. Results: The BAA extract contained specific organic acids such as lactic, gluconic, succinic acid and polyphenols. KSC-depleted skin equivalents that were treated with BAA extract exhibited higher specular reflection, indicating better hydration of the stratum corneum, higher mitotic activity in the epidermis basal layer, improved dermal-epidermal connectivity, and increased rigidity of the dermal-epidermal junction compared to non-treated KSC-depleted equivalents. BAA extract treatments also resulted in changes at the dermis level, with an increase in total collagen and a decrease in global laxity, suggesting that this extract could help maintain youthful-looking skin. Conclusion: In summary, our findings indicated that BAA extract treatments have pleiotropic beneficial effects on skin equivalents and that the bio-fermentation provides new biological activities to this plant.

Keywords:  3D bioprinted skin equivalent; Aframomum angustifolium; aging; fermentation; keratinocyte stem cell

DOI:  https://doi.org/10.3389/fphar.2023.1303198
Nat Aging. 2024 Jan 12.

Targeting COPIng liabilities of senescent cells.

Yahyah Aman.

DOI: https://doi.org/10.1038/s43587-024-00567-6
Aging (Albany NY). 2024 Jan 06. 15

Effects of resveratrol on in vitro circadian clock gene expression in young and older human adipose-derived progenitor cells.

Sophie G C Kapar, Maria F Pino, Fanchao Yi, Miguel A Gutierrez-Monreal, Karyn A Esser, Lauren M Sparks, Melissa L Erickson.

  Observational studies in preclinical models demonstrate age-related declines in circadian functions. We hypothesized that age would be associated with declines in function of cell-autonomous circadian clocks in human tissue. Accordingly, we cultured adipose progenitor cells (APCs) from previously collected white-adipose tissue biopsies from abdominal subcutaneous depots of young (Age: 23.4 ± 2.1 yrs) vs. older female participants (Age: 70.6 ± 5.9 yrs). Using an in vitro model, we compared rhythmic gene expression profiles of core clock components, as an indicator of circadian oscillatory function. We observed consistent circadian rhythmicity of core clock components in young and older-APCs. Expression analysis showed increased levels of some components in older-APCs (CLOCK, CRY1, NR1D1) vs. young. We also investigated resveratrol (RSV), a well-known longevity-enhancing effector, for its effects on rhythmic clock gene expression profiles. We found that RSV resulted in gained rhythmicity of some components (CLOCK and CRY), loss of rhythmicity in others (PER2, CRY2), and altered some rhythmic parameters (NR1D1 and NR1D2), consistent in young and older-APCs. The observation of detectable circadian rhythmicity retained in vitro suggests that the oscillatory function of the cell-autonomous core clock in APCs is preserved at this stage of the aging process. RSV impacts core clock gene expression in APCs, implicating its potential as a therapeutic agent for longevity by targeting the core clock.

Keywords:  adipose-derived progenitor cells; aging; circadian clock; circadian rhythm; resveratrol

DOI:  https://doi.org/10.18632/aging.205292
Molecules. 2023 Dec 22. pii: 86. [Epub ahead of print]29(1):

Discovery of a 4-Hydroxy-3'-Trifluoromethoxy-Substituted Resveratrol Derivative as an Anti-Aging Agent.

Yinhu Liang, Xi Chen, Zhifeng Teng, Xuekun Wang, Jie Yang, Guoyun Liu.

  With the intensification of population aging, aging-related diseases are attracting more and more attention, thus, the study of aging mechanisms and anti-aging drugs is becoming increasingly urgent. Resveratrol is a potential candidate as an anti-aging agent, but its low bioavailability limits its application in vivo. In this work, a 4-hydroxy-3'-trifluoromethoxy-substituted resveratrol derivative (4-6), owing to its superior cell accumulation, could inhibit NO production in an inflammatory cell model, inhibit oxidative cytotoxicity, and reduce ROS accumulation and the population of apoptotic cells in an oxidative stress cell model. In D-galactose (D-gal)-stimulated aging mice, 4-6 could reverse liver and kidney damage; protect the serum, brain, and liver against oxidative stress; and increase the body's immunity in the spleen. Further D-gal-induced brain aging studies showed that 4-6 could improve the pathological changes in the hippocampus and the dysfunction of the cholinergic system. Moreover, protein expression related to aging, oxidative stress, and apoptosis in the brain tissue homogenate measured via Western blotting also showed that 4-6 could ameliorate brain aging by protecting against oxidative stress and reducing apoptosis. This work revealed that meta-trifluoromethoxy substituted 4-6 deserved to be further investigated as an effective anti-aging candidate drug.

Keywords:  D-galactose; anti-aging; apoptosis; inflammation; oxidative stress; resveratrol derivatives

DOI:  https://doi.org/10.3390/molecules29010086
J Nutr Biochem. 2024 Jan 10. pii: S0955-2863(24)00012-3. [Epub ahead of print] 109578

Alginate oligosaccharide alleviates vascular aging by upregulating glutathione peroxidase 7.

Shan Wang, Yao Yu, Jia Liu, Song Hu, Shujuan Shi, Wenjing Feng, Yongjun Mao.

  Alginate oligosaccharide (AOS) may delay aging by decreasing oxidative stress, but the effects on vascular aging remain unclear. Here, we evaluate the effect of AOS on vascular aging and investigate the underlying mechanisms. Twenty-month-old rats acted as the natural aging model in vivo. Senescence of human aortic vascular smooth muscle cells (HA-VSMCs) was induced in vitro using angiotensin II (AngII). The aging rats and senescent cells were treated with AOS, followed by assessment of aging makers, oxidative stress, and aging-induced vascular remodeling. AOS treatment alleviated vascular aging and HA-VSMC senescence and decreased the levels of oxidative stress and vascular remodeling-associated indicators. AOS upregulated the expression of glutathione peroxidase 7 (GPX7) in aging rats and GPX7 depletion disrupted the geroprotective effect of AOS. AOS increased the nuclear translocation of nuclear factor erythroid-2-related factor (Nrf2) protein, which interacts with GPX7 protein to induce its expression. In conclusion, AOS alleviates vascular aging and HA-VSMC senescence and reduces aging-related vascular remodeling via the GPX7 antioxidant pathway, which may provide new avenues for treating aging-associated diseases.

Keywords:  Glutathione peroxidase 7; aging; alginate oligosaccharide; oxidative stress; senescence; vasculature

DOI:  https://doi.org/10.1016/j.jnutbio.2024.109578