bims-caglex 2025-02-16 papers

bims-caglex

Biomed News

on Cellular aging and life extension

Issue of 2025–02–16
forty papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño

Senescence as a Molecular Target in Skin Aging and Disease.
Single-Cell Analysis Dissects the Effects of Vitamin D on Genetic Senescence Signatures Across Murine Tissues.
Dietary Natural Melanin Nanozymes Delay Aging and Ameliorate Neurodegeneration via Improving Gut Microbiota and Redox Homeostasis.
fmo-4 promotes longevity and stress resistance via ER to mitochondria calcium regulation in C. elegans.
Dietary flavonoid actions on senescence, aging, and applications for health.
Inhibition of miMOMP-induced SASP to combat age-related disease.
Aging, cancer, and autophagy: connections and therapeutic perspectives.
Genetic and Pharmacological Inhibition of Metabotropic Glutamate Receptor Signalling Extends Lifespan in Drosophila.
Functional Properties and Potential Applications of Wheat Bran Extracts in Food and Cosmetics: A Review of Antioxidant, Enzyme-Inhibitory, and Anti-Aging Benefits.
From bench to bedside: translational insights into aging research.
Proteasome Augmentation Mitigates Age-Related Cognitive Decline in Mice.
The anti-aging and anti-Alzheimer's disease potential of kinsenoside prepared from Anoectochilus roxburghii.
Synergistic Anti-Aging Effects of Adipose-Derived Stem Cell Extracellular Vesicles Loaded With Natural Compounds.
Reduction of DNA Topoisomerase Top2 Reprograms the Epigenetic Landscape and Extends Health and Life Span Across Species.
Impact of Mlkl or Ripk3 deletion on age-associated liver inflammation, metabolic health, and lifespan.
Impact of physical activity on physical function, mitochondrial energetics, ROS production, and Ca2+ handling across the adult lifespan in men.
Therapeutic potential of nicotinamide and ABT263 in alcohol-associated liver disease through targeting cellular senescence.
Caloric Restriction and Telomere Preservation in TERT Knockout Adipocyte Progenitors Does Not Rescue Mice From Metabolic Dysfunction due to a TERT Function in Adipocyte Mitochondria.
Development of a Short Telomere Zebrafish Model for Accelerated Aging Research and Antiaging Drug Screening.
Test of Rapamycin in Aging Dogs (TRIAD): study design and rationale for a prospective, parallel-group, double-masked, randomized, placebo-controlled, multicenter trial of rapamycin in healthy middle-aged dogs from the Dog Aging Project.
Cellular rejuvenation protects neurons from inflammation-mediated cell death.
Bee Pollen Phytochemicals and Nutrients as Unequaled Pool of Epigenetic Regulators: Implications for Age-Related Diseases.
A Comprehensive Review on Graptopetalum paraguayense's Phytochemical Profiles, Pharmacological Activities, and Development as a Functional Food.
Gut dysbiosis in primary sarcopenia: potential mechanisms and implications for novel microbiome-based therapeutic strategies.
Oleanolic Acid Slows Down Aging Through IGF-1 Affecting the PI3K/AKT/mTOR Signaling Pathway.
Protective effects of Colla Corii Asini Collagen Peptides on D-galactose injection combined with UVB irradiation-induced aging in mice.
In vivo efficacy investigation of long-wavelength infrared femtosecond lasers for skin rejuvenation.
Downregulation of STAT1 improved learning and memory impairments in aging mice.
Assessing the Effects of Dasatinib on Mesenchymal Stem/Stromal Cells.
Rejuvenating Hyaline Cartilage with Senescence-Targeting Si-ADAM19 Delivery for Osteoarthritis Therapy.
Skin Aging: Insights into the Role of Fatty Acids.
The Brain Toxin Cleansing of Sleep Achieved During Wakefulness.
Dietary Restrictions and Cancer Prevention: State of the Art.
Higher dietary intake of live microbes is inversely associated with accelerated biological aging.
A Feedback Loop Driven by H4K12 Lactylation and HDAC3 in Macrophages Regulates Lactate-Induced Collagen Synthesis in Fibroblasts Via the TGF-β Signaling.
Microbiota protect against frailty, loss of skeletal muscle, and maintain inflammatory tone during aging in mice.
Emerging prodrug and nano-drug delivery strategies for the detection and elimination of senescent tumor cells.
Golgi-restored vesicular replenishment retards bone aging and empowers aging bone regeneration.
Hepatic fibroblast growth factor 21 is required for curcumin or resveratrol in exerting their metabolic beneficial effect in male mice.
A Review on the Potential Role of Humanin Peptide and its Analogs in the Regulation of Autophagy Pathways for Therapeutic Application in Metabolic Disorders.

Ageing Res Rev. 2025 Feb 08. pii: S1568-1637(25)00032-7. [Epub ahead of print] 102686

Senescence as a Molecular Target in Skin Aging and Disease.

Henriette Thau, Bastian P Gerjol, Katharina Hahn, Rosalie Wolff von Gudenberg, Leonard Knoedler, Kenneth Stallcup, Maximilian Y Emmert, Timo Buhl, Saranya P Wyles, Tamar Tchkonia, Stefan G Tullius, Jasper Iske.

  Skin aging represents a multifactorial process influenced by both intrinsic and extrinsic factors, collectively known as the skin exposome. Cellular senescence, characterized by stable cell cycle arrest and secretion of pro-inflammatory molecules, has been implicated as a key driver of physiological and pathological skin aging. Increasing evidence points towards the role of senescence in a variety of dermatological diseases, where the accumulation of senescent cells in the epidermis and dermis exacerbates disease progression. Emerging therapeutic strategies such as senolytics and senomorphics offer promising avenues to target senescent cells and mitigate their deleterious effects, providing potential treatments for both skin aging and senescence-associated skin diseases. This review explores the molecular mechanisms of cellular senescence and its role in promoting age-related skin changes and pathologies, while compiling the observed effects of senotherapeutics in the skin and discussing the translational relevance.

Keywords:  Skin aging; anti-aging; senescence; senescent cell, senolytics

DOI:  https://doi.org/10.1016/j.arr.2025.102686
Nutrients. 2025 Jan 24. pii: 429. [Epub ahead of print]17(3):

Single-Cell Analysis Dissects the Effects of Vitamin D on Genetic Senescence Signatures Across Murine Tissues.

Emilio Sosa-Díaz, Helena Reyes-Gopar, Guillermo de Anda-Jáuregui, Enrique Hernández-Lemus.

  Background/Objectives: Vitamin D (VD) plays a crucial role in age-related diseases, and its influence on cellular senescence (CS) could help clarify its function in aging. Considering VD's pleiotropic effects and the heterogeneity of CS. Methods: we utilized single-cell RNA sequencing (scRNA-seq) to explore these dynamics across multiple tissues. We analyzed three murine tissue datasets (bone, prostate, and skin) obtained from public repositories, enriching for senescence gene signatures. We then inferred gene regulatory networks (GRNs) at the tissue and cell-type levels and performed two cell communication analyses: one for senescent cells and another for interactions between senescent and non-senescent cells. Results: VD supplementation significantly decreased senescence scores in the skin (p = 3.96×10-134) and prostate (p=1.56×10-34). GRN analysis of the prostate revealed an altered macrophage-fibroblast regulatory relationship. In bone, distinct aging-related modules emerged for different bone lineages. In skin, contrary differentiation patterns between suprabasal and basal cells were observed. The main VD-modulated pathways were involved in inflammation, extracellular matrix remodeling, protein metabolism, and translation. VD reduced fibroblast-macrophage interactions in the prostate and skin but increased overall cellular crosstalk in bone. Conclusions: Our findings demonstrate that VD alleviates CS burden across tissues by modulating inflammation and metabolic processes and promoting differentiation. Key aging-related genes modulated by VD were linked to anabolism and cellular differentiation, suggesting VD's potential for therapeutic interventions targeting age-related diseases.

Keywords:  aging; cellular senescence; murine model; single-cell genomics; vitamin D

DOI:  https://doi.org/10.3390/nu17030429
ACS Omega. 2025 Feb 04. 10(4): 3610-3621

Dietary Natural Melanin Nanozymes Delay Aging and Ameliorate Neurodegeneration via Improving Gut Microbiota and Redox Homeostasis.

Yao Xiao, Shikun Zhang, Hailong Zhuo, Xiaoyong Zhang, Kai Zhu, Wanyi Chen, Guoxing You, Hongwei Chen, Qun Luo, Hong Zhou, Gan Chen.

Aging is an inevitable multifactor process that causes a decline in organ function and increases the risk of age-related diseases and death. Thus, the development of highly effective and safe therapeutic strategies to delay aging and age-related diseases is urgently required. In this study, we isolated natural melanin nanozymes (NMNs) from the ink sacs of live octopuses. The NMNs exhibited excellent superoxide-dismutase-mimicking and radical scavenging activities. In SAMP8 mice, treatment with NMNs improved their cognition and memory functions while restoring their aging-impaired liver function and lipid metabolism, thereby prolonging their lifespan. Moreover, the NMNs reversed metabolic changes in their aged brains and reconstructed their gut microbiota composition by enhancing microbial community diversity. Our findings indicate that NMNs treatment could be a promising approach for delaying aging and preventing age-associated physiological decline in humans.

DOI: https://doi.org/10.1021/acsomega.4c08419
Elife. 2025 Feb 14. pii: RP99971. [Epub ahead of print]13

fmo-4 promotes longevity and stress resistance via ER to mitochondria calcium regulation in C. elegans.

Angela M Tuckowski, Safa Beydoun, Elizabeth S Kitto, Ajay Bhat, Marshall B Howington, Aditya Sridhar, Mira Bhandari, Kelly Chambers, Scott F Leiser.

  Flavin-containing monooxygenases (FMOs) are a conserved family of xenobiotic enzymes upregulated in multiple longevity interventions, including nematode and mouse models. Previous work supports that C. elegans fmo-2 promotes longevity, stress resistance, and healthspan by rewiring endogenous metabolism. However, there are five C. elegans FMOs and five mammalian FMOs, and it is not known whether promoting longevity and health benefits is a conserved role of this gene family. Here, we report that expression of C. elegans fmo-4 promotes lifespan extension and paraquat stress resistance downstream of both dietary restriction and inhibition of mTOR. We find that overexpression of fmo-4 in just the hypodermis is sufficient for these benefits, and that this expression significantly modifies the transcriptome. By analyzing changes in gene expression, we find that genes related to calcium signaling are significantly altered downstream of fmo-4 expression. Highlighting the importance of calcium homeostasis in this pathway, fmo-4 overexpressing animals are sensitive to thapsigargin, an ER stressor that inhibits calcium flux from the cytosol to the ER lumen. This calcium/fmo-4 interaction is solidified by data showing that modulating intracellular calcium with either small molecules or genetics can change expression of fmo-4 and/or interact with fmo-4 to affect lifespan and stress resistance. Further analysis supports a pathway where fmo-4 modulates calcium homeostasis downstream of activating transcription factor-6 (atf-6), whose knockdown induces and requires fmo-4 expression. Together, our data identify fmo-4 as a longevity-promoting gene whose actions interact with known longevity pathways and calcium homeostasis.

Keywords:  C. elegans; ER; aging; calcium; flavin-containing monooxygenase; genetics; genomics; mitochondria; stress resistance

DOI:  https://doi.org/10.7554/eLife.99971
J Nutr Biochem. 2025 Feb 08. pii: S0955-2863(25)00025-7. [Epub ahead of print] 109862

Dietary flavonoid actions on senescence, aging, and applications for health.

Bruce A Watkins, Alyson E Mitchell, Andrew C Shin, Fereshteh Dehghani, Chwan-Li Shen.

  Fruits and vegetables contain biologically active phenolic compounds that show mitigating effects against free radical damage and inflammation. The unique properties of phenolic compounds are protection against oxidative stress, and inception and potentiating of inflammation in the body. Aging is manifest with changes in epigenetic modifications and as with living systems undergo entropy. The gradual decline of body functions and in many cases with aging the cellular processes of senescence are contributors to age-related diseases. Herein the focus is on phenolic compounds as a diet approach to delay the negative consequences of aging. The actions of phenolic compounds on the biology of aging and senescence are presented. The phenolic compounds called flavonoids which are found in many fruits are potential anti-senescence factors that benefit health by reducing damage to DNA and the senescence-associated phenotypic cell changes in healthy cells during aging. Flavonoids are proposed to delay and palliate aging where senescence is involved. The dietary sources of natural phenolic compounds afford protection in the aging process and include as some examples naringenin, hesperidin, quercetin, kaempferol, luteolin, genistein, epigallocatechin gallate, and resveratrol. Many of these compounds possess anti-senescence effects. The purpose of the review is to discuss where food flavonoids interact with the targets of senescence and how these compounds can attenuate aging-related events. The goal is to provide greater insight into dietary flavonoids and how they improve health and lower the consequences of aging. A novel aspect of this review is the application of flavonoids to neuroprotective effects in brain to reduce pain and improve health with aging.

Keywords:  Phenolic compounds; aging; flavonoids; inflammation; oxidative stress; senescence

DOI:  https://doi.org/10.1016/j.jnutbio.2025.109862
Front Aging. 2025 ;6 1505063

Inhibition of miMOMP-induced SASP to combat age-related disease.

Xiaoli Liao, Zhennan Guo, Mouhai He, Yichun Zhang.

  Cellular senescence, first described in 1961, was initially observed in normal human fibroblasts that ceased proliferating after a finite number of divisions in culture. This process is triggered by various stimuli, including oxidative stress, chromatin modifications and oncogene activation, characterized by irreversible cell-cycle arrest, resistance to apoptosis and the induction of a complex senescent associated secretory phenotype (SASP). Over the past decade, emerging evidence has linked cellular senescence to the aging process and a wide range of chronic age-related diseases. Consequently, research focused on targeting senescence to alleviate or delay age-related disease, referred to as senotherapy, has been conducted rapidly. Therefore, elucidating the mechanisms of cellular senescence is essential for providing practical strategies aimed at addressing this condition.

Keywords:  SASP (senescence-associated secretory phenotype); age-related disease; cGAS-STING; miMOMP; mtDNA

DOI:  https://doi.org/10.3389/fragi.2025.1505063
Front Mol Biosci. 2024 ;11 1516789

Aging, cancer, and autophagy: connections and therapeutic perspectives.

Begoña Zapatería, Esperanza Arias.

  Aging and cancer are intricately linked through shared molecular processes that influence both the onset of malignancy and the progression of age-related decline. As organisms age, cellular stress, genomic instability, and an accumulation of senescent cells create a pro-inflammatory environment conducive to cancer development. Autophagy, a cellular process responsible for degrading and recycling damaged components, plays a pivotal role in this relationship. While autophagy acts as a tumor-suppressive mechanism by preventing the accumulation of damaged organelles and proteins, cancer cells often exploit it to survive under conditions of metabolic stress and treatment resistance. The interplay between aging, cancer, and autophagy reveals key insights into tumorigenesis, cellular senescence, and proteostasis dysfunction. This review explores the molecular connections between these processes, emphasizing the potential for autophagy-targeted therapies as strategies that could be further explored in both aging and cancer treatment. Understanding the dual roles of autophagy in suppressing and promoting cancer offers promising avenues for therapeutic interventions aimed at improving outcomes for elderly cancer patients while addressing age-related deterioration.

Keywords:  aging; autopaghy; cancer; proteostasis; therapeutics

DOI:  https://doi.org/10.3389/fmolb.2024.1516789
Aging Cell. 2025 Feb 12. e14500

Genetic and Pharmacological Inhibition of Metabotropic Glutamate Receptor Signalling Extends Lifespan in Drosophila.

Cui Guan, Abigail Otchere, Mihails Laskovs, Irene Papatheodorou, Cathy Slack.

  Invertebrate models have been instrumental in advancing our understanding of the molecular mechanisms of ageing. The isolation of single gene mutations that both extend lifespan and improve age-related health have identified potential targets for therapeutic intervention to alleviate age-related morbidity. Here, we find that genetic loss of function of the G protein-coupled metabotropic glutamate receptor (DmGluRA) in Drosophila extends the lifespan of female flies. This longevity phenotype was accompanied by lower basal levels of oxidative stress and improved stress tolerance, and differences in early-life behavioural markers. Gene expression changes in DmGluRA mutants identified reduced ribosome biogenesis, a hallmark of longevity, as a key process altered in these animals. We further show that the pro-longevity effects of reduced DmGluRA signalling are dependent on the fly homologue of Fragile X Mental Retardation Protein (FMRP), an important regulator of ribosomal protein translation. Importantly, we can recapitulate lifespan extension using a specific pharmacological inhibitor of mGluR activity. Hence, our study identifies metabotropic glutamate receptors as potential targets for age-related therapeutics.

Keywords:   Drosophila ; ageing; metabotropic glutamate receptor; ribosome biogenesis

DOI:  https://doi.org/10.1111/acel.14500
Foods. 2025 Feb 05. pii: 515. [Epub ahead of print]14(3):

Functional Properties and Potential Applications of Wheat Bran Extracts in Food and Cosmetics: A Review of Antioxidant, Enzyme-Inhibitory, and Anti-Aging Benefits.

Kaori Kobayashi, Md Suzauddula, Ryan Bender, Cheng Li, Yonghui Li, Xiuzhi Susan Sun, Weiqun Wang.

  This review examines existing studies on wheat bran extracts (WBEs) to provide an overview of their functional properties, including antioxidant and enzyme-inhibitory activities, highlighting their potential as natural alternatives for applications in both the food and cosmetic industries. Despite variations in extraction techniques, WBEs consistently demonstrated a significant presence of phenolic compounds and antioxidant activity. In the food industry, WBEs are valued for their nutritional richness, including dietary fiber, proteins, and bioactive compounds such as arabinoxylans. These compounds improve food texture, stability, and baking properties. Additionally, WBEs have demonstrated antimicrobial potential, enhanced product quality, and serve as natural preservatives. Furthermore, WBEs exhibit significant inhibitory effects against collagenase and elastase, suggesting promising anti-aging potential. In the cosmetics sector, WBEs have gained attention due to their emulsion stability, skin-whitening properties, antimicrobial effects, and antioxidant capacities. They have the potential to enhance the stability of cosmetic emulsions, improve skin hydration, and inhibit enzymes linked to skin aging, positioning WBEs as potentially natural alternatives to synthetic ingredients in skincare and anti-aging products. Our recent pilot study also supports that WBEs enhance antioxidant defenses against oxidative stress in rats, highlighting their potential role in anti-aging interventions. To further elucidate the efficacy and bioavailability of the beneficial bioactive compounds in WBEs for both food and cosmetic applications, more comprehensive in vivo studies are required in the future.

Keywords:  anti-aging compounds; antioxidants; bioactive compounds; cosmetic application; enzyme inhibition; food application; functional properties; wheat bran extracts

DOI:  https://doi.org/10.3390/foods14030515
Front Aging. 2025 ;6 1492099

From bench to bedside: translational insights into aging research.

Kanti Bhooshan Pandey.

  Aging research has rapidly advanced from fundamental discoveries at the molecular and cellular levels to promising clinical applications. This review discusses the critical translational insights that bridge the gap between bench research and bedside applications, highlighting key discoveries in the mechanisms of aging, biomarkers, and therapeutic interventions. It underscores the importance of interdisciplinary approaches and collaboration among scientists, clinicians, and policymakers to address the complexities of aging and improve health span.

Keywords:  aging; biomarkers; genomic instability; interventions; longevity; oxidative stress

DOI:  https://doi.org/10.3389/fragi.2025.1492099
Aging Cell. 2025 Feb 13. e14492

Proteasome Augmentation Mitigates Age-Related Cognitive Decline in Mice.

Danitra Parker, Kanisa Davidson, Pawel A Osmulski, Maria Gaczynska, Andrew M Pickering.

  The aging brain experiences a significant decline in proteasome function. The proteasome is critical for many key neuronal functions including neuronal plasticity, and memory formation/retention. Treatment with proteasome inhibitors impairs these processes. Our study reveals a marked reduction in 20S and 26S proteasome activities in aged mice brains, including in the hippocampus, this is driven by reduced functionality of aged proteasome. The decline in proteasome activity is matched by a decline in 20S proteasome assembly. In contrast, 26S proteasome assembly was found to increase with age, though 26S proteasome activity was still found to decline. Our data suggests that age-related declines in proteasome activity is driven predominantly by reduced functionality of proteasome rather than altered composition. By overexpressing the proteasome subunit PSMB5 in the neurons of mice to increase the proteasome content and thus enhance its functionality, we slowed age-related declines in spatial learning and memory. We then showed acute treatment with a proteasome activator to rescue spatial learning and memory deficits in aged mice. These findings highlight the potential of proteasome augmentation as a therapeutic strategy to mitigate age-related cognitive declines.

Keywords:  aging brain; mice; proteasome; proteostasis

DOI:  https://doi.org/10.1111/acel.14492
Fitoterapia. 2025 Feb 11. pii: S0367-326X(25)00066-8. [Epub ahead of print]182 106441

The anti-aging and anti-Alzheimer's disease potential of kinsenoside prepared from Anoectochilus roxburghii.

Xin Yuan, He Ni, Fan Shi, Yan-Bo Huang, Yi Hou, Song-Qing Hu.

  Anoectochilus roxburghii is a high-value plant resource for nutraceutical efficacy and medicinal applications, among which kinsenoside is recognized as the main bioactive glycoside. However, the anti-aging and anti-Alzheimer's disease (AD) activities of kinsenoside have long been neglected. The objective of this study was to investigate the influences of kinsenoside on aging and amyloid-β (Aβ) proteotoxicity and underlying molecular mechanisms in Caenorhabditis elegans (C. elegans). Kinsenoside (50 μM) could significantly prolong the mean lifespan of C. elegans by 26.3 %. Moreover, it improved the physiological functions, stress resistance and in vivo antioxidant activities of C. elegans. Further studies indicated that kinsenoside upregulated the mRNA expression levels of aging-associated genes including sir-2.1, hsp-16.2, sek-1, skn-1, sod-3, hsf-1, gst-4. The genetic studies and molecular docking studies supported that SKN-1 and HSF-1 transcription factors were requirements for the kinsenoside-mediated longevity. Furthermore, kinsenoside could exert a protective effect on Aβ-induced proteotoxicity by regulating stress-responsive and autophagy-related genes in C. elegans CL4176. The results sheds light on the bioactive properties and pharmaceutical potential of kinsenoside including anti-aging and anti-AD, broadening the prospects of kinsenoside for industrial applications.

Keywords:  Aging; Amyloid-beta; Caenorhabditis elegans; Kinsenoside; Oxidative stress

DOI:  https://doi.org/10.1016/j.fitote.2025.106441
J Cosmet Dermatol. 2025 Feb;24(2): e70021

Synergistic Anti-Aging Effects of Adipose-Derived Stem Cell Extracellular Vesicles Loaded With Natural Compounds.

Nhan Vo, Diem My Vu, Nam H B Tran, Diem D N Nguyen, Phuc M Phung, Hoai-Nghia Nguyen, Lan N Tu.

   BACKGROUND: Small extracellular vesicles from adipose-derived stem cells (ASC-sEVs) are gaining attentions rapidly for inherent therapeutic values in skin care and cosmetics. However, the optimal combinations of ASC-sEVs and certain natural compounds for synergistic anti-aging effects have not been systematically studied.
METHODS: Human ASC-sEVs were purified from culture supernatant of ASCs and multi-omics datasets of miRNAs, proteins and lipids of ASC-sEVs were analyzed for pathways regulating skin homeostasis. ASC-sEVs were then loaded with nicotinamide riboside (NR), resveratrol (RES), vitamin C (VITC), retinol (RET) and arbutin (ARB) at different concentrations by the sonication-incubation method. Their anti-oxidant, anti-wrinkle and anti-melanogenic effects were tested in vitro using the human keratinocyte HaCaT cells exposed to UVB radiation and human melanocyte B16F10 cells.
RESULTS: Multi-omics data analysis of ASC-sEVs identified key bioactive molecules regulating collagen formation, pigmentation, oxidative stress and inflammation. In the in vitro screenings for anti-aging effects, the compound-loaded ASC-sEVs outperformed the sEV- and compound-only treatments. Specifically in UVB-exposed HaCaT cells, 2 μg/mL sEVs loaded with 20 μg/mL NR, 2 μg/mL RES, 5 μg/mL VITC reduced reactive oxygen species level by 22.0%; while combination of sEVs and 2 μg/mL RES, 2.8 μg/mL RET significantly reduced MMP3 and upregulated PLOD1 expressions. B16F10 cells incubated with 2 μg/mL sEVs loaded with 2 μg/mL RES, 0.5 mM ARB had intracellular and extracellular melanin content lowered by 21.4% and 22.4% respectively. All the combinations caused no cytotoxicity.
CONCLUSION: Our study demonstrated the superiority of ASC-sEVs to deliver both endogenous biocargos and exogenous compounds to achieve synergistic skin anti-aging effects.

Keywords:  UV protection; exosomes; extracellular vesicles; human adipose‐derived stem cells; nanocosmetics; skin anti‐aging

DOI:  https://doi.org/10.1111/jocd.70021
Aging Cell. 2025 Feb 12. e70010

Reduction of DNA Topoisomerase Top2 Reprograms the Epigenetic Landscape and Extends Health and Life Span Across Species.

Man Zhu, Meng Ma, Lunan Luo, Feiyang Li, Jiashun Zheng, Yan Pan, Lu Yang, Ying Xiao, Ziyan Wang, Bo Xian, Yi Zheng, Hao Li, Jing Yang.

  DNA topoisomerases are essential molecular machines that manage DNA topology in the cell and play important roles in DNA replication and transcription. We found that knocking down the enzyme topoisomerase Top2 or its mammalian homolog TOP2B increases the lifespan of S. cerevisiae, C. elegans, and mice. TOP2B reduction also extends the health span of mice and alleviates the pathologies of aging in multiple tissues. At the cellular/molecular level, TOP2B reduction alleviates the major hallmarks of aging, including senescence, DNA damage, and deregulated nutrient sensing. We observed that TOP2B reduction changes the epigenetic landscape of various tissues in old mice toward that of the young animals, and differentially downregulates genes with active promoter and high expression. Our observations suggest that Top2 reduction confers pro-longevity effect across species possibly through a conserved mechanism and may be a promising strategy for longevity intervention.

Keywords:  aging; essential gene; histone modification; longevity; topoisomerase II

DOI:  https://doi.org/10.1111/acel.70010
Geroscience. 2025 Feb 10.

Impact of Mlkl or Ripk3 deletion on age-associated liver inflammation, metabolic health, and lifespan.

Sabira Mohammed, Phoebe Ohene-Marfo, Chao Jiang, Zongkai Peng, Nidheesh Thadathil, Albert Tran, Evan Nicklas, Shylesh Bhaskaran, Dawei Wang, Ramasamy Selvarani, Amit Singh, Zhibo Yang, Nagib Ahsan, Sathyaseelan S Deepa.

  Chronic, low-grade inflammation is a hallmark of aging and various age-related diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). The prevalence of metabolic dysfunction-associated steatohepatitis (MASH), an advanced form of MASLD, increases with age and contributes to morbidity and mortality among the elderly. This study investigates the role of necroptosis, a programmed cell death pathway that promotes inflammation, in liver inflammaging and age-associated MASLD by utilizing genetic ablation models of two key necroptosis proteins, Mlkl or Ripk3. The absence of Mlkl or Ripk3 significantly reduced liver inflammation, steatosis, and fibrosis in aged male mice, supporting the role of necroptosis in age-associated MASLD. Additionally, Mlkl or Ripk3 deletion impacted other non-necroptotic cellular processes that drive inflammation and MASLD, such as cellular senescence, apoptosis, and autophagy in aged liver. Levels of plasma TNFα and IL6, key proinflammatory cytokines associated with inflammaging, are reduced in Mlkl-/- or Ripk3-/- aged mice, supporting a systemic effect of necroptosis inhibition on inflammation. Proteomic analysis of liver tissues emphasizes the critical role of lipid and immune regulatory processes in maintaining liver homeostasis when Mlkl or Ripk3 is absent in aging liver. While Mlkl deletion did not affect the lifespan of mice, Ripk3 deletion shortened it. Additionally, Mlkl deficiency improved insulin sensitivity, whereas Ripk3 deficiency exacerbated glucose intolerance in aged mice. Thus, selective inhibition of Mlkl, not Ripk3, represents a potential therapeutic avenue for mitigating age-related liver disease and enhancing metabolic outcomes in the elderly.

Keywords:  Inflammaging; Lifespan; Liver; MASLD; Mlkl; Ripk3

DOI:  https://doi.org/10.1007/s11357-025-01553-5
Cell Rep Med. 2025 Feb 06. pii: S2666-3791(25)00041-2. [Epub ahead of print] 101968

Impact of physical activity on physical function, mitochondrial energetics, ROS production, and Ca2+ handling across the adult lifespan in men.

Marina Cefis, Vincent Marcangeli, Rami Hammad, Jordan Granet, Jean-Philippe Leduc-Gaudet, Pierrette Gaudreau, Caroline Trumpff, Qiuhan Huang, Martin Picard, Mylène Aubertin-Leheudre, Marc Bélanger, Richard Robitaille, José A Morais, Gilles Gouspillou.

  Aging-related muscle atrophy and weakness contribute to loss of mobility, falls, and disability. Mitochondrial dysfunction is widely considered a key contributing mechanism to muscle aging. However, mounting evidence positions physical activity as a confounding factor, making unclear whether muscle mitochondria accumulate bona fide defects with aging. To disentangle aging from physical activity-related mitochondrial adaptations, we functionally profiled skeletal muscle mitochondria in 51 inactive and 88 active men aged 20-93. Physical activity status confers partial protection against age-related decline in physical performance. Mitochondrial respiration remains unaltered in active participants, indicating that aging per se does not alter mitochondrial respiratory capacity. Mitochondrial reactive oxygen species (ROS) production is unaffected by aging and higher in active participants. In contrast, mitochondrial calcium retention capacity decreases with aging regardless of physical activity and correlates with muscle mass, performance, and the stress-responsive metabokine/mitokine growth differentiation factor 15 (GDF15). Targeting mitochondrial calcium handling may hold promise for treating aging-related muscle impairments.

Keywords:  calcium retention capacity; functional capacities; intermuscular fat accumulation; mitochondria; mitochondrial permeability transition pore; muscle atrophy and weakness; physical performance; reactive oxygen species; sarcopenia; skeletal muscle aging

DOI:  https://doi.org/10.1016/j.xcrm.2025.101968
MedComm (2020). 2025 Feb;6(2): e70086

Therapeutic potential of nicotinamide and ABT263 in alcohol-associated liver disease through targeting cellular senescence.

Naheemat Modupeola Gold, Qinchao Ding, Yang Yang, Shaoyan Pu, Wenjing Cao, Xinxuan Ge, Pengyun Yang, Michael Ngozi Okeke, Ayesha Nisar, Yongzhang Pan, Qiuni Luo, Xiayan Wang, Han Xu, Rui Tian, Meiting Zi, Xingjie Zhang, Songtao Li, Yonghan He.

  Alcohol-associated liver disease (ALD) is a major cause of liver-related morbidity and mortality, yet clinically effective therapies for ALD remain lacking. Here, we demonstrate that alcohol intake and its metabolite, acetaldehyde (ACH), induce senescence in the liver and liver cells, respectively. To assess the therapeutic potential of targeting liver senescence in ALD, we treated ALD-affected mice with the senolytic compound ABT263 and the senomorphic NAD+ precursor, nicotinamide (NAM). The results show that ABT263 effectively clears senescent hepatocytes and stellate cells, and reduces liver triglyceride (TG), but increases plasma alanine aminotransferase and TG levels. Conversely, NAM efficiently suppresses senescence and the senescence-associated secretory phenotype (SASP), protecting the liver from alcohol-induced injury in ALD mice. RNA-sequencing analysis revealed that ABT263 treatment downregulated genes involved in adipogenesis while activating the complement pathway. In contrast, NAM upregulated metabolism-related genes, such as Sirt1, and downregulated DNA damage marker genes, including Rec8 and E2f1, in the liver. These findings suggest that cellular senescence plays a critical role in alcohol-induced liver injury. Compared with senescent cell clearance by ABT263, suppressing senescence and SASP by NAM may provide a safer and more effective therapeutic approach for ALD.

Keywords:  acetaldehyde; alcohol‐associated liver disease; cellular senescence; senolytic; senomorphic

DOI:  https://doi.org/10.1002/mco2.70086
Aging Cell. 2025 Feb 11. e14499

Caloric Restriction and Telomere Preservation in TERT Knockout Adipocyte Progenitors Does Not Rescue Mice From Metabolic Dysfunction due to a TERT Function in Adipocyte Mitochondria.

Zhanguo Gao, Yongmei Yu, Kristin Eckel-Mahan, Mikhail G Kolonin.

  Inactivation of telomerase (TERT) in adipocyte progenitor cells (APC) expedites telomere attrition, and the onset of diabetes in mice fed high-fat diet (HFD), which promotes APC over-proliferation and replicative senescence. Here, we show that time-restricted feeding or caloric restriction in the postnatal development of mice subsequently subjected to HFD prevents telomere attrition but not glucose intolerance. This metabolic effect of dietary intervention was not observed for mice with TERT KO in endothelial or myeloid cells. To characterize the telomere-independent effects of TERT in the APC lineage, we analyzed mice with TERT knockout in mature adipocytes (AD-TERT-KO), which do not proliferate and avoid telomere attrition. Analysis of adipocytes from AD-TERT-KO mice indicated reliance on glycolysis and decreased mitochondrial oxidative metabolism. We show that AD-TERT-KO mice have reduced cold tolerance and metabolism abnormality indicating a defect in adaptive thermogenesis, characteristic of aging. Conversely, ectopic TERT expression in brown adipocytes-induced mitochondrial oxidation and thermogenic gene expression. We conclude that TERT plays an important non-canonical function in the mitochondria of adipocytes.

Keywords:  TERT; adipocyte; mitochondria; progenitor; senescence; telomerase; telomere

DOI:  https://doi.org/10.1111/acel.14499
Aging Cell. 2025 Feb 08. e70007

Development of a Short Telomere Zebrafish Model for Accelerated Aging Research and Antiaging Drug Screening.

David Hernández-Silva, María D López-Abellán, Francisco J Martínez-Navarro, Jesús García-Castillo, María L Cayuela, Francisca Alcaraz-Pérez.

  Increased life expectancy is associated with a higher risk of age-related diseases, which represent a major public health challenge. Animal models play a crucial role in aging research, enabling the study of diseases at the organism level and facilitating drug development and repurposing. Among these models, zebrafish stands out as an excellent in vivo system due to its unique characteristics. However, the longevity of zebrafish is a limitation for research, as it often takes too long to obtain results within a reasonable timeframe. To address this, we have developed a short telomere zebrafish line (ST2) with a premature aging phenotype during the larval stage. Although less extreme than the tert-deficient G2 larvae, ST2 larvae exhibit reduced telomerase expression and activity, along with shortened telomeres. they also exhibit increased cellular senescence, apoptosis, and premature death. As a proof of concept, we evaluated the antiaging effects of two compounds: resveratrol (a polyphenol) and navitoclax (a senolytic). Our results confirm the antiaging properties of resveratrol, which improves telomere maintenance. However, navitoclax does not attenuate the ST2 phenotype. Taking advantage of the zebrafish larval model, this premature aging system provides a valuable platform for in vivo testing of rejuvenating molecules through drug screening, using telomere length or survival as a readout.

Keywords:  antiaging screening; premature aging; short telomeres; zebrafish

DOI:  https://doi.org/10.1111/acel.70007
Geroscience. 2025 Feb 14.

Test of Rapamycin in Aging Dogs (TRIAD): study design and rationale for a prospective, parallel-group, double-masked, randomized, placebo-controlled, multicenter trial of rapamycin in healthy middle-aged dogs from the Dog Aging Project.

Dog Aging Project Consortium

  Companion dogs are a powerful model for aging research given their morphologic and genetic variability, risk for age-related disease, and habitation of the human environment. In addition, the shorter life expectancy of dogs compared to human beings provides a unique opportunity for an accelerated timeline to test interventions that might extend healthy lifespan. The Test of Rapamycin In Aging Dogs (TRIAD) randomized clinical trial is a parallel-group, double-masked, randomized, placebo-controlled, multicenter trial that will test the ability of rapamycin to prolong lifespan and improve several healthspan metrics in healthy, middle-aged dogs recruited from Dog Aging Project participants. Here, we describe the rationale, design, and goals of the TRIAD randomized clinical trial, the first rigorous test of a pharmacologic intervention against biological aging with lifespan and healthspan metrics as endpoints to be performed outside of the laboratory in any species.

Keywords:  Canine; Healthspan; Life span; Lifespan; Longevity; Rapamycin

DOI:  https://doi.org/10.1007/s11357-024-01484-7
Cell Rep. 2025 Feb 11. pii: S2211-1247(25)00069-5. [Epub ahead of print]44(2): 115298

Cellular rejuvenation protects neurons from inflammation-mediated cell death.

Sienna S Drake, Abdulshakour Mohammadnia, Aliyah Zaman, Christine Gianfelice, Kali Heale, Adam M R Groh, Elizabeth M-L Hua, Matthew A Hintermayer, Yuancheng Ryan Lu, David Gosselin, Stephanie Zandee, Alexandre Prat, Jo Anne Stratton, David A Sinclair, Alyson E Fournier.

  In multiple sclerosis (MS), inflammation of the central nervous system results in demyelination, neuroaxonal injury, and cell death. However, the molecular signals responsible for injury and cell death in neurons are not fully characterized. Here, we profile the transcriptome of retinal ganglion cells (RGCs) in experimental autoimmune encephalomyelitis (EAE) mice. Pathway analysis identifies a transcriptional signature reminiscent of aged RGCs with some senescent features, with a comparable signature present in neurons from patients with MS. This is supported by immunostaining demonstrating alterations to the nuclear envelope, modifications in chromatin marks, and accumulation of DNA damage. Transduction of RGCs with an Oct4-Sox2-Klf4 adeno-associated virus (AAV) to rejuvenate the transcriptome enhances RGC survival in EAE and improves visual acuity. Collectively, these data reveal an aging-like phenotype in neurons under pathological neuroinflammation and support the possibility that rejuvenation therapies or senotherapeutic agents could offer a direct avenue for neuroprotection in neuroimmune disorders.

Keywords:  AAV-OSK; ATAC sequencing; CP: Neuroscience; RNA sequencing; aging; experimental autoimmune encephalomyelitis; multiple sclerosis; neurodegeneration; partial reprogramming; rejuvenation; senescence

DOI:  https://doi.org/10.1016/j.celrep.2025.115298
Foods. 2025 Jan 21. pii: 347. [Epub ahead of print]14(3):

Bee Pollen Phytochemicals and Nutrients as Unequaled Pool of Epigenetic Regulators: Implications for Age-Related Diseases.

Rachid Kacemi, Maria G Campos.

  Bee pollen is characterized by an exceptional diversity and abundance of micronutrients and bioactive phytochemicals. This richness remains very sparsely investigated, but accumulating evidence strongly supports a promising future for bee pollen in human nutrition and medicine. Epigenetic regulation is among the most compelling biomedical topics that remain completely untapped in bee pollen and bee derivative research. In our current research, we identified numerous ubiquitous compounds that are consistently present in this matrix, regardless of its botanical and geographical origins, and that have been well studied and documented as epigenetic regulators in recent years. Given the relative newness of both bee pollen biomedical research and epigenetic studies within nutritional, pharmaceutical, and medical sciences, this review aims to bridge these valuable fields and advance related experimental investigations. To the best of our knowledge, this is the first work that has aimed to comprehensively investigate the epigenetic modulatory potential of bee pollen compounds. Our findings have also unveiled several intriguing phenomena, such as a dual effect of the same compound depending on the cellular context or the effect of some compounds on the cross-generational heritability of epigenetic traits. Although experimental studies of epigenetic regulation by bee pollen as a whole or by its extract are still lacking, our current study clearly indicates that this research avenue is very promising and worth further investigations. We hope that our current work constitutes a foundational cornerstone of future investigations for this avenue of research.

Keywords:  DNA; aging; bee pollen; epigenetic regulation; histones; non-coding RNA; nutrients; pollen extracellular vesicles; polyphenols

DOI:  https://doi.org/10.3390/foods14030347
Plants (Basel). 2025 Jan 24. pii: 349. [Epub ahead of print]14(3):

A Comprehensive Review on Graptopetalum paraguayense's Phytochemical Profiles, Pharmacological Activities, and Development as a Functional Food.

Varun Jaiswal, Hae-Jeung Lee.

  Graptopetalum paraguayense (G. paraguayense) is a succulent plant that has been used in traditional Chinese and Taiwanese medicine, mainly for antihypertensive and hepatoprotective activities. G. paraguayense is also used as an edible vegetable, which is considered a functional food. Different in vitro, in vivo, and clinical studies have highlighted the multiple pharmacological activities of G. paraguayense, which include anticancer, antibacterial, antiviral, antiasthma, antihypertensive, skin-whitening and anti-aging, anti-Alzheimer, neuroprotective, and hepatoprotective activities. Numerous studies revealed the antioxidant and anti-inflammatory potential of G. paraguayense, which may be the major contributing factor for multiple pharmacological activities and the protective effect of G. paraguayense on pancreatic, liver, lung, colon, and brain diseases. Initial safety studies on animal models also support the therapeutic candidature of G. paraguayense. The presence of numerous bioactive phytochemicals, especially polyphenols, and the identification of important disease targets of G. paraguayense emphasize its high therapeutic potential. The lack of a directional approach and limited in vivo studies limit the development of G. paraguayense against important diseases. Still, a compilation of pharmacological activities and target pathways of G. paraguayense is missing in the literature. The current review not only compiles pharmacological activities and phytochemicals but also highlights gaps and proposes future directions for developing G. paraguayense as a candidate against important diseases.

Keywords:  Graptopetalum paraguayense; antioxidants; functional food; horticulture plant; medicinal plant; phytochemicals; therapeutic

DOI:  https://doi.org/10.3390/plants14030349
Front Microbiol. 2025 ;16 1526764

Gut dysbiosis in primary sarcopenia: potential mechanisms and implications for novel microbiome-based therapeutic strategies.

Wei Yang, Si-Cong Si, Wei-Hua Wang, Jing Li, Yi-Xin Ma, Huan Zhao, Jia Liu.

  Primary sarcopenia is characterized by a progressive loss of skeletal muscle mass, strength, and physical function that occurs with aging. Despite the related adverse or even serious health outcomes, no medications are currently available for treating primary sarcopenia. Here, we discuss recent advancements in understanding the mechanistic role of gut microbiota-muscle cross-talk in primary sarcopenia, and the therapeutic implications. The mechanistic insights encompass a causal role of gut dysbiosis in primary sarcopenia, potentially mediated through gut microbiota-derived bioactive metabolites, such as short-chain fatty acids (SCFAs), secondary bile acids, and their associated signaling pathways, which may be translated into the development of new microbiome-based treatment and diagnostic approaches. Furthermore, we identify challenges that need addressing in future studies to facilitate the translation into potential novel treatment and differential diagnosis for older individuals with sarcopenia.

Keywords:  gut microbiota; muscle mass; primary sarcopenia; probiotic; sarcopenia; short-chain fatty acids

DOI:  https://doi.org/10.3389/fmicb.2025.1526764
Molecules. 2025 Feb 06. pii: 740. [Epub ahead of print]30(3):

Oleanolic Acid Slows Down Aging Through IGF-1 Affecting the PI3K/AKT/mTOR Signaling Pathway.

Yan Xu, Jianlei Wei, Wang Wang, Zebin Mao, Didi Wang, Tao Zhang, Pengxia Zhang.

   OBJECTIVE: A pentacyclic triterpene, oleanolic acid (OA), has anti-inflammatory activity. The role of oleanolic acid in aging is poorly understood, and the regulatory mechanism of IGF-1 signaling in aging is still not fully understood. Thus, we hypothesized that OA could delay aging by regulating the PI3K/AKT/mTOR pathway via insulin-like growth factor-1 (IGF-1).
METHOD: This study initially established a replicative aging model and a bleomycin-induced aging model in human dermal fibroblast (HDF) and mouse embryonic fibroblast (MEF) cell lines. On this basis, IGF-1 inhibitors or IGF-1 recombinant proteins were then combined with OA (at a concentration of 20 μM) and treated for 72 h. The project plans to detect the expression of aging-related proteins such as CDKN2A (p16) using Western blot technology, detect the expression of aging-related factors such as Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6), and Interleukin-8 (IL-8) using Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR), Enzyme-Linked Immunosorbent Assay (ELISA), and other technologies, and combine Senescence-Associated β-Galactosidase (SA-β-gal) staining to detect changes in aging.
RESULTS: The expression of IGF-1, PI3K/AKT/mTOR, aging-related proteins P16, and aging-related secretory factors (SASP) IL-1β, IL-6, and IL-8 was increased in senescent cells. After treatment with jujuboside, the expression of IGF-1, PI3K/AKT/mTOR, aging-related protein P16, and aging-related secretory factors IL-1β, IL-6, and IL-8 were decreased.
CONCLUSION: The findings suggested that OA slowed down aging by inhibiting the PI3K/AKT/mTOR expression through IGF-1. These findings suggest OA as a potential new drug and its mechanisms for anti-aging.

Keywords:  Aging; Insulin-like growth factor-1; Oleanolic acid; PI3K/AKT/mTOR

DOI:  https://doi.org/10.3390/molecules30030740
PLoS One. 2025 ;20(2): e0317302

Protective effects of Colla Corii Asini Collagen Peptides on D-galactose injection combined with UVB irradiation-induced aging in mice.

Qingdi Luo, Song Zhang, Zhuo Sun, Zhihao Wang, Qiulin Yue, Xin Sun, Li Tian, Baojun Li, Kunlun Li, Chen Zhao, Lin Zhao, Le Su.

Skin aging, autonomic mobility, memory function and physical deterioration are important features of aging, and effective anti-aging treatments are important in slowing down these processes. The objective of this research was to evaluate the protective effect of Colla Corii Asini (Ejiao) Collagen Peptides (CCACPs) on D-galactose (D-gal) injection combined with UV irradiation-induced senescence in mice. BY-HEALTH collagen oral solution (Bcos) was used as a positive control. Behavioural experiments showed that CCACPs significantly improved voluntary activity, learning memory and exercise endurance in aging mice. Elisa results showed that CCACPs reduced the levels of matrix metalloproteinase-1 (MMP-1) and MMP-3 in the skin, acetylcholinesterase (AChE) in the brain, and alanine aminotransferase (ALT) and azelaic aminotransferase (AST) in the liver of mice, while increasing the levels of collagen I in the skin and SOD in the brain. RT-qPCR revealed that CCACPs reduced the expression of p16, p19 and p21 genes in the liver and hippocampus, as well as the expression of IL-6 in the skin. Histological analysis of brain hippocampus, liver and skin confirmed the protective effects of CCACPs. The findings indicated that CCACPs may potentially slow the aging effects caused by D-galactose and UVB exposure in mice by reducing cellular senescence and oxidative stress levels. The results of this research provide the scientific basis for continuing to advance the extraction of collagen peptides from Colla Corii Asini as a potential anti-aging therapy.

DOI: https://doi.org/10.1371/journal.pone.0317302
Opt Lett. 2025 Feb 15. 50(4): 1421-1424

In vivo efficacy investigation of long-wavelength infrared femtosecond lasers for skin rejuvenation.

Jinmiao Guo, Yingying Dai, Maoxing Xiang, Changtao He, Fan Wang, Lidan Zhang, Xian Jiang, Houkun Liang.

Ablative lasers such as erbium-doped laser and carbon dioxide laser are currently primary tools for skin rejuvenation and treating dermatological disorders. However, during treatment, as the thermal effect exerts on both target and normal tissues simultaneously, significant effectiveness is often accompanied by a high risk of adverse reactions. To attain an appropriate thermal diffusion and thus favorable therapeutic outcome and fewer side effects, collagen-resonant femtosecond (fs) lasers hold promise as innovative tools for laser cosmetic treatments. In this study, we report, for the first time to the best of our knowledge, an in vivo experiment of fs laser resurfacing with collagen-resonant wavelengths of 6.1 and 7.5 μm, via an optical parametric amplifier. Our results demonstrate that long-wavelength infrared (LWIR) lasers effectively enhance the components of the dermal matrix without causing dermal ablation. The structure of collagen fiber is significantly improved with a substantial amount of new collagen formation. The increased expression of various collagen types in immunofluorescence image further demonstrates the efficacy of the LWIR fs laser in skin rejuvenation. In addition, improvement in the epidermis is more pronounced at a wavelength of 6.1 μm, with a more suitable depth of action. We anticipate that LWIR fs laser could become widely applicable in clinical settings for skin regeneration and rejuvenation.

DOI: https://doi.org/10.1364/OL.555702
Neurosci Lett. 2025 Feb 09. pii: S0304-3940(25)00043-6. [Epub ahead of print]850 138155

Downregulation of STAT1 improved learning and memory impairments in aging mice.

Xiao Li, Yao Xu, Ting Li, Bocheng Xiong, Xifei Yang, Yan Feng.

  Cognitive impairment is a typical hallmark of aging in mice and humans. Here, we reported that downregulation of STAT1 improved learning and memory impairments in aging mice by enhancing the expression of synaptic protein and inhibiting the expression of inflammatory factors. Proteomic analysis revealed 139 differentially expressed proteins (DEPs) in the hippocampus of downregulated-STAT1 aging mice, compared with aging control mice. Functional classification of DEPs indicated that these mainly involved in inflammation, autophagy, synapse, mitochondria and apoptosis. The ClueGo analysis uncovered that the Wiki pathway of these DEPs were involved in proteasome degradation, IL-6 signaling pathway, signaling of hepatocyte growth factor receptor and so on. Taken together, downregulation of STAT1 may delay aging with multiple mechanisms.

Keywords:  Aging; Inflammation; Learning and memory; Proteomics; STAT1; Synapse

DOI:  https://doi.org/10.1016/j.neulet.2025.138155
Cell Mol Bioeng. 2024 Dec;17(6): 609-618

Assessing the Effects of Dasatinib on Mesenchymal Stem/Stromal Cells.

David P Heinrichs, Vitali V Maldonado, I Kade K Ardana, Ryan M Porter, Rebekah M Samsonraj.

   Introduction: Progressive aging, or senescence, of mesenchymal stem/stromal cells (MSCs) is a major obstacle faced when trying to culture potent stem cells for use in therapy. Senescent cells are irreversibly nondividing cells that cease performing critical functional effects. Elimination of senescent cells using biochemical means, such as the use of senolytic drugs like dasatinib, may be useful in retaining the viable and proliferating populations of the cells.
Methods: An in vitro approach was used to investigate the effect of dasatinib on phenotypic, genotypic, and immunomodulatory functionality of osteogenic and adipogenic differentiated MSCs. Replicative senescence was achieved through multiple sub-culturing in vitro, then senescent and non-senescent cultures were treated with a standard dosage of dasatinib. MSCs were then differentiated into osteogenic, adipogenic or chondrogenic cultures using conditioned media to be tested for the three criteria being investigated.
Results: Significant changes were observed in these criteria, indicated by evidence gathered from proliferation and indoleamine 2,3 dioxygenase activity assays. Phenotypic results of dasatinib were shown to reduce the population of senescent MSCs while allowing non-senescent MSCs to continue differentiating and proliferating without interference from senescent cells. Genotypic results showed no change to upregulation in markers associated with osteogenic and adipogenic cells when exposed to dasatinib. Indoleamine Dioxygenase activity showed insignificant differences in cells exposed to dasatinib versus control groups, providing evidence against compromised cellular immune function.
Conclusion: This investigation provides insight into how dasatinib effects MSCs functional ability and provides a better understanding of the function of senolytic agents.

Keywords:  Cell therapy; Dasatinib; Mesenchymal stem cells; Senescence; Senolytics

DOI:  https://doi.org/10.1007/s12195-024-00830-1
Adv Sci (Weinh). 2025 Feb 10. e2414419

Rejuvenating Hyaline Cartilage with Senescence-Targeting Si-ADAM19 Delivery for Osteoarthritis Therapy.

Jiasheng Wang, Peng Guo, Dongmei Wu, Junzhi Yi, Qi Jiang, Jiajie Hu, Hongwei Ouyang.

  Osteoarthritis (OA) is one of the most common joint degenerative diseases without effective treatment, whose pathology is related to the local accumulation of senescent cells (SnCs). However, existing SnCs-scavenging drugs "senolytics" may lead to the exhaustion of stem and progenitor cells, impairing chondrocyte proliferation and cartilage regeneration. Here, ADAM19, a kind of endopeptidases from the ADAM (a disintegrin and metalloproteinase) family, is identified as a novel target for senescent chondrocyte rejuvenation. ADAM19 is elevated in senescent chondrocytes in both mice and human osteoarthritic joints, as well as in cellular senescence model in vitro. ADAM19 knockdown not only significantly attenuated senescent phenotype of chondrocytes, but also promoted cell proliferation and extracellular matrix synthesis. RNA sequencing revealed ADAM19 may regulate chondrocyte senescence mainly through the PI3K/AKT signal axis. In addition, a senescence-targeting small interfering RNA (siRNA) delivery system is developed for in vivo delivery of therapeutic siRNA. The complex selectively released ADAM19 siRNA in SnCs and performed high silencing effect on target gene. Furthermore, intra-articular (IA) injection of the complex once every two weeks in OA mice effectively reduced SnCs accumulation and promoted hyaline cartilage regeneration. This study provides a promising strategy for the development of regenerative RNA interference therapy.

Keywords:  a disintegrin and metalloproteinase 19 (ADAM19); cartilage regeneration; cellular senescence; osteoarthritis(OA); rejuvenating; siRNA delivery

DOI:  https://doi.org/10.1002/advs.202414419
Curr Pharm Des. 2025 Feb 06.

Skin Aging: Insights into the Role of Fatty Acids.

Snehal Kshirsagar, Asha Thomas, Sanjeevani Deshkar, Lata Kothapalli, Trupti Borhade, Sohan Chitlange, Avinash Sanap, Ramesh Bhonde.

  The human skin, being the largest organ, provides defense against bacteria, toxins, and ultraviolet radiation. The skin may experience changes like dryness, photodamage, oxidative damage, and inflammation. This review explores sources of fatty acids and how they can prevent skin damage, with the goal of determining their potential for preventing skin aging. The role and significance of various mechanistic pathways and molecular targets involved in skin aging are highlighted. By using current research findings, this review contributes to a comprehensive understanding of how fatty acids may serve as a proactive approach to promoting youthful skin and mitigating the signs of skin aging. In addition to treating specific skin conditions, nutraceuticals offer immense potential to minimize, postpone, or prevent premature skin aging. The substances that are most frequently employed include carotenoids, polyunsaturated fatty acids, plant polyphenols, bioactive peptides, oligosaccharides, and vitamins. Numerous human trials have demonstrated the impact of supplementing with these items on indicators of aging. The most pertinent clinical and non-clinical investigations are assessed in this review. Based on the comprehensive understanding of the significant role of fatty acids in addressing skin aging, this review may open doors and offer avenues for future explorations.

Keywords:  MUFA; PUFA; Skin; fatty acids; mechanistic pathways.; targets

DOI:  https://doi.org/10.2174/0113816128357677250116115754
J Clin Med. 2025 Jan 31. pii: 926. [Epub ahead of print]14(3):

The Brain Toxin Cleansing of Sleep Achieved During Wakefulness.

Gary W Arendash.

  A primary purpose of sleep for humans is to remove toxins and metabolic wastes from the brain (e.g., Aβ, tau, lactate) that would otherwise build up and compromise brain functionality. There are currently no drugs or devices that have been clinically shown in humans to enhance brain toxin removal, either during sleep or wakefulness. This perspective article focuses on a recently (re)discovered major route of toxin drainage from the human brain through meningeal lymphatic vessels (mLVs) and the primary enhancer of their flow-the cytokine Vascular Endothelial Growth Factor (VEGF). The purpose of this perspective article is to present pre-clinical and clinical evidence relevant to a new bioengineered technology (Transcranial Radiofrequency Treatment; TRFT) that appears to enhance mLV flow to increase brain toxin cleansing in humans during wakefulness. In being both safe and non-invasive, TRFT is administered in-home, presently through a device called "MemorEM". Two months of daily TRFT during wakefulness increased the typically low plasma/brain levels of VEGF in Alzheimer's Disease (AD) subjects, which was associated with increased Aβ and tau toxin removal from their brains during wakefulness-ostensibly through VEGF-increased mLV flow. Even irrespective of baseline VEGF levels, brain toxin cleansing was increased by TRFT in AD subjects, who also experienced a notable reversal of their cognitive impairment after TRFT. Additional clinical studies are nonetheless required to firmly establish TRFT's brain cleansing abilities during wakefulness. In performing a major duty of sleep, TRFT during wakefulness is proposed as a viable intervention to counter the decline in nighttime brain toxin cleansing that occurs with aging and in multiple brain diseases, most notably Alzheimer's Disease. The implications of TRFT for insomnia and for sleep deprivation are also discussed, as is the potential for TRFT to extend healthy human longevity.

Keywords:  Alzheimer’s Disease; brain toxin cleansing; meningeal lymphatic vessels; radiofrequency waves; wakefulness

DOI:  https://doi.org/10.3390/jcm14030926
Nutrients. 2025 Jan 29. pii: 503. [Epub ahead of print]17(3):

Dietary Restrictions and Cancer Prevention: State of the Art.

Greta Caprara, Rani Pallavi, Shalini Sanyal, Pier Giuseppe Pelicci.

  Worldwide, almost 10 million cancer deaths occurred in 2022, a number that is expected to rise to 16.3 million by 2040. Primary prevention has long been acknowledged as a crucial approach to reducing cancer incidence. In fact, between 30 and 50 percent of all tumors are known to be preventable by eating a healthy diet, staying active, avoiding alcohol, smoking, and being overweight. Accordingly, many international organizations have created tumor prevention guidelines, which underlie the importance of following a diet that emphasizes eating plant-based foods while minimizing the consumption of red/processed meat, sugars, processed foods, and alcohol. However, further research is needed to define the relationship between the effect of specific diets or nutritional components on cancer prevention. Interestingly, reductions in food intake and dietetic restrictions can extend the lifespan of yeast, nematodes, flies, and rodents. Despite controversial results in humans, those approaches have the potential to ameliorate health via direct and indirect effects on specific signaling pathways involved in cancer onset. Here, we describe the latest knowledge on the cancer-preventive potential of dietary restrictions and the biochemical processes involved. Molecular, preclinical, and clinical studies evaluating the effects of different fasting strategies will also be reviewed.

Keywords:  calorie restriction; cancer; diet; dietary restriction; fasting; microbiota; nutrition; overweight; prevention

DOI:  https://doi.org/10.3390/nu17030503
Food Funct. 2025 Feb 10.

Higher dietary intake of live microbes is inversely associated with accelerated biological aging.

Da Gan, Xiaoyan Wang, Xuebiao Wu, Shuang Han.

Objective: It remains unclear whether dietary live microbe intake is associated with biological aging. Therefore, the present study aimed to investigate the associations between dietary live microbe intake and biological aging. Methods: Our study included 7719 participants aged 20 years and older from the 2007-2010 cycles of the National Health and Nutrition Examination Survey (NHANES). Participants were categorized into groups using two distinct methods. The first method grouped participants based on the live microbial level of the consumed foods, dividing them into three dietary live microbe intake groups: low, medium, and high. The second method classified participants according to the quantity of live microbe-containing foods they consumed (referred to as MedHi), with three groups: G1 (no MedHi intake), G2 (MedHi intake below the median), and G3 (MedHi intake above the median). Biological age was evaluated using the Klemera-Doubal method biological age (KDM-BA) and phenotypic age (PA). KDM-BA acceleration and PA acceleration was determined if participants' KDM-BA or PA exceeded their chronological age, respectively. Multivariable logistic regression models were conducted to explore the associations of dietary live microbe intake groups and dietary MedHi intake groups with the acceleration of KDM-BA and PA. Results: Compared with participants in the low dietary live microbe intake group, those in the high dietary live microbe intake group had a 20% (95% CI: 2% to 35%) reduced risk of KDM-BA acceleration and a 25% (95% CI: 4% to 42%) reduced risk of PA acceleration. Similarly, participants in the G3 group with higher dietary MedHi intake had a 24% (95% CI: 10% to 35%) lower risk of KDM-BA acceleration and a 29% (95% CI: 17% to 39%) lower risk of PA acceleration compared with those in the G1 group. The stratified analyses showed that the associations of dietary MedHi intake with accelerated KDM-BA and PA were not influenced by age, gender, race, smoking, alcohol consumption, physical activity, race, and history of hypertension, diabetes, and cardiovascular disease. Conclusion: Higher dietary intake of live microbes was inversely associated with accelerated biological aging. A diet rich in live microbes may help slow down the aging process.

DOI: https://doi.org/10.1039/d4fo04230a
Adv Sci (Weinh). 2025 Feb 13. e2411408

A Feedback Loop Driven by H4K12 Lactylation and HDAC3 in Macrophages Regulates Lactate-Induced Collagen Synthesis in Fibroblasts Via the TGF-β Signaling.

Ying Zou, Mibu Cao, Meiling Tai, Haoxian Zhou, Li Tao, Shu Wu, Kaiye Yang, Youliang Zhang, Yuanlong Ge, Hao Wang, Shengkang Luo, Zhenyu Ju.

  The decrease in fibroblast collagen is a primary contributor to skin aging. Lactate can participate in collagen synthesis through lysine lactylation by regulating gene transcription. However, the precise mechanism by which lactate influences collagen synthesis requires further investigation. This study demonstrates that the depletion of macrophages mitigates the stimulating effect of lactate on collagen synthesis in fibroblasts. Through joint CUT&Tag and RNA-sequencing analyses, a feedback loop between H4K12 lactylation (H4K12la) and histone deacetylase 3 (HDAC3) in macrophages that drives lactate-induced collagen synthesis are identified. Macrophages can uptake extracellular lactate via monocarboxylate transporter-1 (MCT1), leading to an up-regulation of H4K12la levels through a KAT5-KAT8-dependent mechanism in response to Poly-L-Lactic Acid (PLLA) stimulation, a source of low concentration and persistent lactate, thereby promoting collagen synthesis in fibroblasts. Furthermore, H4K12la is enriched at the promoters of TGF-β1 and TGF-β3, enhancing their transcription. Hyperlactylation of H4K12la inhibits the expression of the eraser HDAC3, while the activation of HDAC3 reduces H4K12la in macrophages and suppresses collagen synthesis in fibroblasts. In conclusion, this study illustrates that macrophages play a critical role in lactate-induced collagen synthesis in the skin, and targeting the lactate-H4K12la-HDAC3-TGF-β axis may represent a novel approach for enhancing collagen production to combat skin aging.

Keywords:  H4K12 lactylation; collagen synthesis; fibroblasts; lactate; macrophages

DOI:  https://doi.org/10.1002/advs.202411408
Am J Physiol Cell Physiol. 2025 Feb 10.

Microbiota protect against frailty, loss of skeletal muscle, and maintain inflammatory tone during aging in mice.

Meghan O Conn, Erica N DeJong, Daniel M Marko, Russta Fayyazi, Dana Kukje Zada, Kevin P Foley, Nicole G Barra, Dawn M E Bowdish, Jonathan D Schertzer.

  Chronic low-level inflammation or "inflammaging" is hypothesized to contribute to sarcopenia and frailty. Resident microbiota are thought to promote inflammaging, frailty, and loss of skeletal muscle mass. We tested immunity and frailty in male C57BL6/N germ-free (GF), specific-pathogen-free (SPF), and mice that were born germ-free and colonized (COL) with an SPF microbiota. Male and female GF mice had lower systemic cellular inflammation indicated by lower blood Ly6Chigh monocytes across their lifespan. Male GF mice had lower body mass, but relative to body mass, GF mice had smaller hindlimb muscles and smaller muscle fibers compared to SPF mice across the lifespan. Male and female GF mice had increased frailty at 18 months or older. Colonization of female GF mice increased blood Ly6Chigh monocytes, but did not affect frailty at 18 months or older. Colonization of male GF mice increased blood Ly6Chigh monocytes, skeletal muscle size, myofiber fiber size, and decreased frailty at 18 months or older. Transcriptomic analysis of the tibialis anterior muscle revealed a microbiota-muscle axis with over 550 differentially expressed genes in COL male mice at 18 months or older. Colonized male mice had transcripts indicative of lower tumor necrosis factor-alpha (TNF) signaling via nuclear factor κB (NF-κB). Our findings show that microbiota can increase systemic cellular immunity, while decreasing muscle inflammation, thereby protecting against muscle loss and frailty. We also found sex differences in the role of microbiota regulating frailty. We propose that microbiota components protect against lower muscle mass and frailty across the lifespan in mice.

Keywords:  Aging; Gut Microbiota; Muscle; Sarcopenia

DOI:  https://doi.org/10.1152/ajpcell.00869.2024
Biomaterials. 2025 Jan 27. pii: S0142-9612(25)00048-1. [Epub ahead of print]318 123129

Emerging prodrug and nano-drug delivery strategies for the detection and elimination of senescent tumor cells.

Tao Wang, Xianbao Shi, Xiaolan Xu, Jiaming Zhang, Zhengdi Ma, Chen Meng, Dian Jiao, Yubo Wang, Yanfei Chen, Zhonggui He, Ying Zhu, He-Nan Liu, Tianhong Zhang, Qikun Jiang.

  Tumor cellular senescence, characterized by reversible cell cycle arrest following anti-cancer therapies, presents a complex paradigm in oncology. Given that senescent tumor cells may promote angiogenesis, tumorigenesis, and metastasis, selective killing senescent cells (SCs)-a strategy termed senotherapy-has emerged as a promising approach to improve cancer treatment. However, the clinical implementation of senotherapy faces significant hurdles, including lack of precise methods for SCs identification and the potential for adverse effects associated with highly cytotoxic senolytic agents. In this account, we elucidate recent advancement in developing novel approaches for the detection and selective elimination of SCs, encompassing prodrugs, nanoparticles, and other cutting-edge drug delivery systems such as PROTAC technology and CAR T cell therapy. Furthermore, we explore the paradoxical nature of SCs, which can induce growth arrest in adjacent neoplastic cells and recruit immunomodulatory cells that contribute to tumor suppression. Therefore, we utilize SCs membrane as vehicles to elicit antitumor immunity and potentially augment existing anti-cancer therapies. Finally, the opportunities and challenges are put forward to facilitate the development and clinical transformation of SCs detection, elimination or utilization.

Keywords:  CAR T cell therapy; Nanoparticles; PROTAC technology; Prodrugs; SCs membrane; Senescent cells (SCs)

DOI:  https://doi.org/10.1016/j.biomaterials.2025.123129
Bone Res. 2025 Feb 08. 13(1): 21

Golgi-restored vesicular replenishment retards bone aging and empowers aging bone regeneration.

Peisheng Liu, Hao Guo, Xiaoyao Huang, Anqi Liu, Ting Zhu, Chenxi Zheng, Fei Fu, Kaichao Zhang, Shijie Li, Xinyan Luo, Jiongyi Tian, Yan Jin, Kun Xuan, Bingdong Sui.

Healthy aging is a common goal for humanity and society, and one key to achieving it is the rejuvenation of senescent resident stem cells and empowerment of aging organ regeneration. However, the mechanistic understandings of stem cell senescence and the potential strategies to counteract it remain elusive. Here, we reveal that the aging bone microenvironment impairs the Golgi apparatus thus diminishing mesenchymal stem cell (MSC) function and regeneration. Interestingly, replenishment of cell aggregates-derived extracellular vesicles (CA-EVs) rescues Golgi dysfunction and empowers senescent MSCs through the Golgi regulatory protein Syntaxin 5. Importantly, in vivo administration of CA-EVs significantly enhanced the bone defect repair rate and improved bone mass in aging mice, suggesting their therapeutic value for treating age-related osteoporosis and promoting bone regeneration. Collectively, our findings provide insights into Golgi regulation in stem cell senescence and bone aging, which further highlight CA-EVs as a potential rejuvenative approach for aging bone regeneration.

DOI: https://doi.org/10.1038/s41413-024-00386-w
Nutr Diabetes. 2025 Feb 10. 15(1): 4

Hepatic fibroblast growth factor 21 is required for curcumin or resveratrol in exerting their metabolic beneficial effect in male mice.

Jia Nuo Feng, Weijuan Shao, Lin Yang, Juan Pang, Wenhua Ling, Dinghui Liu, Michael B Wheeler, Housheng Hansen He, Tianru Jin.

BACKGROUND: Our mechanistic understanding on metabolic beneficial effects of dietary polyphenols has been hampered for decades due to the lack of functional receptors for those compounds and their extremely low plasma concentrations. Recent studies by our team and others suggest that those dietary polyphenols target gut microbiome, and gut-liver axis and that hepatic fibroblast factor 21 (FGF21) serves as a common target for various dietary interventions.
METHODS: Utilizing liver-specific FGF21 null mice (lFgf21-/-), we are asking a straightforward question: Is hepatic FGF21 required for curcumin or resveratrol, two typical dietary polyphenols, in exerting their metabolic beneficial effect in obesogenic diet-induced obesity mouse models.
RESULTS: On low-fat diet feeding, no appreciable defect on glucose disposal was observed in male or female lFgf21-/- mice, while fat tolerance was moderately impaired in male but not in female lFgf21-/- mice, associated with elevated random and fasting serum triglyceride (TG) levels, and reduced hepatic expression of Ehhadh and Ppargc1a, which encodes the two downstream effectors of FGF21. On high-fat-high-fructose (HFHF) diet challenge, Fgf21fl/fl but not lFgf21-/- mice exhibited response to curcumin intervention on reducing fasting serum TG, and on improving fat tolerance. Resveratrol intervention also affected FGF21 expression or its downstream effectors. Metabolic beneficial effects of resveratrol intervention observed in HFHF diet-challenged Fgf21fl/fl mice were either absent or attenuated in lFgf21-/- mice.
CONCLUSION AND SIGNIFICANCE: We conclude that hepatic FGF21 is required for curcumin or resveratrol in exerting their major metabolic beneficial effect. The recognition that FGF21 as the common target of dietary intervention, demonstrated in current as well as previous investigations, brings us a novel angle in understanding metabolic disease treatment and prevention. It remains to be further explored how various dietary interventions regulate FGF21 expression and function, via certain common or unique gut-liver or gut-brain-liver axis.

DOI: https://doi.org/10.1038/s41387-025-00363-0
Protein Pept Lett. 2025 Feb 11.

A Review on the Potential Role of Humanin Peptide and its Analogs in the Regulation of Autophagy Pathways for Therapeutic Application in Metabolic Disorders.

Hira Moin, Rizwan Ashraf, Batool Butt, Imtiaz Mustafa, Mamoona Shafiq, Sayed Ali Raza Shah.

  Autophagy is a self-eating cellular process in which the cell breaks down worn-out organelles, damaged/defective proteins, and toxins. Impaired autophagy is a significant factor in the development of various metabolic disorders, along with oxidative stress, inflammation, mitochondrial and endoplasmic reticulum dysfunction. These disorders pose a significant health and economic burden on the global human population, owing to their steadily rising prevalence. Therefore, modulating the expression of proteins involved in the autophagy-related pathways can be a promising avenue for curbing the development and progression of these disorders. Humanin (HN) is a 24-amino acid mitochondrial-derived peptide. It possesses anti-oxidant, anti-inflammatory, and pro-apoptotic properties. The analogs of HN can be generated by replacing specific amino acids in the polypeptide chain, thereby functionally modifying the peptide. Among these, humanin- glycine (HNG) is the most widely studied analog in both in vivo and in vitro disease models. It is far more potent than HN, with a potency that is 1000 times greater. To the best of our knowledge, this review is the first to discuss and examine the available evidence regarding the potential involvement of HN or its analogs in regulating autophagy pathways. The review primarily highlights that HN is an autophagy inducer, which can promote cell survival in the presence of metabolic and oxidative stress, particularly the HNG analog. Future research is imperative to comprehensively evaluate the effects of HN and its analogs on autophagy. Further investigations are needed to correlate its levels with various autophagic markers in different metabolic diseases, offering the potential for groundbreaking discoveries in understanding disease mechanisms and developing novel therapeutic strategies.

Keywords:  Autophagy; HNG; diabetes; humanin; metabolic diseases.

DOI:  https://doi.org/10.2174/0109298665363711250112050930