bims-caglex 2024-08-04 papers

bims-caglex

Biomed News

on Cellular aging and life extension

Issue of 2024–08–04
thirty papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño

Crosstalk between the DNA damage response and cellular senescence drives aging and age-related diseases.
The Longevity Med Summit: insights on healthspan from cell to society.
Spatiotemporal transcriptomic profiling and modeling of mouse brain at single-cell resolution reveals cell proximity effects of aging and rejuvenation.
Epistemic uncertainty challenges aging clock reliability in predicting rejuvenation effects.
RNA-based logic for selective protein expression in senescent cells.
Aqueous Extract of Wolfberry Alleviates Aging-Related Skeletal Muscle Dysfunction by Modulating PRRs Signaling Pathways and Enhancing DNA Repair.
Highly regenerative species-specific genes improve age-associated features in the adult Drosophila midgut.
Heat-killed probiotic Levilactobacillus brevis MKAK9 and its exopolysaccharide promote longevity by modulating aging hallmarks and enhancing immune responses in Caenorhabditis elegans.
A Senomorphlytic Three-Drug Combination Discovered in Salsola collina for Delaying Aging Phenotypes and Extending Healthspan.
Blocking an inflammatory protein slows the pace of ageing.
A Nanocapsule System Combats Aging by Inhibiting Age-Related Angiogenesis Deficiency and Glucolipid Metabolism Disorders.
Engineering a durable BDDE cross-linked collagen filler for skin rejuvenation.
Rapamycin Attenuates H2O2-Induced Oxidative Stress-Related Senescence in Human Skin Fibroblasts.
Histone β-hydroxybutyrylation is critical in reversal of sarcopenia.
Aging in chronic lung disease: Will anti-aging therapy be the key to the cure?
Clinical Safety and Efficacy Evaluation of a Dissolving Microneedle Patch Having Dual Anti-Wrinkle Effects With Safe and Long-Term Activities.
Unveiling the causal relationship between circulating levels of micronutrients and risk of facial aging: A Mendelian randomization study.
Vitexin promotes the anti-senescence effect via inhibiting JAK2/STAT3 in D-Galactose-induced progeria mice and stress-induced premature senescence.
Anti-inflammatory and antioxidant effects on skin based on supramolecular hyaluronic acid-ectoin.
Cardiometabolic implications of adipose tissue aging.
Oxysophoridine inhibits oxidative stress and inflammation in hepatic fibrosis via regulating Nrf2 and NF-κB pathways.
Functional hyaluronic acid microneedles for skin photoaging based on collagen induction and oxidative stress regulation strategies.
Krill oil: nutraceutical potential in skin health and disease.
Anti-aging effects of Lacticaseibacillus paracasei PS117 on cognitive and intestinal health in naturally-aged mice: A focus on senescence-related proteins and microbiota composition.
Radix rehmanniae praeparata extracts ameliorate hepatic ischemia-reperfusion injury by reversing LRP1-NOTCH1-C/EBPβ axis-mediated senescence fate of LSECs.
Association of visceral adiposity index with phenotypic age acceleration: insight from NHANES 1999-2010.
The circadian rhythm: A key variable in aging?
Retro-age: A unique epigenetic biomarker of aging captured by DNA methylation states of retroelements.
New insights into the role of mitochondrial dynamics in oxidative stress-induced diseases.
Phytonutrients in the promotion of healthspan: a new perspective.

Semin Immunopathol. 2024 Aug 02. 46(3-4): 10

Crosstalk between the DNA damage response and cellular senescence drives aging and age-related diseases.

Ajmal Ahmad, Anneliesse Braden, Sazzad Khan, Jianfeng Xiao, Mohammad Moshahid Khan.

  Cellular senescence is a crucial process of irreversible cell-cycle arrest, in which cells remain alive, but permanently unable to proliferate in response to distinct types of stressors. Accumulating evidence suggests that DNA damage builds over time and triggers DNA damage response signaling, leading to cellular senescence. Cellular senescence serves as a platform for the perpetuation of inflammatory responses and is central to numerous age-related diseases. Defects in DNA repair genes or senescence can cause premature aging disease. Therapeutic approaches limiting DNA damage or senescence contribute to a rescued phenotype of longevity and neuroprotection, thus suggesting a mechanistic interaction between DNA damage and senescence. Here, we offer a unique perspective on the crosstalk between the DNA damage response pathway and senescence as well as their contribution to age-related diseases. We further summarize recent progress on the mechanisms and therapeutics of senescence, address existing challenges, and offering new insights and future directions in the senescence field.

Keywords:  Aging; Alzheimer’s disease; Anti-senescence therapy; DNA damage; Inflammation; Neurodegeneration; Senescence

DOI:  https://doi.org/10.1007/s00281-024-01016-7
Front Aging. 2024 ;5 1417455

The Longevity Med Summit: insights on healthspan from cell to society.

Natalie Falshaw, Michael Sagner, Richard C Siow.

  In recent years, there has been a paradigm shift with regards to ageing, challenging its traditional perception as an inevitable and natural process. Researchers have collectively identified hallmarks of ageing, nine of which were initially proposed in 2013 and expanded in 2023 to include disabled macroautophagy, chronic inflammation, and dysbiosis, enhancing our understanding of the ageing process at microscopic, cellular, and system-wide levels. Strategies to manipulate these hallmarks present opportunities for slowing, preventing, or reversing age-related diseases, thereby promoting longevity. The interdependence of these hallmarks underscores the necessity of a comprehensive, systems-based approach to address the complex processes contributing to ageing. As a primary risk factor for various diseases, ageing diminishes healthspan, leading to extended periods of compromised health and multiple age-related conditions towards the end of life. The significant gap between healthspan and lifespan holds substantial economic and societal implications. The inaugural Longevity Med Summit (4-5 May 2023, Cascais, Portugal) provided an international forum to discuss the academic and industry landscape of healthy longevity research, preventive medicine and clinical practice to enhance healthspan.

Keywords:  biological age; diet; geroscience; healthspan; healthy ageing; longevity; preventive medicine; public health

DOI:  https://doi.org/10.3389/fragi.2024.1417455
bioRxiv. 2024 Jul 19. pii: 2024.07.16.603809. [Epub ahead of print]

Spatiotemporal transcriptomic profiling and modeling of mouse brain at single-cell resolution reveals cell proximity effects of aging and rejuvenation.

Eric D Sun, Olivia Y Zhou, Max Hauptschein, Nimrod Rappoport, Lucy Xu, Paloma Navarro Negredo, Ling Liu, Thomas A Rando, James Zou, Anne Brunet.

Old age is associated with a decline in cognitive function and an increase in neurodegenerative disease risk 1 . Brain aging is complex and accompanied by many cellular changes 2-20 . However, the influence that aged cells have on neighboring cells and how this contributes to tissue decline is unknown. More generally, the tools to systematically address this question in aging tissues have not yet been developed. Here, we generate spatiotemporal data at single-cell resolution for the mouse brain across lifespan, and we develop the first machine learning models based on spatial transcriptomics ('spatial aging clocks') to reveal cell proximity effects during brain aging and rejuvenation. We collect a single-cell spatial transcriptomics brain atlas of 4.2 million cells from 20 distinct ages and across two rejuvenating interventions-exercise and partial reprogramming. We identify spatial and cell type-specific transcriptomic fingerprints of aging, rejuvenation, and disease, including for rare cell types. Using spatial aging clocks and deep learning models, we find that T cells, which infiltrate the brain with age, have a striking pro-aging proximity effect on neighboring cells. Surprisingly, neural stem cells have a strong pro-rejuvenating effect on neighboring cells. By developing computational tools to identify mediators of these proximity effects, we find that pro-aging T cells trigger a local inflammatory response likely via interferon-γ whereas pro-rejuvenating neural stem cells impact the metabolism of neighboring cells possibly via growth factors (e.g. vascular endothelial growth factor) and extracellular vesicles, and we experimentally validate some of these predictions. These results suggest that rare cells can have a drastic influence on their neighbors and could be targeted to counter tissue aging. We anticipate that these spatial aging clocks will not only allow scalable assessment of the efficacy of interventions for aging and disease but also represent a new tool for studying cell-cell interactions in many spatial contexts.

DOI: https://doi.org/10.1101/2024.07.16.603809
Aging Cell. 2024 Jul 28. e14283

Epistemic uncertainty challenges aging clock reliability in predicting rejuvenation effects.

Dmitrii Kriukov, Ekaterina Kuzmina, Evgeniy Efimov, Dmitry V Dylov, Ekaterina E Khrameeva.

  Epigenetic aging clocks have been widely used to validate rejuvenation effects during cellular reprogramming. However, these predictions are unverifiable because the true biological age of reprogrammed cells remains unknown. We present an analytical framework to consider rejuvenation predictions from the uncertainty perspective. Our analysis reveals that the DNA methylation profiles across reprogramming are poorly represented in the aging data used to train clock models, thus introducing high epistemic uncertainty in age estimations. Moreover, predictions of different published clocks are inconsistent, with some even suggesting zero or negative rejuvenation. While not questioning the possibility of age reversal, we show that the high clock uncertainty challenges the reliability of rejuvenation effects observed during in vitro reprogramming before pluripotency and throughout embryogenesis. Conversely, our method reveals a significant age increase after in vivo reprogramming. We recommend including uncertainty estimation in future aging clock models to avoid the risk of misinterpreting the results of biological age prediction.

Keywords:  DNA methylation; cell reprogramming; dataset shift; epigenetic aging clocks; epistemic uncertainty; rejuvenation

DOI:  https://doi.org/10.1111/acel.14283
Int J Biochem Cell Biol. 2024 Jul 30. pii: S1357-2725(24)00128-6. [Epub ahead of print] 106636

RNA-based logic for selective protein expression in senescent cells.

Ward Jacobs, Masoomeh Khalifeh, Merijn Koot, Valentina Palacio-Castañeda, Jenny van Oostrum, Marleen Ansems, Wouter P R Verdurmen, Roland Brock.

  Cellular senescence is a cellular state characterized by irreversible growth arrest, resistance to apoptosis and secretion of inflammatory molecules, which is causally linked to the pathogenesis of many age-related diseases. Besides, there is accumulating evidence that selective removal of senescent cells can benefit therapies for cancer and fibrosis by modulating the inflammatory microenvironment. While the field of so-called senolytics has spawned promising small molecules and peptides for the selective removal of senescent cells, there is still no effective means to detect senescent cells in vivo, a prerequisite for understanding the role of senescence in pathophysiology and to assess the effectiveness of treatments aimed at removing senescent cells. Here, we present a strategy based on an mRNA logic circuit, that yields mRNA-dependent protein expression only when a senescence-specific miRNA signature is present. Following a validation of radiation-induced senescence induction in primary human fibroblasts, we identify miRNAs up- and downregulated in association with cellular senescence using RT-qPCR. Incorporating binding sites to these miRNAs into the 3' untranslated regions of the mRNA logic circuit, we demonstrate the senescence-specific expression of EGFP for detection of senescent cells and of a constitutively active caspase-3 for selective removal. Altogether, our results pave the way for a novel approach to execute an mRNA-based programme specifically in senescent cells aimed at their detection or selective removal.

Keywords:  cellular senescence; miRNA; nanomedicine; therapeutic mRNA

DOI:  https://doi.org/10.1016/j.biocel.2024.106636
Mol Nutr Food Res. 2024 Aug 01. e2400307

Aqueous Extract of Wolfberry Alleviates Aging-Related Skeletal Muscle Dysfunction by Modulating PRRs Signaling Pathways and Enhancing DNA Repair.

Qingwei Zheng, Xiaofang Chen, Waleed Al-Ansi, Mingcong Fan, Haifeng Qian, Li Wang, Yan Li.

  Aging can lead to a series of degenerative changes in skeletal muscle, which would negatively impact physical activity and the quality of life of the elderly. Wolfberry contains numerous bioactive substances. It's vital to further explore the mechanisms underlying its healthy effects on skeletal muscle function during aging progress. This study discusses the benefits and mechanisms of aqueous extract of wolfberry (AEW) to protect skeletal muscle from aging-related persistent DNA damage based on its anti-inflammatory activity. It is found that AEW improves muscle mass, strength, and endurance, modulates the expression of Atrogin-1, MyH, and MuRF-1, and decreases oxidative stress and inflammation levels in aging mice, which is consistent with the in vitro results. Mechanistically, AEW inhibits the pattern recognition receptors (PRRs) pathway induced by inflammatory gene activation, suggesting its potential in response to DNA damage. AEW is also observed to mitigate chromatin decompaction. Network pharmacology is conducted to analyze the potential targets of AEW in promoting DNA repair. In conclusion, the study shows the anti-aging effects of AEW on skeletal muscle by promoting DNA repair and reducing the transcriptional activity of inflammatory factors. AEW intake may become a potential strategy for strengthening skeletal muscle function in the elderly.

Keywords:  DNA repair; aging; inflammation; skeletal muscle; wolfberry

DOI:  https://doi.org/10.1002/mnfr.202400307
BMC Biol. 2024 Aug 02. 22(1): 157

Highly regenerative species-specific genes improve age-associated features in the adult Drosophila midgut.

Hiroki Nagai, Yuya Adachi, Tenki Nakasugi, Ema Takigawa, Junichiro Ui, Takashi Makino, Masayuki Miura, Yu-Ichiro Nakajima.

   BACKGROUND: The remarkable regenerative abilities observed in planarians and cnidarians are closely linked to the active proliferation of adult stem cells and the precise differentiation of their progeny, both of which typically deteriorate during aging in low regenerative animals. While regeneration-specific genes conserved in highly regenerative organisms may confer regenerative abilities and long-term maintenance of tissue homeostasis, it remains unclear whether introducing these regenerative genes into low regenerative animals can improve their regeneration and aging processes.
RESULTS: Here, we ectopically express highly regenerative species-specific JmjC domain-encoding genes (HRJDs) in Drosophila, a widely used low regenerative model organism. Surprisingly, HRJD expression impedes tissue regeneration in the developing wing disc but extends organismal lifespan when expressed in the intestinal stem cell lineages of the adult midgut under non-regenerative conditions. Notably, HRJDs enhance the proliferative activity of intestinal stem cells while maintaining their differentiation fidelity, ameliorating age-related decline in gut barrier functions.
CONCLUSIONS: These findings together suggest that the introduction of highly regenerative species-specific genes can improve stem cell functions and promote a healthy lifespan when expressed in aging animals.

Keywords:   Drosophila ; Aging; Healthy lifespan; Intestinal stem cells; Regeneration; Synthetic biology

DOI:  https://doi.org/10.1186/s12915-024-01956-4
Immun Ageing. 2024 Aug 02. 21(1): 52

Heat-killed probiotic Levilactobacillus brevis MKAK9 and its exopolysaccharide promote longevity by modulating aging hallmarks and enhancing immune responses in Caenorhabditis elegans.

Arun Kumar, Manti Kumar Saha, Vipin Kumar, Anupam Bhattacharya, Sagar Barge, Ashis K Mukherjee, Mohan C Kalita, Mojibur R Khan.

   BACKGROUND: Proteostasis is a critical aging hallmark responsible for removing damaged or misfolded proteins and their aggregates by improving proteasomal degradation through the autophagy-lysosome pathway (ALP) and the ubiquitin-proteasome system (UPS). Research on the impact of heat-killed probiotic bacteria and their structural components on aging hallmarks and innate immune responses is scarce, yet enhancing these effects could potentially delay age-related diseases.
RESULTS: This study introduces a novel heat-killed Levilactobacillus brevis strain MKAK9 (HK MKAK9), along with its exopolysaccharide (EPS), demonstrating their ability to extend longevity by improving proteostasis and immune responses in wild-type Caenorhabditis elegans. We elucidate the underlying mechanisms through a comprehensive approach involving mRNA- and small RNA sequencing, proteomic analysis, lifespan assays on loss-of-function mutants, and quantitative RT-PCR. Mechanistically, HK MKAK9 and its EPS resulted in downregulation of the insulin-like signaling pathway in a DAF-16-dependent manner, enhancing protein ubiquitination and subsequent proteasomal degradation through activation of the ALP pathway, which is partially mediated by microRNA mir-243. Importantly, autophagosomes engulf ubiquitinylated proteins, as evidenced by increased expression of the autophagy receptor sqst-3, and subsequently fuse with lysosomes, facilitated by increased levels of the lysosome-associated membrane protein (LAMP) lmp-1, suggesting the formation of autolysosomes for degradation of the selected cargo. Moreover, HK MKAK9 and its EPS activated the p38 MAPK pathway and its downstream SKN-1 transcription factor, which are known to regulate genes involved in innate immune response (thn-1, ilys-1, cnc-2, spp-9, spp-21, clec-47, and clec-266) and antioxidation (sod-3 and gst-44), thereby reducing the accumulation of reactive oxygen species (ROS) at both cellular and mitochondrial levels. Notably, SOD-3 emerged as a transcriptional target of both DAF-16 and SKN-1 transcription factors.
CONCLUSION: Our research sets a benchmark for future investigations by demonstrating that heat-killed probiotic and its specific cellular component, EPS, can downregulate the insulin-signaling pathway, potentially improving the autophagy-lysosome pathway (ALP) for degrading ubiquitinylated proteins and promoting organismal longevity. Additionally, we discovered that increased expression of microRNA mir-243 regulates insulin-like signaling and its downstream ALP pathway. Our findings also indicate that postbiotic treatment may bolster antioxidative and innate immune responses, offering a promising avenue for interventions in aging-related diseases.

Keywords:   Lactobacillus ; Autophagy-lysosome pathway; HK MKAK9; Longevity; Probiotics; miRNA; p38 MAPK signalling

DOI:  https://doi.org/10.1186/s12979-024-00457-w
Adv Sci (Weinh). 2024 Jul 29. e2401862

A Senomorphlytic Three-Drug Combination Discovered in Salsola collina for Delaying Aging Phenotypes and Extending Healthspan.

Jiqun Wang, Wenwen Liu, Yunyuan Huang, Guangwei Wang, Xiaobo Guo, Donglei Shi, Tianyue Sun, Chaojiang Xiao, Chao Zhang, Bei Jiang, Yuan Guo, Jian Li.

  The pursuit of pharmacological interventions in aging aims focuses on maximizing safety and efficacy, prompting an exploration of natural products endowed with inherent medicinal properties. Subsequently, this work establishes a unique library of plant extracts sourced from Yunnan Province, China. Screening of this herbal library herein revealed that Salsola collina (JM10001) notably enhances both lifespan and healthspan in C. elegans. Further analysis via network pharmacology indicates that the p53 signaling pathway plays a crucial role in mediating the anti-aging effects of JM10001. Additionally, this work identifies that a composition, designated as JM10101 and comprising three chemical constituents of JM10001, preserves the original lifespan-extending activity in C. elegans. Both JM10001 and JM10101 mitigate aging symptoms in senescence-accelerated mice treated with doxorubicin and in naturally aged mice. Notably, JM10101 exhibits a more sophisticated senomorphlytic role encompassing both senomorphic and senolytic functions than JM10001 in the modulation of senescent cells, offering a promising strategy for the discovery of combination drugs in the rational development of anti-aging therapies.

Keywords:  anti‐aging drugs; combination drugs; salsola collina; senomorphlytic activity

DOI:  https://doi.org/10.1002/advs.202401862
Nature. 2024 Aug;632(8023): 35-36

Blocking an inflammatory protein slows the pace of ageing.

Richard A Miller.



Keywords:  Ageing; Immunology; Therapeutics

DOI:  https://doi.org/10.1038/d41586-024-02300-0
ACS Nano. 2024 Jul 31.

A Nanocapsule System Combats Aging by Inhibiting Age-Related Angiogenesis Deficiency and Glucolipid Metabolism Disorders.

Bo Li, Qiang Zhang, Jiahui Cheng, Yanfei Feng, Lixian Jiang, Xinxin Zhao, Yang Lv, Kun Yang, Jiaran Shi, Wei Wei, Peng Guo, Jun Wang, Mengqiu Cao, Weina Ding, Ji Wang, Diansan Su, Yan Zhou, Rifeng Gao.

  Insufficient angiogenic stimulation and dysregulated glycolipid metabolism in senescent vascular endothelial cells (VECs) constitute crucial features of vascular aging. Concomitantly, the generation of excess senescence-associated secretory phenotype (SASP) and active immune-inflammatory responses propagates within injured vessels, tissues, and organs. Until now, targeted therapies that efficiently rectify phenotypic abnormalities in senescent VECs have still been lacking. Here, we constructed a Pd/hCeO2-BMS309403@platelet membrane (PCBP) nanoheterostructured capsule system loaded with fatty acid-binding protein 4 (FABP4) inhibitors and modified with platelet membranes and investigated its therapeutic role in aged mice. PCBP showed significant maintenance in aged organs and demonstrated excellent biocompatibility. Through cyclic tail vein administration, PCBP extended the lifespan and steadily ameliorated abnormal phenotypes in aged mice, including SASP production, immune and inflammatory status, and age-related metabolic disorders. In senescent ECs, PCBP mediated the activation of vascular endothelial growth factor (VEGF) signaling and glycolysis and inhibition of FABP4 by inducing the synthesis of hypoxia-inducible factor-1α, thereby reawakening neovascularization and restoring glycolipid metabolic homeostasis. In conclusion, the PCBP nanocapsule system provides a promising avenue for interventions against aging-induced dysfunction.

Keywords:  SASP; aging; angiogenesis; glucolipid metabolism; heterostructures

DOI:  https://doi.org/10.1021/acsnano.4c02269
Biomed Mater. 2024 Jul 29. 19(5):

Engineering a durable BDDE cross-linked collagen filler for skin rejuvenation.

Qi Wang, Huiyu Yan, Jingting Zhang, Xinyu Tian, Jianxi Xiao.

  Skin aging, characterized by reduced regeneration, chronic inflammation, and heightened skin cancer risk, poses a significant challenge. Collagen fillers have emerged as a potential solution for skin rejuvenation by stimulating collagen regeneration. However, their clinical efficacy is limited by inherent instability and vulnerability toin vivodegradation by collagenase. Chemical cross-linking presents a promising approach to enhance stability, but it carries risks such as cytotoxicity, calcification, and discoloration. Here, we introduce a highly durable 1,4-butanediol diglycidyl ether (BDDE) cross-linked collagen filler for skin rejuvenation. BDDE effectively cross-links collagen, resulting in fillers with exceptional mechanical strength and injectability. These fillers demonstrate favorable stability and durability, promoting proliferation, adhesion, and spreading of human foreskin fibroblast-1 cellsin vitro. In vivostudies confirm enhanced collagen regeneration without inducing calcification. BDDE cross-linked collagen fillers offer promising prospects for medical cosmetology and tissue regeneration.

Keywords:  collagen filler; collagen regeneration; cross-linking; skin rejuvenation

DOI:  https://doi.org/10.1088/1748-605X/ad6548
Tissue Eng Regen Med. 2024 Aug 02.

Rapamycin Attenuates H2O2-Induced Oxidative Stress-Related Senescence in Human Skin Fibroblasts.

Yuyang Tang, Sen Yang, Zhen Qiu, Li Guan, Yigui Wang, Guixin Li, Yuanyu Tu, Lijuan Guo.

   BACKGROUND: Oxidative stress plays an important role in the skin aging process. Rapamycin has been shown to have anti-aging effects, but its role in oxidative senescence of skin cells remains unclear. The aim of this study was to explore the effect of rapamycin on oxidative stress-induced skin cell senescence and to illustrate the mechanism.
METHODS: Primary human skin fibroblasts (HSFs) were extracted and a model of H2O2-induced oxidative senescence was constructed, and the effects of rapamycin on their value-added and migratory capacities were detected by CCK-8 and scratch assays. SA-β-gal was utilized to detect senescence, oxidatively closely related factors were also assessed. Gene and protein expressions of senescence, oxidative, and autophagy were detected by western blotting and quantitative-PCR. The data were analyzed by one-way analysis of variance.
RESULTS: Rapamycin (0.1 nmol/L for 48 h) promoted the proliferative and migration of H2O2-treated HSFs (p < 0.05), decreased senescent phenotypes SA-β-gal staining and the expression of P53, and MMP-1 proteins, and increased the expression level of COL1A-1 (p < 0.001). Rapamycin also enhanced the activities of SOD and HO-1, and effectively removed intracellular ROS, MDA levels (p < 0.05), in addition, autophagy-related proteins and genes were significantly elevated after rapamycin pretreatment (p < 0.001). Rapamycin upregulated the autophagy pathway to exert its protective effects.
CONCLUSION: Our findings indicate that rapamycin shields HSFs from H2O2-induced oxidative damage, the mechanism is related to the reduction of intracellular peroxidation and upregulation of autophagy pathway. Therefore, rapamycin has the potential to be useful in the investigation and prevention of signs of aging and oxidative stress.

Keywords:  Autophagy; Human skin fibroblasts; Oxidative stress; Rapamycin; Senescence

DOI:  https://doi.org/10.1007/s13770-024-00660-2
Aging Cell. 2024 Jul 30. e14284

Histone β-hydroxybutyrylation is critical in reversal of sarcopenia.

Qiquan Wang, Xinqiang Lan, Hao Ke, Siman Xu, Chunping Huang, Jiali Wang, Xiang Wang, Tiane Huang, Xia Wu, Mengxin Chen, Yingqi Guo, Lin Zeng, Xiao-Li Tian, Yang Xiang.

  Sarcopenia, a leading cause for global disability and mortality, is an age-related muscular disorder, characterized by accelerated muscle mass loss and functional decline. It is known that caloric restriction (CR), ketogenic diet or endurance exercise lessen sarcopenia and elevate circulating β-hydroxybutyrate (β-HB) levels. Whether the elevated β-HB is essential to the reversal of sarcopenia, however, remains unclear. Here we show in both Caenorhabditis elegans and mouse models that an increase of β-HB reverse myofiber atrophy and improves motor functions at advanced ages. β-HB-induced histone lysine β-hydroxybutyrylation (Kbhb) is indispensable for the reversal of sarcopenia. Histone Kbhb enhances transcription of genes associated with mitochondrial pathways, including oxidative phosphorylation, ATP metabolic process and aerobic respiration. This ultimately leads to improve mitochondrial integrity and enhance mitochondrial respiration. The histone Kbhb are validated in mouse model with CR. Thus, we demonstrate that β-HB induces histone Kbhb, increases mitochondrial function, and reverses sarcopenia.

Keywords:  mitochondria; sarcopenia; skeletal muscle; β‐hydroxybutyrate; β‐hydroxybutyrylation

DOI:  https://doi.org/10.1111/acel.14284
Eur J Pharmacol. 2024 Jul 25. pii: S0014-2999(24)00535-1. [Epub ahead of print]980 176846

Aging in chronic lung disease: Will anti-aging therapy be the key to the cure?

Weijie Wang, Kai Zhou, Leyuan Wang, Qiuyan Qin, Huijun Liu, Ling Qin, Ming Yang, Lin Yuan, Chi Liu.

  Chronic lung disease is the third leading cause of death globally, imposing huge burden of death, disability and healthcare costs. However, traditional pharmacotherapy has relatively limited effects in improving the cure rate and reducing the mortality of chronic lung disease. Thus, new treatments are urgently needed for the prevention and treatment of chronic lung disease. It is particularly noteworthy that, multiple aging-related phenotypes were involved in the occurrence and development of chronic lung disease, such as blocked proliferation, telomere attrition, mitochondrial dysfunction, epigenetic alterations, altered nutrient perception, stem cell exhaustion, chronic inflammation, etc. Consequently, senescent cells induce a series of pathological changes in the lung, such as immune dysfunction, airway remodeling, oxidative stress and regenerative dysfunction, which is a critical issue that needs special attention in chronic lung diseases. Therefore, anti-aging interventions may bring new insights into the treatment of chronic lung diseases. In this review, we elaborate the involvement of aging in chronic lung disease and further discuss the application and prospects of anti-aging therapy.

Keywords:  Anti-Aging therapy; Chronic lung disease; Lung aging; SASP; Senescent cells

DOI:  https://doi.org/10.1016/j.ejphar.2024.176846
Ann Dermatol. 2024 Aug;36(4): 215-224

Clinical Safety and Efficacy Evaluation of a Dissolving Microneedle Patch Having Dual Anti-Wrinkle Effects With Safe and Long-Term Activities.

Ju Yeop Shin, DongHoon Han, Ki Young Yoon, Do Hyeon Jeong, Yong Il Park.

   BACKGROUND: Anti-aging products are widely used, but the desire for safe and more efficient anti-aging products continues to increase. Dissolving microneedle patches (MNPs) have provided a more efficient transdermal drug delivery solution. MNP is a promising candidate for developing better anti-aging products.
OBJECTIVE: To develop a more efficient anti-aging MNP product, we fabricated a dual anti-wrinkle microneedle patch (named DA-MNP) using droplet extension (DEN®) technology and evaluated its skin puncture ability, safety, and efficacy through clinical studies.
METHODS: A DA-MNP comprising hyaluronic acid (HA) polymer backbone, acetyl octapeptide-3, and L-ascorbic acid 2-glucoside and sodium cyclic lysophosphatidic acid was fabricated using DEN® technology. Placebo MNPs comprising only HA were also fabricated. Twenty-four healthy subjects were enrolled in this comparative clinical study. The DA-MNP or placebo MNP was separately applied to the left and right eyes of subjects for overnight. Assessments, including wrinkle improvement, trans-epidermal water loss (TEWL), eye lifting and adverse effects were evaluated at each scheduled visit day for 28 days.
RESULTS: The DA-MNP showed mechanical strength enough for puncturing the stratum corneum. Compared to placebo MNP group, the DA-MNP treated group showed an effective eye wrinkles improvement and better anti-aging of skin, with reduced TEWL, enhanced skin elasticity and lifting, and no adverse effects.
CONCLUSION: The present study demonstrated that the fabricated DA-MNP exhibited fast acting on deep wrinkles and enhanced anti-aging efficacy, with no skin safety concern. Thus, this DA-MNP may serve as a new transdermal delivery solution for skin wrinkling and aging.

Keywords:  Drug delivery systems; Microneedle; Skin absorption; Skin aging; Skin care

DOI:  https://doi.org/10.5021/ad.23.136
Medicine (Baltimore). 2024 Aug 02. 103(31): e39118

Unveiling the causal relationship between circulating levels of micronutrients and risk of facial aging: A Mendelian randomization study.

Lijiao Zhu, Xueyao Cai, Yuchen Cai, Wenjun Shi, Yiyuan Jiang.

Facial aging involves a continuous sequence of complex, interrelated events that impact numerous facial tissues. The aim of the study was to elucidate the casual relationship between circulating micronutrients and risk of facial aging. A two-sample Mendelian randomization analysis was performed using genetic data from genome-wide association studies. The inverse-variance weighted method is used for causal effect estimation, and additional tools such as Mendelian randomization-Egger, weighted median, simple mode, and weighted mode were used to refine the analysis. We conducted an in-depth examination of the correlation between several micronutrient blood levels and the risk of facial aging, and identified 3 key micronutrients (selenium, carotene, and iron) that may have a significant impact on skin health. Inverse-variance weighted results indicate that selenium levels were positively correlated with the risk of facial aging (odds ratio [OR] 1.005, P = .027), while a negative causal effect of carotene (OR 0.979, P = .024) and iron (OR 0.976, P = .009) on age-related facial alterations was observed. This study offers a new and insightful perspective on the current understanding of antiaging strategies, particularly the importance of appropriate consumption of essential micronutrients to maintain healthy skin condition.

DOI: https://doi.org/10.1097/MD.0000000000039118
Eur J Pharmacol. 2024 Jul 30. pii: S0014-2999(24)00554-5. [Epub ahead of print]980 176865

Vitexin promotes the anti-senescence effect via inhibiting JAK2/STAT3 in D-Galactose-induced progeria mice and stress-induced premature senescence.

Xiaojuan Han, Lu Li, Jiamei Xie, Qing Lei, Yansong Li, Huan Liu, Haoran Sun, Xiaohua Zhang, Xingchun Gou.

  Vitexin is a natural flavonoid glycoside compound extracted from the leaves and seeds of Vitex negundo. It is widely distributed in the leaves and stems of numerous plants and exhibites remarkable anti-tumor, anti-inflammatory, and anti-hypertensive properties. However, whether vitexin presents the anti-aging and senescence prevention effect has not been fully elucidated. The purpose of this study is to investigate the effect of vitexin on progeria mice and cellular senescence, as well as its underlying molecular mechanisms. To generate a premature aging/senescence model in vivo and in vitro, we used D-galactose (D-gal), hydrogen peroxide (H2O2), and adriamycin (ADR), respectively. Our findings demonstrated that vitexin potentially delays D-gal-induced progeria mice; similar effects were observed in stress-induced premature senescent fibroblasts in culture. Interestingly, this effect of vitexin is closely correlated with the reduction of the senescence-associated secretory phenotype (SASP) and the inhibition of the SASP-related JAK2/STAT3 pathway. Furthermore, we determined that vitexin meets the pharmacological parameters using the freely available ADMET web tool. Collectively, our findings demonstrate that vitexin possesses anti-senescence and anti-aging properties due to the inhibition of SASP and suppression of JAK2/STAT3 signaling pathway.

Keywords:  Aging; JAK2/STAT3; Progeria mice; Senescence-associated secretory phenotype; Vitexin

DOI:  https://doi.org/10.1016/j.ejphar.2024.176865
J Mater Chem B. 2024 Aug 01.

Anti-inflammatory and antioxidant effects on skin based on supramolecular hyaluronic acid-ectoin.

Beibei Lu, Siran Zhao, Jichuan Zhang, Jingbo Zhan, Jianglin Zhang, Zhe Liu, Jiaheng Zhang.

We addressed the damage caused by internal and external factors on the skin, as well as the aging phenomenon caused by delayed repair after damage. We prepared supramolecular hyaluronic acid-ectoin (HA-ECT) by combining theoretical calculations and experimental research, using intermolecular forces between hyaluronic acid and ectoin. This supramolecule has good stability, safety, and skin permeability and can penetrate the stratum corneum of the skin, reaching the epidermis and dermis of the skin. Compared with ectoin, the permeability of the supramolecule HA-ECT was 3.39-fold higher. Supramolecular HA-ECT can promote the proliferation of keratinocytes and fibroblasts, significantly increase the content of type collagen-I, reduce the expression of inflammatory factors in keratinocytes, and enhance skin hydration and repair effects. HA-ECT can reduce intracellular reactive oxygen species and inhibit the expression of matrix metalloproteinase-1 (reduced by 1.27-fold) to improve skin photoaging. Therefore, supramolecular HA-ECT has potential application in the field of cosmetics for skin antioxidants, anti-aging, and repair.

DOI: https://doi.org/10.1039/d4tb00459k
Obes Rev. 2024 Jul 30. e13806

Cardiometabolic implications of adipose tissue aging.

Bulbul Ahmed, Melissa G Farb, Noyan Gokce.

  Adipose tissue is a large endocrine organ that serves numerous physiological functions. As we age, adipose tissue remodels and can develop functional changes that alters its phenotype, potentially contributing to metabolic and cardiovascular disorders. Aging adipose tissue is characterized by regional redistribution of fat, accumulation of senescent cells, fibrosis, and decline in adipocyte differentiation capacities, which collectively impact adipose tissue function and whole body health. A notable transformation involves increased accumulation of intra-abdominal visceral adipose tissue and ectopic fat around internal organs such as the heart, blood vessels, liver, and kidneys that alter their functions. Other changes associated with aging include alterations in adipokine secretion and changes in adipocyte size and numbers. Aging adipocytes play a role in mediating chronic inflammation, metabolic dysfunction, and insulin resistance. Visceral adipose tissue, which increases in volume with aging, is in particular associated with inflammation, angiogenic dysfunction, and microvascular abnormalities, and mediators released by visceral fat may have adverse consequences systemically in multiple target organs, including the cardiovascular system. Understanding mechanisms underlying adipose tissue aging and its impact on cardiovascular health are important for developing interventions and treatments to promote healthy aging and reduce cardiometabolic disease risk.

Keywords:  adipose tissue; aging; and cardiovascular

DOI:  https://doi.org/10.1111/obr.13806
Phytomedicine. 2024 Apr 02. pii: S0944-7113(24)00250-2. [Epub ahead of print]132 155585

Oxysophoridine inhibits oxidative stress and inflammation in hepatic fibrosis via regulating Nrf2 and NF-κB pathways.

Jian-Yu Chen, Ying-Jie Yang, Xiong-Yu Meng, Ru-Hui Lin, Xiao-Yun Tian, Ying Zhang, Wen-Fang Lai, Chunxue Yang, Xue-Qin Ma, Ming-Qing Huang.

   BACKGROUND: Hepatic fibrosis (HF) runs through multiple stages of liver diseases and promotes these diseases progression. Oxysophoridine (OSR), derived from Sophora alopecuroides l., is a bioactive alkaloid that has been reported to antagonize alcoholic hepatic injury. However, whether OSR suppresses HF and the mechanisms involved in Nrf2 remain unknown.
PURPOSE: Since the dysregulation of inflammation and oxidative stress is responsible for the excessive accumulation of extracellular matrix (ECM) and fibrosis in the liver. We hypothesized that OSR may attenuate HF by inhibiting inflammation and oxidative stress through activating Nrf2 signaling.
METHODS: In this study, we employed LPS-stimulated HSC-T6 cells, RAW264.7 cells, and a CCl4-induced C57BL/6 mouse fibrotic model to evaluate its suppressing inflammation and oxidative stress, as well as fibrosis.
RESULTS: The result showed that OSR significantly reduced α-SMA and TGF-β1 at a low dose of 10 μM in vitro and at a dose of 50 mg/kg in vivo, which is comparable to Silymarin, the only Chinese herbal active ingredient that has been marketed for anti-liver fibrosis. Moreover, OSR effectively suppressed the expression of iNOS at a dose of 10 μM and COX-2 at a dose of 40 μM, respectively. Furthermore, OSR demonstrated inhibitory effects on the IL-1β, IL-6, and TNF-α in vitro and almost extinguished cytokine storm in vivo. OSR exhibited antioxidative effects by reducing MDA and increasing GSH, thereby protecting the cell membrane against oxidative damage and reducing LDH release. Moreover, OSR effectively upregulated the protein levels of Nrf2, HO-1, and p62, but decreased p-NF-κB p65, p-IκBα, and Keap1. Alternatively, mechanisms involved in Nrf2 were verified by siNrf2 interference, siNrf2 interference revealed that the anti-fibrotic effect of OSR was attributed to its activation of Nrf2.
CONCLUSION: The present study provided an effective candidate for HF involved in both activation of Nrf2 and blockage of NF-κB, which has not been reported in the published work. The present study provides new insights for the identification of novel drug development for HF.

Keywords:  Hepatic stellate cells; NF-κB; Nrf2; Oxysophoridine, Hepatic fibrosis (HF); macrophages

DOI:  https://doi.org/10.1016/j.phymed.2024.155585
Int J Biol Macromol. 2024 Jul 27. pii: S0141-8130(24)04885-2. [Epub ahead of print] 134080

Functional hyaluronic acid microneedles for skin photoaging based on collagen induction and oxidative stress regulation strategies.

Zhimin Tang, Zheng Liu, Youliang Zhang, Shengkang Luo, Yingni Xu, Li Ren.

  Photoaging holds remarkable importance for skin health and senescence. Ultraviolet (UV) irradiation results in the disruption of the extracellular matrix (ECM) microenvironment, the degradation of collagen, and the generation of oxidative stress. Traditional hyaluronic acid (HA) exhibits a diminished capacity to stimulate collagen regeneration, and hampered by its poor permeability as a macromolecule, ultimately resulting in constrained therapeutic outcomes for the treatment of photoaging. In this study, HA/PX was prepared by functional modification of HA with sulfonate-rich or phosphatidylcholine-rich polymers, which could complement the loss of ECM and ameliorate the senescence of human fibroblasts (HDFs) and hairless mouse models subjected to UVB-induced photoaging. The results indicate that HA/PX exhibits superior abilities in delaying cellular aging, promoting collagen regeneration, and resisting reactive oxygen species (ROS) compared to HA. Furthermore, HA/PX shows good biocompatibility both in vivo and in vitro, without causing allergic reactions or other adverse effects. We also demonstrated that the transdermal delivery of HA/PX via microneedle arrays (MNs) can significantly mitigate wrinkles and skin damage in photoaged nude mice, and achieve the treatment of skin photoaging by enhancing epidermal thickness, promoting collagen deposition, and reducing oxidative stress. Therefore, our research offers a novel possibility for future anti-aging therapeutic strategies.

Keywords:  Collagen; Hyaluronic acid; Microneedle; Photoaging; ROS

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.134080
Front Nutr. 2024 ;11 1388155

Krill oil: nutraceutical potential in skin health and disease.

Lan Duo, Jianzhong Yang, Xue Wang, Gang Zhang, Jiuxiang Zhao, Hong Zou, Zhi Wang, Yu Li.

  Krill oil (KO), extracted from the Antarctic marine crustacean Euphausia superba, is a nutrient-dense substance that includes rich profiles of n-3 polyunsaturated fatty acids (n-3 PUFAs), phospholipids (PLs), astaxanthin (ASX), as well as vitamins A and E, minerals, and flavonoids. As a high-quality lipid resource, KO has been widely used as a dietary supplement for its health-protective properties in recent years. KO has various benefits, including antioxidative, anti-inflammatory, metabolic regulatory, neuroprotective, and gut microbiome modulatory effects. Especially, the antioxidant and anti-inflammatory effects make KO have potential in skin care applications. With increasing demands for natural skin anti-aging solutions, KO has emerged as a valuable nutraceutical in dermatology, showing potential for mitigating the effects of skin aging and enhancing overall skin health and vitality. This review provides an overview of existing studies on the beneficial impact of KO on the skin, exploring its functional roles and underlying mechanisms through which it contributes to dermatological health and disease management.

Keywords:  anti-aging; anti-inflammatory; antioxidant; krill oil; skin health; ultraviolet protection; wound healing

DOI:  https://doi.org/10.3389/fnut.2024.1388155
Exp Gerontol. 2024 Jul 31. pii: S0531-5565(24)00171-2. [Epub ahead of print]195 112529

Anti-aging effects of Lacticaseibacillus paracasei PS117 on cognitive and intestinal health in naturally-aged mice: A focus on senescence-related proteins and microbiota composition.

Li-Hao Cheng, Chien-Chen Wu, Yu-Hsuan Wei, Pei-Jun Wen, Chih-Chieh Hsu, Ying-Chieh Tsai, Sabrina Wang.

  The rising global aging population underscores the urgency of maintaining the health and well-being of the elderly while reducing the healthcare burden. Anti-aging probiotics have emerged as a promising strategy. This study identified a novel anti-senescence probiotic, Lacticaseibacillus paracasei PS117 (PS117). The effects of PS117 and heat-treated PS117 (HT-PS117) supplementation on cognitive function of naturally-aged male mice were investigated. It was found that PS117 supplementation improved the cognitive performance of aged mice in the Y-maze test. Furthermore, the level of senescence-related protein p16INK4a (p16) were reduced, while anti-senescence protein sirtuin 1 (Sirt1) were increased in the hippocampus. In addition, there was an overall improvement in the intestinal function. Distinct changes in the gut microbiota were also identified, suggesting a potential contribution to the beneficial effects of PS117 supplementation. In conclusion, these results suggest that PS117 supplements could improve cognitive and intestinal functions in naturally-aged mice, while HT-117 improves only intestinal function, possibly by improving the gut microbiota composition.

Keywords:  Gut-brain-axis; Lacticaseibacillus paracasei; Microbiota; Probiotics; Psychobiotics; Senescence

DOI:  https://doi.org/10.1016/j.exger.2024.112529
Phytomedicine. 2024 Jul 29. pii: S0944-7113(24)00581-6. [Epub ahead of print]133 155923

Radix rehmanniae praeparata extracts ameliorate hepatic ischemia-reperfusion injury by reversing LRP1-NOTCH1-C/EBPβ axis-mediated senescence fate of LSECs.

Yinhao Zhang, Jiaorong Qu, Ranyi Luo, Kexin Jia, Guifang Fan, Fanghong Li, Ruiyu Wu, Jianan Li, Xiaojiaoyang Li.

   BACKGROUND: Hepatic ischemia-reperfusion injury (HIRI) is commonly observed in cases of extensive hepatic resection and involves complex mechanisms. Cell senescence has been recognized as a factor in liver injury including HIRI, where it presents as a pro-inflammatory phenotype called senescence-associated secretory phenotype (SASP). Radix Rehmanniae Praeparata (RRP) is a commonly utilized traditional Chinese medicine known for its hepatoprotective, anti-aging and antioxidant qualities. Despite its recognized benefits, the specific mechanisms by which RRP may impede the progression of HIRI through the regulation of cell senescence and the identification of the most potent anti-aging extracts from RRP remain unclear.
MATERIALS AND METHODS: Here, we first applied different chemical analysis methods to identify the RRP aqueous extract (RRPAE) and active fractions of RRP. Next, we constructed a surgically established mouse model and a hypoxia-reoxygenation (HR)-stimulated liver sinusoidal endothelial cells (LSECs) model to explore the underlying mechanism of RRP against HIRI through transcriptomics and multiple molecular biology experiments.
RESULTS: After identifying active ingredients in RRP, we observed that RRP and its factions effectively restored LSECs fenestration and improved inflammation, cellular swelling and vascular continuity in the hepatic sinusoidal region during HIRI. Transcriptomic results revealed that RRP might reverse HIRI-induced senescence through the NOTCH signaling pathway and cell categorization further showed that the senescent cell population in HIRI liver was primarily LSECs rather than other cell types. Different RRPAE, especially RRP glucoside (RRPGLY), improved LSECs senescence and suppressed the expression of pro-inflammatory SASP genes either induced by HR insult or NOTCH1 activator, which was accompanied with the inhibition of LRP1-NOTCH1-C/EBPβ pathways. Additionally, the specific inhibition of NOTCH1 by siRNA synergistically enhanced the hepatoprotective effect of RRPGLY. The ChIP-qPCR results further showed that C/EBPβ was enriched at the promoter of a representative SASP, Il-1β, in hypoxic LSECs but was significantly inhibited by RRPGLY.
CONCLUSION: Our study not only clarified the potential mechanism of RRP active extractions in alleviating HIRI, but also highlighted RRPGLY was the main component of RRP that exerted anti-aging and anti-HIRI effects, providing a fresh perspective on the use of RRP to improve HIRI.

Keywords:  Cell senescence; Hepatic ischemia-reperfusion injury; Liver sinusoidal endothelial cells; NOTCH1; Radix rehmanniae praeparata

DOI:  https://doi.org/10.1016/j.phymed.2024.155923
J Nutr Health Aging. 2024 Jul 26. pii: S1279-7707(24)00410-X. [Epub ahead of print]28(9): 100323

Association of visceral adiposity index with phenotypic age acceleration: insight from NHANES 1999-2010.

Cheng Xu, Zhen Song, Jia-Ni Wang, Chong-Chao Li.

   BACKGROUND: Obesity correlates with accelerated aging. This study aims to investigate the association between the visceral adiposity index (VAI) and accelerated aging.
METHODS: Biological aging was evaluated by phenotypic age acceleration (PhenoAgeAccel). Utilizing data from the National Health and Nutrition Examination Survey (NHANES) conducted between 1999 and 2010, we employed weighted multivariable logistic regression models, along with subgroup analysis, to examine the association between VAI and PhenoAgeAccel. Moreover, smooth curve fitting was utilized to identify potential nonlinear association, complemented by a two-piece linear regression model to investigate threshold effects.
RESULTS: Of the included 11,340 participants aged 20 years and older, the mean (95% CI) age was 46.569 (45.946, 47.191) years, and 49.189% were male. The mean (95% CI) VAI for all participants was 2.176 (2.114, 2.238), and the mean (95% CI) PhenoAgeAccel was -6.306 (-6.618, -5.994) years. In the fully adjusted model, each incremental unit increase of VAI was associated with a 0.312-year increase in PhenoAgeAccel (β = 0.312, 95% CI: 0.217, 0.408). This positive association was more statistically significant among individuals with cancer. Furthermore, a segmented association was observed between VAI and PhenoAgeAccel, with a turning point identified at 10.543. Below this threshold, VAI exhibited a positive correlation with PhenoAgeAccel (β = 0.617, 95% CI: 0.499, 0.735), while beyond it, the association became nonsignificant.
CONCLUSION: This study demonstrated a positive association between VAI and accelerated aging within a nationally representative population. The findings suggest that controlling adiposity may exert anti-aging effects and help prevent aging-related diseases.

Keywords:  Accelerated aging; Cross-sectional study; NHANES; Obesity; Phenotypic age acceleration; Visceral adiposity index

DOI:  https://doi.org/10.1016/j.jnha.2024.100323
Aging Cell. 2024 Jul 30. e14268

The circadian rhythm: A key variable in aging?

Patrick R Winterhalter, Adrian-Iustin Georgevici, Nitin J Gharpure, Gábor Szabó, Andreas Simm.

  The determination of age-related transcriptional changes may contribute to the understanding of health and life expectancy. The broad application of results from age cohorts may have limitations. Altering sample sizes per time point or sex, using a single mouse strain or tissue, a limited number of replicates, or omitting the middle of life can bias the surveys. To achieve higher general validity and to identify less distinctive players, bulk RNA sequencing of a mouse cohort, including seven organs of two strains from both sexes of 5 ages, was performed. Machine learning by bootstrapped variable importance and selection methodology (Boruta) was used to identify common aging features where the circadian rhythms (CiR) transcripts appear as promising age markers in an unsupervised analysis. Pathways of 11 numerically analyzed local network clusters were affected and classified into four major gene expression profiles, whereby CiR and proteostasis candidates were particularly conspicuous with partially opposing changes. In a data-based interaction association network, the CiR-proteostasis axis occupies an exposed central position, highlighting its relevance. The computation of 11,830 individual transcript associations provides potential superordinate contributors, such as hormones, to age-related changes, as in CiR. In hormone-sensitive LNCaP cells, short-term supraphysiologic levels of the sex hormones dihydrotestosterone or estradiol increase the expression of the CiR transcript Bhlhe40 and the associated senescence regulator Cdkn2b (p15). According to these findings, the bilateral dysregulation of CiR appears as a fundamental protagonist of aging, whose transcripts could serve as a biological marker and its restoration as a therapeutic opportunity.

Keywords:  Bhlhe40 (Dec1); aging hallmarks; circadian rhythms; interaction network; machine learning; mouse cohort; organ strain sex; sex hormones

DOI:  https://doi.org/10.1111/acel.14268
Aging Cell. 2024 Aug 02. e14288

Retro-age: A unique epigenetic biomarker of aging captured by DNA methylation states of retroelements.

Lishomwa C Ndhlovu, Matthew L Bendall, Varun Dwaraka, Alina P S Pang, Nicholas Dopkins, Natalia Carreras, Ryan Smith, Douglas F Nixon, Michael J Corley.

  Reactivation of retroelements in the human genome has been linked to aging. However, whether the epigenetic state of specific retroelements can predict chronological age remains unknown. We provide evidence that locus-specific retroelement DNA methylation can be used to create retroelement-based epigenetic clocks that accurately measure chronological age in the immune system, across human tissues, and pan-mammalian species. We also developed a highly accurate retroelement epigenetic clock compatible with EPICv.2.0 data that was constructed from CpGs that did not overlap with existing first- and second-generation epigenetic clocks, suggesting a unique signal for epigenetic clocks not previously captured. We found retroelement-based epigenetic clocks were reversed during transient epigenetic reprogramming, accelerated in people living with HIV-1, and responsive to antiretroviral therapy. Our findings highlight the utility of retroelement-based biomarkers of aging and support a renewed emphasis on the role of retroelements in geroscience.

Keywords:  DNA methylation; aging; biomarker; endogenous retrovirus; epigenetic clock; epigenetics; retroelement

DOI:  https://doi.org/10.1111/acel.14288
Biomed Pharmacother. 2024 Jul 31. pii: S0753-3322(24)00968-5. [Epub ahead of print]178 117084

New insights into the role of mitochondrial dynamics in oxidative stress-induced diseases.

Sisi Chen, Qilong Li, Hanjing Shi, Fengna Li, Yehui Duan, Qiuping Guo.

  The accumulation of excess reactive oxygen species (ROS) can lead to oxidative stress (OS), which can induce gene mutations, protein denaturation, and lipid peroxidation directly or indirectly. The expression is reduced ATP level in cells, increased cytoplasmic Ca2+, inflammation, and so on. Consequently, ROS are recognized as significant risk factors for human aging and various diseases, including diabetes, cardiovascular diseases, and neurodegenerative diseases. Mitochondria are involved in the production of ROS through the respiratory chain. Abnormal mitochondrial characteristics, including mitochondrial OS, mitochondrial fission, mitochondrial fusion, and mitophagy, play an important role in various tissues. However, previous excellent reviews focused on OS-induced diseases. In this review, we focus on the latest progress of OS-induced mitochondrial dynamics, discuss OS-induced mitochondrial damage-related diseases, and summarize the OS-induced mitochondrial dynamics-related signaling pathways. Additionally, it elaborates on potential therapeutic methods aimed at preventing oxidative stress from further exacerbating mitochondrial disorders.

Keywords:  Disease; Mitochondrial damage; Mitochondrial dynamics; Oxidative stress

DOI:  https://doi.org/10.1016/j.biopha.2024.117084
Front Nutr. 2024 ;11 1409339

Phytonutrients in the promotion of healthspan: a new perspective.

Emma F Jacquier, Amira Kassis, Diana Marcu, Nikhat Contractor, Jina Hong, Chun Hu, Marissa Kuehn, Christopher Lenderink, Arun Rajgopal.

  Considering a growing, aging population, the need for interventions to improve the healthspan in aging are tantamount. Diet and nutrition are important determinants of the aging trajectory. Plant-based diets that provide bioactive phytonutrients may contribute to offsetting hallmarks of aging and reducing the risk of chronic disease. Researchers now advocate moving toward a positive model of aging which focuses on the preservation of functional abilities, rather than an emphasis on the absence of disease. This narrative review discusses the modulatory effect of nutrition on aging, with an emphasis on promising phytonutrients, and their potential to influence cellular, organ and functional parameters in aging. The literature is discussed against the backdrop of a recent conceptual framework which describes vitality, intrinsic capacity and expressed capacities in aging. This aims to better elucidate the role of phytonutrients on vitality and intrinsic capacity in aging adults. Such a review contributes to this new scientific perspective-namely-how nutrition might help to preserve functional abilities in aging, rather than purely offsetting the risk of chronic disease.

Keywords:  aging; healthspan; intrinsic capacity; nutrition; phytonutrients; vitality

DOI:  https://doi.org/10.3389/fnut.2024.1409339