bims-caglex 2024-07-14 papers

bims-caglex

Biomed News

on Cellular aging and life extension

Issue of 2024–07–14
24 papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño

Rejuvenation of young blood on aging organs: Effects, circulating factors, and mechanisms.
Senescent cell heterogeneity and responses to senolytic treatment are related to cell cycle status during cell growth arrest.
Cellular Senescence and Inflammaging in the Bone: Pathways, Genetics, Anti-Aging Strategies and Interventions.
Multiparametric identification of putative senescent cells in skeletal muscle via mass cytometry.
Replicative senescence is ATM driven, reversible, and accelerated by hyperactivation of ATM at normoxia.
Phytocosmetic potential of Blumea balsamifera oil in mitigating UV-induced photoaging: Evidence from cellular and mouse models.
Strategies for modeling aging and age-related diseases.
PKM2 aggregation drives metabolism reprograming during aging process.
Exosomes derived from hTERT-immortalized cells delay cellular senescence of human fibroblasts.
Exosomes Released from Senescent Cells and Circulatory Exosomes Isolated from Human Plasma Reveal Aging-associated Proteomic and Lipid Signatures.
Quality Control in Human Adipose-Derived Stromal/Stem Cells and Tissue Engineering Fat Models for Aging Studies.
Ageing, Cognitive Decline, and Effects of Physical Exercise: Complexities, and Considerations from Animal Models.
Yeast Npl3 regulates replicative senescence outside of TERRA R-loop resolution and co-transcriptional processing.
Optimization of biotransformation processes of Camarosporium laburnicola to improve production yields of potent telomerase activators.
Activatable Fluorescent Probe for Studying Drug-Induced Senescence In Vitro and In Vivo.
The Role of PGC-1α in Aging Skin Barrier Function.
Mutations in fibulin-1 and collagen IV suppress the short healthspan of mig-17/ADAMTS mutants in Caenorhabditis elegans.
Aging limits stemness and tumorigenesis in the lung by reprogramming iron homeostasis.
Histone chaperone HIRA, Promyelocytic Leukemia (PML) protein and p62/SQSTM1 coordinate to regulate inflammation during cell senescence.
Co-analysis of methylation platforms for signatures of biological aging in the domestic dog reveals previously unexplored confounding factors.
A Mechanistic Analysis of Metformin's Biphasic Effects on Lifespan and Healthspan in C. elegans: Elixir in Youth, Poison in Elder.
Activity of DNA Repair Systems in the Cells of Long-Lived Rodents and Bats.
Age-related decline in the expression of BRG1, ATM and ATR are partially reversed by dietary restriction in the livers of female mice.
A hypothesis: MiRNA-124 mediated regulation of sirtuin 1 and vitamin D receptor gene expression accelerates aging.

Heliyon. 2024 Jun 30. 10(12): e32652

Rejuvenation of young blood on aging organs: Effects, circulating factors, and mechanisms.

Meng-Nan Liu, Qi Lan, Hao Wu, Cai-Wei Qiu.

  Aging causes degenerative changes in organs, leading to a decline in physical function. Over the past two decades, researchers have made significant progress in understanding the rejuvenating effects of young blood on aging organs, benefiting from heterochronic parabiosis models that connect the blood circulation of aged and young rodents. It has been discovered that young blood can partially rejuvenate organs in old animals by regulating important aging-related signaling pathways. Clinical trials have also shown the effectiveness of young blood in treating aging-related diseases. However, the limited availability of young blood poses a challenge to implementing anti-aging therapies on a large scale for older individuals. As a promising alternative, scientists have identified some specific anti-aging circulating factors in young blood that have been shown to promote organ regeneration, reduce inflammation, and alleviate fibrosis associated with aging in animal experiments. While previous reviews have focused primarily on the effects and mechanisms of circulating factors on aging, it is important to acknowledge that studying the rejuvenating effects and mechanisms of young blood has been a significant source of inspiration in this field, and it will continue to be in the future. In recent years, new findings have emerged, further expanding our knowledge in this area. This review aims to summarize the rejuvenating effects and mechanisms of young blood and circulating factors, discussing their similarities and connections, addressing discrepancies in previous studies, outlining future research directions, and highlighting the potential for clinical translation in anti-aging interventions.

Keywords:  Aging; Circulating factors; Heterochronic parabiosis; Rejuvenation; Young blood

DOI:  https://doi.org/10.1016/j.heliyon.2024.e32652
bioRxiv. 2024 Jun 26. pii: 2024.06.22.600200. [Epub ahead of print]

Senescent cell heterogeneity and responses to senolytic treatment are related to cell cycle status during cell growth arrest.

Francesco Neri, Shuyuan Zheng, Mark Watson, Pierre-Yves Desprez, Akos A Gerencser, Judith Campisi, Denis Wirtz, Pei-Hsun Wu, Birgit Schilling.

Cellular senescence has been strongly linked to aging and age-related diseases. It is well established that the phenotype of senescent cells is highly heterogeneous and influenced by their cell type and senescence-inducing stimulus. Recent single-cell RNA-sequencing studies identified heterogeneity within senescent cell populations. However, proof of functional differences between such subpopulations is lacking. To identify functionally distinct senescent cell subpopulations, we employed high-content image analysis to measure senescence marker expression in primary human endothelial cells and fibroblasts. We found that G2-arrested senescent cells feature higher senescence marker expression than G1-arrested senescent cells. To investigate functional differences, we compared IL-6 secretion and response to ABT263 senolytic treatment in G1 and G2 senescent cells. We determined that G2-arrested senescent cells secrete more IL-6 and are more sensitive to ABT263 than G1-arrested cells. We hypothesize that cell cycle dependent DNA content is a key contributor to the heterogeneity within senescent cell populations. This study demonstrates the existence of functionally distinct senescent subpopulations even in culture. This data provides the first evidence of selective cell response to senolytic treatment among senescent cell subpopulations. Overall, this study emphasizes the importance of considering the senescent cell heterogeneity in the development of future senolytic therapies.

DOI: https://doi.org/10.1101/2024.06.22.600200
Int J Mol Sci. 2024 Jul 05. pii: 7411. [Epub ahead of print]25(13):

Cellular Senescence and Inflammaging in the Bone: Pathways, Genetics, Anti-Aging Strategies and Interventions.

Merin Lawrence, Abhishek Goyal, Shelly Pathak, Payal Ganguly.

  Advancing age is associated with several age-related diseases (ARDs), with musculoskeletal conditions impacting millions of elderly people worldwide. With orthopedic conditions contributing towards considerable number of patients, a deeper understanding of bone aging is the need of the hour. One of the underlying factors of bone aging is cellular senescence and its associated senescence associated secretory phenotype (SASP). SASP comprises of pro-inflammatory markers, cytokines and chemokines that arrest cell growth and development. The accumulation of SASP over several years leads to chronic low-grade inflammation with advancing age, also known as inflammaging. The pathways and molecular mechanisms focused on bone senescence and inflammaging are currently limited but are increasingly being explored. Most of the genes, pathways and mechanisms involved in senescence and inflammaging coincide with those associated with cancer and other ARDs like osteoarthritis (OA). Thus, exploring these pathways using techniques like sequencing, identifying these factors and combatting them with the most suitable approach are crucial for healthy aging and the early detection of ARDs. Several approaches can be used to aid regeneration and reduce senescence in the bone. These may be pharmacological, non-pharmacological and lifestyle interventions. With increasing evidence towards the intricate relationship between aging, senescence, inflammation and ARDs, these approaches may also be used as anti-aging strategies for the aging bone marrow (BM).

Keywords:  aging; anti-aging strategies; bone; bone regeneration; cellular senescence; inflammaging; seno-therapeutics; therapeutic interventions

DOI:  https://doi.org/10.3390/ijms25137411
Cytometry A. 2024 Jul 12.

Multiparametric identification of putative senescent cells in skeletal muscle via mass cytometry.

Yijia Li, Nameera Baig, Daniel Roncancio, Kris Elbein, Dawn Lowe, Michael Kyba, Edgar A Arriaga.

  Senescence is an irreversible arrest of the cell cycle that can be characterized by markers of senescence such as p16, p21, and KI-67. The characterization of different senescence-associated phenotypes requires selection of the most relevant senescence markers to define reliable cytometric methodologies. Mass cytometry (a.k.a. Cytometry by time of flight, CyTOF) can monitor up to 40 different cell markers at the single-cell level and has the potential to integrate multiple senescence and other phenotypic markers to identify senescent cells within a complex tissue such as skeletal muscle, with greater accuracy and scalability than traditional bulk measurements and flow cytometry-based measurements. This article introduces an analysis framework for detecting putative senescent cells based on clustering, outlier detection, and Boolean logic for outliers. Results show that the pipeline can identify putative senescent cells in skeletal muscle with well-established markers such as p21 and potential markers such as GAPDH. It was also found that heterogeneity of putative senescent cells in skeletal muscle can partly be explained by their cell type. Additionally, autophagy-related proteins ATG4A, LRRK2, and GLB1 were identified as important proteins in predicting the putative senescent population, providing insights into the association between autophagy and senescence. It was observed that sex did not affect the proportion of putative senescent cells among total cells. However, age did have an effect, with a higher proportion observed in fibro/adipogenic progenitors (FAPs), satellite cells, M1 and M2 macrophages from old mice. Moreover, putative senescent cells from muscle of old and young mice show different expression levels of senescence-related proteins, with putative senescent cells of old mice having higher levels of p21 and GAPDH, whereas putative senescent cells of young mice had higher levels of IL-6. Overall, the analysis framework prioritizes multiple senescence-associated proteins to characterize putative senescent cells sourced from tissue made of different cell types.

Keywords:  aging; autophagy; clustering; erythro‐myeloid progenitors; fibro/adipogenic progenitors; macrophages; mass cytometry; outlier detection; satellite cells; senescence; skeletal muscle

DOI:  https://doi.org/10.1002/cyto.a.24853
bioRxiv. 2024 Jun 26. pii: 2024.06.24.600514. [Epub ahead of print]

Replicative senescence is ATM driven, reversible, and accelerated by hyperactivation of ATM at normoxia.

Alexander Stuart, Titia de Lange.

Programmed telomere shortening limits tumorigenesis through the induction of replicative senescence. Here we address three long-standing questions concerning senescence. First, we show that the ATM kinase is solely responsible for the induction of replicative senescence. Senescence was delayed by ATM inhibition (ATMi) or overexpression of TRF2, the shelterin subunit dedicated to ATM repression. In contrast, there was no evidence for ATR signaling contributing to replicative senescence even when ATMi was combined with ATR inhibition. Second, we show ATMi can induce apparently normal cell divisions in a subset of senescent cells, indicating that senescence can be reversed. Third, we show that the extended replicative life span at low (physiological) oxygen is due to diminished ATM activity. At low oxygen, cells show a decreased ATM response to dysfunctional telomeres and genome-wide DSBs compared to 20% oxygen. As this effect could be reversed by NAC, the attenuated response of ATM to critically short telomeres and the resulting extended life span at low oxygen is likely due to ROS-induced formation of cysteine disulfide-bridges that crosslink ATM dimers into a form that is not activated by DSBs. These findings show how primary human cells detect shortened telomeres and reveal the molecular mechanism underlying the telomere tumor suppressor pathway.

DOI: https://doi.org/10.1101/2024.06.24.600514
J Ethnopharmacol. 2024 Jul 06. pii: S0378-8741(24)00834-1. [Epub ahead of print]334 118535

Phytocosmetic potential of Blumea balsamifera oil in mitigating UV-induced photoaging: Evidence from cellular and mouse models.

Kai Wang, Xuan Hu, Xiao-Li Xie, Mei Huang, Dan Wang, Fu-Lai Yu.

   ETHNOPHARMACOLOGICAL RELEVANCE: Blumea balsamifera (L.) DC. (BB), the source of Blumea balsamifera oil (BBO), is an aromatic medicinal plant, renowned for its pharmacological properties and its traditional use in Southeast Asian countries such as China, Thailand, Vietnam, Malaysia, and the Philippines for centuries. Traditionally, BB has been used as a raw herbal medicine for treating various skin conditions like eczema, dermatitis, athlete's foot, and wound healing for skin injuries.
AIM OF THE STUDY: This research aimed to explore the inhibitory effects of BBO on skin aging using two models: in vitro analysis with human dermal fibroblasts (HDF) under UVB-induced stress, and in vivo studies on UVA-induced dorsal skin aging in mice. The study sought to uncover the mechanisms behind BBO's anti-aging effects, specifically, its impact on cellular and tissue responses to UV-induced skin aging.
MATERIALS AND METHODS: We applied doses of 10-20 μL/mL of BBO to HDF cells that had been exposed to UVB radiation to simulate skin aging. We measured cell viability, and levels of reactive oxygen species (ROS), SA-β-gal, pro-inflammatory cytokines, and matrix metalloproteinases (MMPs). In addition, we investigated the involvement of mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) signaling pathways in mediating the anti-aging effects of BBO. Histopathological and biochemical analyses were conducted in a mouse model to examine the effects of BBO on UV-induced photoaging.
RESULTS: UV exposure accelerated aging, and caused cellular damage and inflammatory responses through ROS-mediated pathways. In HDF cells, BBO treatment countered the UVB-induced senescence, and the recovery of cell viability was correlated to notable reductions in SA-β-gal, ROS, pro-inflammatory cytokines, and MMPs. Mechanistically, the anti-aging effect of BBO was associated with the downregulation of the JNK/NF-κB signaling pathways. In the in vivo mouse model, BBO exhibited protective capabilities against UV-induced photoaging, which were manifested by the enhanced antioxidant enzyme activities and tissue remodeling.
CONCLUSIONS: BBO effectively protects fibroblasts from UV-induced photoaging through the JNK/NF-κB pathway. Recovery from photoaging involves an increase in dermal fibroblasts, alleviation of inflammation, accelerated synthesis of antioxidant enzymes, and slowed degradation of ECM proteins. Overall, BBO enhances the skin's defensive capabilities against oxidative stress, underscoring its potential as a therapeutic agent for oxidative stress-related skin aging.

Keywords:  Anti-inflammation; Antioxidation; Blumea balsamifera oil; Cellular senescence; Matrix metalloproteinases; Skin aging

DOI:  https://doi.org/10.1016/j.jep.2024.118535
NPJ Aging. 2024 Jul 10. 10(1): 32

Strategies for modeling aging and age-related diseases.

D Jothi, Linda Anna Michelle Kulka.

The ability to reprogram patient-derived-somatic cells to IPSCs (Induced Pluripotent Stem Cells) has led to a better understanding of aging and age-related diseases like Parkinson's, and Alzheimer's. The established patient-derived disease models mimic disease pathology and can be used to design drugs for aging and age-related diseases. However, the age and genetic mutations of the donor cells, the employed reprogramming, and the differentiation protocol might often pose challenges in establishing an appropriate disease model. In this review, we will focus on the various strategies for the successful reprogramming and differentiation of patient-derived cells to disease models for aging and age-related diseases, emphasizing the accuracy in the recapitulation of disease pathology and ways to overcome the limitations of its potential application in cell replacement therapy and drug development.

DOI: https://doi.org/10.1038/s41514-024-00161-5
Nat Commun. 2024 Jul 09. 15(1): 5761

PKM2 aggregation drives metabolism reprograming during aging process.

Juntao Bie, Ridong Li, Yutong Li, Chen Song, Zhaoming Chen, Tianzhuo Zhang, Zhiheng Tang, Li Su, Liangyi Zhu, Jiaxin Wang, You Wan, Jun Chen, Xiaoyun Liu, Tingting Li, Jianyuan Luo.

While protein aggregation's association with aging and age-related diseases is well-established, the specific proteins involved and whether dissolving them could alleviate aging remain unclear. Our research addresses this gap by uncovering the role of PKM2 aggregates in aging. We find that PKM2 forms aggregates in senescent cells and organs from aged mice, impairing its enzymatic activity and glycolytic flux, thereby driving cells into senescence. Through a rigorous two-step small molecule library screening, we identify two compounds, K35 and its analog K27, capable of dissolving PKM2 aggregates and alleviating senescence. Further experiments show that treatment with K35 and K27 not only alleviate aging-associated signatures but also extend the lifespan of naturally and prematurely aged mice. These findings provide compelling evidence for the involvement of PKM2 aggregates in inducing cellular senescence and aging phenotypes, and suggest that targeting these aggregates could be a promising strategy for anti-aging drug discovery.

DOI: https://doi.org/10.1038/s41467-024-50242-y
Exp Gerontol. 2024 Jul 08. pii: S0531-5565(24)00150-5. [Epub ahead of print] 112508

Exosomes derived from hTERT-immortalized cells delay cellular senescence of human fibroblasts.

Yang Liu, Zhaoying Sheng, Linlin Sun.

  hTERT gene therapies hold significant promise for treating age-related diseases. However, further research is required to address the challenges of delivery and ethical considerations. We hypothesized that exosomes derived from hTERT-immortalized cells could function similarly to hTERT gene therapies by maintaining telomere length and attenuating cellular senescence biomarkers. In this study, we overexpressed the hTERT gene in Human Foreskin Fibroblast-1 cells (HFF cells) to produce hTERT-immortalized HFF cells (hT-HFF cells). We then used exosomes derived from these hT-HFF cells to treat human fibroblasts, HFF cells. Our results demonstrated that these exosomes effectively attenuated biomarkers of cellular senescence in HFF cells. Furthermore, analysis revealed that hTERT mRNA was indeed packaged into the exosomes from hT-HFF cells. This mRNA was capable of elongating telomeres and delaying cellular senescence in HFF cells. Therefore, exosomes from hT-HFF cells show potential as a treatment for age-related diseases.

Keywords:  Cellular senescence; Exosome; Telomere length; hTERT

DOI:  https://doi.org/10.1016/j.exger.2024.112508
bioRxiv. 2024 Jun 24. pii: 2024.06.22.600215. [Epub ahead of print]

Exosomes Released from Senescent Cells and Circulatory Exosomes Isolated from Human Plasma Reveal Aging-associated Proteomic and Lipid Signatures.

Sandip Kumar Patel, Joanna Bons, Jacob P Rose, Jessie R Chappel, Rebecca L Beres, Mark A Watson, Corey Webster, Jordan B Burton, Roland Bruderer, Pierre-Yves Desprez, Lukas Reiter, Judith Campisi, Erin S Baker, Birgit Schilling.

Senescence emerged as a significant mechanism of aging and age-related diseases, offering an attractive target for clinical interventions. Senescent cells release a senescence-associated secretory phenotype (SASP), including exosomes that may act as signal transducers between distal tissues, propagating secondary or bystander senescence and signaling throughout the body. However, the composition of exosome SASP remains underexplored, presenting an opportunity for novel unbiased discovery. Here, we present a detailed proteomic and lipidomic analysis of exosome SASP using mass spectrometry from human plasma from young and older individuals and from tissue culture of senescent primary human lung fibroblasts. We identified ~1,300 exosome proteins released by senescent fibroblasts induced by three different senescence inducers causing most exosome proteins to be differentially regulated with senescence. In parallel, a human plasma cohort from young and old individuals revealed over 1,350 exosome proteins and 171 plasma exosome proteins were regulated when comparing old vs young individuals. Of the age-regulated plasma exosome proteins, we observed 52 exosome SASP factors that were also regulated in exosomes from the senescent fibroblasts, including serine protease inhibitors (SERPINs), Prothrombin, Coagulation factor V, Plasminogen, and Reelin. In addition, 247 lipids were identified with high confidence in all exosome samples. Following the senescence inducers, a majority of the identified phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin species increased significantly indicating cellular membrane changes. The most notable categories of significantly changed proteins were related to extracellular matrix remodeling and inflammation, both potentially detrimental pathways that can damage surrounding tissues and even induce secondary or bystander senescence. Our findings reveal mechanistic insights and potential senescence biomarkers, enabling a better approach to surveilling the senescence burden in the aging population and offering promising therapeutic targets for interventions.

DOI: https://doi.org/10.1101/2024.06.22.600215
Methods Mol Biol. 2024 Jul 13.

Quality Control in Human Adipose-Derived Stromal/Stem Cells and Tissue Engineering Fat Models for Aging Studies.

Katie Hamel, Jordan Robinson, Emma Rogers, Haley Lassiter, Trivia Frazier, Cecilia Sanchez.

  Adipose tissue is recognized not only as an endocrine organ but also as a reservoir for adipose-derived stromal/stem cells (ASCs). ASCs have stimulated the interest of both the scientific and medical communities due to their therapeutic potential and applications in tissue engineering and regenerative medicine. ASCs are leveraged for their multipotency and their paracrine function. ASC behavior is highly variable and donor dependent. Donor age, body mass index, disease status, sex, and ethnicity can lead to differential overall function and quality. The impact of donor age and passage on ASC behavior has been well documented, impacting cell proliferation and differentiation potential and thus must be taken into careful consideration when conducting in vitro studies. Pooling of ASCs from different donors reduces heterogeneity among individual donors and produces ASCs with a consistent differentiation and paracrine profiles, an advantage for studies in biological aging. This chapter provides a detailed overview for studies related to quality control for ASC pools considering biological and chronological aging in ASCs. There are hallmarks of biological aging and specific assays associated with the evaluation of each hallmark. Nevertheless, here we present the assays that provide a standardized characterization and qualification of donor pools for their regenerative potential, considering chronological and biological age of the pool. The assays included in this chapter are considered quality control standards to evaluate cell proliferation, differentiation, colony-forming units, and cellular senescence from different donor age and cell passage cohorts.

Keywords:  Adipose-derived stromal/stem cell; Aging; Cellular senescence; Colony-forming unit-fibroblast; Differentiation; In vitro culture; Proliferation

DOI:  https://doi.org/10.1007/7651_2024_559
Brain Plast. 2024 ;9(1-2): 43-73

Ageing, Cognitive Decline, and Effects of Physical Exercise: Complexities, and Considerations from Animal Models.

Maria Giovanna Caruso, Sarah Nicolas, Paul J Lucassen, Joram D Mul, Olivia F O'Leary, Yvonne M Nolan.

  In our ageing global population, the cognitive decline associated with dementia and neurodegenerative diseases represents a major healthcare problem. To date, there are no effective treatments for age-related cognitive impairment, thus preventative strategies are urgently required. Physical exercise is gaining traction as a non-pharmacological approach to promote brain health. Adult hippocampal neurogenesis (AHN), a unique form of brain plasticity which is necessary for certain cognitive functions declines with age and is enhanced in response to exercise. Accumulating evidence from research in rodents suggests that physical exercise has beneficial effects on cognition through its proneurogenic capabilities. Given ethical and technical limitations in human studies, preclinical research in rodents is crucial for a better understanding of such exercise-induced brain and behavioural changes. In this review, exercise paradigms used in preclinical research are compared. We provide an overview of the effects of different exercise paradigms on age-related cognitive decline from middle-age until older-age. We discuss the relationship between the age-related decrease in AHN and the potential impact of exercise on mitigating this decline. We highlight the emerging literature on the impact of exercise on gut microbiota during ageing and consider the role of the gut-brain axis as a future possible strategy to optimize exercise-enhanced cognitive function. Finally, we propose a guideline for designing optimal exercise protocols in rodent studies, which would inform clinical research and contribute to developing preventative strategies for age-related cognitive decline.

Keywords:  Aging; cognition; exercise; gut microbiota; hippocampus; middle age; neurogenesis; rodents

DOI:  https://doi.org/10.3233/BPL-230157
Nucleosides Nucleotides Nucleic Acids. 2024 Jul 08. 1-21

Yeast Npl3 regulates replicative senescence outside of TERRA R-loop resolution and co-transcriptional processing.

Jennifer J Wanat, Jennifer J McCann, Mark Tingey, Jessica Atkins, Corinne O Merlino, Julia Y Lee-Soety.

  Eukaryotic cells without telomerase experience progressively shorter telomeres with each round of cell division until cell cycle arrest is initiated, leading to replicative senescence. When yeast TLC1, which encodes the RNA template of telomerase, is deleted, senescence is accompanied by increased expression of TERRA (non-coding telomere repeat-containing RNA). Deletion of Npl3, an RNA-processing protein with telomere maintenance functions, accelerates senescence in tlc1Δ cells and significantly increases TERRA levels. Using genetic approaches, we set out to determine how Npl3 is involved in regulating TERRA expression and maintaining telomere homeostasis. Even though Npl3 regulates hyperrecombination, we found that Npl3 does not help resolve RNA:DNA hybrids formed during TERRA synthesis in the same way as RNase H1 and H2. Furthermore, Rad52 is still required for cells to escape senescence by telomere recombination in the absence of Npl3. Npl3 also works separately from the THO/TREX pathway for processing nascent RNA for nuclear export. However, deleting Dot1, a histone methyltransferase involved in tethering telomeres to the nuclear periphery, rescued the accelerated senescence phenotype of npl3Δ cells. Thus, our study suggests that Npl3 plays an additional role in regulating cellular senescence outside of RNA:DNA hybrid resolution and co-transcriptional processing.

Keywords:  Dot1; Npl3; R-loops; RNA:DNA hybrids; TERRA; senescence; telomeres

DOI:  https://doi.org/10.1080/15257770.2024.2374023
Microb Cell Fact. 2024 Jul 10. 23(1): 196

Optimization of biotransformation processes of Camarosporium laburnicola to improve production yields of potent telomerase activators.

Melis Küçüksolak, Hasan Buğra Çoban, Erdal Bedir.

   BACKGROUND: Telomerase activators are promising agents for the healthy aging process and the treatment/prevention of short telomere-related and age-related diseases. The discovery of new telomerase activators and later optimizing their activities through chemical and biological transformations are crucial for the pharmaceutical sector. In our previous studies, several potent telomerase activators were discovered via fungal biotransformation, which in turn necessitated optimization of their production. It is practical to improve the production processes by implementing the design of experiment (DoE) strategy, leading to increased yield and productivity. In this study, we focused on optimizing biotransformation conditions utilizing Camarosporium laburnicola, a recently discovered filamentous fungus, to afford the target telomerase activators (E-CG-01, E-AG-01, and E-AG-02).
RESULTS: DoE approaches were used to optimize the microbial biotransformation processes of C. laburnicola. Nine parameters were screened by Plackett-Burman Design, and three significant parameters (biotransformation time, temperature, shaking speed) were optimized using Central Composite Design. After conducting validation experiments, we were able to further enhance the production yield of target metabolites through scale-up studies in shake flasks (55.3-fold for E-AG-01, 13-fold for E-AG-02, and 1.96-fold for E-CG-01).
CONCLUSION: Following a process optimization study using C. laburnicola, a significant increase was achieved in the production yields. Thus, the present study demonstrates a promising methodology to increase the production yield of potent telomerase activators. Furthermore, C. laburnicola is identified as a potential biocatalyst for further industrial utilization.

Keywords:  Anti-aging; Endophytic fungi; Process optimization; Telomerase activator; Whole-cell biotransformation

DOI:  https://doi.org/10.1186/s12934-024-02468-0
Anal Chem. 2024 Jul 08.

Activatable Fluorescent Probe for Studying Drug-Induced Senescence In Vitro and In Vivo.

Zihong Li, Ping Huang, Guoliang Wu, Weiying Lin.

Aging represents a significant risk factor for compromised tissue function and the development of chronic diseases in the human body. This process is intricately linked to oxidative stress, with HClO serving as a vital reactive oxygen species (ROS) within biological systems due to its strong oxidative properties. Hence, conducting a thorough examination of HClO in the context of aging is crucial for advancing the field of aging biology. In this work, we successfully developed a fluorescent probe, OPD, tailored specifically for detecting HClO in senescent cells and in vivo. Impressively, OPD exhibited a robust reaction with HClO, showcasing outstanding selectivity, sensitivity, and photostability. Notably, OPD effectively identified HClO in senescent cells for the first time, confirming that DOX- and ROS-induced senescent cells exhibited higher HClO levels compared to uninduced normal cells. Additionally, in vivo imaging of zebrafish demonstrated that d-galactose- and ROS-stimulated senescent zebrafish displayed elevated HClO levels compared to normal zebrafish. Furthermore, when applied to mouse tissues and organs, OPD revealed increased fluorescence in the organs of senescent mice compared to their nonsenescent counterparts. Our findings also illustrated the probe's potential for detecting changes in HClO content pre- and post-aging in living mice. Overall, this probe holds immense promise as a valuable tool for in vivo detection of HClO and for studying aging biology in live organisms.

DOI: https://doi.org/10.1021/acs.analchem.4c02423
Cells. 2024 Jul 02. pii: 1135. [Epub ahead of print]13(13):

The Role of PGC-1α in Aging Skin Barrier Function.

Yonghong Luo, Wendy B Bollag.

  Skin provides a physical and immune barrier to protect the body from foreign substances, microbial invasion, and desiccation. Aging reduces the barrier function of skin and its rate of repair. Aged skin exhibits decreased mitochondrial function and prolonged low-level inflammation that can be seen in other organs with aging. Peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC-1α), an important transcriptional coactivator, plays a central role in modulating mitochondrial function and antioxidant production. Mitochondrial function and inflammation have been linked to epidermal function, but the mechanisms are unclear. The aim of this review is to discuss the mechanisms by which PGC-1α might exert a positive effect on aged skin barrier function. Initially, we provide an overview of the function of skin under physiological and aging conditions, focusing on the epidermis. We then discuss mitochondrial function, oxidative stress, cellular senescence, and inflamm-aging, the chronic low-level inflammation observed in aging individuals. Finally, we discuss the effects of PGC-1α on mitochondrial function, as well as the regulation and role of PGC-1α in the aging epidermis.

Keywords:  aging; antioxidant defense; coactivator; epidermis; keratinocytes; melanocytes; mitochondria; permeability barrier; skin; wound healing

DOI:  https://doi.org/10.3390/cells13131135
PLoS One. 2024 ;19(7): e0305396

Mutations in fibulin-1 and collagen IV suppress the short healthspan of mig-17/ADAMTS mutants in Caenorhabditis elegans.

Yukimasa Shibata, Yijing Huang, Moeka Yoshida, Kiyoji Nishiwaki.

The ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) family metalloprotease MIG-17 plays a crucial role in the migration of gonadal distal tip cells (DTCs) in Caenorhabditis elegans. MIG-17 is secreted from the body wall muscle cells and localizes to the basement membranes (BMs) of various tissues including the gonadal BM where it regulates DTC migration through its catalytic activity. Missense mutations in the BM protein genes, let-2/collagen IV a2 and fbl-1/fibulin-1, have been identified as suppressors of the gonadal defects observed in mig-17 mutants. Genetic analyses indicate that LET-2 and FBL-1 act downstream of MIG-17 to regulate DTC migration. In addition to the control of DTC migration, MIG-17 also plays a role in healthspan, but not in lifespan. Here, we examined whether let-2 and fbl-1 alleles can suppress the age-related phenotypes of mig-17 mutants. let-2(k196) fully and fbl-1(k201) partly, but not let-2(k193) and fbl-1(k206), suppressed the senescence defects of mig-17. Interestingly, fbl-1(k206), but not fbl-1(k201) or let-2 alleles, exhibited an extended lifespan compared to the wild type when combined with mig-17. These results reveal allele specific interactions between let-2 or fbl-1 and mig-17 in age-related phenotypes, indicating that basement membrane physiology plays an important role in organismal aging.

DOI: https://doi.org/10.1371/journal.pone.0305396
bioRxiv. 2024 Jun 28. pii: 2024.06.23.600305. [Epub ahead of print]

Aging limits stemness and tumorigenesis in the lung by reprogramming iron homeostasis.

Xueqian Zhuang, Qing Wang, Simon Joost, Alexander Ferrena, David T Humphreys, Zhuxuan Li, Melissa Blum, Klavdija Bastl, Selena Ding, Yuna Landais, Yingqian Zhan, Yang Zhao, Ronan Chaligne, Joo-Hyeon Lee, Sebastian E Carrasco, Umeshkumar K Bhanot, Richard P Koche, Matthew J Bott, Pekka Katajisto, Yadira M Soto-Feliciano, Thomas Pisanic, Tiffany Thomas, Deyou Zheng, Emily S Wong, Tuomas Tammela.

Aging is associated with a decline in the number and fitness of adult stem cells 1-4 . Aging-associated loss of stemness is posited to suppress tumorigenesis 5,6 , but this hypothesis has not been tested in vivo . Here, using physiologically aged autochthonous genetically engineered mouse models and primary cells 7,8 , we demonstrate aging suppresses lung cancer initiation and progression by degrading stemness of the alveolar cell of origin. This phenotype is underpinned by aging-associated induction of the transcription factor NUPR1 and its downstream target lipocalin-2 in the cell of origin in mice and humans, leading to a functional iron insufficiency in the aged cells. Genetic inactivation of the NUPR1-lipocalin-2 axis or iron supplementation rescue stemness and promote tumorigenic potential of aged alveolar cells. Conversely, targeting the NUPR1- lipocalin-2 axis is detrimental to young alveolar cells via induction of ferroptosis. We find that aging-associated DNA hypomethylation at specific enhancer sites associates with elevated NUPR1 expression, which is recapitulated in young alveolar cells by inhibition of DNA methylation. We uncover that aging drives a functional iron insufficiency, which leads to loss of stemness and tumorigenesis, but promotes resistance to ferroptosis. These findings have significant implications for the therapeutic modulation of cellular iron homeostasis in regenerative medicine and in cancer prevention. Furthermore, our findings are consistent with a model whereby most human cancers initiate in young individuals, revealing a critical window for such cancer prevention efforts.

DOI: https://doi.org/10.1101/2024.06.23.600305
bioRxiv. 2024 Jun 25. pii: 2023.06.24.546372. [Epub ahead of print]

Histone chaperone HIRA, Promyelocytic Leukemia (PML) protein and p62/SQSTM1 coordinate to regulate inflammation during cell senescence.

Nirmalya Dasgupta, Xue Lei, Christina Huan Shi, Rouven Arnold, Marcos G Teneche, Karl N Miller, Adarsh Rajesh, Andrew Davis, Valesca Anschau, Alexandre R Campos, Rebecca Gilson, Aaron Havas, Shanshan Yin, Zong Ming Chua, Tianhui Liu, Jessica Proulx, Michael Alcaraz, Mohammed Iqbal Rather, Josue Baeza, David C Schultz, Kevin Y Yip, Shelley L Berger, Peter D Adams.

Cellular senescence, a stress-induced stable proliferation arrest associated with an inflammatory Senescence-Associated Secretory Phenotype (SASP), is a cause of aging. In senescent cells, Cytoplasmic Chromatin Fragments (CCFs) activate SASP via the anti-viral cGAS/STING pathway. PML protein organizes PML nuclear bodies (NBs), also involved in senescence and anti-viral immunity. The HIRA histone H3.3 chaperone localizes to PML NBs in senescent cells. Here, we show that HIRA and PML are essential for SASP expression, tightly linked to HIRA's localization to PML NBs. Inactivation of HIRA does not directly block expression of NF-κB target genes. Instead, an H3.3-independent HIRA function activates SASP through a CCF-cGAS-STING-TBK1-NF-κB pathway. HIRA physically interacts with p62/SQSTM1, an autophagy regulator and negative SASP regulator. HIRA and p62 co-localize in PML NBs, linked to their antagonistic regulation of SASP, with PML NBs controlling their spatial configuration. These results outline a role for HIRA and PML in regulation of SASP.

DOI: https://doi.org/10.1101/2023.06.24.546372
Aging (Albany NY). 2024 Jul 09. 16

Co-analysis of methylation platforms for signatures of biological aging in the domestic dog reveals previously unexplored confounding factors.

Aitor Serres Armero, Reuben M Buckley, Lajoyce Mboning, Gabriella J Spatola, Steve Horvath, Matteo Pellegrini, Elaine A Ostrander.

  Chronological age reveals the number of years an individual has lived since birth. By contrast, biological age varies between individuals of the same chronological age at a rate reflective of physiological decline. Differing rates of physiological decline are related to longevity and result from genetics, environment, behavior, and disease. The creation of methylation biological age predictors is a long-standing challenge in aging research due to the lack of individual pre-mortem longevity data. The consistent differences in longevity between domestic dog breeds enable the construction of biological age estimators which can, in turn, be contrasted with methylation measurements to elucidate mechanisms of biological aging. We draw on three flagship methylation studies using distinct measurement platforms and tissues to assess the feasibility of creating biological age methylation clocks in the dog. We expand epigenetic clock building strategies to accommodate phylogenetic relationships between individuals, thus controlling for the use of breed standard metrics. We observe that biological age methylation clocks are affected by population stratification and require heavy parameterization to achieve effective predictions. Finally, we observe that methylation-related markers reflecting biological age signals are rare and do not colocalize between datasets.

Keywords:  biological age; dog; lifespan; methylation; penalized regression

DOI:  https://doi.org/10.18632/aging.206012
Mech Ageing Dev. 2024 Jul 08. pii: S0047-6374(24)00063-0. [Epub ahead of print] 111963

A Mechanistic Analysis of Metformin's Biphasic Effects on Lifespan and Healthspan in C. elegans: Elixir in Youth, Poison in Elder.

Zhen-Zhen Yu, Jia-Jun Tu, Mei-Ling Ou, Jin-Xiong Cen, Kun Xue, Shao-Jun Li, Jing Zhou, Guo-Dong Lu.

  Aging, a complex biological process influenced by genetic, environmental, and pharmacological factors, presents a significant challenge in understanding its underlying mechanisms. In this study, we explored the divergent impacts of metformin treatment on the lifespan and healthspan of young and old C. elegans, demonstrating a intriguing "elixir in youth, poison in elder" phenomenon. By scrutinizing the gene expression changes in response to metformin in young (day 1 of adulthood) and old (days 8) groups, we identified nhr-57 and C46G7.1 as potential modulators of age-specific responses. Notably, nhr-57 and C46G7.1 exhibit contrasting regulation patterns, being up-regulated in young worms but down-regulated in old counterparts following metformin treatment. Functional studies employing knockdown approaches targeting nhr-57, a gene under the control of hif-1 with a documented protective function against pore-forming toxins in C. elegans, and C46G7.1, unveiled their critical roles in modulating lifespan and healthspan, as well as in mediating the biphasic effects of metformin. Furthermore, deletion of hif-1 retarded the influence of metformin, implicating the involvement of hif-1/nhr-57 in age-specific drug responses. These findings underscored the necessity of deciphering the mechanisms governing age-related susceptibility to pharmacological agents to tailor interventions for promoting successful aging.

Keywords:  Aging; Biphasic Effects; Lifespan; Metformin; Susceptibility

DOI:  https://doi.org/10.1016/j.mad.2024.111963
Biochemistry (Mosc). 2024 Jun;89(6): 1014-1023

Activity of DNA Repair Systems in the Cells of Long-Lived Rodents and Bats.

Aleksei A Popov, Irina O Petruseva, Olga I Lavrik.

  Damages of various origin accumulated in the genomic DNA can lead to the breach of genome stability, and are considered to be one of the main factors involved in cellular senescence. DNA repair systems in mammalian cells ensure effective damage removal and repair of the genome structure, therefore, activity of these systems is expected to be correlated with high maximum lifespan observed in the long-lived mammals. This review discusses current results of the studies focused on determination of the DNA repair system activity and investigation of the properties of its key regulatory proteins in the cells of long-lived rodents and bats. Based on the works discussed in the review, it could be concluded that the long-lived rodents and bats in general demonstrate high efficiency in functioning and regulation of DNA repair systems. Nevertheless, a number of questions around the study of DNA repair in the cells of long-lived rodents and bats remain poorly understood, answers to which could open up new avenues for further research.

Keywords:  DNA repair; cellular senescence; longevity; poly(ADP-ribose)polymerase 1; sirtuin 6

DOI:  https://doi.org/10.1134/S0006297924060038
Biogerontology. 2024 Jul 06.

Age-related decline in the expression of BRG1, ATM and ATR are partially reversed by dietary restriction in the livers of female mice.

Pynskhem Bok Swer, Babiangshisha Kharbuli, Donkupar Syiem, Ramesh Sharma.

  BRG1 (Brahma-related gene 1) is a member of the SWI/SNF (switch/sucrose nonfermentable) chromatin remodeling complex which utilizes the energy from ATP hydrolysis for its activity. In addition to its role of regulating the expression of a vast array of genes, BRG1 mediates DNA repair upon genotoxic stress and regulates senescence. During organismal ageing, there is accumulation of unrepaired/unrepairable DNA damage due to progressive breakdown of the DNA repair machinery. The present study investigates the expression level of BRG1 as a function of age in the liver of 5- and 21-month-old female mice. It also explores the impact of dietary restriction on BRG1 expression in the old (21-month) mice. Salient findings of the study are: Real-time PCR and Western blot analyses reveal that BRG1 levels are higher in 5-month-old mice but decrease significantly with age. Dietary restriction increases BRG1 expression in the 21-month-old mice, nearly restoring it to the level observed in the younger group. Similar expression patterns are observed for DNA damage response genes ATM (Ataxia Telangiectasia Mutated) and ATR (Ataxia Telangiectasia and Rad3-related) with the advancement in age and which appears to be modulated by dietary restriction. BRG1 transcriptionally regulates ATM as a function of age and dietary restriction. These results suggest that BRG1, ATM and ATR are downregulated as mice age, and dietary restriction can restore their expression. This implies that dietary restriction may play a crucial role in regulating BRG1 and related gene expression, potentially maintaining liver repair and metabolic processes as mice age.

Keywords:  Ageing; BRG1; Dietary restriction; Epigenetics; Liver; Mice

DOI:  https://doi.org/10.1007/s10522-024-10117-7
Aging Med (Milton). 2024 Jun;7(3): 320-327

A hypothesis: MiRNA-124 mediated regulation of sirtuin 1 and vitamin D receptor gene expression accelerates aging.

Poulami Dhar, Shailaja Moodithaya, Prakash Patil, Kellarai Adithi.

   Objectives: Specific miRNAs are evident to be overexpressed with age, lifestyle, and environmental changes. Previous studies reported miR-124 overexpression in different scenarios in aged skin, age-related cognitive impairment, ischemic heart disease, muscle atrophy, and fractures. Thus miR-124 was considered to be a reliable miRNA target to establish a hypothesis on aging epigenome. Parallelly the hypothesis focuses on the expression of SIRT1 and VDR genes as a target for this specific miRNA expression as these genes were believed to be related to aging. This study aims to derive facts and evidence from past studies on aging. The objective was to establish a hypothetical linkage between miR-124 with age-related genes like SIRT1 and VDR.
Methods: An in silico search was performed in the TargetScan and miRbase databases to analyze the aging-associated miRNAs and their gene targets, the Python seaborn library was used, and the results were represented in terms of a bar plot.
Results: Based on an in silico analysis and studies available in the literature, we identified that miR-124-3p.1 and miR-124-3p.2 targets 3' UTR of VDR and SIRT1 genes, and hence thereby indicates that the miR-124 can regulate the expression of these genes. Further, few in vitro research studies have observed that miR-124 overexpression leads to the downregulation of VDR and SIRT1 gene expression. These results indicate that the suppression of these target genes accelerates early aging and age-related disorders.
Conclusions: Overall, this study hypothesizes that the overexpression of miR-124 diminishes the expression of VDR and SIRT1 genes, and thereby advances the process of aging, resulting in the development of age-associated complications.

Keywords:  SIRT1; VDR; aging; epigenetics; microRNA

DOI:  https://doi.org/10.1002/agm2.12330