bims-caglex Biomed News
on Cellular aging and life extension
Issue of 2024–10–13
forty-six papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño
  1. Mapping epidermal and dermal cellular senescence in human skin aging.
  2. Gut aging: A wane from the normal to repercussion and gerotherapeutic strategies.
  3. Diet and longevity.
  4. Dietary restriction can extend lifespan - but genetics matters more.
  5. Exploring the Therapeutic Potential of Green Tea (Camellia sinensis L.) in Anti-Aging: A Comprehensive Review of Mechanisms and Findings.
  6. Hippocampal rejuvenation by a single intracerebral injection of one-carbon metabolites in C57BL6 old wild-type mice.
  7. Polyphenols in bee products and prevention of cell senescence.
  8. Nicotinamide Adenine Dinucleotide (NAD)-Dependent Protein Deacetylase, Sirtuin, as a Biomarker of Healthy Life Expectancy: A Mini-Review.
  9. Stochasticity in Dietary Restriction-Mediated Lifespan Outcomes in Drosophila.
  10. Aging: Disease or "natural" process? A glimpse from regenerative medicine.
  11. A new model and precious tool to study molecular mechanisms of macrophage aging.
  12. Amodiaquine ameliorates stress-induced premature cellular senescence via promoting SIRT1-mediated HR repair.
  13. CaMKIIα-TARPγ8 signaling mediates hippocampal synaptic impairment in aging.
  14. Genetic Signature of a Healthy Lifestyle: New Horizons for Preventing Noncommunicable Chronic Diseases by Modulating MicroRNA-155.
  15. Fisetin as a Senotherapeutic Agent: Evidence and Perspectives for Age-Related Diseases.
  16. The Nrf2-HO-1 system and inflammaging.
  17. Inherited Telomere Biology Disorders: Pathophysiology, Clinical Presentation, Diagnostics, and Treatment.
  18. Pythia: Non-random DNA repair allows predictable CRISPR/Cas9 integration and gene editing.
  19. Contextualizing aging clocks and properly describing biological age.
  20. Biological constraint, evolutionary spandrels and antagonistic pleiotropy.
  21. Brown adipose tissue: a potential target for aging interventions and healthy longevity.
  22. GABA, Aging and Exercise: Functional and Intervention Considerations.
  23. Insidious chromatin change with a propensity to exhaust intestinal stem cells during aging.
  24. Dietary restriction impacts health and lifespan of genetically diverse mice.
  25. Aged gut microbiota promotes arrhythmia susceptibility via oxidative stress.
  26. Use of paired Cas9-NG nickase and truncated sgRNAs for single-nucleotide microbial genome editing.
  27. Spermidine supplementation influence on protective enzymes of Apis mellifera (Hymenoptera: Apidae).
  28. Oxidative stress and senescence in aging kidneys: the protective role of SIRT1.
  29. Histone lysine methylation modifiers controlled by protein stability.
  30. Functional significance of earthworm clitellum in regulating the various biological aspects of cell survival and regeneration.
  31. Visualization of Type IV-A1 CRISPR-mediated repression of gene expression and plasmid replication.
  32. High-resolution and programmable RNA-IN and RNA-OUT genetic circuit in living mammalian cells.
  33. MicroRNAs won the Nobel - will they ever be useful as medicines?
  34. Comparative evaluation of the osteogenic capacity of second-generation platelet concentrates on dental pulp stem cells - An ex vivo study.
  35. Characterization of argonaute nucleases from mesophilic bacteria Pseudobutyrivibrio ruminis.
  36. Structural extracellular matrix-mediated molecular signaling in wound repair and tissue regeneration.
  37. A model for transcription-dependent R-loop formation at double-stranded DNA breaks: Implications for their detection and biological effects.
  38. Rejuvenation of human mesenchymal stem cells using a nonintegrative and conditionally removable Sendai virus vector.
  39. Polypharmacy and Therapeutic Inertia in Extreme Longevity: A Potential Clinical Ageism Scenario Secondary to Important Gaps in Clinical Evidence.
  40. The brain-body energy conservation model of aging.
  41. Medicine Nobel awarded for gene-regulating 'microRNAs'.
  42. Transcriptome profiling of DPP stimulated DPSCs identifies the role of autophagy in odontogenic differentiation.
  43. Clinical vs. chronological skin age: exploring determinants and stratum corneum protein markers of differential skin ageing in 351 healthy women.
  44. There are multiple clocks that time us: Cross-sectional and longitudinal associations among 14 alternative indicators of age and aging.
  45. A plasma proteomic signature links secretome of senescent monocytes to aging- and obesity-related clinical outcomes in humans.
  46. Systemic deficits in lipid homeostasis promote aging-associated impairments in B cell progenitor development.
  1. Aging Cell. 2024 Oct 06. e14358
    Mapping epidermal and dermal cellular senescence in human skin aging.
    Grace T Yu, Clarisse Ganier, David B Allison, Tamara Tchkonia, Sundeep Khosla, James L Kirkland, Magnus D Lynch, Saranya P Wyles.
      Single-cell RNA sequencing and spatial transcriptomics enable unprecedented insight into cellular and molecular pathways implicated in human skin aging and regeneration. Senescent cells are individual cells that are irreversibly cell cycle arrested and can accumulate across the human lifespan due to cell-intrinsic and -extrinsic stressors. With an atlas of single-cell RNA-sequencing and spatial transcriptomics, epidermal and dermal senescence and its effects were investigated, with a focus on melanocytes and fibroblasts. Photoaging due to ultraviolet light exposure was associated with higher burdens of senescent cells, a sign of biological aging, compared to chronological aging. A skin-specific cellular senescence gene set, termed SenSkin™, was curated and confirmed to be elevated in the context of photoaging, chronological aging, and non-replicating CDKN1A+ (p21) cells. In the epidermis, senescent melanocytes were associated with elevated melanin synthesis, suggesting haphazard pigmentation, while in the dermis, senescent reticular dermal fibroblasts were associated with decreased collagen and elastic fiber synthesis. Spatial analysis revealed the tendency for senescent cells to cluster, particularly in photoaged skin. This work proposes a strategy for characterizing age-related skin dysfunction through the lens of cellular senescence and suggests a role for senescent epidermal cells (i.e., melanocytes) and senescent dermal cells (i.e., reticular dermal fibroblasts) in age-related skin sequelae.
    Keywords:  cellular senescence; dermis; epidermis; single‐cell gene expression analysis; skin aging; skin pathology; spatial analysis
    DOI:  https://doi.org/10.1111/acel.14358
  2. Heliyon. 2024 Oct 15. 10(19): e37883
    Gut aging: A wane from the normal to repercussion and gerotherapeutic strategies.
    Joseph K Abankwah, Ying Wang, Jida Wang, Susan Enechojo Ogbe, Lisa Dal Pozzo, XiaoQian Chu, YuHong Bian.
      Globally, age-related diseases represent a significant public health concern among the elderly population. In aging, healthy organs and tissues undergo structural and functional changes that put the aged adults at risk of diseases. Some of the age-related diseases include cancer, atherosclerosis, brain disorders, muscle atrophy (sarcopenia), gastrointestinal (GIT) disorders, etc. In organs, a decline in stem cell function is the starting point of many conditions and is extremely important in GIT disorder development. Many studies have established that aging affects stem cells and their surrounding supportive niche components. Although there is a significant advancement in treating intestinal aging, the rising elderly population coupled with a higher occurrence of chronic gut ailments necessitates more effective therapeutic approaches to preserve gut health. Notable therapeutic strategies such as Western medicine, traditional Chinese medicine, and other health-promotion interventions have been reported in several studies to hold promise in mitigating age-related gut disorders. This review highlights findings across various facets of gut aging with a focus on aging-associated changes of intestinal stem cells and their niche components, thus a deviation from the normal to repercussion, as well as essential therapeutic strategies to mitigate intestinal aging.
    Keywords:  Aging; Intestine; Niche components and gero-therapies; Stem cell
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e37883
  3. Nat Cell Biol. 2024 Oct;26(10): 1629
    Diet and longevity.
    Melina Casadio.
      
    DOI:  https://doi.org/10.1038/s41556-024-01535-3
  4. Nature. 2024 Oct 09.
    Dietary restriction can extend lifespan - but genetics matters more.
    Nicholas J Schork.
      
    Keywords:  Ageing; Immunology; Metabolism; Nutrition
    DOI:  https://doi.org/10.1038/d41586-024-03055-4
  5. Mini Rev Med Chem. 2024 Oct 04.
    Exploring the Therapeutic Potential of Green Tea (Camellia sinensis L.) in Anti-Aging: A Comprehensive Review of Mechanisms and Findings.
    Bhagavathi Sundaram Sivamaruthi, Natarajan Sisubalan, Shucai Wang, Periyanaina Kesika, Chaiyavat Chaiyasut.
      Green tea (GT) is rich in Phyto-active compounds such as epigallocatechin gallate (EGCG), epigallocatechin (EGC), epicatechin gallate (ECG), epicatechin (EC), catechin, and tannic acid, which exhibit synergistic effects when combined. Preclinical studies demonstrate that GT and its compounds can reduce reactive oxygen species (ROS), enhance antioxidant capacity, and alleviate aging-related issues such as memory impairments, cognitive decline, and shortened lifespan. Clinical trials corroborate the efficacy of topical GT formulations in improving skin tone, texture, and elasticity and reducing wrinkles. The present manuscript summarizes the recent update on the anti-aging potential of GT and its possible mechanisms. The literature survey suggested that GT consumption is linked to improved cognition, reduced depression levels, and activation of pathways in model organisms like C. elegans. Additionally, tea polyphenols enhance fibroblast mitophagy, boost hippocampal synaptic plasticity in rodents, and mitigate age-related cognitive decline. Moreover, EGCG exhibits anti-aging properties by reducing TNF-induced MMP-1 expression, suppressing ERK signaling, and inhibiting MEK and Src phosphorylation in human dermal fibroblasts. In the context of skin permeation and deposition, optimized transpersonal formulation (TF) incorporating EGCG and hyaluronic acid (HA) demonstrated significantly increased skin permeation and deposition of EGCG compared to plain EGCG. Furthermore, EGCG protects cardiomyocytes via the PPARγ pathway and combats age-related muscle loss through miRNA-486-5p regulation, AKT activation, and FoxO1a-mediated expression of MuRF1 and Atrogin-1. In conclusion, the regular consumption of GT holds promise for promoting physical and mental health, delaying brain and skin aging, and improving overall health by enhancing total antioxidant capacity.
    Keywords:  Epigallocatechin gallate; anti-aging; brain and skin aging; memory impairments; mental health
    DOI:  https://doi.org/10.2174/0113895575331878240924035332
  6. Aging Cell. 2024 Oct 08. e14365
    Hippocampal rejuvenation by a single intracerebral injection of one-carbon metabolites in C57BL6 old wild-type mice.
    Alejandro Antón-Fernández, Rocío Peinado Cauchola, Félix Hernández, Jesús Ávila.
      The Izpisua-Belmonte group identified a cocktail of metabolites that promote partial reprogramming in cultured muscle cells. We tested the effect of brain injection of these metabolites in the dentate gyrus of aged wild-type mice. The dentate gyrus is a brain region essential for memory function and is extremely vulnerable to aging. A single injection of the cocktail containing four compounds (putrescine, glycine, methionine and threonine) partially reversed brain aging phenotypes and epigenetic alterations in age-associated genes. Our analysis revealed three levels: chromatin methylation, RNA sequencing, and protein expression. Functional studies complemented the previous ones, showing cognitive improvement. In summary, we report the reversal of various age-associated epigenetic changes, such as the transcription factor Zic4, and several changes related to cellular rejuvenation in the dentate gyrus (DG). These changes include increased expression of the Sox2 protein. Finally, the increases in the survival of newly generated neurons and the levels of the NMDA receptor subunit GluN2B were accompanied by improvements in both short-term and long-term memory performance. Based on these results, we propose the use of these metabolites to explore new strategies for the development of potential treatments for age-related brain diseases.
    Keywords:  adult neurogenesis; aging; cellular partial reprogramming; epigenetic clock; epigenetics; improved cognition; one‐carbon metabolites; transcription factors
    DOI:  https://doi.org/10.1111/acel.14365
  7. Biomedicine (Taipei). 2024 ;14(3): 1-11
    Polyphenols in bee products and prevention of cell senescence.
    Siti Nuriah M Noor, Marahaini Musa, Ahmad Azlina, Siew H Gan, Kannan P Thirumulu.
      Sustaining the continuity of cells and their homeostasis throughout the lifespan is compulsory for the survival of an organism. Cellular senescence is one of mechanisms involved in cell homeostasis and survival, and plays both important and detrimental roles in the maintenance of malfunctioned and normal cells. However, when exposed to various insults (genetic, metabolic and environmental), the cells undergo oxidative stress which may induce premature senescence, or so-called stress-induced premature senescence. Many age-related diseases are associated with premature senescence. Hence, there is growing interest in the intake of natural sources such as dietary food, which has protective functions on human health and diseases as well as on premature senescence. There are many natural food sources which have beneficial effects on delaying cell senescence, of which bee products are one of them. Bee products (honey, propolis, royal jelly, bee pollen, bee bread, venom and wax) are rich in polyphenols, a compound that exerts powerful antioxidant actions against oxidative stress and is able to delay premature senescence that is linked to ageing. This review describes the factors triggering senescence, the biomarkers involved and the prevention of senescence by the polyphenols present in bee products. Thus, it is hoped that this will provide new insights into the clinical management of age-related diseases.
    Keywords:  Ageing; Antioxidant; Bee products; Cell senescence; Polyphenols
    DOI:  https://doi.org/10.37796/2211-8039.1458
  8. Curr Aging Sci. 2024 Oct 04.
    Nicotinamide Adenine Dinucleotide (NAD)-Dependent Protein Deacetylase, Sirtuin, as a Biomarker of Healthy Life Expectancy: A Mini-Review.
    Yodo Sugishita, Yuki Suzuki-Takahashi, Kazuo Yudoh.
      Although a variety of disease-specific biomarkers have been identified for common lifestyle- or aging-related diseases, there are currently no indices available to measure general health or the existence of pre-symptomatic conditions in various types of tissue and organ damage. A rising body of research suggests that sirtuins may have the potential to be used as an index to assess overall health status and the existence of pre-symptomatic illness states. Sirtuins (SIRTs) are nicotinamide adenine dinucleotide (NAD)-dependent deacetylases expressed in a variety of human somatic cells both in health and disease conditions. The activity and expression of SIRTs affect important metabolic pathways, such as cell survival, senescence, proliferation, energy production, stress tolerance, DNA repair, and apoptosis, thereby closely linked to aging and longevity. Given the broad significance of SIRTs in physiological function maintenance, their activity in somatic cells may reflect the early cross-sectional status of tissue damage caused by aging or systemic inflammatory responses that are too early to be detected by disease-specific biomarkers. In this mini-review, we discuss the utility of SIRTs as a surrogate clinical biomarker for health status to evaluate and monitor health life expectancy and the presence of pre-symptomatic illness states.
    Keywords:  Aging; healthy life expectancy biomarkers; sirtuin.; surrogate markers
    DOI:  https://doi.org/10.2174/0118746098319674240827104612
  9. Res Sq. 2024 Sep 17. pii: rs.3.rs-4876799. [Epub ahead of print]
    Stochasticity in Dietary Restriction-Mediated Lifespan Outcomes in Drosophila.
    Yang Lyu, Olivia Mosley, Joel Villa, Advaitha Kamalakkannan, Eliyashaib James, Jessica Hoffman.
      Dietary restriction (DR) is widely considered to be one of the most potent approaches to extend healthy lifespan across various species, yet it has become increasingly apparent that DR-mediated longevity is influenced by biological and non-biological factors. We propose that current priorities in the field should include understanding the relative contributions of these factors to elucidate the mechanisms underlying the beneficial effects of DR. Our work conducted in two laboratories, represents an attempt to unify DR protocols in Drosophila and to investigate the stochastic effects of DR. Across 64 pairs of survival data (DR/ad libitum, or AL), we find that DR does not universally extend lifespan. Specifically, we observed that DR conferred a significant lifespan extension in only 26.7% (17/64) of pairs. Our pooled data show that the overall lifespan difference between DR and AL groups is statistically significant, but the median lifespan increase under DR (7.1%) is small. The effects of DR were overshadowed by stochastic factors and genotype. Future research efforts directed toward gaining a comprehensive understanding of DR-dependent mechanisms should focus on unraveling the interactions between genetic and environmental factors. This is essential for developing personalized healthspan-extending interventions and optimizing dietary recommendations for individual genetic profiles.
    DOI:  https://doi.org/10.21203/rs.3.rs-4876799/v1
  10. Rev Esp Geriatr Gerontol. 2024 Oct 05. pii: S0211-139X(24)00077-5. [Epub ahead of print]60(1): 101543
    Aging: Disease or "natural" process? A glimpse from regenerative medicine.
    Francisco Sotomayor-Lugo, Nataly Iglesias-Barrameda, Imilla Casado-Hernandez, Carlos Agustin Villegas-Valverde, Yendry Ventura-Carmenate, Rene Antonio Rivero-Jimenez.
      We explore aging as a global phenomenon, questioning whether it constitutes a treatable condition or follows a natural course. Acknowledging its multifactorial nature, we delve into the challenges and opportunities inherent in this intricate biological process. The inclusion of old age in the 11th International Classification of Diseases sparks debate, categorizing it as a disease based on mechanistic explanations, blood-based biomarkers, and anti-aging products. Ethical dilemmas arise, emphasizing the difficulty of defining the transition from normal to pathological states during this process. We suggest that aging should be regarded as a treatable condition without necessarily labeling it a 'disease.' While anti-aging research unveils promising interventions like Metformin, Rapamycin, and cellular therapy, achieving biological immortality remains a formidable challenge. The future promises to prolong life and enhance quality by comprehensively understanding aging's implications for human health.
    Keywords:  Aging; Células madre; Envejecimiento; Medicina regenerativa; Regenerative medicine; Stem cells
    DOI:  https://doi.org/10.1016/j.regg.2024.101543
  11. Aging (Albany NY). 2024 Oct 03. 16
    A new model and precious tool to study molecular mechanisms of macrophage aging.
    Rémy Smith, Kévin Bassand, Ashok Dussol, Christophe Piesse, Eric Duplus, Khadija El Hadri.
      The accumulation of senescent cells, characterized by a senescence-associated secretory phenotype (SASP), contributes to chronic inflammation and age-related diseases (ARD). During aging, macrophages can adopt a senescent-like phenotype and an altered function, which promotes senescent cell accumulation. In the context of aging and ARD, controlling the resolution of the inflammatory response and preventing chronic inflammation, especially by targeting macrophages, must be a priority. Aging being a dynamic process, we developed a model of in vitro murine peritoneal macrophage aging. Our results show that macrophages cultured for 7 or 14 days exhibit a senescence-like phenotype: proliferation decrease, the levels of cyclin-dependent kinase inhibitors p16INK4A and p21CIP1 and of pro-inflammatory SASP components (MCP-1, IL-6, IL-1β, TNF-α, and MMP-9) increase, phagocytosis capacity decline and glycolytic activity is induced. In our model, chronic treatment with CB3, a thioredoxin-1 mimetic anti-inflammatory peptide, completely prevents p21CIP1 increase and enables day 14 macrophages to maintain proliferative activity.We describe a new model of macrophage aging with a senescence-like phenotype associated with inflammatory, metabolic and functional perturbations. This model is a valuable tool for characterizing macrophage aging mechanisms and developing innovative strategies with promising therapeutical purpose in limiting inflammaging and ARD.
    Keywords:  aging; inflammation; macrophage; senescence; thioredoxin-1 mimetic peptide
    DOI:  https://doi.org/10.18632/aging.206124
  12. Cell Death Discov. 2024 Oct 11. 10(1): 434
    Amodiaquine ameliorates stress-induced premature cellular senescence via promoting SIRT1-mediated HR repair.
    Jie Du, Fuqiang Chen, Chenghong Du, Wenna Zhao, Zihan Chen, Zhenhua Ding, Meijuan Zhou.
      DNA damage is considered to be a potentially unifying driver of ageing, and the stalling of DNA damage repair accelerates the cellular senescence. However, augmenting DNA repair has remained a great challenge due to the intricate repair mechanisms specific for multiple types of lesions. Herein, we miniaturized our modified detecting system for homologous recombination (HR) into a 96-well-based platform and performed a high-throughput chemical screen for FDA-approved drugs. We uncovered that amodiaquine could significantly augment HR repair at the noncytotoxic concentration. Further experiments demonstrated that amodiaquine remarkably suppressed stress-induced premature cellular senescence (SIPS), as evidenced by senescence-associated beta-galactosidase (SA-β-gal) staining or senescence-related markers p21WAF1 and p16ink4a, and the expression of several cytokines. Mechanistic studies revealed that the stimulation of HR repair by amodiaquine might be mostly attributable to the promotion of SIRT1 at the transcriptional level. Additionally, SIRT1 depletion abolished the amodiaquine-mediated effects on DNA repair and cellular senescence, indicating that amodiaquine delayed the onset of SIPS via a SIRT1-dependent pathway. Taken together, this experimental approach paved the way for the identification of compounds that augment HR activity, which could help to underscore the therapeutic potential of targeting DNA repair for treating aging-related diseases.
    DOI:  https://doi.org/10.1038/s41420-024-02201-1
  13. Aging Cell. 2024 Oct 08. e14349
    CaMKIIα-TARPγ8 signaling mediates hippocampal synaptic impairment in aging.
    Zhao JianHua, MingCan Li, Qilin Hu, Peter Donoghue, Sanwei Jiang, Junmei Li, Songji Li, Xinyi Ren, Ziyuan Zhang, Jingzhi Du, Yi Yu, Paul Chazot, Chengbiao Lu.
      Aging-related decline in memory and synaptic function are associated with the dysregulation of calcium homeostasis, attributed to the overexpression of voltage-gated calcium channels (VGCC). The membrane insertion of AMPAR governed by the AMPAR auxiliary proteins is essential for synaptic transmission and plasticity (LTP). In this study, we demonstrated the hippocampal expression of the transmembrane AMPAR regulatory proteins γ-8 (TARPγ8) was reduced in aged mice along with the reduced CaMKIIα activity and memory impairment. We further showed that TARPγ8 expression was dependent on CaMKIIα activity. Inhibition of CaMKIIα activity significantly reduced the hippocampal TARPγ8 expression and CA3-CA1 LTP in young mice to a similar level to that of the aged mice. Furthermore, the knockdown of hippocampal TARPγ8 impaired LTP and memory in young mice, which mimicked the aging-related changes. We confirmed the enhanced hippocampal VGCC (Cav-1.3) expression in aged mice and found that inhibition of VGCC activity largely increased both p-CaMKIIα and TARPγ8 expression in aged mice, whereas inhibition of NMDAR or Calpains had no effect. In addition, we found that the exogenous expression of human TARPγ8 in the hippocampus in aged mice restored LTP and memory function. Collectively, these results indicate that the synaptic and cognitive impairment in aging is associated with the downregulation of CaMKIIα-TARPγ8 signaling caused by VGCC activation. Our results suggest that TARPγ8 may be a key molecular biomarker for brain aging and that boosting CaMKIIα-TARPγ8 signaling may be critical for the restoration of synaptic plasticity of aging and aging-related diseases.
    Keywords:  CaMKIIα; LTP; TARPγ8; VGCC; aging; hippocampus
    DOI:  https://doi.org/10.1111/acel.14349
  14. Nutr Rev. 2024 Oct 09. pii: nuae142. [Epub ahead of print]
    Genetic Signature of a Healthy Lifestyle: New Horizons for Preventing Noncommunicable Chronic Diseases by Modulating MicroRNA-155.
    Karen S Coutinho-Wolino, Michele L Brito, Pricilla C Trigueira, Larissa O de Menezes, Clara S do Nascimento, Milena B Stockler-Pinto.
      The development and progression of several noncommunicable diseases (NCDs) are associated with microRNA (miR) 155 (miR-155) activation, which promotes inflammation and oxidative stress. In particular, miR-155 regulates nuclear transcription factor-kappa B (NF-κB) by silencing gene expression of proteins involved in NF-κB suppression, such as suppressor of cytokine signaling 1 (SOCS1) and SH-2 containing inositol 5' polyphosphate 1 (SHIP1), increases the production of reactive oxygen species, and suppresses gene expression of antioxidant enzymes through nuclear factor erythroid 2-related factor 2 (Nrf2) inhibition. In this context, a healthy lifestyle based on a diet rich in nutrients and bioactive compounds as well as regular physical activity may modulate the activity of several miRs. Following this concept, studies involving nutrients, bioactive compounds, and physical activity have been developed to modulate miR-155 activation. This narrative review aims to discuss how a healthy lifestyle based on a diet rich in nutrients, bioactive compounds, and physical activity may modulate the miR-155 pathway and consequently prevent the development and progression of NCDs. Nutrients and bioactive compounds from food may act by inhibiting pathways that promote miR-155 activation such as NF-κB and promote activation of pathways that are associated with the downregulation of miR-155, such as Nrf2, and SOCS1 pathways. Regular physical activity also seems to influence miR-155 levels through an improvement in the immune system during muscle recovery. There is relevant evidence that shows a positive effect of nutrients, bioactive compounds, and physical activity with the modulation of miR-155, which can potentially provide benefits in the clinical setting in cases of NCDs.
    Keywords:  bioactive compounds; miR-155; noncommunicable diseases; nutrients; physical activity
    DOI:  https://doi.org/10.1093/nutrit/nuae142
  15. Mech Ageing Dev. 2024 Oct 07. pii: S0047-6374(24)00095-2. [Epub ahead of print] 111995
    Fisetin as a Senotherapeutic Agent: Evidence and Perspectives for Age-Related Diseases.
    Juliette Tavenier, Jan O Nehlin, Morten Baltzer Houlind, Lene Juel Rasmussen, Tamara Tchkonia, James L Kirkland, Ove Andersen, Line Jee Hartmann Rasmussen.
      Fisetin, a flavonoid naturally occurring in plants, fruits, and vegetables, has recently gained attention for its potential role as a senotherapeutic agent for the treatment of age-related chronic diseases. Senotherapeutics target senescent cells, which accumulate with age and disease, in both circulating immune cell populations and solid organs and tissues. Senescent cells contribute to development of many chronic diseases, primarily by eliciting systemic chronic inflammation through their senescence-associated secretory phenotype. Here, we explore whether fisetin as a senotherapeutic can eliminate senescent cells, and thereby alleviate chronic diseases, by examining current evidence from in vitro studies and animal models that investigate fisetin's impact on age-related diseases, as well as from phase I/II trials in various patient populations. We discuss the application of fisetin in humans, including challenges and future directions. Our review of available data suggests that targeting senescent cells with fisetin offers a promising strategy for managing multiple chronic diseases, potentially transforming future healthcare for older and multimorbid patients. However, further studies are needed to establish the safety, pharmacokinetics, and efficacy of fisetin as a senotherapeutic, identify relevant and reliable outcome measures in human trials, optimize dosing, and better understand the possible limitations of fisetin as a senotherapeutic agent.
    Keywords:  Cellular senescence; SASP; aging; inflammation; multimorbidity
    DOI:  https://doi.org/10.1016/j.mad.2024.111995
  16. Front Immunol. 2024 ;15 1457010
    The Nrf2-HO-1 system and inflammaging.
    Sinead A O'Rourke, Lianne C Shanley, Aisling Dunne.
      Nrf2 is a master transcriptional regulator of a number of genes involved in the adaptive response to oxidative stress. Among the genes upregulated by Nrf2, heme oxygenase-1 (HO-1) has received significant attention, given that the products of HO-1-induced heme catabolism have well established antioxidant and anti-inflammatory properties. This is evidenced in numerous models of inflammatory and autoimmune disease whereby induction of HO-1 expression or administration of tolerable amounts of HO-1 reaction products can ameliorate disease symptoms. Unsurprisingly, Nrf2 and HO-1 are now considered viable drug targets for a number of conditions. In recent years, the term 'inflammaging' has been used to describe the low-grade chronic inflammation observed in aging/aged cells. Increased oxidative stress is also a key factor associated with aging and there is convincing evidence that Nrf2, not only declines with age, but that Nrf2 and HO-1 can reduce cellular senescence and the senescence-associated secretory phenotype (SASP) which is now considered an underlying driver of age-related inflammatory disease. In this review, we describe the role of oxidative stress in 'inflammaging' and highlight the potential anti-aging properties of the Nrf2-HO-1 system. We also highlight established and newly emerging Nrf2 activators and their therapeutic application in age-related disease.
    Keywords:  Nrf2; aging; heme oxygenase; inflammaging; oxidative stress
    DOI:  https://doi.org/10.3389/fimmu.2024.1457010
  17. Transfus Med Hemother. 2024 Oct;51(5): 292-309
    Inherited Telomere Biology Disorders: Pathophysiology, Clinical Presentation, Diagnostics, and Treatment.
    Benjamin Rolles, Mareike Tometten, Robert Meyer, Martin Kirschner, Fabian Beier, Tim H Brümmendorf.
       Background: Telomeres are the end-capping structures of all eukaryotic chromosomes thereby protecting the genome from damage and degradation. During the aging process, telomeres shorten continuously with each cell division until critically short telomeres prevent further proliferation whereby cells undergo terminal differentiation, senescence, or apoptosis. Premature aging due to critically short telomere length (TL) can also result from pathogenic germline variants in the telomerase complex or related genes that typically counteract replicative telomere shortening in germline and certain somatic cell populations, e.g., hematopoetic stem cells. Inherited diseases that result in altered telomere maintenance are summarized under the term telomere biology disorder (TBD).
    Summary: Since TL both reflects but more importantly restricts the replicative capacity of various human tissues, a sufficient telomere reserve is particularly important in cells with high proliferative activity (e.g., hematopoiesis, immune cells, intestinal cells, liver, lung, and skin). Consequently, altered telomere maintenance as observed in TBDs typically results in premature replicative cellular exhaustion in the respective organ systems eventually leading to life-threatening complications such as bone marrow failure (BMF), pulmonary fibrosis, and liver cirrhosis.
    Key Messages: The recognition of a potential congenital origin in approximately 10% of adult patients with clinical BMF is of utmost importance for the proper diagnosis, appropriate patient and family counseling, to prevent the use of inefficient treatment and to avoid therapy-related toxicities including appropriate donor selection when patients have to undergo stem cell transplantation from related donors. This review summarizes the current state of knowledge about TBDs with particular focus on the clinical manifestation patterns in children (termed early onset TBD) compared to adults (late-onset TBD) including typical treatment- and disease course-related complications as well as their prognosis and adequate therapy. Thereby, it aims to raise awareness for a disease group that is currently still highly underdiagnosed particularly when it first manifests itself in adulthood.
    Keywords:  Dyskeratosis congenita; Telomere biology disorders; Telomeres; Telomeropathies
    DOI:  https://doi.org/10.1159/000540109
  18. bioRxiv. 2024 Sep 23. pii: 2024.09.23.614424. [Epub ahead of print]
    Pythia: Non-random DNA repair allows predictable CRISPR/Cas9 integration and gene editing.
    Thomas Naert, Taiyo Yamamoto, Shuting Han, Melanie Horn, Phillip Bethge, Nikita Vladimirov, Fabian F Voigt, Joana Figueiro-Silva, Ruxandra Bachmann-Gagescu, Fritjof Helmchen, Soeren S Lienkamp.
      CRISPR-based genome engineering holds enormous promise for basic science and therapeutic applications. Integrating and editing DNA sequences is still challenging in many cellular contexts, largely due to insufficient control of the repair process. We find that repair at the genome-cargo interface is predictable by deep-learning models and adheres to sequence context specific rules. Based on in silico predictions, we devised a strategy of triplet base-pair repeat repair arms that correspond to microhomologies at double-strand breaks (trimologies), which facilitated integration of large cargo (>2 kb) and protected the targeted locus and transgene from excessive damage. Successful integrations occurred in >30 loci in human cells and in in vivo models. Germline transmissible transgene integration in Xenopus , and endogenous tagging of tubulin in adult mice brains demonstrated integration during early embryonic cleavage and in non-dividing differentiated cells. Further, optimal repair arms for single- or double nucleotide edits were predictable, and facilitated small edits in vitro and in vivo using oligonucleotide templates. We provide a design-tool (Pythia, pythia-editing.org ) to optimize custom integration, tagging or editing strategies. Pythia will facilitate genomic integration and editing for experimental and therapeutic purposes for a wider range of target cell types and applications.
    DOI:  https://doi.org/10.1101/2024.09.23.614424
  19. Aging Cell. 2024 Oct 11. e14377
    Contextualizing aging clocks and properly describing biological age.
    Adiv A Johnson, Maxim N Shokhirev.
      Usage of the phrase "biological age" has picked up considerably since the advent of aging clocks and it has become commonplace to describe an aging clock's output as biological age. In contrast to this labeling, biological age is also often depicted as a more abstract concept that helps explain how individuals are aging internally, externally, and functionally. Given that the bulk of molecular aging is tissue-specific and aging itself is a remarkably complex, multifarious process, it is unsurprising that most surveyed scientists agree that aging cannot be quantified via a single metric. We share this sentiment and argue that, just like it would not be reasonable to assume that an individual with an ideal grip strength, VO2 max, or any other aging biomarker is biologically young, we should be careful not to conflate an aging clock with whole-body biological aging. To address this, we recommend that researchers describe the output of an aging clock based on the type of input data used or the name of the clock itself. Epigenetic aging clocks produce epigenetic age, transcriptomic aging clocks produce transcriptomic age, and so forth. If a clock has a unique name, such as our recently developed epigenetic aging clock CheekAge, the name of the clock can double as the output. As a compromise solution, aging biomarkers can be described as indicators of biological age. We feel that these recommendations will help scientists and the public differentiate between aging biomarkers and the much more elusive concept of biological age.
    Keywords:  aging biomarker; aging clock; biohorology; biological age; chronological age; mortality
    DOI:  https://doi.org/10.1111/acel.14377
  20. Ageing Res Rev. 2024 Oct 05. pii: S1568-1637(24)00345-3. [Epub ahead of print]101 102527
    Biological constraint, evolutionary spandrels and antagonistic pleiotropy.
    David Gems, Carina C Kern.
      Maximum lifespan differs greatly between species, indicating that the process of senescence is largely genetically determined. Senescence evolves in part due to antagonistic pleiotropy (AP), where selection favors gene variants that increase fitness earlier in life but promote pathology later. Identifying the biological mechanisms by which AP causes senescence is key to understanding the endogenous causes of aging and its attendant diseases. Here we argue that the frequent occurrence of AP as a property of genes reflects the presence of constraint in the biological systems that they specify. This arises particularly because the functionally interconnected nature of biological systems constrains the simultaneous optimization of coupled traits (interconnection constraints), or because individual traits cannot evolve (impossibility constraints). We present an account of aging that integrates AP and biological constraint with recent programmatic aging concepts, including costly programs, quasi-programs, hyperfunction and hypofunction. We argue that AP mechanisms of costly programs and triggered quasi-programs are consequences of constraint, in which costs resulting from hyperfunction or hypofunction cause senescent pathology. Impossibility constraint can also cause hypofunction independently of AP. We also describe how AP corresponds to Stephen Jay Gould's constraint-based concept of evolutionary spandrels, and argue that pathologies arising from AP are bad spandrels. Biological constraint is a conceptual missing link between ultimate and proximate causes of senescence, including diseases of aging.
    Keywords:  Aging; Antagonistic pleiotropy; Biological constraint; Evolution; Programmatic aging; Spandrel; Trade-off
    DOI:  https://doi.org/10.1016/j.arr.2024.102527
  21. Biogerontology. 2024 Oct 08.
    Brown adipose tissue: a potential target for aging interventions and healthy longevity.
    Hongde Li, Junli Li, Chengxiang Song, Haoran Yang, Qiang Luo, Mao Chen.
      Brown Adipose Tissue (BAT) is a type of fat tissue that can generate heat and plays an important role in regulating body temperature and energy metabolism. Enhancing BAT activity through medication, exercise and other means has become a potential effective method for treating metabolic disorders. Recently, there has been increasing evidence suggesting a link between BAT and aging. As humans age, the volume and activity of BAT decrease, which may contribute to the development of age-related diseases. Multiple organelles signaling pathways have been reported to be involved in the aging process associated with BAT. Therefore, we aimed to review the evidence related to the association between aging process and BAT decreasing, analyze the potential of BAT as a predictive marker for age-related diseases, and explore potential therapeutic strategies targeting BAT for aging interventions and healthy longevity.
    Keywords:  Aging; Brown adipose tissue; Thermogenesis; Uncoupling protein 1
    DOI:  https://doi.org/10.1007/s10522-024-10137-3
  22. Neurosci Insights. 2024 ;19 26331055241285880
    GABA, Aging and Exercise: Functional and Intervention Considerations.
    Tom S Novak, Keith M McGregor, Lisa C Krishnamurthy, Alexandra Evancho, Kevin Mammino, Courtney E Walters, Ashton Weber, Joe R Nocera.
      The global growth of an aging population is expected to coincide with an increase in aging-related pathologies, including those related to brain health. Thus, the potential for accelerated cognitive health declines due to adverse aging is expected to have profound social and economic implications. However, the progression to pathological conditions is not an inevitable part of aging. In fact, engaging in activities that improve cardiovascular fitness appears to be a means that offers the benefits of maintaining and/or improving cognitive health in older age. However, to date, the underlying mechanisms responsible for improved central nervous system health and function with exercise are not yet fully elucidated. Consequently, there is considerable interest in studies aimed at understanding the neurophysiological benefits of exercise on aging. One such area of study suggests that the improvements in brain health via exercise are, in part, driven by the recovery of inhibitory processes related to the neurotransmitter gamma-aminobutyric acid (GABA). In the present review, we highlight the opposing effects of aging and exercise on cortical inhibition and the GABAergic system's functional integrity. We highlight these changes in GABA function by reviewing work with in vivo measurements: transcranial magnetic stimulation (TMS) and magnetic resonance spectroscopy (MRS). We also highlight recent and significant technological and methodological advances in assessing the GABAergic system's integrity with TMS and MRS. We then discuss potential future research directions to inform mechanistic GABA study targeted to improve health and function in aging. We conclude by highlighting the significance of understanding the effects of exercise and aging, its influence on GABA levels, and why a better understanding is crucial to allow for more targeted and effective interventions aimed to ultimately improve age-related decline in aging.
    Keywords:  Gamma-aminobutyric acid (GABA); cortical inhibition; magnetic resonance spectroscopy; transcranial magnetic stimulation
    DOI:  https://doi.org/10.1177/26331055241285880
  23. iScience. 2024 Sep 20. 27(9): 110793
    Insidious chromatin change with a propensity to exhaust intestinal stem cells during aging.
    Saki Tomita-Naito, Shivakshi Sulekh, Sa Kan Yoo.
      During aging, tissue stem cells can demonstrate two opposing phenotypes of tissue homeostasis disruption: proliferation and exhaustion. Stem cells can exhaust as a result of excessive cell proliferation or independently of cell proliferation. There are many silent changes in chromatin structures and gene expression that are not necessarily reflected in manifested phenotypes during aging. Here through analyses of chromatin accessibility and gene expression in intestinal progenitor cells during aging, we discovered changes of chromatin accessibility and gene expression that have a propensity to exhaust intestinal stem cells (ISCs). During aging, Trithorax-like (Trl) target genes, ced-6 and ci, close their chromatin structures and decrease their expression in intestinal progenitor cells. Inhibition of Trl, ced-6, or ci exhausts ISCs. This study provides new insight into changes of chromatin accessibility and gene expression that have a potential to exhaust ISCs during aging.
    Keywords:  Cell biology; Molecular biology; Omics; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2024.110793
  24. Nature. 2024 Oct 09.
    Dietary restriction impacts health and lifespan of genetically diverse mice.
    Andrea Di Francesco, Andrew G Deighan, Lev Litichevskiy, Zhenghao Chen, Alison Luciano, Laura Robinson, Gaven Garland, Hannah Donato, Matthew Vincent, Will Schott, Kevin M Wright, Anil Raj, G V Prateek, Martin Mullis, Warren G Hill, Mark L Zeidel, Luanne L Peters, Fiona Harding, David Botstein, Ron Korstanje, Christoph A Thaiss, Adam Freund, Gary A Churchill.
      Caloric restriction extends healthy lifespan in multiple species1. Intermittent fasting, an alternative form of dietary restriction, is potentially more sustainable in humans, but its effectiveness remains largely unexplored2-8. Identifying the most efficacious forms of dietary restriction is key for developing interventions to improve human health and longevity9. Here we performed an extensive assessment of graded levels of caloric restriction (20% and 40%) and intermittent fasting (1 and 2 days fasting per week) on the health and survival of 960 genetically diverse female mice. We show that caloric restriction and intermittent fasting both resulted in lifespan extension in proportion to the degree of restriction. Lifespan was heritable and genetics had a larger influence on lifespan than dietary restriction. The strongest trait associations with lifespan included retention of body weight through periods of handling-an indicator of stress resilience, high lymphocyte proportion, low red blood cell distribution width and high adiposity in late life. Health effects differed between interventions and exhibited inconsistent relationships with lifespan extension. 40% caloric restriction had the strongest lifespan extension effect but led to a loss of lean mass and changes in the immune repertoire that could confer susceptibility to infections. Intermittent fasting did not extend the lifespan of mice with high pre-intervention body weight, and two-day intermittent fasting was associated with disruption of erythroid cell populations. Metabolic responses to dietary restriction, including reduced adiposity and lower fasting glucose, were not associated with increased lifespan, suggesting that dietary restriction does more than just counteract the negative effects of obesity. Our findings indicate that improving health and extending lifespan are not synonymous and raise questions about which end points are the most relevant for evaluating aging interventions in preclinical models and clinical trials.
    DOI:  https://doi.org/10.1038/s41586-024-08026-3
  25. iScience. 2024 Oct 18. 27(10): 110888
    Aged gut microbiota promotes arrhythmia susceptibility via oxidative stress.
    Zhi-Ping Fu, Yi-Ge Ying, Rui-Yao Wang, Yu-Qing Wang.
      Arrhythmias and sudden cardiac death (SCD) impose a significant burden. Their prevalence rises with age and is linked to gut dysbiosis. Our study aimed to determine whether aged gut microbiota affects arrhythmogenesis. Here, we demonstrated that arrhythmia susceptibility in aged mice could be transmitted to young mice using fecal microbiota transplantation (FMT). Mechanistically, increased intestinal reactive oxygen species (ROS) in aged mice reduced ion channel protein expression and promoted arrhythmias. Gut microbiota depletion by an antibiotic cocktail reduced ROS and arrhythmia in aged mice. Interestingly, oxidative stress in heart induced by hydrogen peroxide (H2O2) increased arrhythmia. Moreover, aged gut microbiota could induce oxidative stress in young mice colon by gut microbiota metabolites transplantation. Vitexin could reduce aging and arrhythmia through OLA1-Nrf2 signaling pathway. Overall, our study demonstrated that the gut microbiota of aged mice reduced cardiac ion channel protein expression through systemic oxidative stress, thereby increased the risk of arrhythmias.
    Keywords:  Cardiovascular medicine; Microbiome
    DOI:  https://doi.org/10.1016/j.isci.2024.110888
  26. Front Genome Ed. 2024 ;6 1471720
    Use of paired Cas9-NG nickase and truncated sgRNAs for single-nucleotide microbial genome editing.
    Song Hee Jeong, Ho Joung Lee, Sang Jun Lee.
      The paired nickases approach, which utilizes clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated proteins (Cas) nickase and dual guide RNA, has the advantage of reducing off-target effects by being able to double the target sequence. In this study, our research utilized the Cas9-NG nickase variant to minimize PAM sequence constraints, enabling the generation of paired nicks at desired genomic loci. We performed a systematic investigation into the formation sites for double nicks and the design of donor DNA within a bacterial model system. Although we successfully identified the conditions necessary for the effective formation of double nicks in vivo, achieving single-nucleotide level editing directly at the target sites in the genome proved challenging. Nonetheless, our experiments revealed that efficient editing at the single-nucleotide level was achievable on target DNA sequences that are hybridized with 5'-end-truncated dual single-guide RNAs (sgRNAs). Our findings contribute to a deeper understanding of the paired nickases approach, offering a single-mismatch intolerance design strategy for accurate nucleotide editing. This strategy not only enhances the precision of genome editing but also marks a significant step forward in the development of nickase-derived genome editing technologies.
    Keywords:  Cas9-NG; mismatch intolerance; paired nickase; single-nucleotide editing; truncated sgRNA
    DOI:  https://doi.org/10.3389/fgeed.2024.1471720
  27. J Insect Sci. 2024 Sep 01. pii: 3. [Epub ahead of print]24(5):
    Spermidine supplementation influence on protective enzymes of Apis mellifera (Hymenoptera: Apidae).
    Tatjana V Čelić, Srđana Đorđievski, Elvira L Vukašinović, Ivan Pihler, Danijela Kojić, Jelena Purać.
      Dietary supplementation has been proposed as a sustainable way to improve the health and resilience of honey bees (Apis mellifera, L.), as the decline in their numbers in recent decades has raised scientific, environmental, and economic concerns. Spermidine, a natural polyamine, has been shown to be a promising substance for honey bee supplementation, as its health-promoting effects have been demonstrated in numerous studies and in different organisms. As already shown, supplementation with spermidine at a certain concentration prolonged lifespan, reduced oxidative stress, and increased antioxidative capacity in honey bees. The aim of the present study was to investigate whether spermidine supplementation affects gene expression and/or enzyme activity of antioxidative and detoxification enzymes and immune response markers in honey bee workers. The different gene expression and enzyme activity patterns observed in abdominal and head tissues in response to spermidine supplementation suggest tissue-specific and concentration-dependent effects. In addition, the immune response markers suggest that spermidine has the ability to boost honey bee immunity. The observed changes make a valuable contribution to understanding the molecular mechanisms by which spermidine may exert its beneficial effects on the bee's health and lifespan. These results support the idea of the use of spermidine supplementation to promote bee health and resilience to environmental stressors, emphasizing that the dose must be carefully chosen to achieve a balance between the pro- and antioxidant effects of spermidine.
    Keywords:  antioxidative protection; immunity; nutrition; polyamine
    DOI:  https://doi.org/10.1093/jisesa/ieae098
  28. EXCLI J. 2024 ;23 1030-1067
    Oxidative stress and senescence in aging kidneys: the protective role of SIRT1.
    Waleed Hassan Almalki, Salem Salman Almujri.
      Aging leads to a gradual decline in kidney function, making the kidneys increasingly vulnerable to various diseases. Oxidative stress, together with cellular senescence, has been established as paramount in promoting the aging process of the kidney. Oxidative stress, defined as an imbalance between ROS formation and antioxidant defense mechanisms, has been implicated in the kidney's cellular injury, inflammation, and premature senescence. Concurrently, the accumulation of SCs in the kidney also exacerbates oxidative stress via the secretion of pro-inflammatory and tissue-damaging factors as the senescence-associated secretory phenotype (SASP). Recently, SIRT1, a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, has been pivotal in combating oxidative stress and cellular senescence in the aging kidney. SIRT1 acts as a potential antioxidant molecule through myriad pathways that influence diverse transcription factors and enzymes essential in maintaining redox homeostasis. SIRT1 promotes longevity and renal health by modulating the acetylation of cell cycle and senescence pathways. This review covers the complex relationship between oxidative stress and cellular senescence in the aging kidney, emphasizing the protective role of SIRT1. See also the graphical abstract(Fig. 1).
    Keywords:  SASP; SIRT1; cellular senescence; homeostasis; oxidative stress
    DOI:  https://doi.org/10.17179/excli2024-7519
  29. Exp Mol Med. 2024 Oct 11.
    Histone lysine methylation modifiers controlled by protein stability.
    Sungryul Park, Jin Hwa Cho, Jeong-Hoon Kim, Jung-Ae Kim.
      Histone lysine methylation is pivotal in shaping the epigenetic landscape and is linked to cell physiology. Coordination of the activities of multiple histone lysine methylation modifiers, namely, methyltransferases and demethylases, modulates chromatin structure and dynamically alters the epigenetic landscape, orchestrating almost all DNA-templated processes, such as transcription, DNA replication, and DNA repair. The stability of modifier proteins, which is regulated by protein degradation, is crucial for their activity. Here, we review the current knowledge of modifier-protein degradation via specific pathways and its subsequent impact on cell physiology through epigenetic changes. By summarizing the functional links between the aberrant stability of modifier proteins and human diseases and highlighting efforts to target protein stability for therapeutic purposes, we aim to promote interest in defining novel pathways that regulate the degradation of modifiers and ultimately increase the potential for the development of novel therapeutic strategies.
    DOI:  https://doi.org/10.1038/s12276-024-01329-5
  30. Dev Dyn. 2024 Oct 07.
    Functional significance of earthworm clitellum in regulating the various biological aspects of cell survival and regeneration.
    Jackson Durairaj Selvan Christyraj, Ashwin Barath Vaidhyalingham, Chandini Sengupta, Kamarajan Rajagopalan, Kayalvizhi Vadivelu, Nandha Kumar Suresh, Bharathi Venkatachalam.
      Earthworms are a highly abundant species in nature, with nearly 7000 different species being discovered. Despite the similarities in morphology among earthworm species, their regeneration capabilities vary based on the clitellum. The clitellum plays a crucial role in the clitellum-dependent worms, as it is involved in the processes of regeneration and reproduction in earthworms. The fascinating characteristic of the clitellum, which serves as a hub for stem cells in clitellum-dependent worms, plays a crucial role in various biological processes that require further exploration. This review focuses on the overall physiological functions and uncovers the lesser-known roles of the clitellum that have been documented in various research articles. In recent times, numerous studies have been conducted using the earthworm model to explore various areas. In that regard, the clitellum's different roles in regulating and controlling stem cells, the regeneration process, regulation of organogenesis, stress response, aging, autotomy, and various features have been briefly discussed. Ultimately, we emphasized the unique and versatile role of the clitellum in the animal model, making it an ideal choice for studying development, regeneration, stem cells, organogenesis, toxicology, autotomy, and aging response.
    Keywords:  clitellum; earthworm; morphology; regeneration; stem cells
    DOI:  https://doi.org/10.1002/dvdy.751
  31. Nucleic Acids Res. 2024 Oct 09. pii: gkae879. [Epub ahead of print]
    Visualization of Type IV-A1 CRISPR-mediated repression of gene expression and plasmid replication.
    Mariana Sanchez-Londono, Selina Rust, Rogelio Hernández-Tamayo, José Vicente Gomes-Filho, Martin Thanbichler, Lennart Randau.
      Type IV CRISPR-Cas (clustered regularly interspaced short palindromic repeats and CRISPR-associated proteins) effector complexes are often encoded on plasmids and are proposed to prevent the replication of competing plasmids. The Type IV-A1 CRISPR-Cas system of Pseudomonas oleovorans additionally harbors a CRISPR RNA (crRNA) that tightly regulates the transcript levels of a chromosomal target and represents a natural CRISPR interference (CRISPRi) tool. This study investigates CRISPRi effects of this system using synthetic crRNAs against genome and plasmid sequences. Targeting of reporter genes revealed extended interference in P. oleovorans and Escherichia coli cells producing recombinant CRISPR ribonucleoprotein (crRNP) complexes. RNA sequencing (RNA-seq) analyses of Type IV-A1 CRISPRi-induced transcriptome alterations demonstrated highly effective long-range downregulation of histidine operon expression, whereas CRISPRi effects of dCas9 remained limited to the vicinity of its binding site. Single-molecule microscopy uncovered the localization dynamics of crRNP complexes. The tracks of fluorescently labeled crRNPs co-localized with regions of increased plasmid replication, supporting efficient plasmid targeting. These results identify mechanistic principles that facilitate the application of Type IV-A1 CRISPRi for the regulation of gene expression and plasmid replication.
    DOI:  https://doi.org/10.1093/nar/gkae879
  32. Nat Commun. 2024 Oct 10. 15(1): 8768
    High-resolution and programmable RNA-IN and RNA-OUT genetic circuit in living mammalian cells.
    Min Zhang, Xue Zhang, Yongyue Xu, Yanhui Xiang, Bo Zhang, Zhen Xie, Qiong Wu, Chunbo Lou.
      RNAs and their encoded proteins intricately regulate diverse cell types and states within the human body. Dysregulated RNA expressions or mutations can lead to various diseased cell states, including tumorigenesis. Detecting and manipulating these endogenous RNAs offers significant promise for restoring healthy cell states and targeting tumors both in research and clinical contexts. This study presents an RNA-IN and RNA-OUT genetic circuit capable dynamically sensing and manipulating any RNA target in a programmable manner. The RNA-IN module employes a programmable CRISPR-associated protease (CASP) complex for RNA detection, while the RNA-OUT module utilizes an engineered protease-responsive dCas9-VPR activator. Additionally, the CASP module can detect point mutations by harnessing an uncovered dual-nucleotide synergistic switching effect within the CASP complex, resulting in the amplification of point-mutation signals from initially undetectable levels (1.5-fold) to a remarkable 94-fold. We successfully showcase the circuit's ability to rewire endogenous RNA-IN signals to activate endogenous progesterone biosynthesis pathway, dynamically monitor adipogenic differentiation of mesenchymal stem cells (MSCs) and the epithelial-to-mesenchmal trans-differentiation, as well as selective killing of tumor cells. The programmable RNA-IN and RNA-OUT circuit exhibits tremendous potential for applications in gene therapy, biosensing and design of synthetic regulatory networks.
    DOI:  https://doi.org/10.1038/s41467-024-52962-7
  33. Nature. 2024 Oct 09.
    MicroRNAs won the Nobel - will they ever be useful as medicines?
    Heidi Ledford.
      
    Keywords:  Diseases; Drug discovery
    DOI:  https://doi.org/10.1038/d41586-024-03303-7
  34. J Conserv Dent Endod. 2024 Aug;27(8): 853-859
    Comparative evaluation of the osteogenic capacity of second-generation platelet concentrates on dental pulp stem cells - An ex vivo study.
    Bandana Panda, Gaurav Patri, Debkant Jena, Ranjan Rashmi Behera, Vanshika Agarwal, Aditi Gupta.
       Introduction: Clinical evidence of platelet-rich fibrin (PRF) benefits on bone repair is still emerging, prompting researchers to experiment with different PRF formulations as osteoconductive scaffolds.
    Aims: This study compared the osteoconductive effects of injectable PRF (i-PRF) and leukocyte-rich PRF (L-PRF) on the differentiation of dental pulp stem cells (DPSCs) into osteoblasts.
    Materials and Methods: Blood samples were collected from the volunteers to prepare L-PRF and i-PRF conditioned media (CM) by centrifugation. DPSCs were isolated from impacted third molars and cultured. Proliferation of DPSCs in response to L-PRF and i-PRF was assessed by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Osteoinductive potential was evaluated through alkaline phosphatase (ALP) activity, alizarin red S (ARS) staining, growth factor levels (vascular endothelial growth factor [VEGF], transforming growth factor [TGF-beta]), and cytokine expression (interleukin 6 [IL-6], IL-8) after 7 days.
    Results: MTT assay results showed that both L-PRF and i-PRF increased DPSC proliferation relative to the control group. After 7 days in L-PRF and i-PRF CM, DPSCs exhibited increased ALP activity, higher red-colored calcium deposits with ARS staining, and elevated levels of VEGF and TGF-beta. In addition, higher concentrations of inflammatory cytokines IL-6 and IL-8 were observed in both L-PRF and i-PRF compared to the control.
    Conclusions: Using both L-PRF and i-PRF as scaffolds can enhance the osteoinductive ability of stem cells, offering a potential strategy for regenerative therapies.
    Keywords:  Alizarin red S staining; alkaline phosphatase activity; dental pulp stem cells; injectable platelet-rich fibrin; leukocyte platelet-rich fibrin; osteogenic capacity; platelet by-products; platelet concentrates; platelet-rich fibrin; regenerativetreatments/therapies
    DOI:  https://doi.org/10.4103/JCDE.JCDE_320_24
  35. Bioresour Bioprocess. 2024 Oct 07. 11(1): 94
    Characterization of argonaute nucleases from mesophilic bacteria Pseudobutyrivibrio ruminis.
    Xiaoyi Xu, Hao Yang, Huarong Dong, Xiao Li, Qian Liu, Yan Feng.
      Mesophilic Argonautes (Agos) from microbial resources have received significant attention due to their potential applications in genome editing and molecular diagnostics. This study characterizes a novel Ago from Pseudobutyrivibrio ruminis (PrAgo), which can cleave single-stranded DNA using guide DNA (gDNA). PrAgo, functioning as a multi-turnover enzyme, effectively cleaves DNA using 5'-phosphate gDNA, 14-30 nucleotides in length, in the presence of both Mn2+ and Mg2+ ions. PrAgo demonstrates DNA cleavage activity over a broad pH range (pH 4-12), with optimal activity at pH 11. As a mesophilic enzyme, PrAgo cleaves efficiently DNA at temperatures ranging from 25 to 65 °C, particularly at 65 °C. PrAgo does not show strong preferences for the 5'-nucleotide in gDNA. It shows high tolerance for single-base mismatches, except at positions 13 and 15 of gDNA. Continuous double-nucleotide mismatches at positions 10-16 of gDNA significantly reduce cleavage activity. Furthermore, PrAgo mediates DNA-guided DNA cleavage of AT-rich double stranded DNA at 65 °C. Additionally, molecular dynamic simulations suggest that interactions between the PAZ domain and different nucleic acids strongly influence cleavage efficiency. These findings expand our understanding of Protokaryotic Agos and their potential applications in biotechnology.
    Keywords:   Pseudobutyrivibrio ruminis Argonaute; DNA cleavage; Endonuclease; Mesophilic Argonaute; Prokaryotic Argonaute
    DOI:  https://doi.org/10.1186/s40643-024-00797-x
  36. Biochimie. 2024 Oct 05. pii: S0300-9084(24)00230-X. [Epub ahead of print]
    Structural extracellular matrix-mediated molecular signaling in wound repair and tissue regeneration.
    Sousan Cheong, Yujie Peng, Feng Lu, Yunfan He.
      The extracellular matrix (ECM) is a complex, non-cellular network of molecules that offers structural support for cells and tissues. The ECM is composed of various structural components, including collagen, fibronectin, laminin, perlecan, nidogen, tenascin, and fibulin, which are capable of binding to each other and to cell-to-adhesion receptors, endowing the ECM with unique physical and biochemical properties that are essential for its function in maintaining health and managing disease. Over the past three decades, extensive research has shown that the core of the ECM can significantly impact cellular events at the molecular level. Structural modifications have also been strongly associated with tissue repair. Through interactions with cells, matrix proteins regulate critical processes such as cell proliferation and differentiation, migration, and apoptosis, essential for maintaining tissue homeostasis, formation, and regeneration. This review emphasizes the interlocking networks of ECM macromolecules and their primary roles in tissue regeneration and wound repair. Through studying ECM dynamics, researchers have discovered molecular signaling pathways that demonstrate how the ECM influences protein patterns and open up more possibilities for developing therapeutics that target the ECM to enhance wound repair and tissue regeneration.
    Keywords:  extracellular matrix; molecular signaling; structural protein; tissue regeneration; wound repair
    DOI:  https://doi.org/10.1016/j.biochi.2024.10.003
  37. J Theor Biol. 2024 Oct 09. pii: S0022-5193(24)00247-9. [Epub ahead of print]595 111962
    A model for transcription-dependent R-loop formation at double-stranded DNA breaks: Implications for their detection and biological effects.
    Boris P Belotserkovskii, Philip C Hanawalt.
      R-loops are structures containing an RNA-DNA duplex and an unpaired DNA strand. During R-loop formation an RNA strand invades the DNA duplex, displacing the homologous DNA strand and binding the complementary DNA strand. Here we analyze a model for transcription-dependent R-loop formation at double-stranded DNA breaks (DSBs). In this model, R-loop formation is preceded by detachment of the non-template DNA strand from the RNA polymerase (RNAP). Then, strand exchange is initiated between the nascent RNA and the non-template DNA strand. During that strand exchange the length of the R-loop could either increase, or decrease in a biased random-walk fashion, in which the bias would depend upon the DNA sequence. Eventually, the restoration of the DNA duplex would completely displace the RNA. However, as long as the RNAP remains bound to the template DNA strand it prevents that displacement. Thus, according to the model, RNAPs stalled at DSBs can increase the lifespan of R-loops, increasing their detectability in experiments, and perhaps enhancing their biological effects.
    Keywords:  DNA repair; RNA polymerase; RNA-DNA hybrids; Random walk; Strand exchange
    DOI:  https://doi.org/10.1016/j.jtbi.2024.111962
  38. Sci Rep. 2024 10 09. 14(1): 23623
    Rejuvenation of human mesenchymal stem cells using a nonintegrative and conditionally removable Sendai virus vector.
    Mitsuo Oshimura, Toshiaki Tabata, Narumi Uno, Shuta Takata, Genki Hichiwa, Iori Kanazawa, Takeshi Endo, Kazuhisa Honma, Yayan Wang, Kanako Kazuki, Haochen Tu, Yuichi Iida, Satoshi Abe, Yasuhiro Kazuki.
      Human mesenchymal stem cells (hMSCs) with extended lifespan and differentiation potential that can recapitulate in vivo characteristics could significantly contribute to basic research, drug development, and cell therapy. Specifically, they could ensure a stable supply of specific cellular resources, and possibly extracellular vesicles. Here, we established a technology for extending the lifespan while maintaining differentiation potential, termed "rejuvenation," of hMSCs (rej-hMSCs) using nonintegrative and conditionally removable temperature-sensitive Sendai virus (SeV) vectors. Various immortalizing factors (i.e., Bmi-1, hTERT, SV40T, and/or HPV E6/E7) were first introduced by the SeV vector into the cells. A combination of three SeVs with Bmi-1, hTERT, or SV40T conferred markedly improved cell proliferation and cloning ability while maintaining differentiation potential and a normal karyotype. An extended lifespan was also demonstrated in other cell types. The rejuvenation of long-passaged or aged hMSCs was also confirmed. SeV vectors were rapidly removed as a function of cell doubling by increasing the temperature from 35 °C to 37 °C or higher, while proliferative ability was maintained. Following FACS sorting, the complete removal of SeV vectors was confirmed by qPCR analyses. Therefore, our cell rejuvenation technology could contribute to research and clinical applications by enabling the supply of modified cells without damaging host chromosomes.
    Keywords:  Extended lifespan; Human mesenchymal stem cell; Regenerative medicine; Rejuvenation; Sendai virus vector
    DOI:  https://doi.org/10.1038/s41598-024-74757-y
  39. J Prev Med Public Health. 2024 Sep;57(5): 508-510
    Polypharmacy and Therapeutic Inertia in Extreme Longevity: A Potential Clinical Ageism Scenario Secondary to Important Gaps in Clinical Evidence.
    María Viviana Pantoja, Ivan David Lozada-Martinez.
      Population aging is a global health priority due to the dramatic increase in the proportion of older persons worldwide. It is also expected that both global life expectancy and disability-free life expectancy will increase, leading to a significant rise in the proportion of individuals with extreme longevity, such as non-agenarians and centenarians. The inaccuracy of clinical evidence on therapeutic interventions for this demographic could lead to biased decision-making, influenced by age-related beliefs or misperceptions about their therapeutic needs. This represents a potential clinical ageism scenario stemming from gaps in clinical evidence. Such biases can result in 2 significant issues that adversely affect the health status and prognosis of older persons: polypharmacy and therapeutic inertia. To date, documents on polypharmacy in non-agenarians and centenarians account for less than 0.35% of the overall available evidence on polypharmacy. Furthermore, evidence regarding therapeutic inertia is non-existent. The purpose of this letter is to discuss polypharmacy and therapeutic inertia as potential clinical ageism scenarios resulting from the clinical evidence gaps in extreme longevity.
    Keywords:  Ageism; Centenarians; Nonagenarians; Polypharmacy; Secondary prevention
    DOI:  https://doi.org/10.3961/jpmph.24.364
  40. Nat Aging. 2024 Oct 08.
    The brain-body energy conservation model of aging.
    Evan D Shaulson, Alan A Cohen, Martin Picard.
      Aging involves seemingly paradoxical changes in energy metabolism. Molecular damage accumulation increases cellular energy expenditure, yet whole-body energy expenditure remains stable or decreases with age. We resolve this apparent contradiction by positioning the brain as the mediator and broker in the organismal energy economy. As somatic tissues accumulate damage over time, costly intracellular stress responses are activated, causing aging or senescent cells to secrete cytokines that convey increased cellular energy demand (hypermetabolism) to the brain. To conserve energy in the face of a shrinking energy budget, the brain deploys energy conservation responses, which suppress low-priority processes, producing fatigue, physical inactivity, blunted sensory capacities, immune alterations and endocrine 'deficits'. We term this cascade the brain-body energy conservation (BEC) model of aging. The BEC outlines (1) the energetic cost of cellular aging, (2) how brain perception of senescence-associated hypermetabolism may drive the phenotypic manifestations of aging and (3) energetic principles underlying the modifiability of aging trajectories by stressors and geroscience interventions.
    DOI:  https://doi.org/10.1038/s43587-024-00716-x
  41. Nature. 2024 Oct 07.
    Medicine Nobel awarded for gene-regulating 'microRNAs'.
    Ewen Callaway, Katharine Sanderson.
      
    Keywords:  Physiology
    DOI:  https://doi.org/10.1038/d41586-024-03212-9
  42. J Struct Biol. 2024 Oct 08. pii: S1047-8477(24)00074-1. [Epub ahead of print] 108134
    Transcriptome profiling of DPP stimulated DPSCs identifies the role of autophagy in odontogenic differentiation.
    Yinghua Chen, Cassandra Villani, Amudha Ganapathy, Anne George.
      Dentin phosphophoryn (DPP), synthesized and processed predominantly by the odontoblasts, serves both a structural and signaling role in dentin. In the ECM, DPP functions as an avid calcium and collagen binding protein and it also plays a crucial role as a scaffold for cell attachment and survival. The signaling function of DPP was demonstrated when undifferentiated mesenchymal cells stimulated with DPP, mediated calcium signaling through release of intracellular Ca2+. The objective of this study was to identify potentially novel signaling mechanisms that mediate odontoblast differentiation. Therefore, transcriptomes of DPSCs (dental pulp stem cells) with or without DPP stimulation were compared by bulk RNA-seq. Analysis of the unbiased RNA-seq data were subjected to functional enrichment analysis using Gene Ontology (GO) and KEGG pathways. Results identified several upregulated genes which were associated with autophagy, that were subsequently validated by RT-PCR. Western blotting analysis confirmed the up regulation of several autophagy markers such as ATG5, BECN1 and LC3A/B at specific time points. Autophagosome formation was also observed with DPP treatment. Additionally, autophagy supported a role for odontoblast differentiation of DPSCs. These findings suggest that DPP mediated autophagy might be a potential mechanism for the survival and terminal differentiation of DPSCs.
    DOI:  https://doi.org/10.1016/j.jsb.2024.108134
  43. Sci Rep. 2024 10 09. 14(1): 23643
    Clinical vs. chronological skin age: exploring determinants and stratum corneum protein markers of differential skin ageing in 351 healthy women.
    A Foucher, S Nouveau, V Piffaut, S Marque, L Aguilar, N Cavusoglu.
      Apparent skin age can be determined by several clinical measurements and may differ from chronological age, hence defining age acceleration/deceleration (Age A/D). Using data from 360 women with dermatological scoring of 21 clinical signs, we defined 3 well-separated co-occurring classes capturing the dryness, the elasticity and the oily nature of the skin. We related the risk of each clinical signs to the stratum corneum levels of 5 pre-selected proteins, we identified specific chronological age-adjusted signatures of each clinical sign. Using variable selection approaches, we identified 6 (of the 21) clinical signs which were jointly predictive of chronological age and used to define the clinical skin age, and subsequently age A/D. Applying univariate and multivariate approaches we found that stratum corneum levels of insulin degrading enzyme (IDE) was protective against (β = - 1.74, p = 3.3 × 10-6; selection proportion > 90%) accelerated skin ageing. In conclusion, our results support the fact that molecular markers found in the stratum corneum could predict skin ageing acceleration/deceleration.
    DOI:  https://doi.org/10.1038/s41598-024-65083-4
  44. J Gerontol A Biol Sci Med Sci. 2024 Oct 09. pii: glae244. [Epub ahead of print]
    There are multiple clocks that time us: Cross-sectional and longitudinal associations among 14 alternative indicators of age and aging.
    Johanna Drewelies, Jan Homann, Valentin Max Vetter, Sandra Duezel, Simone Kühn, Laura Deecke, Elisabeth Steinhagen-Thiessen, Philippe Jawinski, Sebastian Markett, Ulman Lindenberger, Christina M Lill, Lars Bertram, Ilja Demuth, Denis Gerstorf.
      Aging is a complex process influenced by mechanisms operating at numerous levels of functioning. Multiple biomarkers of age have been identified, yet we know little about how the different alternative age indicators are intertwined. In the Berlin Aging Study II (nmin= 328; nmax= 1,517, women = 51%; 14.27 years of education), we examined how levels and seven-year changes in indicators derived from blood assays, MRI brain scans, other-ratings, and self-reports converge among older adults. We included eight epigenetic biomarkers (incl. five epigenetic "clocks"), a BioAge composite from clinical laboratory parameters, brain age, skin age, subjective age, subjective life expectancy, and future health horizon. We found moderate associations within aging domains, both cross-sectionally and longitudinally over seven years. However, associations across different domains were infrequent and modest. Notably, participants with older BioAge had correspondingly older epigenetic ages. Our results suggest that different aging clocks are only loosely interconnected and that more specific measures are needed to differentiate healthy from unhealthy aging.
    Keywords:  BASE–II; age indicator; ageing; biological age; epigenetic clock
    DOI:  https://doi.org/10.1093/gerona/glae244
  45. medRxiv. 2024 Aug 03. pii: 2024.08.01.24311368. [Epub ahead of print]
    A plasma proteomic signature links secretome of senescent monocytes to aging- and obesity-related clinical outcomes in humans.
    Bradley Olinger, Reema Banarjee, Amit Dey, Dimitrios Tsitsipatis, Toshiko Tanaka, Anjana Ram, Thedoe Nyunt, Gulzar Daya, Zhongsheng Peng, Linna Cui, Julián Candia, Eleanor M Simonsick, Myriam Gorospe, Keenan A Walker, Luigi Ferrucci, Nathan Basisty.
      Cellular senescence increases with age and contributes to age-related declines and pathologies. We identified circulating biomarkers of senescence associated with diverse clinical traits in humans to facilitate future non-invasive assessment of individual senescence burden and efficacy testing of novel senotherapeutics. Using a novel nanoparticle-based proteomic workflow, we profiled the senescence-associated secretory phenotype (SASP) in monocytes and examined these proteins in plasma samples (N = 1060) from the Baltimore Longitudinal Study of Aging (BLSA). Machine learning models trained on monocyte SASP associated with several age-related phenotypes in a test cohort, including body fat composition, blood lipids, inflammation, and mobility-related traits, among others. Notably, a subset of SASP-based predictions, including a 'high impact' SASP panel that predicts age- and obesity-related clinical traits, were validated in InCHIANTI, an independent aging cohort. These results demonstrate the clinical relevance of the circulating SASP and identify relevant biomarkers of senescence that could inform future clinical studies.
    DOI:  https://doi.org/10.1101/2024.08.01.24311368
  46. bioRxiv. 2024 Sep 26. pii: 2024.09.26.614999. [Epub ahead of print]
    Systemic deficits in lipid homeostasis promote aging-associated impairments in B cell progenitor development.
    Silvia Vicenzi, Fangyuan Gao, Parker Côté, Joshua D Hartman, Lara C Avsharian, Ashni A Vora, R Grant Rowe, Hojun Li, Dorota Skowronska-Krawczyk, Leslie A Crews.
      Organismal aging has been associated with diverse metabolic and functional changes across tissues. Within the immune system, key features of physiological hematopoietic cell aging include increased fat deposition in the bone marrow, impaired hematopoietic stem and progenitor cell (HSPC) function, and a propensity towards myeloid differentiation. This shift in lineage bias can lead to pre-malignant bone marrow conditions such as clonal hematopoiesis of indeterminate potential (CHIP) or clonal cytopenias of undetermined significance (CCUS), frequently setting the stage for subsequent development of age-related cancers in myeloid or lymphoid lineages. At the systemic as well as sub-cellular level, human aging has also been associated with diverse lipid alterations, such as decreased phospholipid membrane fluidity that arises as a result of increased saturated fatty acid (FA) accumulation and a decay in n-3 polyunsaturated fatty acid (PUFA) species by the age of 80 years, however the extent to which impaired FA metabolism contributes to hematopoietic aging is less clear. Here, we performed comprehensive multi-omics analyses and uncovered a role for a key PUFA biosynthesis gene, ELOVL2 , in mouse and human immune cell aging. Whole transcriptome RNA-sequencing studies of bone marrow from aged Elovl2 mutant (enzyme-deficient) mice compared with age-matched controls revealed global down-regulation in lymphoid cell markers and expression of genes involved specifically in B cell development. Flow cytometric analyses of immune cell markers confirmed an aging-associated loss of B cell markers that was exacerbated in the bone marrow of Elovl2 mutant mice and unveiled CD79B, a vital molecular regulator of lymphoid progenitor development from the pro-B to pre-B cell stage, as a putative surface biomarker of accelerated immune aging. Complementary lipidomic studies extended these findings to reveal select alterations in lipid species in aged and Elovl2 mutant mouse bone marrow samples, suggesting significant changes in the biophysical properties of cellular membranes. Furthermore, single cell RNA-seq analysis of human HSPCs across the spectrum of human development and aging uncovered a rare subpopulation (<7%) of CD34 + HSPCs that expresses ELOVL2 in healthy adult bone marrow. This HSPC subset, along with CD79B -expressing lymphoid-committed cells, were almost completely absent in CD34 + cells isolated from elderly (>60 years old) bone marrow samples. Together, these findings uncover new roles for lipid metabolism enzymes in the molecular regulation of cellular aging and immune cell function in mouse and human hematopoiesis. In addition, because systemic loss of ELOVL2 enzymatic activity resulted in down-regulation of B cell genes that are also associated with lymphoproliferative neoplasms, this study sheds light on an intriguing metabolic pathway that could be leveraged in future studies as a novel therapeutic modality to target blood cancers or other age-related conditions involving the B cell lineage.
    DOI:  https://doi.org/10.1101/2024.09.26.614999
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