bims-caglex Biomed News
on Cellular aging and life extension
Issue of 2024–06–02
fifty papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño
  1. Birds of a feather age together: telomere dynamics and social behavior predict life span in female Japanese quail (Coturnix japonica).
  2. Failure of senolytic treatment to prevent cognitive decline in a female rodent model of aging.
  3. Translatability of life-extending pharmacological treatments between different species.
  4. The potential for senotherapy as a novel approach to extend life quality in veterinary medicine.
  5. SATB1, senescence and senescence-related diseases.
  6. Unlocking longevity with GLP-1: A key to turn back the clock?
  7. Dipeptidylpeptidase-4-targeted activatable fluorescent probes visualize senescent cells.
  8. A non-canonical role of ELN protects from cellular senescence by limiting iron-dependent regulation of gene expression.
  9. Senolytic Therapy Enabled by Senescent Cell-Sensitive Biomimetic Melanin Nano-senolytics.
  10. Compensation effect of mortality is a challenge to substantial lifespan extension of humans.
  11. Changes in M6A methylation: A key factor in the vicious cycle of flora -gut aging.
  12. SGLT2 inhibition to target kidney aging.
  13. Sch9S6K controls DNA repair and DNA damage response efficiency in aging cells.
  14. Psychogenic Aging: A Novel Prospect to Integrate Psychobiological Hallmarks of Aging.
  15. Low-dose naltrexone extends healthspan and lifespan in C. elegans via SKN-1 activation.
  16. ADP-ribosylation, a multifaceted modification: Functions and mechanisms in aging and aging-related diseases.
  17. Cognitive reserve proxies are associated with age-related cognitive decline - Not age-related gait speed decline.
  18. Emerging Perspectives of YAP/TAZ in Human Skin Epidermal and Dermal Aging.
  19. Single-cell morphology encodes functional subtypes of senescence in aging human dermal fibroblasts.
  20. Fermented Yak-Kong using Bifidobacterium animalis derived from Korean infant intestine effectively relieves muscle atrophy in an aging mouse model.
  21. Aging atlas reveals cell-type-specific effects of pro-longevity strategies.
  22. Salvianolic acid B protects against UVB-induced skin aging via activation of NRF2.
  23. Deriving skeletal muscle cells from adipose-derived stem cells: Current differentiation strategies.
  24. Caloric restriction extends lifespan in a clonal plant.
  25. Gut Microbiome Multi-Omics and Cognitive Function in the Hispanic Community Health Study/Study of Latinos- Investigation of Neurocognitive Aging.
  26. Controlled cell proliferation and immortalization of human dental pulp stem cells with a doxycycline-inducible expression system.
  27. Alginate oligosaccharide-mediated butyrate-HIF-1α axis improves skin aging in mice.
  28. Epigenetic Age Mediates the Association of Life's Essential 8 With Cardiovascular Disease and Mortality.
  29. The immune system can sabotage gene therapies - can scientists rein it in?
  30. Multicomponent depolymerization of actin filament pointed ends by cofilin and cyclase-associated protein depends upon filament age.
  31. High-resolution genome-wide mapping of chromosome-arm-scale truncations induced by CRISPR-Cas9 editing.
  32. Protective effects of astaxanthin on particulate matter 2.5‑induced senescence in HaCaT keratinocytes via maintenance of redox homeostasis.
  33. SGLT2 inhibition eliminates senescent cells and alleviates pathological aging.
  34. Chromatin plasticity in mechanotransduction.
  35. Early life interventions metformin and trodusquemine metabolically reprogram the developing mouse liver through transcriptomic alterations.
  36. Effects of voluntary and forced physical exercise on the retinal health of aging Wistar rats.
  37. Photobiomodulation: a novel approach to promote trans-differentiation of adipose-derived stem cells into neuronal-like cells.
  38. Human skin bacterial microbiota homeostasis: A delicate balance between health and disease.
  39. Genomic loss of GPR108 disrupts AAV transduction in birds.
  40. Maintenance of R-loop structures by phosphorylated hTERT preserves genome integrity.
  41. The age-related decline of helicase function-how G-quadruplex structures promote genome instability.
  42. The NDR family of kinases: essential regulators of aging.
  43. Trio preserves motor synapses and prolongs motor ability during aging.
  44. Unraveling the roles of ectopic adipose depots and physical activity in age-related mitochondrial decline.
  45. The stratum corneum barrier: impaired function in relation to associated lipids and proteins.
  46. Human Stem Cells in Regenerative Medicine.
  47. Single-nucleus transcriptome analysis identifies a novel FKBP5+ endothelial cell subtype involved in endothelial-to-mesenchymal transition in adipose tissue during aging.
  48. Bazi Bushen alleviates reproductive aging in aged male mice.
  49. Muscle-specific PGC-1α modulates mitochondrial oxidative stress in aged sarcopenia through regulating Nrf2.
  50. LARP7 overexpression alleviates aortic senescence and atherosclerosis.
  1. Front Endocrinol (Lausanne). 2024 ;15 1363468
    Birds of a feather age together: telomere dynamics and social behavior predict life span in female Japanese quail (Coturnix japonica).
    Shannon E McCollum, Olivia Canter, Vincent J Fasanello, Sarah Gronsky, Mark F Haussmann.
      Social support is vital for mental and physical health and is linked to lower rates of disease and early mortality. Conversely, anti-social behavior can increase mortality risks, both for the initiator and target of the behavior. Chronic stress, which also can increase mortality, may serve as an important link between social behavior and healthy lifespan. There is a growing body of literature in both humans, and model organisms, that chronic social stress can result in more rapid telomere shortening, a measure of biological aging. Here we examine the role of anti-social behavior and social support on physiological markers of stress and aging in the social Japanese quail, Coturnix Japonica. Birds were maintained in groups for their entire lifespan, and longitudinal measures of antisocial behavior (aggressive agonistic behavior), social support (affiliative behavior), baseline corticosterone, change in telomere length, and lifespan were measured. We found quail in affiliative relationships both committed less and were the targets of less aggression compared to birds who were not in these relationships. In addition, birds displaying affiliative behavior had longer telomeres, and longer lifespans. Our work suggests a novel pathway by which social support may buffer against damage at the cellular level resulting in telomere protection and subsequent longer lifespans.
    Keywords:  aggression; anti-social behavior; lifespan; social stress; social support; telomere length
    DOI:  https://doi.org/10.3389/fendo.2024.1363468
  2. Front Aging Neurosci. 2024 ;16 1384554
    Failure of senolytic treatment to prevent cognitive decline in a female rodent model of aging.
    Asha Rani, Linda Bean, Vivekananda Budamagunta, Ashok Kumar, Thomas C Foster.
      There are sex differences in vulnerability and resilience to the stressors of aging and subsequent age-related cognitive decline. Cellular senescence occurs as a response to damaging or stress-inducing stimuli. The response includes a state of irreversible growth arrest, the development of a senescence-associated secretory phenotype, and the release of pro-inflammatory cytokines associated with aging and age-related diseases. Senolytics are compounds designed to eliminate senescent cells. Our recent work indicates that senolytic treatment preserves cognitive function in aging male F344 rats. The current study examined the effect of senolytic treatment on cognitive function in aging female rats. Female F344 rats (12 months) were treated with dasatinib (1.2 mg/kg) + quercetin (12 mg/kg) or ABT-263 (12 mg/kg) or vehicle for 7 months. Examination of the estrus cycle indicated that females had undergone estropause during treatment. Senolytic treatment may have increased sex differences in behavioral stress responsivity, particularly for the initial training on the cued version of the watermaze. However, pre-training on the cue task reduced stress responsivity for subsequent spatial training and all groups learned the spatial discrimination. In contrast to preserved memory observed in senolytic-treated males, all older females exhibited impaired episodic memory relative to young (6-month) females. We suggest that the senolytic treatment may not have been able to compensate for the loss of estradiol, which can act on aging mechanisms for anxiety and memory independent of cellular senescence.
    Keywords:  aging; cognitive testing; hippocampus; senolytic; spatial memory
    DOI:  https://doi.org/10.3389/fnagi.2024.1384554
  3. Aging Cell. 2024 May 26. e14208
    Translatability of life-extending pharmacological treatments between different species.
    Daiana Burdusel, Cristin Coman, Diana-Larisa Ancuta, Dirk Hermann, Thorsten Doeppner, Andrei Gresita, Aurel Popa-Wagner.
      Anti-aging research has made significant strides in identifying treatments capable of extending lifespan across a range of organisms, from simple invertebrates to mammals. This review showcases the current state of anti-aging interventions, highlighting the lifespan extensions observed in animal models through various treatments and the challenges encountered in translating these findings to humans. Despite promising results in lower organisms, the translation of anti-aging treatments to human applications presents a considerable challenge. This discrepancy can be attributed to the increasing complexity of biological systems, species-specific metabolic and genetic differences, and the redundancy of metabolic pathways linked to longevity. Our review focuses on analyzing these challenges, offering insights into the efficacy of anti-aging mechanisms across species and identifying key barriers to their translation into human treatments. By synthesizing current knowledge and identifying gaps in translatability, this review aims to underscore the importance of advancing these therapies for human benefit. Bridging this gap is essential to assess the potential of such treatments in extending the human healthspan.
    Keywords:  aging; drug treatments; humans; invertebrates; lifespan; translatability; vertebrates
    DOI:  https://doi.org/10.1111/acel.14208
  4. Front Vet Sci. 2024 ;11 1369153
    The potential for senotherapy as a novel approach to extend life quality in veterinary medicine.
    Zoë J Williams, Lyndah Chow, Steven Dow, Lynn M Pezzanite.
      Cellular senescence, a condition where cells undergo arrest and can assume an inflammatory phenotype, has been associated with initiation and perpetuation of inflammation driving multiple disease processes in rodent models and humans. Senescent cells secrete inflammatory cytokines, proteins, and matrix metalloproteinases, termed the senescence associated secretory phenotype (SASP), which accelerates the aging processes. In preclinical models, drug interventions termed "senotherapeutics" selectively clear senescent cells and represent a promising strategy to prevent or treat multiple age-related conditions in humans and veterinary species. In this review, we summarize the current available literature describing in vitro evidence for senotheraputic activity, preclinical models of disease, ongoing human clinical trials, and potential clinical applications in veterinary medicine. These promising data to date provide further justification for future studies identifying the most active senotherapeutic combinations, dosages, and routes of administration for use in veterinary medicine.
    Keywords:  dasatinib; fisetin; quercetin; senescence-associated secretory phenotype; senotherapeutics
    DOI:  https://doi.org/10.3389/fvets.2024.1369153
  5. J Cell Physiol. 2024 May 27.
    SATB1, senescence and senescence-related diseases.
    Wenjing Qi, Jinping Bai, Ruoxi Wang, Xianlu Zeng, Lihui Zhang.
      Aging leads to an accumulation of cellular mutations and damage, increasing the risk of senescence, apoptosis, and malignant transformation. Cellular senescence, which is pivotal in aging, acts as both a guard against cellular transformation and as a check against cancer progression. It is marked by stable cell cycle arrest, widespread macromolecular changes, a pro-inflammatory profile, and altered gene expression. However, it remains to be determined whether these differing subsets of senescent cells result from unique intrinsic programs or are influenced by their environmental contexts. Multiple transcription regulators and chromatin modifiers contribute to these alterations. Special AT-rich sequence-binding protein 1 (SATB1) stands out as a crucial regulator in this process, orchestrating gene expression by structuring chromatin into loop domains and anchoring DNA elements. This review provides an overview of cellular senescence and delves into the role of SATB1 in senescence-related diseases. It highlights SATB1's potential in developing antiaging and anticancer strategies, potentially contributing to improved quality of life and addressing aging-related diseases.
    Keywords:  SATB1; aging‐related diseases; cellular senescence; immunosenescence; neurodegeneration
    DOI:  https://doi.org/10.1002/jcp.31327
  6. Maturitas. 2024 May 21. pii: S0378-5122(24)00123-3. [Epub ahead of print]186 108028
    Unlocking longevity with GLP-1: A key to turn back the clock?
    Vivek P Chavda, Pankti C Balar, Dixa A Vaghela, Payal Dodiya.
      Traditionally known for managing blood sugar, GLP-1, a gut hormone, is emerging as a potential key to both lengthening lifespan and combating age-related ailments. While widely recognized for its role in blood sugar control, GLP-1 is increasingly recognized for its diverse effects on various biological pathways beyond glucose metabolism. Research across organisms and humans suggests that activating GLP-1 receptors significantly impacts cellular processes linked to aging. Its ability to boost mitochondrial function, enhance cellular stress resistance, and quell inflammation hints at its wider influence on aging mechanisms. This intricate interplay between GLP-1 and longevity appears to act through multiple pathways. One key effect is its ability to modulate insulin sensitivity, potentially curbing age-related metabolic issues like type 2 diabetes. Its neuroprotective properties also make it a promising candidate for addressing age-related cognitive decline and neurodegenerative diseases. Furthermore, preclinical studies using GLP-1 analogs or agonists have shown promising results in extending lifespan and improving healthspan in various model organisms. These findings provide a compelling rationale for exploring GLP-1-based interventions in humans to extend healthy aging. However, despite the exciting therapeutic prospects of GLP-1 in promoting longevity, challenges remain. Determining optimal dosages, establishing long-term safety profiles, and investigating potential adverse effects require comprehensive clinical investigations before we can confidently translate these findings to humans. This article emphasises the wide applicability of GLP-1.
    Keywords:  Age-related diseases; Bone health; Cancer; Cardiovascular health; Cellular senescence; Cognitive function; Frailty; GLP-1; Glucagon-like peptide-1; Healthy aging; Incretin hormones; Insulin sensitivity; Longevity; Metabolic health; Mitochondrial dysfunction; Neuroprotective effects; Sarcopenia
    DOI:  https://doi.org/10.1016/j.maturitas.2024.108028
  7. Cancer Sci. 2024 May 27.
    Dipeptidylpeptidase-4-targeted activatable fluorescent probes visualize senescent cells.
    Hisamichi Tanaka, Sho Sugawara, Yoko Tanaka, Tze Mun Loo, Ryo Tachibana, Atsuki Abe, Mako Kamiya, Yasuteru Urano, Akiko Takahashi.
      Senescent cells promote cancer development and progression through chronic inflammation caused by a senescence-associated secretory phenotype (SASP). Although various senotherapeutic strategies targeting senescent cells have been developed for the prevention and treatment of cancers, technology for the in vivo detection and evaluation of senescent cell accumulation has not yet been established. Here, we identified activatable fluorescent probes targeting dipeptidylpeptidase-4 (DPP4) as an effective probe for detecting senescent cells through an enzymatic activity-based screening of fluorescent probes. We also determined that these probes were highly, selectively, and rapidly activated in senescent cells during live cell imaging. Furthermore, we successfully visualized senescent cells in the organs of mice using DPP4-targeted probes. These results are expected to lead to the development of a diagnostic technology for noninvasively detecting senescent cells in vivo and could play a role in the application of DPP4 prodrugs for senotherapy.
    Keywords:  DPP4 and senotherapy; fluorescent probe; imaging; senescence
    DOI:  https://doi.org/10.1111/cas.16229
  8. Redox Biol. 2024 May 22. pii: S2213-2317(24)00182-4. [Epub ahead of print]73 103204
    A non-canonical role of ELN protects from cellular senescence by limiting iron-dependent regulation of gene expression.
    Joanna Czarnecka-Herok, Kexin Zhu, Jean-Michel Flaman, Delphine Goehrig, Mathieu Vernier, Gabriela Makulyte, Aline Lamboux, Helena Dragic, Muriel Rhinn, Jean-Jacques Médard, Gilles Faury, Philippe Bertolino, Vincent Balter, Romain Debret, Serge Adnot, Nadine Martin, David Bernard.
      The ELN gene encodes tropoelastin which is used to generate elastic fibers that insure proper tissue elasticity. Decreased amounts of elastic fibers and/or accumulation of bioactive products of their cleavage, named elastokines, are thought to contribute to aging. Cellular senescence, characterized by a stable proliferation arrest and by the senescence-associated secretory phenotype (SASP), increases with aging, fostering the onset and progression of age-related diseases and overall aging, and has so far never been linked with elastin. Here, we identified that decrease in ELN either by siRNA in normal human fibroblasts or by knockout in mouse embryonic fibroblasts results in premature senescence. Surprisingly this effect is independent of elastic fiber degradation or elastokines production, but it relies on the rapid increase in HMOX1 after ELN downregulation. Moreover, the induction of HMOX1 depends on p53 and NRF2 transcription factors, and leads to an increase in iron, further mediating ELN downregulation-induced senescence. Screening of iron-dependent DNA and histones demethylases revealed a role for histone PHF8 demethylase in mediating ELN downregulation-induced senescence. Collectively, these results unveil a role for ELN in protecting cells from cellular senescence through a non-canonical mechanism involving a ROS/HMOX1/iron accumulation/PHF8 histone demethylase pathway reprogramming in gene expression towards a senescence program.
    Keywords:  Cellular senescence; ELN; HMOX1; Iron; PHF8; ROS
    DOI:  https://doi.org/10.1016/j.redox.2024.103204
  9. Adv Healthc Mater. 2024 May 26. e2401085
    Senolytic Therapy Enabled by Senescent Cell-Sensitive Biomimetic Melanin Nano-senolytics.
    Hairui Zhang, Xiaoling Xu, Xin Shou, Wucan Liao, Chengkang Jin, Changjiang Chen, Chen Zhang, Wenhua Gao, Junfeng Zhang, Weihong Ge, Liyun Shi.
      Cellular senescence is a significant risk factor for aging and age-related diseases (ARD). The canonical senolytics Dasatinib and Quercetin (DQ) have shown promise in clearing senescent cells (SnCs); however, the lack of selectivity poses a challenge in achieving optimal outcomes. Despite the recent occurrence of the nanomaterial-based approaches targeting SnCs, limited therapeutic effects and potential toxicity still remain a major concern. Herein, we developed a "double locks-like" nanoplatform that integrated Galactan coating and mesoporous polydopamine to encase the senolytic drug DQ. By this way, DQ was only released in SnCs that were featured with higher levels of β-galactosidase (β-gal) and low PH. Additionally, the nanoparticles were equipped with 2,2,6,6-Tetramethylpiperidine-1-oxyl (Tempo) to gain enhanced photothermal converting potential. Consequently, the synthesized nanosenolytics demonstrated remarkable specificity and efficacy in eradicating SnCs, and accordingly reversed pulmonary fibrosis in mice without affecting normal tissues. Upon exposure of near-infrared (NIR) light, the nanoparticles demonstrated to efficiently remove senescent tumor cells inducted by chemotherapy, thereby hindering the outgrowth and metastasis or breast cancer. Collectively, the present study develops an "On/Off" switchable nanoplatform in response to SnCs, and produces a more safe, efficient and feasible way to delay aging or alleviate age-associated diseases. This article is protected by copyright. All rights reserved.
    Keywords:  Dasatinib and Quercetin; Pulmonary fibrosis; Targeting senescent cells; breast cancer; β‐galactosidase; “On/Off” switchable nanoplatform
    DOI:  https://doi.org/10.1002/adhm.202401085
  10. Biogerontology. 2024 May 29.
    Compensation effect of mortality is a challenge to substantial lifespan extension of humans.
    Natalia S Gavrilova, Leonid A Gavrilov.
      Despite frequent claims regarding radical extensions of human lifespan in the near future, many pragmatic scientists caution against excessive and baseless optimism on this front. In this study, we examine the compensation effect of mortality (CEM) as a potential challenge to substantial lifespan extension. The CEM is an empirical mortality regularity, often depicted as relative mortality convergence at advanced ages. Analysis of mortality data from 44 human populations, available in the Human Mortality Database, demonstrated that CEM can be represented as a continuous decline in relative mortality variation (assessed through the coefficient of variation and the standard deviation of the logarithm of mortality) with age, reaching a minimum corresponding to the species-specific lifespan. Through this method, the species-specific lifespan is determined to be 96-97 years, closely aligning with estimates derived from correlations between Gompertz parameters (95-98 years). Importantly, this representation of CEM can be achieved non-parametrically, eliminating the need for estimating Gompertz parameters. CEM is a challenge to lifespan extension, because it suggests that the true aging rate in humans (based on loss of vital elements, e.g., functional cells) remains stable at approximately 1% per year in the majority of human populations and is not affected by environmental or familial longevity factors. Given this rate of functional cell loss, one might anticipate that the total pool of functional cells could be entirely depleted by the age of 115-120 years creating physiological limit to human lifespan. Mortality pattern of supercentenarians (110 + years) aligns with this prediction.
    Keywords:  Aging; Coefficient of variation; Compensation effect of mortality; Gompertz law; Mortality; Standard deviation
    DOI:  https://doi.org/10.1007/s10522-024-10111-z
  11. Ageing Res Rev. 2024 May 30. pii: S1568-1637(24)00169-7. [Epub ahead of print]98 102351
    Changes in M6A methylation: A key factor in the vicious cycle of flora -gut aging.
    Menglu Ding, Junbin Yan, Yuxuan Chen, Jinguo Liu, Guanqun Chao, Shuo Zhang.
      The aging process significantly impacts the gastrointestinal tract and various bodily systems, exacerbating age-related diseases. Research suggests a correlation between an imbalance in intestinal flora and gut aging, yet the precise mechanism remains incompletely elucidated. Epigenetic modifications, particularly m6A methylation, play a pivotal role in driving aging and are closely associated with gut aging. Maintaining a healthy balance of intestinal microbes is contingent upon m6A methylation, which is believed to be crucial in the vicious cycle of gut aging and intestinal flora. This article highlights the importance of m6A methylation in the nexus between gut aging and flora. It proposes the potential for targeted m6A methylation to break the vicious cycle of gut aging and flora imbalance, offering novel perspectives on attenuating or reversing gut aging.
    Keywords:  Dysbiosis; Flora imbalance; Gut aging; Intestinal flora; Low inflammation; M6A methylation
    DOI:  https://doi.org/10.1016/j.arr.2024.102351
  12. Clin Kidney J. 2024 May;17(5): sfae133
    SGLT2 inhibition to target kidney aging.
    Elisa Russo, Valentina Zanetti, Lucia Macciò, Giulia Benizzelli, Federico Carbone, Edoardo La Porta, Pasquale Esposito, Daniela Verzola, Giacomo Garibotto, Francesca Viazzi.
      Anti-aging therapy is the latest frontier in the world of medical science, especially for widespread diseases such as chronic kidney disease (CKD). Both renal aging and CKD are characterized by increased cellular senescence, inflammation and oxidative stress. A variety of cellular signalling mechanisms are involved in these processes, which provide new potential targets for therapeutic strategies aimed at counteracting the onset and progression of CKD. At the same time, sodium-glucose co-transporter 2 inhibitors (SGLT2is) continuously demonstrate large beneficial effects at all stages of the cardiorenal metabolic continuum. The broad-spectrum benefits of SGLT2is have led to changes in several treatment guidelines and to growing scientific interest in the underlying working principles. Multiple mechanisms have been studied to explain these great renal benefits, but many things remain to be solved. With this in mind, we provide an overview of the experimental evidence for the effects of SGLT2is on the molecular pathway's ability to modulate senescence, aging and parenchymal damage, especially at the kidney level. We propose to shed some light on the role of SGLT2is in kidney care by focusing on their potential to reduce the progression of kidney disease across the spectrum of aging and dysregulation of senescence.
    Keywords:  SGLT2 inhibitors; aging; chronic kidney disease; molecular pathways; senescence
    DOI:  https://doi.org/10.1093/ckj/sfae133
  13. Cell Rep. 2024 May 27. pii: S2211-1247(24)00609-0. [Epub ahead of print]43(6): 114281
    Sch9S6K controls DNA repair and DNA damage response efficiency in aging cells.
    Chiara Lucca, Elisa Ferrari, Ghadeer Shubassi, Arta Ajazi, Ramveer Choudhary, Christopher Bruhn, Vittoria Matafora, Angela Bachi, Marco Foiani.
      Survival from UV-induced DNA lesions relies on nucleotide excision repair (NER) and the Mec1ATR DNA damage response (DDR). We study DDR and NER in aging cells and find that old cells struggle to repair DNA and activate Mec1ATR. We employ pharmacological and genetic approaches to rescue DDR and NER during aging. Conditions activating Snf1AMPK rescue DDR functionality, but not NER, while inhibition of the TORC1-Sch9S6K axis restores NER and enhances DDR by tuning PP2A activity, specifically in aging cells. Age-related repair deficiency depends on Snf1AMPK-mediated phosphorylation of Sch9S6K on Ser160 and Ser163. PP2A activity in old cells is detrimental for DDR and influences NER by modulating Snf1AMPK and Sch9S6K. Hence, the DDR and repair pathways in aging cells are influenced by the metabolic tuning of opposing AMPK and TORC1 networks and by PP2A activity. Specific Sch9S6K phospho-isoforms control DDR and NER efficiency, specifically during aging.
    Keywords:  ATR/Mec1; CP: Molecular biology; DDR; DNA repair; PP2A; Rad53; Sch9; Snf1; TORC1; UV lesions; aging
    DOI:  https://doi.org/10.1016/j.celrep.2024.114281
  14. Transl Psychiatry. 2024 May 30. 14(1): 226
    Psychogenic Aging: A Novel Prospect to Integrate Psychobiological Hallmarks of Aging.
    Manuel Faria, Ariel Ganz, Fedor Galkin, Alex Zhavoronkov, Michael Snyder.
      Psychological factors are amongst the most robust predictors of healthspan and longevity, yet are rarely incorporated into scientific and medical frameworks of aging. The prospect of characterizing and integrating the psychological influences of aging is therefore an unmet step for the advancement of geroscience. Psychogenic Aging research is an emerging branch of biogerontology that aims to address this gap by investigating the impact of psychological factors on human longevity. It is an interdisciplinary field that integrates complex psychological, neurological, and molecular relationships that can be best understood with precision medicine methodologies. This perspective argues that psychogenic aging should be considered an integral component of the Hallmarks of Aging framework, opening the doors for future biopsychosocial integration in longevity research. By providing a unique perspective on frequently overlooked aspects of organismal aging, psychogenic aging offers new insights and targets for anti-aging therapeutics on individual and societal levels that can significantly benefit the scientific and medical communities.
    DOI:  https://doi.org/10.1038/s41398-024-02919-7
  15. iScience. 2024 Jun 21. 27(6): 109949
    Low-dose naltrexone extends healthspan and lifespan in C. elegans via SKN-1 activation.
    Weisha Li, Rebecca L McIntyre, Bauke V Schomakers, Rashmi Kamble, Anne H G Luesink, Michel van Weeghel, Riekelt H Houtkooper, Arwen W Gao, Georges E Janssens.
      As the global aging population rises, finding effective interventions to improve aging health is crucial. Drug repurposing, utilizing existing drugs for new purposes, presents a promising strategy for rapid implementation. We explored naltrexone from the Library of Integrated Network-based Cellular Signatures (LINCS) based on several selection criteria. Low-dose naltrexone (LDN) has gained attention for treating various diseases, yet its impact on longevity remains underexplored. Our study on C. elegans demonstrated that a low dose, but not high dose, of naltrexone extended the healthspan and lifespan. This effect was mediated through SKN-1 (NRF2 in mammals) signaling, influencing innate immune gene expression and upregulating oxidative stress responses. With LDN's low side effects profile, our findings underscore its potential as a geroprotector, suggesting further exploration for promoting healthy aging in humans is warranted.
    Keywords:  Biological process; Cellular physiology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2024.109949
  16. Ageing Res Rev. 2024 May 28. pii: S1568-1637(24)00165-X. [Epub ahead of print]98 102347
    ADP-ribosylation, a multifaceted modification: Functions and mechanisms in aging and aging-related diseases.
    Wu Hao, Zhao Jialong, Yuan Jiuzhi, Yu Yang, Lv Chongning, Lu Jincai.
      Aging, a complex biological process, plays key roles the development of multiple disorders referred as aging-related diseases involving cardiovascular diseases, stroke, neurodegenerative diseases, cancers, lipid metabolism-related diseases. ADP-ribosylation is a reversible modification onto proteins and nucleic acids to alter their structures and/or functions. Growing evidence support the importance of ADP-ribosylation and ADP-ribosylation-associated enzymes in aging and age-related diseases. In this review, we summarized ADP-ribosylation-associated proteins including ADP-ribosyl transferases, the ADP-ribosyl hydrolyses and ADP-ribose binding domains. Furthermore, we outlined the latest knowledge about regulation of ADP-ribosylation in the pathogenesis and progression of main aging-related diseases, organism aging and cellular senescence, and we also speculated the underlying mechanisms to better disclose this novel molecular network. Moreover, we discussed current issues and provided an outlook for future research, aiming to revealing the unknown bio-properties of ADP-ribosylation, and establishing a novel therapeutic perspective in aging-related diseases and health aging via targeting ADP-ribosylation.
    Keywords:  ADP-ribosylation; Aging-related diseases; Cellular senescence; PARPs
    DOI:  https://doi.org/10.1016/j.arr.2024.102347
  17. Neurobiol Aging. 2024 May 27. pii: S0197-4580(24)00104-0. [Epub ahead of print]141 46-54
    Cognitive reserve proxies are associated with age-related cognitive decline - Not age-related gait speed decline.
    Helena M Blumen, Oshadi Jayakody, Emmeline Ayers, Nir Barzilai, Christian Habeck, Sofiya Milman, Yaakov Stern, Erica F Weiss, Joe Verghese.
      Cognition and gait share brain substrates in aging and dementia. Cognitive reserve (CR) allows individuals to cope with brain pathology and delay cognitive impairment and dementia. Yet, evidence for that CR is associated with age-related cognitive decline is mixed, and evidence for that CR is associated with age-related gait decline is limited. In 1,079 older (M Age = 75.4 years; 56.0% women) LonGenity study participants without dementia at baseline and up to 12 years of annual follow-up (M follow-up = 3.9 years, SD = 2.5 years), high CR inferred from cognitive (education years), physical (number of blocks walked per day; weekly physical activity days), and social (volunteering/working; living with someone) proxies were associated with slower rates of age-related decline in global cognition - not gait speed decline. Thus, cognitive, physical, and social CR proxies are associated with cognitive decline in older adults without dementia. The multifactorial etiology and earlier decline in gait than cognition may render it less modifiable by CR proxies later in life.
    Keywords:  Brain maintenance; Cognitive decline; Cognitive reserve; Frontal cortical thickness; Gait decline; Hippocampal volume
    DOI:  https://doi.org/10.1016/j.neurobiolaging.2024.05.012
  18. Ann Dermatol. 2024 Jun;36(3): 135-144
    Emerging Perspectives of YAP/TAZ in Human Skin Epidermal and Dermal Aging.
    Jun Young Kim, Taihao Quan.
      Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are key downstream effectors of the Hippo signaling pathway, which plays a central role in tissue homeostasis, organ development, and regeneration. While the dysregulation of YAP/TAZ has been linked to various human diseases, their involvement in the aging of human skin has only recently begun to manifest. In the skin, the YAP/TAZ effectors emerge as central regulators in maintaining homeostasis of epidermal stem cells and dermal extracellular matrix, and thus intimately linked to skin aging processes. This review underscores recent molecular breakthroughs highlighting how age-related decline of YAP/TAZ activity impacts human epidermal and dermal aging. Gaining insight into the evolving roles of YAP/TAZ in human skin aging presents a promising avenue for the development of innovative therapeutic approaches aimed at enhancing skin health and addressing age-related skin conditions.
    Keywords:  Dermis; Extracellular matrix; Hippo signaling pathway; Skin aging; Stem cells
    DOI:  https://doi.org/10.5021/ad.23.156
  19. bioRxiv. 2024 May 16. pii: 2024.05.10.593637. [Epub ahead of print]
    Single-cell morphology encodes functional subtypes of senescence in aging human dermal fibroblasts.
    Pratik Kamat, Nico Macaluso, Chanhong Min, Yukang Li, Anshika Agrawal, Aaron Winston, Lauren Pan, Bartholomew Starich, Teasia Stewart, Pei-Hsun Wu, Jean Fan, Jeremy Walston, Jude M Phillip.
      Cellular senescence is an established driver of aging, exhibiting context-dependent phenotypes across multiple biological length-scales. Despite its mechanistic importance, profiling senescence within cell populations is challenging. This is in part due to the limitations of current biomarkers to robustly identify senescent cells across biological settings, and the heterogeneous, non-binary phenotypes exhibited by senescent cells. Using a panel of primary dermal fibroblasts, we combined live single-cell imaging, machine learning, multiple senescence induction conditions, and multiple protein-based senescence biomarkers to show the emergence of functional subtypes of senescence. Leveraging single-cell morphologies, we defined eleven distinct morphology clusters, with the abundance of cells in each cluster being dependent on the mode of senescence induction, the time post-induction, and the age of the donor. Of these eleven clusters, we identified three bona-fide senescence subtypes (C7, C10, C11), with C10 showing the strongest age-dependence across a cohort of fifty aging individuals. To determine the functional significance of these senescence subtypes, we profiled their responses to senotherapies, specifically focusing on Dasatinib + Quercetin (D+Q). Results indicated subtype-dependent responses, with senescent cells in C7 being most responsive to D+Q. Altogether, we provide a robust single-cell framework to identify and classify functional senescence subtypes with applications for next-generation senotherapy screens, and the potential to explain heterogeneous senescence phenotypes across biological settings based on the presence and abundance of distinct senescence subtypes.
    DOI:  https://doi.org/10.1101/2024.05.10.593637
  20. Food Funct. 2024 May 30.
    Fermented Yak-Kong using Bifidobacterium animalis derived from Korean infant intestine effectively relieves muscle atrophy in an aging mouse model.
    Seung Hee Yang, Hee Yang, Byeong Min Ahn, Sung-Young Lee, Seon Joo Lee, Jin Soo Kim, Young Tae Koo, Chang Hyung Lee, Jong Hun Kim, Jung Han Yoon Park, Young Jin Jang, Ki Won Lee.
      Yak-Kong (YK) is a small black soybean widely cultivated in Korea. It is considered to have excellent health functionality, as it has been reported to have better antioxidant efficacy than conventional black or yellow soybeans. Since YK has been described as good for the muscle health of the elderly in old oriental medicine books, this study sought to investigate the effect of fermented YK with Bifidobacterium animalis subsp. lactis LDTM 8102 (FYK) on muscle atrophy. In C2C12 mouse myoblasts, FYK elevated the expression of MyoD, total MHC, phosphorylated AKT, and PGC1α. In addition, two kinds of in vivo studies were conducted using both an induced and normal aging mouse model. The behavioral test results showed that in the induced aging mouse model, FYK intake alleviated age-related muscle weakness and loss of exercise performance. In addition, FYK alleviated muscle mass decrease and improved the expression of biomarkers including total MHC, myf6, phosphorylated AKT, PGC1α, and Tfam, which are related to myoblast differentiation, muscle protein synthesis, and mitochondrial generation in the muscle. In the normal aging model, FYK consumption did not increase muscle mass, but did upregulate the expression levels of biomarkers related to myoblast differentiation, muscle hypertrophy, and muscle function. Furthermore, it mitigated age-related declines in skeletal muscle force production and functional limitation by enhancing exercise performance and grip strength. Taken together, the results suggest that FYK has the potential to be a new functional food material that can alleviate the loss of muscle mass and strength caused by aging and prevent sarcopenia.
    DOI:  https://doi.org/10.1039/d3fo04204a
  21. Nat Aging. 2024 May 30.
    Aging atlas reveals cell-type-specific effects of pro-longevity strategies.
    Shihong Max Gao, Yanyan Qi, Qinghao Zhang, Youchen Guan, Yi-Tang Lee, Lang Ding, Lihua Wang, Aaron S Mohammed, Hongjie Li, Yusi Fu, Meng C Wang.
      Organismal aging involves functional declines in both somatic and reproductive tissues. Multiple strategies have been discovered to extend lifespan across species. However, how age-related molecular changes differ among various tissues and how those lifespan-extending strategies slow tissue aging in distinct manners remain unclear. Here we generated the transcriptomic Cell Atlas of Worm Aging (CAWA, http://mengwanglab.org/atlas ) of wild-type and long-lived strains. We discovered cell-specific, age-related molecular and functional signatures across all somatic and germ cell types. We developed transcriptomic aging clocks for different tissues and quantitatively determined how three different pro-longevity strategies slow tissue aging distinctively. Furthermore, through genome-wide profiling of alternative polyadenylation (APA) events in different tissues, we discovered cell-type-specific APA changes during aging and revealed how these changes are differentially affected by the pro-longevity strategies. Together, this study offers fundamental molecular insights into both somatic and reproductive aging and provides a valuable resource for in-depth understanding of the diversity of pro-longevity mechanisms.
    DOI:  https://doi.org/10.1038/s43587-024-00631-1
  22. Phytomedicine. 2024 May 16. pii: S0944-7113(24)00335-0. [Epub ahead of print]130 155676
    Salvianolic acid B protects against UVB-induced skin aging via activation of NRF2.
    Jia-Ming Sun, Yu-Xin Liu, Yang-Dan Liu, Chia-Kang Ho, Yi-Tung Tsai, Dong-Sheng Wen, Lu Huang, Dan-Ning Zheng, Ya Gao, Yi-Fan Zhang, Li Yu.
       BACKGROUND: Prolonged exposure to sun radiation may result in harmful skin photoaging. Therefore, discovering novel anti-photoaging treatment modalities is critical. An active component isolated from Salvia miltiorrhiza (SM), Salvianolic acid B (Sal-B), is a robust antioxidant and anti-inflammatory agent. This investigation aimed to discover the therapeutic impact and pathways of salvianolic acid B for UVB-induced skin photoaging, an area that remains unexplored.
    METHODS: We conducted in vitro experiments on human dermal fibroblasts (HDFs) exposed to UVB radiation, assessing cellular senescence, superoxide dismutase (SOD) activity, cell viability, proliferation, migration, levels of reactive oxygen species (ROS), and mitochondrial health. The potential mechanism of Sal-B was analyzed using RNA sequencing, with further validation through Western blotting, PCR, and nuclear factor erythroid 2-related factor 2 (NRF2) silencing methods. In vivo, a model of skin photoaging induced by UVB in nude mice was employed. The collagen fiber levels were assessed utilizing hematoxylin and eosin (H&E), Masson, and Sirus red staining. Additionally, NRF2 and related gene and protein expression levels were identified utilizing PCR and Western blotting.
    RESULTS: Sal-B was found to significantly counteract photoaging in UVB-exposed skin fibroblasts, reducing aging-related decline in fibroblast proliferation and an increase in apoptosis. It was observed that Sal-B aids in protecting mitochondria from excessive ROS production by promoting NRF2 nuclear translocation. NRF2 knockdown experiments established its necessity for Sal-B's anti-photoaging effects. The in vivo studies also verified Sal-B's anti-photoaging efficacy, surpassing that of tretinoin (Retino-A). These outcomes offer novel insights into the contribution of Sal-B in developing clinical treatment modalities for UVB-induced photodamage in skin fibroblasts.
    CONCLUSION: In this investigation, we identified the Sal-B protective impact on the senescence of dermal fibroblasts and skin photoaging induced by radiation of UVB. The outcomes suggest Sal-B as a potential modulator of the NRF2 signaling pathway.
    Keywords:  Mitochondria; NRF2; Salvianolic acid B; Skin aging; Skin fibroblasts; Ultraviolet B
    DOI:  https://doi.org/10.1016/j.phymed.2024.155676
  23. Chin Med J (Engl). 2024 May 27.
    Deriving skeletal muscle cells from adipose-derived stem cells: Current differentiation strategies.
    Wei Liang, Meng Han, Huiting Wu, Wanwen Dang, Xiaoyu Meng, Yonghuan Zhen, Yang An.
      
    DOI:  https://doi.org/10.1097/CM9.0000000000003184
  24. Ecol Lett. 2024 Jun;27(6): e14444
    Caloric restriction extends lifespan in a clonal plant.
    Suzanne L Chmilar, Amanda C Luzardo, Priyanka Dutt, Abbe Pawluk, Victoria C Thwaites, Robert A Laird.
      When subjected to dietary caloric restriction (CR), individual animals often outlive well-fed conspecifics. Here, we address whether CR also extends lifespan in plants. Whereas caloric intake in animals comes from ingestion, in plants it derives from photosynthesis. Thus, factors that reduce photosynthesis, such as reduced light intensity, can induce CR. In two lab experiments investigating the aquatic macrophyte Lemna minor, we tracked hundreds of individuals longitudinally, with light intensity-and hence, CR-manipulated using neutral-density filters. In both experiments, CR dramatically increased lifespan through a process of temporal scaling. Moreover, the magnitude of lifespan extension accorded with the assumptions that (a) light intensity positively relates to photosynthesis following Michaelis-Menten kinetics, and (b) photosynthesis negatively relates to lifespan via a power law. Our results emphasize that CR-mediated lifespan extension applies to autotrophs as well as heterotrophs, and suggest that variation in light intensity has quantitatively predictable effects on plant aging trajectories.
    Keywords:   Lemna ; Lemnaceae; Lemnoideae; aging; demography; duckweed; light intensity; longevity; senescence; temporal scaling
    DOI:  https://doi.org/10.1111/ele.14444
  25. medRxiv. 2024 May 17. pii: 2024.05.17.24307533. [Epub ahead of print]
    Gut Microbiome Multi-Omics and Cognitive Function in the Hispanic Community Health Study/Study of Latinos- Investigation of Neurocognitive Aging.
    Natalia Palacios, Scott Gordon, Tao Wang, Robert Burk, Qibin Qi, Curtis Huttenhower, Hector M Gonzalez, Robert Knight, Charles De Carli, Marta Daviglus, Melissa Lamar, Gregory Telavera, Wassim Tarraf, Tomasz Kosciolek, Jianwen Cai, Robert C Kaplan.
       INTRODUCTION: We conducted a study within the Hispanic Community Health Study/Study of Latinos- Investigation of Neurocognitive Aging (HCHS/SOL-INCA) cohort to examine the association between gut microbiome and cognitive function.
    METHODS: We analyzed the fecal metagenomes of 2,471 HCHS/SOL-INCA participants to, cross-sectionally, identify microbial taxonomic and functional features associated with global cognitive function. Omnibus (PERMANOVA) and feature-wise analyses (MaAsLin2) were conducted to identify microbiome-cognition associations, and specific microbial species and pathways (Kyoto Encyclopedia of Genes and Genomes (KEGG modules) associated with cognition.
    RESULTS: Eubacterium species( E. siraeum and E. eligens ), were associated with better cognition. Several KEGG modules, most strongly Ornithine, Serine biosynthesis and Urea Cycle, were associated with worse cognition.
    DISCUSSION: In a large Hispanic/Latino cohort, we identified several microbial taxa and KEGG pathways associated with cognition.
    DOI:  https://doi.org/10.1101/2024.05.17.24307533
  26. Cell Biochem Funct. 2024 Jun;42(4): e4064
    Controlled cell proliferation and immortalization of human dental pulp stem cells with a doxycycline-inducible expression system.
    Ai Orimoto, William N Addison, Shinichi Mochizuki, Wataru Ariyoshi, Kentaro Ono, Chiaki Kitamura, Tohru Kiyono, Tomokazu Fukuda.
      Human dental pulp stem cells are a potentially useful resource for cell-based therapies and tissue repair in dental and medical applications. However, the primary culture of isolated dental pulp stem cells has notably been limited. A major requirement of an ideal human dental pulp stem cell culture system is the preservation of efficient proliferation and innate stemness over prolonged passaging, while also ensuring ease of handling through standard, user-friendly culture methods. In this study, we have engineered a novel human dental pulp stem cell line, distinguished by the constitutive expression of telomerase reverse transcriptase (TERT), and the conditional expression of the R24C mutant cyclin-dependent kinase 4 (CDK4R24C) and Cyclin D1. We have named this cell line Tet-off K4DT hDPSCs. Furthermore, we have conducted a comprehensive comparative analysis of their biological attributes in relation to a previously immortalized human dental pulp stem cells, hDPSC-K4DT, which were immortalized by the constitutive expression of CDK4R24C, Cyclin D1 and TERT. In Tet-off K4DT cells, the expression of the K4D genes can be precisely suppressed by the inclusion of doxycycline. Remarkably, Tet-off K4DT cells demonstrated an extended cellular lifespan, increased proliferative capacity, and enhanced osteogenic differentiation potential when compared to K4DT cells. Moreover, Tet-off K4DT cells had no observable genomic aberrations and also displayed a sustained expression of stem cell markers even at relatively advanced passages. Taken together, the establishment of this new cell line holds immense promise as powerful experimental tool for both fundamental and applied research involving dental pulp stem cells.
    Keywords:  R24C mutant cyclin‐dependent kinase 4; cyclin D1; human dental pulp stem cells; telomerase reverse transcriptase
    DOI:  https://doi.org/10.1002/cbf.4064
  27. J Pharm Anal. 2024 May;14(5): 100911
    Alginate oligosaccharide-mediated butyrate-HIF-1α axis improves skin aging in mice.
    Ting Gao, Yixuan Li, Xiaoyu Wang, Fazheng Ren.
      The "gut-skin" axis has been proved and is considered as a novel therapy for the prevention of skin aging. The antioxidant efficacy of oligomannonic acid (MAOS) make it an intriguing target for use to improve skin aging. The present study further explored whereby MAOS-mediated gut-skin axis balance prevented skin aging in mice. The data indicated the skin aging phenotypes, oxidative stress, skin mitochondrial dysfunction, and intestinal dysbiosis (especially the butyrate and HIF-1α levels decreased) in aging mice. Similarly, fecal microbiota transplantation (FMT) from aging mice rebuild the aging-like phenotypes. Further, we demonstrated MAOS-mediated colonic butyrate-HIF-1α axis homeostasis promoted the entry of butyrate into the skin, upregulated mitophagy level and ultimately improving skin aging via HDAC3/PHD/HIF-1α/mitophagy loop in skin of mice. Overall, our study offered a better insights of the effectiveness of alginate oligosaccharides (AOS), promised to become a personalized targeted therapeutic agents, on gut-skin axis disorder inducing skin aging.
    Keywords:  Alginate oligosaccharide; Butyrate; HIF-1α; Mitophagy; Skin aging
    DOI:  https://doi.org/10.1016/j.jpha.2023.12.001
  28. J Am Heart Assoc. 2024 May 29. e032743
    Epigenetic Age Mediates the Association of Life's Essential 8 With Cardiovascular Disease and Mortality.
    Madeleine Carbonneau, Yi Li, Brenton Prescott, Chunyu Liu, Tianxiao Huan, Roby Joehanes, Joanne M Murabito, Nancy L Heard-Costa, Vanessa Xanthakis, Daniel Levy, Jiantao Ma.
       BACKGROUND: Life's Essential 8 (LE8) is an enhanced metric for cardiovascular health. The interrelations among LE8, biomarkers of aging, and disease risks are unclear.
    METHODS AND RESULTS: LE8 score was calculated for 5682 Framingham Heart Study participants. We implemented 4 DNA methylation-based epigenetic age biomarkers, with older epigenetic age hypothesized to represent faster biological aging, and examined whether these biomarkers mediated the associations between the LE8 score and cardiovascular disease (CVD), CVD-specific mortality, and all-cause mortality. We found that a 1 SD increase in the LE8 score was associated with a 35% (95% CI, 27-41; P=1.8E-15) lower risk of incident CVD, a 36% (95% CI, 24-47; P=7E-7) lower risk of CVD-specific mortality, and a 29% (95% CI, 22-35; P=7E-15) lower risk of all-cause mortality. These associations were partly mediated by epigenetic age biomarkers, particularly the GrimAge and the DunedinPACE scores. The potential mediation effects by epigenetic age biomarkers tended to be more profound in participants with higher genetic risk for older epigenetic age, compared with those with lower genetic risk. For example, in participants with higher GrimAge polygenic scores (greater than median), the mean proportion of mediation was 39%, 39%, and 78% for the association of the LE8 score with incident CVD, CVD-specific mortality, and all-cause mortality, respectively. No significant mediation was observed in participants with lower GrimAge polygenic score.
    CONCLUSIONS: DNA methylation-based epigenetic age scores mediate the associations between the LE8 score and incident CVD, CVD-specific mortality, and all-cause mortality, particularly in individuals with higher genetic predisposition for older epigenetic age.
    Keywords:  Life's Essential 8; cardiovascular health; epigenetic age scores; methylation
    DOI:  https://doi.org/10.1161/JAHA.123.032743
  29. Nature. 2024 May 28.
    The immune system can sabotage gene therapies - can scientists rein it in?
    Heidi Ledford.
      
    Keywords:  Ethics; Gene therapy; Medical research
    DOI:  https://doi.org/10.1038/d41586-024-01483-w
  30. Eur J Cell Biol. 2024 May 22. pii: S0171-9335(24)00040-2. [Epub ahead of print]103(2): 151423
    Multicomponent depolymerization of actin filament pointed ends by cofilin and cyclase-associated protein depends upon filament age.
    Ekram M Towsif, Blake Andrew Miller, Heidi Ulrichs, Shashank Shekhar.
      Intracellular actin networks assemble through the addition of ATP-actin subunits at the growing barbed ends of actin filaments. This is followed by "aging" of the filament via ATP hydrolysis and subsequent phosphate release. Aged ADP-actin subunits thus "treadmill" through the filament before being released back into the cytoplasmic monomer pool as a result of depolymerization at filament pointed ends. The necessity for aging before filament disassembly is reinforced by preferential binding of cofilin to aged ADP-actin subunits over newly-assembled ADP-Pi actin subunits in the filament. Consequently, investigations into how cofilin influences pointed-end depolymerization have, thus far, focused exclusively on aged ADP-actin filaments. Using microfluidics-assisted Total Internal Reflection Fluorescence (mf-TIRF) microscopy, we reveal that, similar to their effects on ADP filaments, cofilin and cyclase-associated protein (CAP) also promote pointed-end depolymerization of ADP-Pi filaments. Interestingly, the maximal rates of ADP-Pi filament depolymerization by CAP and cofilin together remain approximately 20-40 times lower than for ADP filaments. Further, we find that the promotion of ADP-Pi pointed-end depolymerization is conserved for all three mammalian cofilin isoforms. Taken together, the mechanisms presented here open the possibility of newly-assembled actin filaments being directly disassembled from their pointed-ends, thus bypassing the slow step of Pi release in the aging process.
    Keywords:  Actin; Cofilin; Cyclase-associated protein (CAP); Depolymerization; Pointed-end depolymerization
    DOI:  https://doi.org/10.1016/j.ejcb.2024.151423
  31. Nat Genet. 2024 May 29.
    High-resolution genome-wide mapping of chromosome-arm-scale truncations induced by CRISPR-Cas9 editing.
    Nathan H Lazar, Safiye Celik, Lu Chen, Marta M Fay, Jonathan C Irish, James Jensen, Conor A Tillinghast, John Urbanik, William P Bone, Christopher C Gibson, Imran S Haque.
      Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) is a powerful tool for introducing targeted mutations in DNA, but recent studies have shown that it can have unintended effects such as structural changes. However, these studies have not yet looked genome wide or across data types. Here we performed a phenotypic CRISPR-Cas9 scan targeting 17,065 genes in primary human cells, revealing a 'proximity bias' in which CRISPR knockouts show unexpected similarities to unrelated genes on the same chromosome arm. This bias was found to be consistent across cell types, laboratories, Cas9 delivery methods and assay modalities, and the data suggest that it is caused by telomeric truncations of chromosome arms, with cell cycle and apoptotic pathways playing a mediating role. Additionally, a simple correction is demonstrated to mitigate this pervasive bias while preserving biological relationships. This previously uncharacterized effect has implications for functional genomic studies using CRISPR-Cas9, with applications in discovery biology, drug-target identification, cell therapies and genetic therapeutics.
    DOI:  https://doi.org/10.1038/s41588-024-01758-y
  32. Exp Ther Med. 2024 Jul;28(1): 275
    Protective effects of astaxanthin on particulate matter 2.5‑induced senescence in HaCaT keratinocytes via maintenance of redox homeostasis.
    Ao Xuan Zhen, Kyoung Ah Kang, Mei Jing Piao, Pincha Devage Sameera Madushan Fernando, Herath Mudiyanselage Udari Lakmini Herath, Jin Won Hyun.
      Particulate matter 2.5 (PM2.5) imposes a heavy burden on the skin and respiratory system of human beings, causing side effects such as aging, inflammation and cancer. Astaxanthin (ATX) is a well-known antioxidant widely used for its anti-inflammatory and anti-aging properties. However, few studies have investigated the protective effects of ATX against PM2.5-induced senescence in HaCaT cells. In the present study, the levels of reactive oxygen species (ROS) and antioxidant enzymes were measured after treatment with PM2.5. The results revealed that PM2.5 generated excessive ROS and reduced the translocation of nuclear factor erythroid 2-related factor 2 (NRF2), subsequently reducing the expression of antioxidant enzymes. However, pretreatment with ATX reversed the ROS levels as well as the expression of antioxidant enzymes. In addition, ATX protected cells from PM2.5-induced DNA damage and rescued PM2.5-induced cell cycle arrest. The levels of senescence-associated phenotype markers, such as interleukin-1β, matrix metalloproteinases, and β-galactosidase, were increased by exposure to PM2.5, however these effects were reversed by ATX. After interfering with NRF2 mRNA expression and exposing cells to PM2.5, the levels of ROS and β-galactosidase were higher compared with siControl RNA cells exposed to PM2.5. However, ATX inhibited ROS and β-galactosidase levels in both the siControl RNA and the siNRF2 RNA groups. Thus, ATX protects HaCaT keratinocytes from PM2.5-induced senescence by partially inhibiting excessive ROS generation via the NRF2 signaling pathway.
    Keywords:  astaxanthin; nuclear factor erythroid 2-related factor 2; particulate matter 2.5; reactive oxygen species; senescence
    DOI:  https://doi.org/10.3892/etm.2024.12563
  33. Nat Aging. 2024 May 30.
    SGLT2 inhibition eliminates senescent cells and alleviates pathological aging.
    Goro Katsuumi, Ippei Shimizu, Masayoshi Suda, Yohko Yoshida, Takaaki Furihata, Yusuke Joki, Chieh-Lun Hsiao, Liang Jiaqi, Shinya Fujiki, Manabu Abe, Masataka Sugimoto, Tomoyoshi Soga, Tohru Minamino.
      It has been reported that accumulation of senescent cells in various tissues contributes to pathological aging and that elimination of senescent cells (senolysis) improves age-associated pathologies. Here, we demonstrate that inhibition of sodium-glucose co-transporter 2 (SGLT2) enhances clearance of senescent cells, thereby ameliorating age-associated phenotypic changes. In a mouse model of dietary obesity, short-term treatment with the SGLT2 inhibitor canagliflozin reduced the senescence load in visceral adipose tissue and improved adipose tissue inflammation and metabolic dysfunction, but normalization of plasma glucose by insulin treatment had no effect on senescent cells. Canagliflozin extended the lifespan of mice with premature aging even when treatment was started in middle age. Metabolomic analyses revealed that short-term treatment with canagliflozin upregulated 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, enhancing immune-mediated clearance of senescent cells by downregulating expression of programmed cell death-ligand 1. These findings suggest that inhibition of SGLT2 has an indirect senolytic effect by enhancing endogenous immunosurveillance of senescent cells.
    DOI:  https://doi.org/10.1038/s43587-024-00642-y
  34. Curr Opin Cell Biol. 2024 May 28. pii: S0955-0674(24)00055-3. [Epub ahead of print]88 102376
    Chromatin plasticity in mechanotransduction.
    Maria Vivo, Valentina Rosti, Sara Cervone, Chiara Lanzuolo.
      Living organisms can detect and respond to physical forces at the cellular level. The pathways that transmit these forces to the nucleus allow cells to react quickly and consistently to environmental changes. Mechanobiology involves the interaction between physical forces and biological processes and is crucial for driving embryonic development and adapting to environmental cues during adulthood. Molecular studies have shown that cells can sense mechanical signals directly through membrane receptors linked to the cytoskeleton or indirectly through biochemical cascades that can influence gene expression for environmental adaptation. This review will explore the role of epigenetic modifications, emphasizing the 3D genome architecture and nuclear structures as responders to mechanical stimuli, which ensure cellular memory and adaptability. Understanding how mechanical cues are transduced and regulate cell functioning, governing processes such as cell programming and reprogramming, is essential for advancing our knowledge of human diseases.
    DOI:  https://doi.org/10.1016/j.ceb.2024.102376
  35. Aging Cell. 2024 May 27. e14227
    Early life interventions metformin and trodusquemine metabolically reprogram the developing mouse liver through transcriptomic alterations.
    Sarah A Ashiqueali, Augusto Schneider, Xiang Zhu, Ewelina Juszczyk, Mishfak A M Mansoor, Yun Zhu, Yimin Fang, Bianka M Zanini, Driele N Garcia, Natalie Hayslip, David Medina, Samuel McFadden, Robert Stockwell, Rong Yuan, Andrzej Bartke, Michael Zasloff, Shadab Siddiqi, Michal M Masternak.
      Recent studies have demonstrated the remarkable potential of early life intervention strategies at influencing the course of postnatal development, thereby offering exciting possibilities for enhancing longevity and improving overall health. Metformin (MF), an FDA-approved medication for type II diabetes mellitus, has recently gained attention for its promising anti-aging properties, acting as a calorie restriction mimetic, and delaying precocious puberty. Additionally, trodusquemine (MSI-1436), an investigational drug, has been shown to combat obesity and metabolic disorders by inhibiting the enzyme protein tyrosine phosphatase 1b (Ptp1b), consequently reducing hepatic lipogenesis and counteracting insulin and leptin resistance. In this study, we aimed to further explore the effects of these compounds on young, developing mice to uncover biomolecular signatures that are central to liver metabolic processes. We found that MSI-1436 more potently alters mRNA and miRNA expression in the liver compared with MF, with bioinformatic analysis suggesting that cohorts of differentially expressed miRNAs inhibit the action of phosphoinositide 3-kinase (Pi3k), protein kinase B (Akt), and mammalian target of rapamycin (Mtor) to regulate the downstream processes of de novo lipogenesis, fatty acid oxidation, very-low-density lipoprotein transport, and cholesterol biosynthesis and efflux. In summary, our study demonstrates that administering these compounds during the postnatal window metabolically reprograms the liver through induction of potent epigenetic changes in the transcriptome, potentially forestalling the onset of age-related diseases and enhancing longevity. Future studies are necessary to determine the impacts on lifespan and overall quality of life.
    Keywords:  development; early life interventions; juvenile mice; lifespan and healthspan; liver metabolism; metformin; microRNAs and mRNAs; postnatal window; trodusquemine (3‐N‐1(spermine)‐7, 24‐dihydroxy‐5‐cholestane 24‐sulfate)
    DOI:  https://doi.org/10.1111/acel.14227
  36. Geroscience. 2024 May 25.
    Effects of voluntary and forced physical exercise on the retinal health of aging Wistar rats.
    Anna Szilágyi, Barbara Takács, Réka Szekeres, Vera Tarjányi, Dávid Nagy, Dániel Priksz, Mariann Bombicz, Rita Kiss, Adrienn Mónika Szabó, Andrea Lehoczki, Rudolf Gesztelyi, Béla Juhász, Zoltán Szilvássy, Balázs Varga.
      Aging is accompanied by an increased prevalence of degenerative conditions, including those affecting ocular health, which significantly impact quality of life and increase the burden on healthcare systems. Among these, retinal aging is of particular concern due to its direct link to vision impairment, a leading cause of disability in the elderly. Vision loss in the aging population is associated with heightened risks of cognitive decline, social isolation, and morbidity. This study addresses the critical gap in our understanding of modifiable lifestyle factors, such as physical exercise, that may mitigate retinal aging and its related pathologies. We investigated the effects of different exercise regimens-voluntary (recreational-type) and forced (high-intensity)-on the retinal health of aging Wistar rats (18-month-old), serving as a model for studying the translational potential of exercise interventions in humans. Male Wistar rats were divided into four groups: a young control (3-month-old) for baseline comparison, an aged sedentary control, an aged group engaging in voluntary exercise via a running wheel in their cage, and an aged group subjected to forced exercise on a treadmill for six sessions of 20 min each per week. After a 6-month experimental period, we assessed retinal function via electroretinography (ERG), measured retinal thickness histologically, and analyzed protein expression changes relevant to oxidative stress, inflammation, and anti-aging mechanisms. Our findings reveal that voluntary exercise positively impacts retinal function and morphology, reducing oxidative stress and inflammation markers while enhancing anti-aging protein expression. In contrast, forced exercise showed diminished benefits. These insights underscore the importance of exercise intensity and preference in preserving retinal health during aging. The study highlights the potential of recreational physical activity as a non-invasive strategy to counteract retinal aging, advocating for further research into exercise regimens as preventative therapies for age-related ocular degenerations.
    Keywords:  Aging; Electroretinography; MAO-B; Physical exercise; Retinal function; Wistar rat
    DOI:  https://doi.org/10.1007/s11357-024-01208-x
  37. Neural Regen Res. 2025 Feb 01. 20(2): 598-608
    Photobiomodulation: a novel approach to promote trans-differentiation of adipose-derived stem cells into neuronal-like cells.
    Daniella Da Silva, Madeleen Jansen van Rensburg, Anine Crous, Heidi Abrahamse.
      JOURNAL/nrgr/04.03/01300535-202502000-00035/figure1/v/2024-05-28T214302Z/r/image-tiff Photobiomodulation, originally used red and near-infrared lasers, can alter cellular metabolism. It has been demonstrated that the visible spectrum at 451-540 nm does not necessarily increase cell proliferation, near-infrared light promotes adipose stem cell proliferation and affects adipose stem cell migration, which is necessary for the cells homing to the site of injury. In this in vitro study, we explored the potential of adipose-derived stem cells to differentiate into neurons for future translational regenerative treatments in neurodegenerative disorders and brain injuries. We investigated the effects of various biological and chemical inducers on trans-differentiation and evaluated the impact of photobiomodulation using 825 nm near-infrared and 525 nm green laser light at 5 J/cm2. As adipose-derived stem cells can be used in autologous grafting and photobiomodulation has been shown to have biostimulatory effects. Our findings reveal that adipose-derived stem cells can indeed trans-differentiate into neuronal cells when exposed to inducers, with pre-induced cells exhibiting higher rates of proliferation and trans-differentiation compared with the control group. Interestingly, green laser light stimulation led to notable morphological changes indicative of enhanced trans-differentiation, while near-infrared photobiomodulation notably increased the expression of neuronal markers. Through biochemical analysis and enzyme-linked immunosorbent assays, we observed marked improvements in viability, proliferation, membrane permeability, and mitochondrial membrane potential, as well as increased protein levels of neuron-specific enolase and ciliary neurotrophic factor. Overall, our results demonstrate the efficacy of photobiomodulation in enhancing the trans-differentiation ability of adipose-derived stem cells, offering promising prospects for their use in regenerative medicine for neurodegenerative disorders and brain injuries.
    DOI:  https://doi.org/10.4103/NRR.NRR-D-23-01219
  38. mLife. 2023 Jun;2(2): 107-120
    Human skin bacterial microbiota homeostasis: A delicate balance between health and disease.
    Yibin Zhu, Xi Yu, Gong Cheng.
      As the largest organ of the body, the skin acts as a barrier to prevent diseases and harbors a variety of beneficial bacteria. Furthermore, the skin bacterial microbiota plays a vital role in health and disease. Disruption of the barrier or an imbalance between symbionts and pathogens can lead to skin disorders or even systemic diseases. In this review, we first provide an overview of research on skin bacterial microbiota and human health, including the composition of skin bacteria in a healthy state, as well as skin bacterial microbiota educating the immune system and preventing the invasion of pathogens. We then discuss the diseases that result from skin microbial dysbiosis, including atopic dermatitis, common acne, chronic wounds, psoriasis, viral transmission, cutaneous lupus, cutaneous lymphoma, and hidradenitis suppurativa. Finally, we highlight the progress that utilizes skin microorganisms for disease therapeutics, such as bacteriotherapy and skin microbiome transplantation. A deeper knowledge of the interaction between human health and disease and the homeostasis of the skin bacterial microbiota will lead to new insights and strategies for exploiting skin bacteria as a novel therapeutic target.
    Keywords:  homeostasis; human diseases; skin bacterial microbiota; therapeutics
    DOI:  https://doi.org/10.1002/mlf2.12064
  39. bioRxiv. 2024 May 17. pii: 2024.05.16.589954. [Epub ahead of print]
    Genomic loss of GPR108 disrupts AAV transduction in birds.
    Alexander A Nevue, Anusha Sairavi, Samuel J Huang, Hiroyuki Nakai, Claudio V Mello.
      The G protein-coupled receptor 108 ( GPR108 ) gene encodes a protein factor identified as critical for adeno-associated virus (AAV) entry into mammalian cells, but whether it is universally involved in AAV transduction is unknown. Remarkably, we have discovered that GPR108 is absent in the genomes of birds and in most other sauropsids, providing a likely explanation for the overall lower AAV transduction efficacy of common AAV serotypes in birds compared to mammals. Importantly, transgenic expression of human GPR108 and manipulation of related glycan binding sites in the viral capsid significantly boost AAV transduction in zebra finch cells. These findings contribute to a more in depth understanding of the mechanisms and evolution of AAV transduction, with potential implications for the design of efficient tools for gene manipulation in experimental animal models, and a range of gene therapy applications in humans.
    DOI:  https://doi.org/10.1101/2024.05.16.589954
  40. Nat Cell Biol. 2024 May 28.
    Maintenance of R-loop structures by phosphorylated hTERT preserves genome integrity.
    Mitsuhiro Machitani, Akira Nomura, Taro Yamashita, Mami Yasukawa, Saori Ueki, Ken-Ichi Fujita, Toshihide Ueno, Akio Yamashita, Yoshikazu Tanzawa, Masahiko Watanabe, Toshiyasu Taniguchi, Noriko Saitoh, Shuichi Kaneko, Yukinari Kato, Hiroyuki Mano, Kenkichi Masutomi.
      As aberrant accumulation of RNA-DNA hybrids (R-loops) causes DNA damage and genome instability, cells express regulators of R-loop structures. Here we report that RNA-dependent RNA polymerase (RdRP) activity of human telomerase reverse transcriptase (hTERT) regulates R-loop formation. We found that the phosphorylated form of hTERT (p-hTERT) exhibits RdRP activity in nuclear speckles both in telomerase-positive cells and telomerase-negative cells with alternative lengthening of telomeres (ALT) activity. The p-hTERT did not associate with telomerase RNA component in nuclear speckles but, instead, with TERRA RNAs to resolve R-loops. Targeting of the TERT gene in ALT cells ablated RdRP activity and impaired tumour growth. Using a genome-scale CRISPR loss-of-function screen, we identified Fanconi anaemia/BRCA genes as synthetic lethal partners of hTERT RdRP. Inactivation of RdRP and Fanconi anaemia/BRCA genes caused accumulation of R-loop structures and DNA damage. These findings indicate that RdRP activity of p-hTERT guards against genome instability by removing R-loop structures.
    DOI:  https://doi.org/10.1038/s41556-024-01427-6
  41. FEBS Lett. 2024 May 27.
    The age-related decline of helicase function-how G-quadruplex structures promote genome instability.
    Joana Frobel, Robert Hänsel-Hertsch.
      The intricate mechanisms underlying transcription-dependent genome instability involve G-quadruplexes (G4) and R-loops. This perspective elucidates the potential link between these structures and genome instability in aging. The co-occurrence of G4 DNA and RNA-DNA hybrid structures (G-loop) underscores a complex interplay in genome regulation and instability. Here, we hypothesize that the age-related decline of sirtuin function leads to an increase in acetylated helicases that bind to G4 DNA and RNA-DNA hybrid structures, but are less efficient in resolving them. We propose that acetylated, less active, helicases induce persistent G-loop structures, promoting transcription-dependent genome instability in aging.
    Keywords:  G4; G‐quadruplex; RNA–DNA hybrids; R‐loops; aging; double‐strand breaks; epigenetics; genome instability; helicases; sirtuins
    DOI:  https://doi.org/10.1002/1873-3468.14939
  42. Front Mol Neurosci. 2024 ;17 1371086
    The NDR family of kinases: essential regulators of aging.
    Kevin Jonischkies, Miguel Del Angel, Yunus Emre Demiray, Allison Loaiza Zambrano, Oliver Stork.
      Aging is defined as a progressive decline of cognitive and physiological functions over lifetime. Since the definition of the nine hallmarks of aging in 2013 by López-Otin, numerous studies have attempted to identify the main regulators and contributors in the aging process. One interesting group of proteins whose participation has been implicated in several aging hallmarks are the nuclear DBF2-related (NDR) family of serine-threonine AGC kinases. They are one of the core components of the Hippo signaling pathway and include NDR1, NDR2, LATS1 and LATS2 in mammals, along with its highly conserved metazoan orthologs; Trc in Drosophila melanogaster, SAX-1 in Caenorhabditis elegans, CBK1, DBF20 in Saccharomyces cerevisiae and orb6 in Saccharomyces pombe. These kinases have been independently linked to the regulation of widely diverse cellular processes disrupted during aging such as the cell cycle progression, transcription, intercellular communication, nutrient homeostasis, autophagy, apoptosis, and stem cell differentiation. However, a comprehensive overview of the state-of-the-art knowledge regarding the post-translational modifications of and by NDR kinases in aging has not been conducted. In this review, we summarize the current understanding of the NDR family of kinases, focusing on their relevance to various aging hallmarks, and emphasize the growing body of evidence that suggests NDR kinases are essential regulators of aging across species.
    Keywords:  DNA repair; aging; autophagy; brain aging; cellular senescence; neuroinflammation; nuclear Dbf2-related (NDR) kinases; nutrient sensing and signaling
    DOI:  https://doi.org/10.3389/fnmol.2024.1371086
  43. Cell Rep. 2024 May 24. pii: S2211-1247(24)00584-9. [Epub ahead of print]43(6): 114256
    Trio preserves motor synapses and prolongs motor ability during aging.
    Soumya Banerjee, Samuel Vernon, Evelyne Ruchti, Greta Limoni, Wei Jiao, Jamshid Asadzadeh, Marine Van Campenhoudt, Brian D McCabe.
      The decline of motor ability is a hallmark feature of aging and is accompanied by degeneration of motor synaptic terminals. Consistent with this, Drosophila motor synapses undergo characteristic age-dependent structural fragmentation co-incident with diminishing motor ability. Here, we show that motor synapse levels of Trio, an evolutionarily conserved guanine nucleotide exchange factor (GEF), decline with age. We demonstrate that increasing Trio expression in adult Drosophila can abrogate age-dependent synaptic structural fragmentation, postpone the decline of motor ability, and maintain the capacity of motor synapses to sustain high-intensity neurotransmitter release. This preservative activity is conserved in transgenic human Trio, requires Trio Rac GEF function, and can also ameliorate synapse degeneration induced by depletion of miniature neurotransmission. Our results support a paradigm where the structural dissolution of motor synapses precedes and promotes motor behavioral diminishment and where intervening in this process can postpone the decline of motor function during aging.
    Keywords:  CP: Cell biology; CP: Neuroscience; Drosophila; GEF; Rac; aging; behavior; cytoskeleton; motor neuron; neurotransmission; structure; synapse
    DOI:  https://doi.org/10.1016/j.celrep.2024.114256
  44. Obesity (Silver Spring). 2024 Jun;32(6): 1043-1044
    Unraveling the roles of ectopic adipose depots and physical activity in age-related mitochondrial decline.
    Brian A Irving, Hawley E Kunz.
      
    DOI:  https://doi.org/10.1002/oby.24048
  45. Tissue Barriers. 2024 May 31. 2361197
    The stratum corneum barrier: impaired function in relation to associated lipids and proteins.
    Jie Chen, Changjie Liu, Yuan Yang, Xue Gong, Huan Qian.
      The skin is the largest organ of the human body and is widely considered to be the first-line defense of the body, providing essential protection against mechanical, physical, and chemical damage. Keratinocytes are the primary cells of the outer layer of the epidermis, which acts as a mechanical and permeability barrier. The epidermis is a permanently renewed tissue where undifferentiated keratinocytes located at the basal layer proliferate and migrate to the overlying layers. Here we report that some components of keratinocytes affect the formation and differentiation of the stratum corneum, which is the most specialized layer of the epidermis.
    Keywords:  Stratum corneum; ceramide; differentiation; filaggrin; keratin; keratinocyte
    DOI:  https://doi.org/10.1080/21688370.2024.2361197
  46. Am J Med. 2024 May 23. pii: S0002-9343(24)00332-2. [Epub ahead of print]
    Human Stem Cells in Regenerative Medicine.
    Edward J Goetzl, Joseph S Alpert, Qin M Chen.
      Modern medicine now has the capacity to improve therapy for many human diseases by introducing adult somatic stem cells that can repair or replace defective or damaged tissues. However, the area is still in an early phase of development, so that all new applications must be carefully designed for maximal safety as well as effectiveness.
    Keywords:  cardiovascular diseases; cellular therapy; neurological diseases
    DOI:  https://doi.org/10.1016/j.amjmed.2024.05.024
  47. Biochem Biophys Res Commun. 2024 May 22. pii: S0006-291X(24)00693-4. [Epub ahead of print]722 150157
    Single-nucleus transcriptome analysis identifies a novel FKBP5+ endothelial cell subtype involved in endothelial-to-mesenchymal transition in adipose tissue during aging.
    Siyuan Chen, Xiaoxi Pan, Pingjin Gao, Fang Wu.
      Age-associated adipose tissue (AT) dysfunction is multifactorial and often leads to detrimental health consequences. AT is highly vascularized and endothelial cells (ECs) has been recently identified as a key regulator in the homeostasis of AT. However, the alteration of cell composition in AT during aging and the communication between endothelial cells and adipocytes remain poorly understood. In this study, we take advantage of single nucleus RNA sequencing analysis, and discovered a group of FKBP5+ ECs specifically resident in aged AT. Of interest, FKBP5+ ECs exhibited the potential for endothelial-to-mesenchymal transition (EndoMT) and exhibited a critical role in regulating adipocytes. Furthermore, lineage tracing experiments demonstrated that ECs in aged AT tend to express FKBP5 and undergo EndoMT with progressive loss of endothelial marker. This study may provide a basis for a new mechanism of microvascular ECs-induced AT dysfunction during aging.
    DOI:  https://doi.org/10.1016/j.bbrc.2024.150157
  48. Chin J Nat Med. 2024 May;pii: S1875-5364(24)60639-4. [Epub ahead of print]22(5): 416-425
    Bazi Bushen alleviates reproductive aging in aged male mice.
    Kun Ma, Mengnan Li, Yahui Song, Xinjing Mao, Shaolan Zhang, Yaping Zhang, Yuning Jiang, Chuanyuan Ji, Kunxu Niu, Hongrong Li, Yunlong Hou, Cong Wei.
      Bazi Bushen (BZBS), a traditional Chinese medicine (TCM), has demonstrated therapeutic efficacy in testicular dysfunction within D-galactose and NaNO2 mouse models. This study aimed to ascertain if BZBS could also mitigate the decline in testicular function associated with natural aging. Therefore, male aged mice were employed to evaluate the preventive effects of BZBS on male reproductive aging. This was achieved by assessing sex hormone production, testicular histomorphology, and spermatogenesis. Relative to the untreated aged control group, BZBS administration elevated the levels of sex hormones and spermatocyte populations and preserved normal testicular structure in aged mice. Notably, spermatogenesis was maintained. Further analyses, including malondialdehyde (MDA) assays and real-time PCR, indicated that BZBS diminished testicular oxidative stress and the inflammatory burden. Corroborating these findings, mice treated with BZBS exhibited reductions in the populations of senescent and apoptotic cells within the seminiferous tubules, suggesting alleviated cellular damage. In contrast, we observed that rapamycin, a drug known for its longevity benefits, induced excessive testicular apoptosis and did not decrease lipid peroxidation. Collectively, our results highlight BZBS's promising clinical potential in counteracting male reproductive aging, underlining its mechanisms of action.
    Keywords:  Apoptosis; Cell senescence; Male reproductive aging; Spermatogenic cells; Traditional Chinese medicine
    DOI:  https://doi.org/10.1016/S1875-5364(24)60639-4
  49. Exp Gerontol. 2024 May 28. pii: S0531-5565(24)00110-4. [Epub ahead of print]193 112468
    Muscle-specific PGC-1α modulates mitochondrial oxidative stress in aged sarcopenia through regulating Nrf2.
    Lei Song, Jianfeng Xue, Lingfen Xu, Lin Cheng, Yongxia Zhang, Xiaojun Wang.
       BACKGROUND: Aged sarcopenia is characterized by loss of skeletal muscle mass and strength, and mitochondrial dysregulation in skeletal myocyte is considered as a major factor. Here, we aimed to analyze the effects of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) on mitochondrial reactive oxygen species (ROS) and nuclear factor erythroid 2-related factor 2 (Nrf2) in aged skeletal muscles.
    METHODS: C2C12 cells were stimulated by 50 μM 7β-hydroxycholesterol (7β-OHC) to observe the changes of cellular ROS, mitochondrial ROS, and expression of PGC-1α and Nrf2. Different PGC-1α expression in cells was established by transfection with small interfering RNA (siRNA) or plasmids overexpressing PGC-1α (pEX-3-PGC-1α). The effects of different PGC-1α expression on cellular ROS, mitochondrial ROS and Nrf2 expression were measured in cells. Wild type (WT) mice and PGC-1α conditional knockout (CKO) mice were used to analyze the effects of PGC-1α on aged sarcopenia and expression of Nrf2 and CD38 in gastrocnemius muscles. Diethylmaleate, a Nrf2 activator, was used to analyze the connection between PGC-1α and Nrf2 in cells and in mice.
    RESULTS: In C2C12 cells, the expressions of PGC-1α and Nrf2 were declined by the 7β-OHC treatment or PGC-1α silence. Moreover, PGC-1α silence increased the harmful ROS and decreased the Nrf2 protein expression in the 7β-OHC-treated cells. PGC-1α overexpression decreased the harmful ROS and increased the Nrf2 protein expression in the 7β-OHC-treated cells. Diethylmaleate treatment decreased the harmful ROS in the 7β-OHC-treated or PGC-1α siRNA-transfected cells. At the same age, muscle-specific PGC-1α deficiency aggravated aged sarcopenia, decreased Nrf2 expression and increased CD38 expression in gastrocnemius muscles compared with the WT mice. Diethylmaleate treatment improved the muscle function and decreased the CD38 expression in the old two genotypes.
    CONCLUSIONS: Our study demonstrated that PGC-1α modulated mitochondrial oxidative stress in aged sarcopenia through regulating Nrf2.
    Keywords:  7β-hydroxycholesterol (7β-OHC); C2C12 cells; CD38; PGC-1α conditional knockout (CKO) mice; PGC-1α siRNA
    DOI:  https://doi.org/10.1016/j.exger.2024.112468
  50. J Cell Mol Med. 2024 Jun;28(11): e18388
    LARP7 overexpression alleviates aortic senescence and atherosclerosis.
    Ping Yang, Shuo Wu, Yige Li, Yingmei Lou, Junhao Xiong, Yuze Wang, Zilong Geng, Bing Zhang.
      Atherosclerosis, characterized by the accumulation of lipid plaques on the inner walls of arteries, is the leading cause of heart attack, stroke and severe ischemic injuries. Senescent cells have been found to accumulate within atherosclerotic lesions and contribute to the progression of atherosclerosis. In our previous study, we discovered that suppressing Larp7 accelerates senescence by inhibiting Sirt1 activity, resulting in increased atherosclerosis in high-fat diet (HFD) fed and ApoE deficient (ApoEKO) mice. However, there has been no direct evidence demonstrating Larp7 per se could attenuate atherosclerosis. To this end, we generated a tetO-controlled and Cre-activated Larp7 gain-of-function mouse. Through RT-PCR and western blotting, we confirmed Larp7 overexpression in the aortas of HFD-fed ApoEKO; Larp7tetO mice. Larp7 overexpression led to increased Sirt1 activity and decreased cellular senescence signals mediated by p53/p65 in the aortas. Additionally, Larp7 overexpression reduced the presence of p16-positive senescent cells in the aortic lesions. Furthermore, Larp7 overexpression resulted in a decrease in pro-inflammatory macrophages and SASP factors. Consequently, Larp7 overexpression led to a reduction in the area of atherosclerotic lesions in HFD-fed ApoEKO; Larp7tetO mice. In summary, our study provides evidence that Larp7 overexpression holds promise as an approach to inhibit cellular senescence and prevent atherosclerosis.
    Keywords:  Larp7; Sirt1; atherosclerosis; cellular senescence
    DOI:  https://doi.org/10.1111/jcmm.18388
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