bims-caglex Biomed News
on Cellular aging and life extension
Issue of 2023–12–17
sixty-one papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño
  1. Digital telomere measurement by long-read sequencing distinguishes healthy aging from disease.
  2. Longitudinal machine learning uncouples healthy aging factors from chronic disease risks.
  3. Intermittent supplementation with fisetin improves arterial function in old mice by decreasing cellular senescence.
  4. Sustained Vision Recovery by OSK Gene Therapy in a Mouse Model of Glaucoma.
  5. Tea consumption and attenuation of biological aging: a longitudinal analysis from two cohort studies.
  6. Choice of gDNA isolation method has a significant impact on average murine Telomere Length estimates.
  7. The Myc-Like Mlx Network Impacts Aging and Metabolism.
  8. Impact of NLRP3 Depletion on Aging-Related Metaflammation, Cognitive Function, and Social Behavior in Mice.
  9. The effect of metformin on senescence of T lymphocytes.
  10. Biological Role and Related Natural Products of SIRT1 in Nonalcoholic Fatty Liver.
  11. Three common assumptions about inflammation, aging, and health that are probably wrong.
  12. Benidipine calcium channel blocker promotes the death of cigarette smoke-induced senescent cells and improves lung emphysema.
  13. Calcium's Role and Signaling in Aging Muscle, Cellular Senescence, and Mineral Interactions.
  14. Targeting cellular senescence in senile osteoporosis: therapeutic potential of traditional Chinese medicine.
  15. Geroprotector drugs and exercise: friends or foes on healthy longevity?
  16. PTEN expression can be used as a switch between senescence and apoptosis in breast cancer cells according to a logical model of the G2/M checkpoint.
  17. Lifestyle strategies to promote proteostasis and reduce the risk of Alzheimer's disease and other proteinopathies.
  18. Transcriptome-wide analysis reveals GYG2 as a mitochondria-related aging biomarker in human subcutaneous adipose tissue.
  19. Revealing the role of epigenetic and post-translational modulations of autophagy proteins in the regulation of autophagy and cancer: a therapeutic approach.
  20. The stromal microenvironment and ovarian aging: mechanisms and therapeutic opportunities.
  21. The role of cellular senescence in skin aging and age-related skin pathologies.
  22. Cellular senescence in brain aging and cognitive decline.
  23. The Role of Cdc42 in the Insulin and Leptin Pathways Contributing to the Development of Age-Related Obesity.
  24. Age-related decline in spermatogenic activity accompanied with endothelial cell senescence in male mice.
  25. Targeting gut microbiota in aging-related cardiovascular dysfunction: focus on the mechanisms.
  26. Heavy-chain antibody targeting of CD38 NAD+ hydrolase ectoenzyme to prevent fibrosis in multiple organs.
  27. Sirtuin 6 activation rescues the age-related decline in DNA damage repair in primary human chondrocytes.
  28. [Transcription Factor NRF2 in Endothelial Functions].
  29. Network dynamical stability analysis reveals key "mallostatic" natural variables that erode homeostasis and drive age-related decline of health.
  30. Downregulation of mitochondrial metabolism is a driver for fast skeletal muscle loss during mouse aging.
  31. Cyclase-associated protein is a pro-formin anti-capping processive depolymerase of actin barbed and pointed ends.
  32. Upregulation of SLC7A11/xCT creates a vulnerability to selenocystine-induced cytotoxicity.
  33. Associations of combined phenotypic aging and genetic risk with incidence of chronic respiratory diseases in the UK biobank: a prospective cohort study.
  34. Modeling aging and retinal degeneration with mitochondrial DNA mutation burden.
  35. A novel ultrasonic-electric-based microsystem for the investigation of mechanical aging on lipid membranes.
  36. Traditional Chinese medicine for the prevention and treatment of presbycusis.
  37. PCSK9, A Promising Novel Target for Age-Related Cardiovascular Dysfunction.
  38. Gut microbiota defined epigenomes of Alzheimer's and Parkinson's diseases reveal novel targets for therapy.
  39. Could the Combination of eGFR and mGPS Facilitate the Differential Diagnosis of Age-Related Renal Decline from Diseases? A Large Study on the Population of Western Sicily.
  40. Identification of FOXO1 as a geroprotector in human synovium through single-nucleus transcriptomic profiling.
  41. The Role of Immune Dysfunction in Parkinson's Disease Development.
  42. Exploring Causal Relationships between Leukocyte Telomere Length, Sex Hormone-Binding Globulin Levels, and Osteoporosis Using Univariable and Multivariable Mendelian Randomization.
  43. Photostimulation of lymphatic clearance of β-amyloid from mouse brain: a new strategy for the therapy of Alzheimer's disease.
  44. Innate Immunity and CKD: Is There a Significant Association?
  45. Why osteoarthritis of the knee is called "a wound that does not heal" and why Tai Chi is an effective treatment.
  46. Melatonin protects Kir2.1 function in an oxidative stress-related model of aging neuroglia.
  47. Targeting cardiovascular risk factors with eugenol: an anti-inflammatory perspective.
  48. Endothelial Response to the Combined Biomechanics of Vessel Stiffness and Shear Stress Is Regulated via Piezo1.
  49. Diet quality is associated with adipose tissue and muscle mass: the Coronary Artery Risk Development in Young Adults (CARDIA) study.
  50. Does functional system segregation mediate the effects of lifestyle on cognition in older adults?
  51. Vitamin D - a scoping review for Nordic nutrition recommendations 2023.
  52. Roles and regulation of Aquaporin-3 in maintaining the gut health: an updated review.
  53. Nectin-4 regulates cellular senescence-associated enlargement of cell size.
  54. Effects of Dietary Methionine Restriction on Cognition in Mice.
  55. Nutrition and physical activity: An Obesity Medicine Association (OMA) Clinical Practice Statement 2022.
  56. Imaging Structural and Electrical Changes of Aging Cells Using Scanning Ion Conductance Microscopy.
  57. Reduced Achilles tendon stiffness in aging persists at matched activations and associates with higher metabolic cost of walking.
  58. UniKP: a unified framework for the prediction of enzyme kinetic parameters.
  59. Methylation of histone H3 lysine 36 is a barrier for therapeutic interventions of head and neck squamous cell carcinoma.
  60. Clinical, Safety and Engineering Perspectives on Wearable Ultrasound Technology: A Review.
  61. Epitranscriptome analysis of NAD-capped RNA by spike-in-based normalization and prediction of chronological age.
  1. bioRxiv. 2023 Dec 01. pii: 2023.11.29.569263. [Epub ahead of print]
    Digital telomere measurement by long-read sequencing distinguishes healthy aging from disease.
    Santiago E Sanchez, Jessica Gu, Anudeep Golla, Annika Martin, William Shomali, Dirk Hockemeyer, Sharon A Savage, Steven E Artandi.
      Telomere length is an important biomarker of organismal aging and cellular replicative potential, but existing measurement methods are limited in resolution and accuracy. Here, we deploy digital telomere measurement by nanopore sequencing to understand how distributions of human telomere length change with age and disease. We measure telomere attrition and de novo elongation with unprecedented resolution in genetically defined populations of human cells, in blood cells from healthy donors and in blood cells from patients with genetic defects in telomere maintenance. We find that human aging is accompanied by a progressive loss of long telomeres and an accumulation of shorter telomeres. In patients with defects in telomere maintenance, the accumulation of short telomeres is more pronounced and correlates with phenotypic severity. We apply machine learning to train a binary classification model that distinguishes healthy individuals from those with telomere biology disorders. This sequencing and bioinformatic pipeline will advance our understanding of telomere maintenance mechanisms and the use of telomere length as a clinical biomarker of aging and disease.
    DOI:  https://doi.org/10.1101/2023.11.29.569263
  2. Nat Aging. 2023 Dec 07.
    Longitudinal machine learning uncouples healthy aging factors from chronic disease risks.
    Netta Mendelson Cohen, Aviezer Lifshitz, Rami Jaschek, Ehud Rinott, Ran Balicer, Liran I Shlush, Gabriel I Barbash, Amos Tanay.
      To understand human longevity, inherent aging processes must be distinguished from known etiologies leading to age-related chronic diseases. Such deconvolution is difficult to achieve because it requires tracking patients throughout their entire lives. Here, we used machine learning to infer health trajectories over the entire adulthood age range using extrapolation from electronic medical records with partial longitudinal coverage. Using this approach, our model tracked the state of patients who were healthy and free from known chronic disease risk and distinguished individuals with higher or lower longevity potential using a multivariate score. We showed that the model and the markers it uses performed consistently on data from Israeli, British and US populations. For example, mildly low neutrophil counts and alkaline phosphatase levels serve as early indicators of healthy aging that are independent of risk for major chronic diseases. We characterize the heritability and genetic associations of our longevity score and demonstrate at least 1 year of extended lifespan for parents of high-scoring patients compared to matched controls. Longitudinal modeling of healthy individuals is thereby established as a tool for understanding healthy aging and longevity.
    DOI:  https://doi.org/10.1038/s43587-023-00536-5
  3. Aging Cell. 2023 Dec 07. e14060
    Intermittent supplementation with fisetin improves arterial function in old mice by decreasing cellular senescence.
    Sophia A Mahoney, Ravinandan Venkatasubramanian, Mary A Darrah, Katelyn R Ludwig, Nicholas S VanDongen, Nathan T Greenberg, Abigail G Longtine, David A Hutton, Vienna E Brunt, Judith Campisi, Simon Melov, Douglas R Seals, Matthew J Rossman, Zachary S Clayton.
      Cellular senescence and the senescence-associated secretory phenotype (SASP) contribute to age-related arterial dysfunction, in part, by promoting oxidative stress and inflammation, which reduce the bioavailability of the vasodilatory molecule nitric oxide (NO). In the present study, we assessed the efficacy of fisetin, a natural compound, as a senolytic to reduce vascular cell senescence and SASP factors and improve arterial function in old mice. We found that fisetin decreased cellular senescence in human endothelial cell culture. In old mice, vascular cell senescence and SASP-related inflammation were lower 1 week after the final dose of oral intermittent (1 week on-2 weeks off-1 weeks on dosing) fisetin supplementation. Old fisetin-supplemented mice had higher endothelial function. Leveraging old p16-3MR mice, a transgenic model allowing genetic clearance of p16INK4A -positive senescent cells, we found that ex vivo removal of senescent cells from arteries isolated from vehicle- but not fisetin-treated mice increased endothelium-dependent dilation, demonstrating that fisetin improved endothelial function through senolysis. Enhanced endothelial function with fisetin was mediated by increased NO bioavailability and reduced cellular- and mitochondrial-related oxidative stress. Arterial stiffness was lower in fisetin-treated mice. Ex vivo genetic senolysis in aorta rings from p16-3MR mice did not further reduce mechanical wall stiffness in fisetin-treated mice, demonstrating lower arterial stiffness after fisetin was due to senolysis. Lower arterial stiffness with fisetin was accompanied by favorable arterial wall remodeling. The findings from this study identify fisetin as promising therapy for clinical translation to target excess cell senescence to treat age-related arterial dysfunction.
    Keywords:  aging; arterial stiffness; cellular senescence; endothelial function; nutraceutical; vascular dysfunction
    DOI:  https://doi.org/10.1111/acel.14060
  4. Cell Reprogram. 2023 Dec 07.
    Sustained Vision Recovery by OSK Gene Therapy in a Mouse Model of Glaucoma.
    Margarete M Karg, Yuancheng Ryan Lu, Nasrin Refaian, James Cameron, Emma Hoffmann, Cindy Hoppe, Shintaro Shirahama, Madhura Shah, Drenushe Krasniqi, Anitha Krishnan, Maleeka Shrestha, Yinjie Guo, Jennifer M Cermak, Michel Walthier, Kasia Broniowska, Sharon Rosenzweig-Lipson, Meredith Gregory-Ksander, David A Sinclair, Bruce R Ksander.
      Glaucoma, a chronic neurodegenerative disease, is a leading cause of age-related blindness worldwide and characterized by the progressive loss of retinal ganglion cells (RGCs) and their axons. Previously, we developed a novel epigenetic rejuvenation therapy, based on the expression of the three transcription factors Oct4, Sox2, and Klf4 (OSK), which safely rejuvenates RGCs without altering cell identity in glaucomatous and old mice after 1 month of treatment. In the current year-long study, mice with continuous or cyclic OSK expression induced after glaucoma-induced vision damage had occurred were tracked for efficacy, duration, and safety. Surprisingly, only 2 months of OSK fully restored impaired vision, with a restoration of vision for 11 months with prolonged expression. In RGCs, transcription from the doxycycline (DOX)-inducible Tet-On AAV system, returned to baseline 4 weeks after DOX withdrawal. Significant vision improvements remained for 1 month post switching off OSK, after which the vision benefit gradually diminished but remained better than baseline. Notably, no adverse effects on retinal structure or body weight were observed in glaucomatous mice with OSK continuously expressed for 21 months providing compelling evidence of efficacy and safety. This work highlights the tremendous therapeutic potential of rejuvenating gene therapies using OSK, not only for glaucoma but also for other ocular and systemic injuries and age-related diseases.
    Keywords:  aging; gene therapy; glaucoma; neuron; rejuvenation; retina
    DOI:  https://doi.org/10.1089/cell.2023.0074
  5. Lancet Reg Health West Pac. 2024 Jan;42 100955
    Tea consumption and attenuation of biological aging: a longitudinal analysis from two cohort studies.
    Yi Xiang, Hao Xu, Hongxiang Chen, Dan Tang, Zitong Huang, Yuan Zhang, Zhenghong Wang, Ziyun Wang, Yangla, Mingming Han, Jianzhong Yin, Xiong Xiao, Xing Zhao.
       Background: The biological aging process can be modified through lifestyle interventions to prevent age-related diseases and extend healthspan. However, evidence from population-based studies on whether tea consumption could delay the biological aging process in humans remains limited.
    Methods: This study included 7931 participants aged 30-79 years from the China Multi-Ethnic Cohort (CMEC) Study and 5998 participants aged 37-73 years from the UK Biobank (UKB) who participated in both the baseline and first follow-up surveys. Tea consumption information was collected through questionnaires. Biological age (BA) acceleration was calculated using clinical biomarkers and anthropometric measurements based on the Klemera Doubal method (KDM). Change-to-change analyses were performed to estimate the associations between changes in tea consumption status and changes in BA acceleration using multiple linear models. Follow-up adjusted for baseline analyses were further conducted to examine the prospective exposure-response relationship between tea consumption and BA acceleration among individuals with constant tea consumption status.
    Findings: During a median follow-up of 1.98 (1.78, 2.16) years in the CMEC and 4.50 (3.92, 5.00) years in the UKB, tea consumption was consistently associated with attenuated BA acceleration in both cohorts. Transitioning from nondrinking to tea-drinking was associated with decreased BA acceleration (CMEC: β = -0.319, 95% CI: -0.620 to -0.017 years; UKB: β = -0.267, 95% CI: -0.831 to 0.297 years) compared to consistent nondrinking. Even stronger associations were found in consistent tea drinkers. The exposure-response relationship suggested that consuming around 3 cups of tea or 6-8 g of tea leaves per day may offer the most evident anti-aging benefits.
    Interpretation: Tea consumption was associated with attenuated BA acceleration measured by KDM, especially for consistent tea drinkers with moderate consumption. Our findings highlight the potential role of tea in developing nutrition-oriented anti-aging interventions and guiding healthy aging policies.
    Funding: National Natural Science Foundation of China (Grant No. 82273740).
    Keywords:  Biological aging; Change-to-change analysis; Exposure-response relationship; Follow-up adjusted for baseline analysis; Tea consumption
    DOI:  https://doi.org/10.1016/j.lanwpc.2023.100955
  6. Prep Biochem Biotechnol. 2023 Dec 13. 1-8
    Choice of gDNA isolation method has a significant impact on average murine Telomere Length estimates.
    E Kidd, E Meimaridou, J Williams, L A Metherell, A J Walley, U L Fairbrother.
      Telomere Length (TL) and integrity is significantly associated with age-related disease, multiple genetic and environmental factors. We observe mouse genomic DNA (gDNA) isolation methods to have a significant impact on average TL estimates. The canonical qPCR method does not measure TL directly but via the ratio of telomere repeats to a single copy gene (SCG) generating a T/S ratio. We use a monochromatic-multiplex-qPCR (mmqPCR) method which multiplexes the PCR and enables quantification of the target and the single copy gene within the same qPCR reaction. We demonstrate that TL measurements, from murine gDNA, isolated via Spin Columns (SC) and Magnetic Beads (MB), generate significantly smaller T/S ratios compared to gDNA isolated via traditional phenol/chloroform methods. The former methods may impede correct TL estimation by producing non representative fragment sets and reducing qPCR efficacy. This work highlights discrepancies in TL measurements due to different extraction techniques. We recommend the use of gDNA isolation methods that are shown to preserve DNA length and integrity, such as phenol/chloroform isolation. We propose that widely used high throughput DNA isolation methodologies can create spurious associations within a sample set, thus creating misleading data. We suggest that published TL associations should be revisited in the light of these data.
    Keywords:  DNA isolation; magnetic beads; mmqPCR; phenol/chloroform; spin columns; telomere length
    DOI:  https://doi.org/10.1080/10826068.2023.2288572
  7. bioRxiv. 2023 Nov 27. pii: 2023.11.26.568749. [Epub ahead of print]
    The Myc-Like Mlx Network Impacts Aging and Metabolism.
    Huabo Wang, Taylor Stevens, Jie Lu, Alexander Roberts, Clinton Van't Land, Radhika Muzumdar, Zhenwei Gong, Jerry Vockley, Edward V Prochownik.
      The "Mlx" and "Myc" Networks share many common gene targets. Just as Myc's activity depends upon its heterodimerization with Max, the Mlx Network requires that the Max-like factor Mlx associate with the Myc-like factors MondoA or ChREBP. We show here that body-wide Mlx inactivation, like that of Myc, accelerates numerous aging-related phenotypes pertaining to body habitus and metabolism. The deregulation of numerous aging-related Myc target gene sets is also accelerated. Among other functions, these gene sets often regulate ribosomal and mitochondrial structure and function, genomic stability and aging. Whereas " Myc KO" mice have an extended lifespan because of a lower cancer incidence, " Mlx KO" mice have normal lifespans and a somewhat higher cancer incidence. Like Myc, Mlx, MondoA and ChREBP expression and that of their target genes, deteriorate with age in both mice and humans, underscoring the importance of life-long and balanced cross-talk between the two Networks to maintain normal aging.
    Teaser: Inactivation of the Myc-like "Mlx Network" in mice leads to phenotypic and molecular signs of premature aging and a cancer predisposition.
    DOI:  https://doi.org/10.1101/2023.11.26.568749
  8. Int J Mol Sci. 2023 Nov 21. pii: 16580. [Epub ahead of print]24(23):
    Impact of NLRP3 Depletion on Aging-Related Metaflammation, Cognitive Function, and Social Behavior in Mice.
    Elena D Khilazheva, Angelina I Mosiagina, Yulia A Panina, Olga S Belozor, Yulia K Komleva.
      Immunosenescence and chronic inflammation associated with old age accompany brain aging and the loss of complex behaviors. Neuroinflammation in the hippocampus plays a pivotal role in the development of cognitive impairment and anxiety. However, the underlying mechanisms have not been fully explained. In this study, we aimed to investigate the disruption of insulin signaling and the mechanisms underlying metabolic inflammation ("metaflammation") in the brains of wild-type (WT) and NLRP3 knockout (KO) mice of different ages. We found a significant upregulation of the NLRP3 inflammasome in the hippocampus during aging, leading to an increase in the expression of phosphorylated metaflammation proteinases and inflammatory markers, along with an increase in the number of senescent cells. Additionally, metaflammation causes anxiety and impairs social preference behavior in aged mice. On the other hand, deletion of NLRP3 improves some behavioral and biochemical characteristics associated with aging, such as signal memory, neuroinflammation, and metabolic inflammation, but not anxious behavior. These results are associated with reduced IL-18 signaling and the PKR/IKKβ/IRS1 pathway as well as the SASP phenotype. In NLRP3 gene deletion conditions, PKR is down-regulated. Therefore, it is likely that slowing aging through various NLRP3 inhibition mechanisms will lessen the corresponding cognitive decline with aging. Thus, the genetic knockout of the NLRP3 inflammasome can be seen as a new therapeutic strategy for slowing down central nervous system (CNS) aging.
    Keywords:  NLRP3; aging; immunosenescence; inflammasome; inflammation; metaflammasome; senescence-associated secretory phenotype
    DOI:  https://doi.org/10.3390/ijms242316580
  9. Immun Ageing. 2023 Dec 12. 20(1): 73
    The effect of metformin on senescence of T lymphocytes.
    Jia Yang, Hai-Cheng Liu, Jian-Qing Zhang, Jian-Yong Zou, Xin Zhang, Wo-Ming Chen, Yong Gu, Hai Hong.
       BACKGROUND: Immunosenescence occurs as people age, leading to an increased incidence of age-related diseases. The number of senescent T cells also rises with age. T cell senescence and immune response dysfunction can result in a decline in immune function, especially in anti-tumor immune responses. Metformin has been shown to have various beneficial effects on health, such as lowering blood sugar levels, reducing the risk of cancer development, and slowing down the aging process. However, the immunomodulatory effects of metformin on senescent T cells still need to be investigated.
    METHODS: PBMCs isolation from different age population (n = 88); Flow Cytometry is applied to determine the phenotypic characterization of senescent T lymphocytes; intracellular staining is applied to determine the function of senescent T cells; Enzyme-Linked Immunosorbent Assay (ELISA) is employed to test the telomerase concentration. The RNA-seq analysis of gene expression associated with T cell senescence.
    RESULTS: The middle-aged group had the highest proportion of senescent T cells. We found that metformin could decrease the number of CD8 + senescent T cells. Metformin affects the secretion of SASP, inhibiting the secretion of IFN-γ in CD8 + senescent T cells. Furthermore, metformin treatment restrained the production of the proinflammatory cytokine IL-6 in lymphocytes. Metformin had minimal effects on Granzyme B secretion in senescent T cells, but it promoted the production of TNF-α in senescent T cells. Additionally, metformin increased the concentration of telomerase and the frequency of undifferentiated T cells. The results of RNA-seq showed that metformin promoted the expression of genes related to stemness and telomerase activity, while inhibiting the expression of DNA damage-associated genes.
    CONCLUSION: Our findings reveal that metformin could inhibit T cell senescence in terms of cell number, effector function, telomerase content and gene expression in middle-aged individuals, which may serve as a promising approach for preventing age-related diseases in this population.
    Keywords:  Inhibition; Metformin; SASP; Senescent T cell
    DOI:  https://doi.org/10.1186/s12979-023-00394-0
  10. Diabetes Metab Syndr Obes. 2023 ;16 4043-4064
    Biological Role and Related Natural Products of SIRT1 in Nonalcoholic Fatty Liver.
    Decheng Meng, Fengxia Zhang, Wenfei Yu, Xin Zhang, Guoliang Yin, Pengpeng Liang, Yanan Feng, Suwen Chen, Hongshuai Liu.
      Non-alcoholic fatty liver disease(NAFLD) is an umbrella term for a range of diseases ranging from hepatic fat accumulation and steatosis to non-alcoholic steatohepatitis (NASH) in the absence of excessive alcohol consumption and other definite liver damage factors. The incidence of NAFLD has increased significantly in recent years and will continue to grow in the coming decades. NAFLD has become a huge health problem and economic burden. SIRT1 is a member of Sirtuins, a group of highly conserved histone deacetylases regulated by NAD+, and plays a vital role in regulating cholesterol and lipid metabolism, improving oxidative stress, inflammation, and insulin resistance through deacetylating some downstream transcription factors and thus improving NAFLD. Although there are no currently approved drugs for treating NAFLD and some unresolved limitations in developing SIRT1 activators, SIRT1 holds promise as a proper therapeutic target for NAFLD and other metabolic diseases. In recent years, natural products have played an increasingly important role in drug development due to their safety and efficacy. It has been discovered that some natural products may be able to prevent and treat NAFLD by targeting SIRT1 and its related pathways. This paper reviews the mechanism of SIRT1 in the improvement of NALFD and the natural products that regulate NAFLD through SIRT1 and its associated pathways, and discusses the potential of SIRT1 as a therapeutic target for treating NAFLD and the effectiveness of these related natural products as clinical drugs or dietary supplements. These works may provide some new ideas and directions for finding new therapeutic targets for NAFLD and the development of anti-NAFLD drugs with good pharmacodynamic properties.
    Keywords:  FFA; NAFLD; SIRT1; TG; natural products
    DOI:  https://doi.org/10.2147/DMSO.S437865
  11. Proc Natl Acad Sci U S A. 2023 Dec 19. 120(51): e2317232120
    Three common assumptions about inflammation, aging, and health that are probably wrong.
    Thomas W McDade.
      Chronic inflammation contributes to the onset and progression of cardiovascular disease and other degenerative diseases of aging. But does it have to? This article considers the associations among inflammation, aging, and health through the lens of human population biology and suggests that chronic inflammation is not a normal nor inevitable component of aging. It is commonly assumed that conclusions drawn from research in affluent, industrialized countries can be applied globally; that aging processes leading to morbidity and mortality begin in middle age; and that inflammation is pathological. These foundational assumptions have shifted focus away from inflammation as a beneficial response to infection or injury and toward an understanding of inflammation as chronic, dysregulated, and dangerous. Findings from community-based studies around the world-many conducted in areas with relatively high burdens of infectious disease-challenge these assumptions by documenting substantial variation in levels of inflammation and patterns of association with disease. They also indicate that nutritional, microbial, and psychosocial environments in infancy and childhood play important roles in shaping inflammatory phenotypes and their contributions to diseases of aging. A comparative, developmental, and ecological approach has the potential to generate novel insights into the regulation of inflammation and how it relates to human health over the life course.
    Keywords:  aging; developmental origins; infectious disease; inflammation
    DOI:  https://doi.org/10.1073/pnas.2317232120
  12. Aging (Albany NY). 2023 Dec 12. 15
    Benidipine calcium channel blocker promotes the death of cigarette smoke-induced senescent cells and improves lung emphysema.
    Alberta Palazzo, Gabriela Makulyte, Delphine Goerhig, Jean-Jacques Médard, Vincent Gros, François Trottein, Serge Adnot, David Vindrieux, Jean-Michel Flaman, David Bernard.
      Smoking is the main risk factor for many lung diseases including chronic obstructive pulmonary disease. Cigarette smoke (CS) contains carcinogenic and reactive oxygen species that favor DNA mutations and perturb the homeostasis and environment of cells. CS induces lung cell senescence resulting in a stable proliferation arrest and a senescence-associated secretory phenotype. It was recently reported that senescent cell accumulation promotes several lung diseases. In this study, we performed a chemical screen, using an FDA-approved drug library, to identify compounds selectively promoting the death of CS-induced senescent lung cells. Aside from the well-known senolytic, ABT-263, we identified other potentially new senescence-eliminating compounds, including a new class of molecules, the dihydropyridine family of calcium voltage-gated channel (CaV) blockers. Among these blockers, Benidipine, decreased senescent lung cells and ameliorates lung emphysema in a mouse model. The dihydropyridine family of CaV blockers thus constitutes a new class of senolytics that could improve lung diseases. Hence, our work paves the way for further studies on the senolytic activity of CaV blockers in different senescence contexts and age-related diseases.
    Keywords:  calcium channel; cellular senescence; cigarette smoke; lung disease; senolytic
    DOI:  https://doi.org/10.18632/aging.205259
  13. Int J Mol Sci. 2023 Dec 01. pii: 17034. [Epub ahead of print]24(23):
    Calcium's Role and Signaling in Aging Muscle, Cellular Senescence, and Mineral Interactions.
    Kristofer Terrell, Suyun Choi, Sangyong Choi.
      Calcium research, since its pivotal discovery in the early 1800s through the heating of limestone, has led to the identification of its multi-functional roles. These include its functions as a reducing agent in chemical processes, structural properties in shells and bones, and significant role in cells relating to this review: cellular signaling. Calcium signaling involves the movement of calcium ions within or between cells, which can affect the electrochemical gradients between intra- and extracellular membranes, ligand binding, enzyme activity, and other mechanisms that determine cell fate. Calcium signaling in muscle, as elucidated by the sliding filament model, plays a significant role in muscle contraction. However, as organisms age, alterations occur within muscle tissue. These changes include sarcopenia, loss of neuromuscular junctions, and changes in mineral concentration, all of which have implications for calcium's role. Additionally, a field of study that has gained recent attention, cellular senescence, is associated with aging and disturbed calcium homeostasis, and is thought to affect sarcopenia progression. Changes seen in calcium upon aging may also be influenced by its crosstalk with other minerals such as iron and zinc. This review investigates the role of calcium signaling in aging muscle and cellular senescence. We also aim to elucidate the interactions among calcium, iron, and zinc across various cells and conditions, ultimately deepening our understanding of calcium signaling in muscle aging.
    Keywords:  aging muscle; calcium; iron; senescence; zinc
    DOI:  https://doi.org/10.3390/ijms242317034
  14. Front Med (Lausanne). 2023 ;10 1288993
    Targeting cellular senescence in senile osteoporosis: therapeutic potential of traditional Chinese medicine.
    Yingyi Zhang, Xinfeng Yu, Chengcong Zhou, Keqi Fu, Huan Luo, Chengliang Wu.
      Senile osteoporosis (SOP) is a prevalent manifestation of age-related bone disorders, resulting from the dysregulation between osteoblast (OB)-mediated bone formation and osteoclast (OC)-mediated bone resorption, coupled with the escalating burden of cellular senescence. Traditional Chinese medicine (TCM) herbs, renowned for their remarkable attributes encompassing excellent tolerability, low toxicity, heightened efficacy, and minimal adverse reactions, have gained considerable traction in OP treatment. Emerging evidence substantiates the therapeutic benefits of various TCM formulations and their active constituents, including Zuogui wan, Fructus Ligustri Lucidi, and Resveratrol, in targeting cellular senescence to address SOP. However, a comprehensive review focusing on the therapeutic efficacy of TCM against SOP, with a particular emphasis on senescence, is currently lacking. In this review, we illuminate the pivotal involvement of cellular senescence in SOP and present a comprehensive exploration of TCM formulations and their active ingredients derived from TCM, delineating their potential in SOP treatment through their anti-senescence properties. Notably, we highlight their profound effects on distinct aging models that simulate SOP and various senescence characteristics. Finally, we provide a forward-looking discussion on utilizing TCM as a strategy for targeting cellular senescence and advancing SOP treatment. Our objective is to contribute to the unveiling of safer and more efficacious therapeutic agents for managing SOP.
    Keywords:  anti-senescence; cellular senescence; senile osteoporosis; therapeutic efficacy; traditional Chinese medicine
    DOI:  https://doi.org/10.3389/fmed.2023.1288993
  15. BMC Biol. 2023 Dec 08. 21(1): 287
    Geroprotector drugs and exercise: friends or foes on healthy longevity?
    Christian J Elliehausen, Rozalyn M Anderson, Gary M Diffee, Timothy W Rhoads, Dudley W Lamming, Troy A Hornberger, Adam R Konopka.
      Physical activity and several pharmacological approaches individually combat age-associated conditions and extend healthy longevity in model systems. It is tantalizing to extrapolate that combining geroprotector drugs with exercise could extend healthy longevity beyond any individual treatment. However, the current dogma suggests that taking leading geroprotector drugs on the same day as exercise may limit several health benefits. Here, we review leading candidate geroprotector drugs and their interactions with exercise and highlight salient gaps in knowledge that need to be addressed to identify if geroprotector drugs can have a harmonious relationship with exercise.
    Keywords:  Acarbose; Aging; Geroscience; Healthspan; Metformin; Physical activity; Rapamycin; SGLT2 inhibitors; Skeletal muscle
    DOI:  https://doi.org/10.1186/s12915-023-01779-9
  16. Biosystems. 2023 Dec 06. pii: S0303-2647(23)00272-1. [Epub ahead of print] 105097
    PTEN expression can be used as a switch between senescence and apoptosis in breast cancer cells according to a logical model of the G2/M checkpoint.
    Yolanda M B Marcello, Daner A Silveira, Shantanu Gupta, José Carlos M Mombach.
      Worldwide, the second-highest mortality rate is caused by breast cancer (BC). The most studied BC cell line is MCF-7 because it exhibits strong consistency with clinical cases and is a good system for analyzing tumors with functional estrogen receptors (ER-positive cancers). In this paper, we introduce the first theoretical method for describing PTEN-loss-induced cellular senescence (PICS), which is an increase in cellular senescence caused by PTEN knockout, utilizing a logical model of the G2/M checkpoint. We predict that PTEN expression acts as a switch between cell phenotypes associated with senescence and apoptosis. We show that PICS is induced by the activity of the positive feedback between AKT and mTORC2, and that overexpression of PTEN will disrupt the feedback, abrogating senescence and only leading to arrest or apoptosis. Furthermore, we demonstrate that miR-21 can be used as a target against proliferation control because its knockout is equivalent to PTEN overexpression. We think the findings can be used to motivate new strategies for MCF-7 strain proliferation control.
    Keywords:  Apoptosis; Breast cancer; Logical model; Senescence
    DOI:  https://doi.org/10.1016/j.biosystems.2023.105097
  17. Ageing Res Rev. 2023 Dec 07. pii: S1568-1637(23)00321-5. [Epub ahead of print] 102162
    Lifestyle strategies to promote proteostasis and reduce the risk of Alzheimer's disease and other proteinopathies.
    Michael F Almeida, Karen L G Farizatto, Renato S Almeida, Ben A Bahr.
      Unhealthy lifestyle choices, poor diet, and aging can have negative influences on cognition, gradually increasing the risk for mild cognitive impairment (MCI) and the continuum comprising early dementia. Aging is the greatest risk factor for age-related dementias such as Alzheimer's disease, and the aging process is known to be influenced by life events that can positively or negatively affect age-related diseases. Remarkably, life experiences that make the brain vulnerable to dementia, such as seizure episodes, neurotoxin exposures, metabolic disorders, and trauma-inducing events (e.g. traumatic injuries or mild neurotrauma from a fall or blast exposure), have been associated with negative effects on proteostasis and synaptic integrity. Functional compromise of the autophagy-lysosomal pathway, a major contributor to proteostasis, has been implicated in Alzheimer's disease, Parkinson's disease, obesity-related pathology, Huntington's disease, as well as in synaptic degeneration which is the best correlate of cognitive decline. Correspondingly, pharmacological and non-pharmacological strategies that positively modulate lysosomal proteases are recognized as synaptoprotective through degradative clearance of pathogenic proteins. Here, we discuss life-associated vulnerabilities that influence key hallmarks of brain aging and the increased burden of age-related dementias. Additionally, we discuss exercise and diet among the lifestyle strategies that regulate proteostasis as well as synaptic integrity, leading to evident prevention of cognitive deficits during brain aging in pre-clinical models.
    Keywords:  brain aging; cognition; lysosomal proteases; synapses
    DOI:  https://doi.org/10.1016/j.arr.2023.102162
  18. Aging Cell. 2023 Dec 08. e14049
    Transcriptome-wide analysis reveals GYG2 as a mitochondria-related aging biomarker in human subcutaneous adipose tissue.
    Mira Ham, Yeonju Cho, Tae-Wook Kang, Taeyun Oh, Hyoung-June Kim, Kyu-Han Kim.
      Subcutaneous adipose tissue (SAT), a vital energy reservoir and endocrine organ for maintaining systemic glucose, lipid, and energy homeostasis, undergoes significant changes with age. However, among the existing aging-related markers, only few genes are associated with SAT aging. In this study, weighted gene co-expression network analysis was used on a transcriptome of SAT obtained from the Genotype-Tissue Expression portal to identify biologically relevant, SAT-specific, and age-related marker genes. We found modules that exhibited significant changes with age and identified GYG2 as a novel key aging associated gene. The link between GYG2 and mitochondrial function as well as brown/beige adipocytes was supported using additional bioinformatics and experimental analyses. Additionally, we identified PPARG as the transcription factor of GYG2 expression. The newly discovered GYG2 marker can be used to not only determine the age of SAT but also uncover new mechanisms underlying SAT aging.
    Keywords:  GYG2; WGCNA; adipocyte; aging; computational biology; mitochondria; subcutaneous adipose tissue; transcriptome
    DOI:  https://doi.org/10.1111/acel.14049
  19. Mol Biol Rep. 2023 Dec 08. 51(1): 3
    Revealing the role of epigenetic and post-translational modulations of autophagy proteins in the regulation of autophagy and cancer: a therapeutic approach.
    Sougata Ghosh Chowdhury, Parimal Karmakar.
      Autophagy is a process that is characterized by the destruction of redundant components and the removal of dysfunctional ones to maintain cellular homeostasis. Autophagy dysregulation has been linked to various illnesses, such as neurodegenerative disorders and cancer. The precise transcription of the genes involved in autophagy is regulated by a network of epigenetic factors. This includes histone modifications and histone-modifying enzymes. Epigenetics is a broad category of heritable, reversible changes in gene expression that do not include changes to DNA sequences, such as chromatin remodeling, histone modifications, and DNA methylation. In addition to affecting the genes that are involved in autophagy, the epigenetic machinery can also alter the signals that control this process. In cancer, autophagy plays a dual role by preventing the development of tumors on one hand and this process may suppress tumor progression. This may be the control of an oncogene that prevents autophagy while, conversely, tumor suppression may promote it. The development of new therapeutic strategies for autophagy-related disorders could be initiated by gaining a deeper understanding of its intricate regulatory framework. There is evidence showing that certain machineries and regulators of autophagy are affected by post-translational and epigenetic modifications, which can lead to alterations in the levels of autophagy and these changes can then trigger disease or affect the therapeutic efficacy of drugs. The goal of this review is to identify the regulatory pathways associated with post-translational and epigenetic modifications of different proteins in autophagy which may be the therapeutic targets shortly.
    Keywords:  Autophagy; Cancer therapy; Epigenetic factors; Post-translational modulation
    DOI:  https://doi.org/10.1007/s11033-023-08961-w
  20. J Ovarian Res. 2023 Dec 13. 16(1): 237
    The stromal microenvironment and ovarian aging: mechanisms and therapeutic opportunities.
    Lu Shen, Junfeng Liu, Aiyue Luo, Shixuan Wang.
      For decades, most studies of ovarian aging have focused on its functional units, known as follicles, which include oocytes and granulosa cells. However, in the ovarian stroma, there are a variety of somatic components that bridge the gap between general aging and ovarian senescence. Physiologically, general cell types, microvascular structures, extracellular matrix, and intercellular molecules affect folliculogenesis and corpus luteum physiology alongside the ovarian cycle. As a result of damage caused by age-related metabolite accumulation and external insults, the microenvironment of stromal cells is progressively remodeled, thus inevitably perturbing ovarian physiology. With the established platforms for follicle cryopreservation and in vitro maturation and the development of organoid research, it is desirable to develop strategies to improve the microenvironment of the follicle by targeting the perifollicular environment. In this review, we summarize the role of stromal components in ovarian aging, describing their age-related alterations and associated effects. Moreover, we list some potential techniques that may mitigate ovarian aging based on their effect on the stromal microenvironment.
    Keywords:  Aging; Microenvironment; Ovary; Stroma
    DOI:  https://doi.org/10.1186/s13048-023-01300-4
  21. Front Physiol. 2023 ;14 1297637
    The role of cellular senescence in skin aging and age-related skin pathologies.
    Toby Chin, Xin Er Lee, Pei Yi Ng, Yaelim Lee, Oliver Dreesen.
      Aging is the result of a gradual functional decline at the cellular, and ultimately, organismal level, resulting in an increased risk of developing a variety of chronic illnesses, such as cardiovascular disease, stroke, cancer and diabetes. The skin is the largest organ of the human body, and the site where signs of aging are most visible. These signs include thin and dry skin, sagging, loss of elasticity, wrinkles, as well as aberrant pigmentation. The appearance of these features is accelerated by exposure to extrinsic factors such as ultraviolet (UV) radiation or pollution, as well as intrinsic factors including time, genetics, and hormonal changes. At the cellular level, aging is associated with impaired proteostasis and an accumulation of macromolecular damage, genomic instability, chromatin reorganization, telomere shortening, remodelling of the nuclear lamina, proliferation defects and premature senescence. Cellular senescence is a state of permanent growth arrest and a key hallmark of aging in many tissues. Due to their inability to proliferate, senescent cells no longer contribute to tissue repair or regeneration. Moreover, senescent cells impair tissue homeostasis, promote inflammation and extracellular matrix (ECM) degradation by secreting molecules collectively known as the "senescence-associated secretory phenotype" (SASP). Senescence can be triggered by a number of different stimuli such as telomere shortening, oncogene expression, or persistent activation of DNA damage checkpoints. As a result, these cells accumulate in aging tissues, including human skin. In this review, we focus on the role of cellular senescence during skin aging and the development of age-related skin pathologies, and discuss potential strategies to rejuvenate aged skin.
    Keywords:  SASP; aging; lamin B1; senescence; senolytics; skin; wounds
    DOI:  https://doi.org/10.3389/fphys.2023.1297637
  22. Front Aging Neurosci. 2023 ;15 1281581
    Cellular senescence in brain aging and cognitive decline.
    Areez Shafqat, Saifullah Khan, Mohamed H Omer, Mahnoor Niaz, Ibrahem Albalkhi, Khaled AlKattan, Ahmed Yaqinuddin, Tamara Tchkonia, James L Kirkland, Shahrukh K Hashmi.
      Cellular senescence is a biological aging hallmark that plays a key role in the development of neurodegenerative diseases. Clinical trials are currently underway to evaluate the effectiveness of senotherapies for these diseases. However, the impact of senescence on brain aging and cognitive decline in the absence of neurodegeneration remains uncertain. Moreover, patient populations like cancer survivors, traumatic brain injury survivors, obese individuals, obstructive sleep apnea patients, and chronic kidney disease patients can suffer age-related brain changes like cognitive decline prematurely, suggesting that they may suffer accelerated senescence in the brain. Understanding the role of senescence in neurocognitive deficits linked to these conditions is crucial, especially considering the rapidly evolving field of senotherapeutics. Such treatments could help alleviate early brain aging in these patients, significantly reducing patient morbidity and healthcare costs. This review provides a translational perspective on how cellular senescence plays a role in brain aging and age-related cognitive decline. We also discuss important caveats surrounding mainstream senotherapies like senolytics and senomorphics, and present emerging evidence of hyperbaric oxygen therapy and immune-directed therapies as viable modalities for reducing senescent cell burden.
    Keywords:  aging; astrocyte senescence; cellular senescence; cognitive decline; microglia senescence; obesity; therapy-induced senescence (TIS); traumatic brain injury
    DOI:  https://doi.org/10.3389/fnagi.2023.1281581
  23. Nutrients. 2023 Nov 29. pii: 4964. [Epub ahead of print]15(23):
    The Role of Cdc42 in the Insulin and Leptin Pathways Contributing to the Development of Age-Related Obesity.
    Bauyrzhan Umbayev, Timur Saliev, Yuliya Safarova Yantsen, Aislu Yermekova, Farkhad Olzhayev, Denis Bulanin, Andrey Tsoy, Sholpan Askarova.
      Age-related obesity significantly increases the risk of chronic diseases such as type 2 diabetes, cardiovascular diseases, hypertension, and certain cancers. The insulin-leptin axis is crucial in understanding metabolic disturbances associated with age-related obesity. Rho GTPase Cdc42 is a member of the Rho family of GTPases that participates in many cellular processes including, but not limited to, regulation of actin cytoskeleton, vesicle trafficking, cell polarity, morphology, proliferation, motility, and migration. Cdc42 functions as an integral part of regulating insulin secretion and aging. Some novel roles for Cdc42 have also been recently identified in maintaining glucose metabolism, where Cdc42 is involved in controlling blood glucose levels in metabolically active tissues, including skeletal muscle, adipose tissue, pancreas, etc., which puts this protein in line with other critical regulators of glucose metabolism. Importantly, Cdc42 plays a vital role in cellular processes associated with the insulin and leptin signaling pathways, which are integral elements involved in obesity development if misregulated. Additionally, a change in Cdc42 activity may affect senescence, thus contributing to disorders associated with aging. This review explores the complex relationships among age-associated obesity, the insulin-leptin axis, and the Cdc42 signaling pathway. This article sheds light on the vast molecular web that supports metabolic dysregulation in aging people. In addition, it also discusses the potential therapeutic implications of the Cdc42 pathway to mitigate obesity since some new data suggest that inhibition of Cdc42 using antidiabetic drugs or antioxidants may promote weight loss in overweight or obese patients.
    Keywords:  Cdc42; age-related obesity; aging; insulin resistance; insulin–leptin axis; leptin resistance
    DOI:  https://doi.org/10.3390/nu15234964
  24. iScience. 2023 Dec 15. 26(12): 108456
    Age-related decline in spermatogenic activity accompanied with endothelial cell senescence in male mice.
    Manabu Ozawa, Hideto Mori, Tsutomu Endo, Yu Ishikawa-Yamauchi, Daisuke Motooka, Chihiro Emori, Masahiro Ikawa.
      Male fertility decreases with aging, with spermatogenic decline being one of its causes. Altered testis environment is suggested as a cause of the phenotype; however, the associated mechanisms remain unclear. Herein, we investigated the age-related changes in testicular somatic cells on spermatogenic activity. The number and proliferation of spermatogonia significantly reduced with aging in mice. Interestingly, senescence-associated β-galactosidase-positive cells appeared in testicular endothelial cell (EC) populations, but not in germ cell populations, with aging. Transcriptome analysis of ECs indicated that senescence occurred in the ECs of aged mice. Furthermore, the support capacity of ECs for spermatogonial proliferation significantly decreased with aging; however, the senolytic-induced removal of senescent cells from aged ECs restored their supporting capacity to a comparable level as that of young ECs. Our results suggest that the accumulation of senescent ECs in the testis is a potential factor contributing to the age-related decline in spermatogenic activity.
    Keywords:  Physiology; Transcriptomics; biological sciences; cell biology
    DOI:  https://doi.org/10.1016/j.isci.2023.108456
  25. Gut Microbes. 2023 Dec;15(2): 2290331
    Targeting gut microbiota in aging-related cardiovascular dysfunction: focus on the mechanisms.
    Siqi Liu, Yufeng He, Yali Zhang, Zhaolun Zhang, Keming Huang, Li Deng, Bin Liao, Yi Zhong, Jian Feng.
      The global population is aging and age-related cardiovascular disease is increasing. Even after controlling for cardiovascular risk factors, readmission and mortality rates remain high. In recent years, more and more in-depth studies have found that the composition of the gut microbiota and its metabolites, such as trimethylamine N-oxide (TMAO), bile acids (BAs), and short-chain fatty acids (SCFAs), affect the occurrence and development of age-related cardiovascular diseases through a variety of molecular pathways, providing a new target for therapy. In this review, we discuss the relationship between the gut microbiota and age-related cardiovascular diseases, and propose that the gut microbiota could be a new therapeutic target for preventing and treating cardiovascular diseases.
    Keywords:  Gut microbiota; aging; cardiovascular dysfunction; drug therapy; metabolites
    DOI:  https://doi.org/10.1080/19490976.2023.2290331
  26. Sci Rep. 2023 Dec 12. 13(1): 22085
    Heavy-chain antibody targeting of CD38 NAD+ hydrolase ectoenzyme to prevent fibrosis in multiple organs.
    Bo Shi, Asif Amin, Pranjali Dalvi, Wenxia Wang, Nicholas Lukacs, Li Kai, Paul Cheresh, Thais R Peclat, Claudia C Chini, Eduardo N Chini, Wim van Schooten, John Varga.
      The functionally pleiotropic ectoenzyme CD38 is a glycohydrolase widely expressed on immune and non-hematopoietic cells. By converting NAD+ to ADP-ribose and nicotinamide, CD38 governs organismal NAD+ homeostasis and the activity of NAD+-dependent cellular enzymes. CD38 has emerged as a major driver of age-related NAD+ decline underlying adverse metabolic states, frailty and reduced health span. CD38 is upregulated in systemic sclerosis (SSc), a chronic disease characterized by fibrosis in multiple organs. We sought to test the hypothesis that inhibition of the CD38 ecto-enzymatic activity using a heavy-chain monoclonal antibody Ab68 will, via augmenting organismal NAD+, prevent fibrosis in a mouse model of SSc characterized by NAD+ depletion. Here we show that treatment of mice with a non-cytotoxic heavy-chain antibody that selectively inhibits CD38 ectoenzyme resulted in NAD+ boosting that was associated with significant protection from fibrosis in multiple organs. These findings suggest that targeted inhibition of CD38 ecto-enzymatic activity could be a potential pharmacological approach for SSc fibrosis treatment.
    DOI:  https://doi.org/10.1038/s41598-023-49450-1
  27. Aging (Albany NY). 2023 Dec 09. 15
    Sirtuin 6 activation rescues the age-related decline in DNA damage repair in primary human chondrocytes.
    Michaela E Copp, Jacqueline Shine, Hannon L Brown, Kirti R Nimmala, Oliver B Hansen, Susan Chubinskaya, John A Collins, Richard F Loeser, Brian O Diekman.
      While advanced age is widely recognized as the greatest risk factor for osteoarthritis (OA), the biological mechanisms behind this connection remain unclear. Previous work has demonstrated that chondrocytes from older cadaveric donors have elevated levels of DNA damage as compared to chondrocytes from younger donors. The purpose of this study was to determine whether a decline in DNA repair efficiency is one explanation for the accumulation of DNA damage with age, and to quantify the improvement in repair with activation of Sirtuin 6 (SIRT6). After acute damage with irradiation, DNA repair was shown to be more efficient in chondrocytes from young (≤45 years old) as compared to middle-aged (50-65 years old) or older (>70 years old) cadaveric donors. Activation of SIRT6 with MDL-800 improved the repair efficiency, while inhibition with EX-527 reduced the rate of repair and increased the percentage of cells that retain high levels of damage. In addition to affecting repair after acute damage, treating chondrocytes from older donors with MDL-800 for 48 hours significantly reduced the amount of baseline DNA damage. Chondrocytes isolated from the knees of mice between 4 months and 22 months of age revealed both an increase in DNA damage with aging, and a decrease in DNA damage following MDL-800 treatment. Lastly, treating murine cartilage explants with MDL-800 lowered the percentage of chondrocytes with high p16 promoter activity, which supports the concept that using SIRT6 activation to maintain low levels of DNA damage may prevent the initiation of senescence.
    Keywords:  MDL-800; SIRT6; aging; cartilage; comet assay
    DOI:  https://doi.org/10.18632/aging.205394
  28. Mol Biol (Mosk). 2023 Nov-Dec;57(6):57(6): 1058-1076
    [Transcription Factor NRF2 in Endothelial Functions].
    N D Kondratenko, L A Zinovkina, R A Zinovkin.
      The transcription factor NRF2 is a major regulator of cell antioxidant defense. NRF2 is activated by various stimuli, such as oxidants and electrophiles, to induce transcription of a number of genes whose products are involved in xenobiotic metabolism and contribute to the reduction of oxidative stress. NRF2 is one of the key transcription factors that ensure the endothelial cell function. The endothelium is a cell layer that lines the lumens of blood vessels and performs various homeostatic functions, controlling migration of leukocytes, regulating thrombosis and vascular tone, and playing a role in angiogenesis. Endothelial dysfunction is often accompanied by inflammation and oxidative stress, which may lead to cell aging and cell death by apoptosis, necrosis, or ferroptosis. Endothelial dysfunction contributes to the development of diabetes and common cardiovascular disorders, such as hypertension and atherosclerosis. Many pathophysiological processes in the endothelium, including senile changes, are associated with decreased NRF2 activity, leading to inflammatory activation and decreasing activity of the cell antioxidant defense systems. Activation of the NRF2 signaling pathway generally contributes to the resolution of inflammation and oxidative stress. The review focuses on the role that NRF2 plays in basic functions of the endothelium in normal and pathological conditions. Advantages and disadvantages of NRF2 activation as a way to prevent and treat cardiovascular diseases are discussed additionally.
    Keywords:  age-related changes; aging; angiogenesis; atherosclerosis; diabetes; endothelium; inflammation; oxidative stress; transcription factor NRF2
    DOI:  https://doi.org/10.31857/S0026898423060101, EDN: QXHFSB
  29. Sci Rep. 2023 Dec 13. 13(1): 22140
    Network dynamical stability analysis reveals key "mallostatic" natural variables that erode homeostasis and drive age-related decline of health.
    Glen Pridham, Andrew D Rutenberg.
      Using longitudinal study data, we dynamically model how aging affects homeostasis in both mice and humans. We operationalize homeostasis as a multivariate mean-reverting stochastic process. We hypothesize that biomarkers have stable equilibrium values, but that deviations from equilibrium of each biomarker affects other biomarkers through an interaction network-this precludes univariate analysis. We therefore looked for age-related changes to homeostasis using dynamic network stability analysis, which transforms observed biomarker data into independent "natural" variables and determines their associated recovery rates. Most natural variables remained near equilibrium and were essentially constant in time. A small number of natural variables were unable to equilibrate due to a gradual drift with age in their homeostatic equilibrium, i.e. allostasis. This drift caused them to accumulate over the lifespan course and makes them natural aging variables. Their rate of accumulation was correlated with risk of adverse outcomes: death or dementia onset. We call this tendency for aging organisms to drift towards an equilibrium position of ever-worsening health "mallostasis". We demonstrate that the effects of mallostasis on observed biomarkers are spread out through the interaction network. This could provide a redundancy mechanism to preserve functioning until multi-system dysfunction emerges at advanced ages.
    DOI:  https://doi.org/10.1038/s41598-023-49129-7
  30. Commun Biol. 2023 Dec 08. 6(1): 1240
    Downregulation of mitochondrial metabolism is a driver for fast skeletal muscle loss during mouse aging.
    Raquel Fernando, Anastasia V Shindyapina, Mario Ost, Didac Santesmasses, Yan Hu, Alexander Tyshkovskiy, Sun Hee Yim, Jürgen Weiss, Vadim N Gladyshev, Tilman Grune, José Pedro Castro.
      Skeletal muscle aging is characterized by the loss of muscle mass, strength and function, mainly attributed to the atrophy of glycolytic fibers. Underlying mechanisms driving the skeletal muscle functional impairment are yet to be elucidated. To unbiasedly uncover its molecular mechanisms, we recurred to gene expression and metabolite profiling in a glycolytic muscle, Extensor digitorum longus (EDL), from young and aged C57BL/6JRj mice. Employing multi-omics approaches we found that the main age-related changes are connected to mitochondria, exhibiting a downregulation in mitochondrial processes. Consistent is the altered mitochondrial morphology. We further compared our mouse EDL aging signature with human data from the GTEx database, reinforcing the idea that our model may recapitulate muscle loss in humans. We are able to show that age-related mitochondrial downregulation is likely to be detrimental, as gene expression signatures from commonly used lifespan extending interventions displayed the opposite direction compared to our EDL aging signature.
    DOI:  https://doi.org/10.1038/s42003-023-05595-3
  31. bioRxiv. 2023 Dec 01. pii: 2023.11.30.569482. [Epub ahead of print]
    Cyclase-associated protein is a pro-formin anti-capping processive depolymerase of actin barbed and pointed ends.
    Ekram M Towsif, Shashank Shekhar.
      Cellular actin networks display distinct assembly and disassembly dynamics resulting from multicomponent reactions occurring primarily at the two ends and the sides of actin filaments [1-3]. While barbed ends are considered the hotspot of actin assembly [4], disassembly is thought to primarily occur via reactions on filament sides and pointed ends [3, 5-11]. Cyclase-associated protein (CAP) has emerged as the main protagonist of actin disassembly and remodeling - it collaborates with cofilin to increase pointed-end depolymerization by 300-fold [6, 7], promotes filament "coalescence" in presence of Abp1 [12], and accelerates nucleotide exchange to regenerate monomers for new rounds of assembly [13-15]. CAP has also been reported to enhance cofilin-mediated severing [16, 17], but these claims have since been challenged [7]. Using microfluidics-assisted three-color single-molecule imaging, we now reveal that CAP also has important functions at filament barbed ends. We reveal that CAP is a processive barbed-end depolymerase capable of tracking both ends of the filament. Each CAP binding event leads to removal of about 5,175 and 620 subunits from the barbed and pointed ends respectively. We find that the WH2 domain is essential, and the CARP domain is dispensable for barbed-end depolymerization. We show that CAP co-localizes with barbed-end bound formin and capping protein, in the process increasing residence time of formin by 10-fold and promoting dissociation of CP by 4-fold. Our barbed-end observations combined with previously reported activities of CAP at pointed ends and sides, firmly establish CAP as a key player in actin dynamics.
    DOI:  https://doi.org/10.1101/2023.11.30.569482
  32. Biochem J. 2023 Dec 11. pii: BCJ20230317. [Epub ahead of print]
    Upregulation of SLC7A11/xCT creates a vulnerability to selenocystine-induced cytotoxicity.
    Shawn Lu Wen Tan, Hui Min Tan, Erez Israeli, Indah Fatihah, Vignesh Ramachandran, Shamsia Bte Ali, Shane Jun An Goh, Jillian Wee, Alicia Qian Ler Tan, Wai Leong Tam, Weiping Han.
      The SLC7A11/xCT cystine and glutamate antiporter has emerged as an attractive target for cancer therapy due to its selective overexpression in multiple cancers and its role in preventing ferroptosis. Utilizing pharmacological and genetic approaches in hepatocellular carcinoma cell lines, we demonstrate that overexpression of SLC7A11 engenders hypersensitivity towards L-selenocystine, a naturally-occurring diselenide that bears close structural similarity to L-cystine. We find that abundance of SLC7A11 positively correlates with sensitivity to L-selenocystine, but surprisingly, not to Erastin, an inhibitor of SLC7A11 activity. Our data indicate that SLC7A11 acts as a transport channel for L-selenocystine, which preferentially incites acute oxidative stress and damage eventuating to cell death in cells that highly express SLC7A11. Hence, our findings raise the prospect of L-selenocystine administration as a novel strategy for targeting cancers that upregulate SLC7A11 expression.
    Keywords:  SLC7A11; Selenocystine; cancer therapeutic; hepatocellular carcinoma; reactive oxygen species
    DOI:  https://doi.org/10.1042/BCJ20230317
  33. Eur Respir J. 2023 Dec 07. pii: 2301720. [Epub ahead of print]
    Associations of combined phenotypic aging and genetic risk with incidence of chronic respiratory diseases in the UK biobank: a prospective cohort study.
    Ting Wang, Weiwei Duan, Xinying Jia, Xinmei Huang, Yi Liu, Fanqing Meng, Chunhui Ni.
      Accelerated biological aging has been associated with an increased risk of several chronic respiratory diseases. However, the associations between Phenotypic Age, a new biological age indicator based on clinical chemistry biomarkers, and common chronic respiratory diseases have not been evaluated.We analyzed data from 308 592 participants at baseline in the UK Biobank. The Phenotypic Age was calculated from chronological age and 9 clinical chemistry biomarkers, including albumin, alkaline phosphatase, creatinine, glucose, C-reactive protein, lymphocyte percent, mean cell volume, red cell distribution width, and white blood cell count. Furthermore, Phenotypic Age Acceleration (PhenoAgeAccel) was calculated by regressing Phenotypic Age on chronological age. The associations of PhenoAgeAccel with incident common chronic respiratory diseases and cross-sectional lung function were investigated. Moreover, we constructed polygenic risk scores and evaluated whether PhenoAgeAccel modified the effect of genetic susceptibility on chronic respiratory diseases and lung function.The results showed significant associations of PhenoAgeAccel with increased risk of idiopathic pulmonary fibrosis (IPF) (HR=1.52, 95%CI: 1.45-1.59), chronic obstructive pulmonary disease (COPD) (HR=1.54, 95%CI: 1.51-1.57), and asthma (HR=1.18, 95%CI: 1.15-1.20) per 5-year increase and decreased lung function. There was an additive interaction between PhenoAgeAccel and the genetic risk for IPF and COPD. Participants with high genetic risk and biologically older had the highest risk of incident IPF (HR=5.24, 95%CI: 3.91-7.02), COPD (HR=2.99, 95%CI: 2.66-3.36), and asthma (HR= 2.07, 95%CI: 1.86-2.31). Mediation analysis indicated that PhenoAgeAccel could mediate 10∼20% of the associations between smoking and chronic respiratory diseases, while ∼10% of the associations between PM2.5 and the disorders were mediated by PhenoAgeAccel.PhenoAgeAccel was significantly associated with incident risk of common chronic respiratory diseases and decreased lung function and could serve as a novel clinical biomarker.
    DOI:  https://doi.org/10.1183/13993003.01720-2023
  34. bioRxiv. 2023 Dec 01. pii: 2023.11.30.569464. [Epub ahead of print]
    Modeling aging and retinal degeneration with mitochondrial DNA mutation burden.
    John Sturgis, Rupesh Singh, Quinn Caron, Ivy S Samuels, Thomas Micheal Shiju, Aditi Mukkara, Paul Freedman, Vera L Bonilha.
      Somatic mitochondrial DNA (mtDNA) mutation accumulation has been observed in individuals with retinal degenerative disorders. To study the effects of aging and mtDNA mutation accumulation in the retina, a Polymerase gamma (POLG) deficiency model, the POLG D257A mutator mice (PolgD257A), was used. POLG is an enzyme responsible for regulating mtDNA replication and repair. Retinas of young and older mice with this mutation were analyzed in vivo and ex vivo to provide new insights into the contribution of age-related mitochondrial dysfunction due to mtDNA damage. Optical coherence tomography (OCT) image analysis revealed a decrease in retinal and photoreceptor thickness starting at 6 months of age in mice with the POLG D257A mutation compared to wild-type (WT) mice. Electroretinography (ERG) testing showed a significant decrease in all recorded responses at 6 months of age. Sections labeled with markers of different types of retinal cells, including cones, rods, and bipolar cells, exhibited decreased labeling starting at 6 months. However, electron microscopy analysis revealed differences in retinal pigment epithelium (RPE) mitochondria morphology beginning at 3 months. Interestingly, there was no increase in oxidative stress observed in the retina or RPE of POLGD257A mice. Additionally, POLGD257A RPE exhibited an accelerated rate of autofluorescence cytoplasmic granule formation and accumulation. Mitochondrial markers displayed decreased abundance in protein lysates obtained from retina and RPE samples. These findings suggest that the accumulation of mitochondrial DNA mutations leads to impaired mitochondrial function and accelerated aging, resulting in retinal degeneration.
    DOI:  https://doi.org/10.1101/2023.11.30.569464
  35. Annu Int Conf IEEE Eng Med Biol Soc. 2023 Jul;2023 1-4
    A novel ultrasonic-electric-based microsystem for the investigation of mechanical aging on lipid membranes.
    Feng Zhou, Qiannan Xue, Xuexin Duan.
      Aging cells experience a gradual degeneration of their chemical and physical characteristics, resulting in the declining body functions that are commonly observed in old age. In this paper, we propose a novel microsystem that utilizes acoustics and electricity to investigate the effects of mechanical cyclic loading on cellular aging. Our study is the first to examine how mechanical loading influences the physicochemical characteristics of lipid bilayer at the subcellular level. By providing a new method for understanding the mechanism of cellular aging and aging-related diseases, our microsystem has significant implications for the development of treatments and therapies.Clinical Relevance- This ultrasonic-electric-based microsystem, as an in vitro model with sensitive quantitative capabilities, could have significant clinical implications in terms of understanding cellular responses to mechanical forces, elucidating the pathogenesis of aging-related diseases, and developing therapeutic strategies.
    DOI:  https://doi.org/10.1109/EMBC40787.2023.10340884
  36. Heliyon. 2023 Dec;9(12): e22422
    Traditional Chinese medicine for the prevention and treatment of presbycusis.
    Li Yan, Yan Huo, Jianrong Shi, Yang Dong, Hongsheng Tan.
       Background: Presbycusis/Age-related hearing loss is a sensorineural hearing loss caused by age-related deterioration of the auditory system that poses a risk to the physical and mental health of older people, including social and cognitive decline. It is also associated with frailty, falls and depression. There are currently no specific medications for the treatment of presbycusis, and early detection and intervention are key to its prevention and management. Traditional Chinese medicine interventions may offer opportunities in the prevention and treatment of presbycusis, but there is no relevant review.
    Methods: Literature searches was conducted using PubMed, Cochrane Library, Web of Science, and China National Knowledge Infrastructure (CNKI) databases for review articles, research articles, clinical trials, meta-analyses, and case studies in animal models and clinical trials.
    Results: We summarized the pathological mechanisms associated with presbycusis, related to genetic factors, environment, lifestyle, and molecular mechanisms related to oxidative stress, mitochondrial dysfunction, and inflammatory pathways. It is suggested that traditional Chinese medicine interventions may offer opportunities in the prevention and treatment of presbycusis using active ingredients of herbs or formulas, acupuncture, and exercise such as Tai Chi Chuan or Ba Duan Jin. The active ingredients of herbs or formulas may exert ear protection through Nrf2-mediated antioxidant pathways, NF-kB and NLRP3-related anti-inflammatory signaling, and regulation of autophagy.
    Conclusions: Here, we review the pathogenetic factors and pathological mechanisms involved in presbycusis, as well as traditional Chinese medicine interventions and treatments, with the aim of providing a new perspective for the prevention and treatment of hearing loss in the elderly and further improving their quality of life.
    Keywords:  Age-related hearing loss; Mechanism; Presbycusis; Traditional Chinese medicine
    DOI:  https://doi.org/10.1016/j.heliyon.2023.e22422
  37. JACC Basic Transl Sci. 2023 Oct;8(10): 1334-1353
    PCSK9, A Promising Novel Target for Age-Related Cardiovascular Dysfunction.
    Csaba Matyas, Eszter Trojnar, Suxian Zhao, Muhammad Arif, Partha Mukhopadhyay, Attila Kovacs, Alexandra Fabian, Marton Tokodi, Zsolt Bagyura, Bela Merkely, Laszlo Kohidai, Eszter Lajko, Angela Takacs, Yong He, Bin Gao, Janos Paloczi, Falk W Lohoff, György Haskó, Wen-Xing Ding, Pal Pacher.
      Cardiovascular diseases (CVDs) are the leading cause of death among elderly people. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an important regulator of cholesterol metabolism. Herein, we investigated the role of PCSK9 in age-related CVD. Both in humans and rats, blood PCSK9 level correlated positively with increasing age and the development of cardiovascular dysfunction. Age-related fatty degeneration of liver tissue positively correlated with serum PCSK9 levels in the rat model, while development of age-related nonalcoholic fatty liver disease correlated with cardiovascular functional impairment. Network analysis identified PCSK9 as an important factor in age-associated lipid alterations and it correlated positively with intima-media thickness, a clinical parameter of CVD risk. PCSK9 inhibition with alirocumab effectively reduced the CVD progression in aging rats, suggesting that PCSK9 plays an important role in cardiovascular aging.
    Keywords:  NASH; PCSK9; cardiovascular aging; heart failure; nonalcoholic steatohepatitis; transcriptomics
    DOI:  https://doi.org/10.1016/j.jacbts.2023.06.005
  38. Epigenomics. 2023 Dec 13.
    Gut microbiota defined epigenomes of Alzheimer's and Parkinson's diseases reveal novel targets for therapy.
    Shabnam Nohesara, Hamid Mostafavi Abdolmaleky, Sam Thiagalingam, Jin-Rong Zhou.
      The origins of Alzheimer's disease (AD) and Parkinson's disease (PD) involve genetic mutations, epigenetic changes, neurotoxin exposure and gut microbiota dysregulation. The gut microbiota's dynamic composition and its metabolites influence intestinal and blood-brain barrier integrity, contributing to AD and PD development. This review explores protein misfolding, aggregation and epigenetic links in AD and PD pathogenesis. It also highlights the role of a leaky gut and the microbiota-gut-brain axis in promoting these diseases through inflammation-induced epigenetic alterations. In addition, we investigate the potential of diet, probiotics and microbiota transplantation for preventing and treating AD and PD via epigenetic modifications, along with a discussion related to current challenges and future considerations. These approaches offer promise for translating research findings into practical clinical applications.
    Keywords:  Alzheimer's disease; Parkinson's diseases; epigenetic; leaky gut; microbiota; probiotics
    DOI:  https://doi.org/10.2217/epi-2023-0342
  39. J Clin Med. 2023 Nov 28. pii: 7352. [Epub ahead of print]12(23):
    Could the Combination of eGFR and mGPS Facilitate the Differential Diagnosis of Age-Related Renal Decline from Diseases? A Large Study on the Population of Western Sicily.
    Miriam Carella, Annamaria Porreca, Cinzia Piazza, Francesco Gervasi, Daniele Magro, Marika Venezia, Raffaella Lo Verso, Giuseppe Vitale, Annalisa Giusy Agnello, Letizia Scola, Tommaso Silvano Aronica, Carmela Rita Balistreri.
      The assessment of renal function is critical to diagnosing and managing renal age-related decline, disease (KD), and failure, which are prevalent in the elderly population. The glomerular filtration rate (GFR) is widely used as an indicator of kidney function, but its direct measurement is challenging, as are its age and gender caveats. This makes difficult the differential diagnosis between age-related physiological decline and KD and/or failure. Currently, the inflammation-based modified Glasgow prognostic score (mGPS) is emerging as a promising biomarker of several inflammatory acute/chronic diseases. In this study, the large variability of eGFR with age and gender was evaluated as the association of eGFR values with mGPS levels. A population of 57,449 adult participants (age ≥ 18 years) was enrolled. Appropriate circulating biomarkers were measured to detect eGFR and mGPS values. The data obtained demonstrated a significant decrease in eGFR in men vs. women across the four selected age classes (18-40, 40-60, 60-80, 80-100 years); eGFR classes were significantly associated with mGPS (p < 0.001), as were age classes and gender with mGPS categories. Accordingly, the percentage of people having an mGPS score = 2 significantly increased across the eGFR classes: with an 11% in the G1/eGFR class needed to achieve 44% in G5/eGFR. Thus, the combination of mGPS with eGFR could represent the best benchmark risk model for the differential diagnosis of kidney disease from the age-related eGFR reduction.
    Keywords:  eGFR; kidney disease (KD); mGPS; renal age-related decline
    DOI:  https://doi.org/10.3390/jcm12237352
  40. Protein Cell. 2023 Dec 13. pii: pwad060. [Epub ahead of print]
    Identification of FOXO1 as a geroprotector in human synovium through single-nucleus transcriptomic profiling.
    Feifei Liu, Yi Lu, Xuebao Wang, Shuhui Sun, Huize Pan, Min Wang, Zehua Wang, Weiqi Zhang, Shuai Ma, Guoqiang Sun, Qun Chu, Si Wang, Jing Qu, Guang-Hui Liu.
      The synovium, a thin layer of tissue that adjacent to the joints and secretes synovial fluid, undergoes changes in aging that contribute to intense shoulder pain and other joint diseases. However, the mechanism underlying human synovial aging remains poorly characterized. Here, we generated a comprehensive profile of synovial cell types present in subacromial synovium from young and aged individuals. By delineating aging-related transcriptomic changes across cell types and their associated regulatory networks, we identified two subsets of mesenchymal stromal cell (MSC) in human synovium, which are lining and sublining MSCs, and found that angiogenesis and fibrosis-associated genes were upregulated whereas genes associated with cell adhesion and cartilage development were downregulated during aging. Moreover, the specific cell-cell communications in aged synovium mirrors that of aging-related inflammation and tissue remodeling, including vascular hyperplasia and tissue fibrosis. In particular, we identified Forkhead box O1 (FOXO1) as one of the major regulons for aging DEGs of synovium MSCs, and validated its downregulation in both lining and sublining MSC populations of the aged synovium. In human FOXO1-depleted MSCs derived from human embryonic stem cells, we recapitulated the senescent phenotype observed in the subacromial synovium of aged donors. These data indicate the important role for FOXO1 in the regulation of human synovial aging. Overall, our study improves upon our understanding of synovial aging during joint degeneration, thereby informing development of new treatments aimed at rejuvenating the aged joint.
    Keywords:  FOXO1; aging; senescence; single-nucleus RNA sequencing; synovium
    DOI:  https://doi.org/10.1093/procel/pwad060
  41. Int J Mol Sci. 2023 Nov 26. pii: 16766. [Epub ahead of print]24(23):
    The Role of Immune Dysfunction in Parkinson's Disease Development.
    Davide Cossu, Taku Hatano, Nobutaka Hattori.
      Recent research has unveiled intriguing insights suggesting that the body's immune system may be implicated in Parkinson's disease (PD) development. Studies have observed disparities in pro-inflammatory and anti-inflammatory markers between PD patients and healthy individuals. This finding underscores the potential influence of immune system dysfunction in the genesis of this condition. A dysfunctional immune system can serve as a primary catalyst for systemic inflammation in the body, which may contribute to the emergence of various brain disorders. The identification of several genes associated with PD, as well as their connection to neuroinflammation, raises the likelihood of disease susceptibility. Moreover, advancing age and mitochondrial dysfunction can weaken the immune system, potentially implicating them in the onset of the disease, particularly among older individuals. Compromised integrity of the blood-brain barrier could facilitate the immune system's access to brain tissue. This exposure may lead to encounters with native antigens or infections, potentially triggering an autoimmune response. Furthermore, there is mounting evidence supporting the notion that gut dysbiosis might represent an initial trigger for brain inflammation, ultimately promoting neurodegeneration. In this comprehensive review, we will delve into the numerous hypotheses surrounding the role of both innate and adaptive immunity in PD.
    Keywords:  Parkinson’s disease; dysbiosis; immunity; infections; mitochondria; neuroinflammation
    DOI:  https://doi.org/10.3390/ijms242316766
  42. Orthop Surg. 2023 Dec 12.
    Exploring Causal Relationships between Leukocyte Telomere Length, Sex Hormone-Binding Globulin Levels, and Osteoporosis Using Univariable and Multivariable Mendelian Randomization.
    Kaibo Sun, Mengying Li, Yongtao Wu, Yuangang Wu, Yi Zeng, Shengliang Zhou, Linbo Peng, Bin Shen.
       OBJECTIVE: Recent evidence supports that leukocyte telomere length (LTL) may be positively associated with healthy living and inversely correlated with the risk of age-related diseases, including osteoporosis. Furthermore, it is important to note that sex hormone-binding globulin (SHBG) levels play a crucial role in the regulation of osteoporosis by influencing the availability of sex hormones. Hence, this study holds significant importance as it aims to unravel the roles of LTL and SHBG levels and determine which one acts as a predominant intermediary factor in influencing osteoporosis. Using Mendelian randomization (MR), we can gain valuable insights into the intricate relationships between aging, sex hormones, and bone health.
    METHODS: Univariable and multivariable and MR analyses were employed in this study. First, we used genetic variants associated with both LTL, as determined from a study involving 472,174 European participants by Codd et al., and SHBG levels, as identified in a study conducted by Ruth et al. with 370,125 participants, as instrumental variables (IVs). Then we aimed to establish a causal relationship between LTL and SHBG levels and their potential impact on osteoporosis using univariable MR. Finally, we conducted multivariable MR to provide insights into the independent and combined effects of LTL, SHBG levels on osteoporosis risk. We used various MR methods, with the primary analysis employing the inverse-variance weighted (IVW) model.
    RESULTS: Univariable MR analysis reveals a potential causal effect of longer LTL on reduced risk of osteoporosis [odds ratio (OR): 0.85; 95% confidence interval (CI): 0.73-0.99; p = 0.03]. Conversely, higher genetically determined SHBG levels affect the risk of osteoporosis positively. (OR: 1.38; 95% CI: 1.09-1.75; p < 0.01). We observed a negative causal effect for LTL on the occurrence of SHBG (OR: 0.96; 95% CI 0.94-0.98, p < 0.01). After adjustment of using multivariable MR, the causal effect of LTL on osteoporosis (OR: 0.92; 95% CI: 0.84-1.03; p = 0.14), and the effect of SHBG on osteoporosis (OR: 1.43; 95% CI: 1.16-1.75; p < 0.01) were observed.
    CONCLUSION: Longer LTL may confer a protective effect against osteoporosis. Additionally, the levels of SHBG appear to play a crucial role in mediating the relationship between LTL and osteoporosis. By understanding the interplay between these factors, we can gain valuable insights into the mechanisms underlying bone health and aging and potentially identify new avenues for prevention and intervention strategies.
    Keywords:  Leukocyte telomere length; Mendelian randomization; Osteoporosis; Sex hormone-binding globulin
    DOI:  https://doi.org/10.1111/os.13947
  43. Front Optoelectron. 2023 Dec 14. 16(1): 45
    Photostimulation of lymphatic clearance of β-amyloid from mouse brain: a new strategy for the therapy of Alzheimer's disease.
    Dongyu Li, Hao Lin, Silin Sun, Shaojun Liu, Zhang Liu, Yuening He, Jingtan Zhu, Jianyi Xu, Oxana Semyachkina-Glushkovskaya, Tingting Yu, Dan Zhu.
      Alzheimer's disease (AD) is an age-related neurodegenerative disorder that poses a significant burden on socio-economic and healthcare systems worldwide. However, the currently available therapy of AD is limited, and new strategies are needed to enhance the clearance of β-amyloid (Aβ) protein and improve cognitive function. Photobiomodulation (PBM) is a non-invasive and effective therapeutic method that has shown promise in treating various brain diseases. Here, we demonstrate that 1267-nm PBM significantly alleviates cognitive decline in the 5xFAD mouse model of AD and is safe as it does not induce a significant increase in cortical temperature. Moreover, with the combination of 3D tissue optical clearing imaging and automatic brain region segmentation, we show that PBM-mediated reductions of Aβ plaques in different subregions of prefrontal cortex and the hippocampus are different. The PBM-induced lymphatic clearance of Aβ from the brain is associated with improvement of memory and cognitive functions in 5xFAD mice. Our results suggest that the modulation of meningeal lymphatic vessels (MLVs) should play an important role in promoting Aβ clearance. Collectively, this pilot study demonstrates that PBM can safely accelerate lymphatic clearance of Aβ from the brain of 5xFAD mice, promoting improvement of neurocognitive status of AD animals suggesting that PBM can be an effective and bedside therapy for AD.
    Keywords:  Alzheimer’s disease; Amyloid-β clearance; Meningeal lymphatic vessels; Photostimulation
    DOI:  https://doi.org/10.1007/s12200-023-00099-8
  44. Cells. 2023 Nov 27. pii: 2714. [Epub ahead of print]12(23):
    Innate Immunity and CKD: Is There a Significant Association?
    Moran Plonsky-Toder, Daniella Magen, Shirley Pollack.
      Chronic kidney disease (CKD) constitutes a worldwide epidemic, affecting approximately 10% of the global population, and imposes significant medical, psychological, and financial burdens on society. Individuals with CKD often face elevated morbidity and mortality rates, mainly due to premature cardiovascular events. Chronic inflammation has been shown to play a significant role in the progression of CKD, as well as in the acceleration of CKD-related complications, including atherosclerosis, cardiovascular disease (CVD), protein-energy wasting, and the aging process. Over the past two decades, a substantial body of evidence has emerged, identifying chronic inflammation as a central element of the uremic phenotype. Chronic inflammation has been shown to play a significant role in the progression of CKD, as well as in the acceleration of CKD-related complications in dialysis patients, including atherosclerosis, CVD, protein-energy wasting, and the aging process. Remarkably, chronic inflammation also impacts patients with CKD who have not yet required renal replacement therapy. While extensive research has been conducted on the involvement of both the adaptive and innate immune systems in the pathogenesis of CKD-related complications, this wealth of data has not yet yielded well-established, effective treatments to counteract this ongoing pathological process. In the following review, we will examine the established components of the innate immune system known to be activated in CKD and provide an overview of the current therapeutic approaches designed to mitigate CKD-related chronic inflammation.
    Keywords:  cardiovascular disease; chronic inflammation; chronic kidney disease; innate immune system
    DOI:  https://doi.org/10.3390/cells12232714
  45. Front Med (Lausanne). 2023 ;10 1208326
    Why osteoarthritis of the knee is called "a wound that does not heal" and why Tai Chi is an effective treatment.
    Patricia Huston.
       Context: Osteoarthritis (OA) of the knee is common and is associated with other chronic diseases and early mortality. OA is often described as a "wound that does not heal" because a local innate immune response gets dysregulated. Tai Chi is an aerobic mind-body practice that is recommended in national and international clinical practice guidelines as a treatment for OA of the knee. This review addressed two questions: What causes immune dysregulation in the knee? and Why is Tai Chi an effective treatment?
    Recent findings: There is now a good understanding of what causes OA of the knee at the cellular level. OA begins in the synovium from a phenotypic shift in synovial macrophages in response to tissue damage. The synovial macrophages release inflammatory cytokines, as part of the first phase of the normal healing and repair process. Cytokines communicate to other cells that there has been damage. This stimulates chondrocytes, osteoblasts, and fibroblasts to release inflammatory cytokines as well. When tissue damage is repetitive, there is repetitive release of inflammatory cytokines, and the normal healing process stops. The most common cause of tissue damage is from abnormal biomechanical forces on the knee that arise from trauma, injury, and misalignment. Tissue damage is made worse when there is systemic low-grade inflammation associated with other chronic conditions. Pain and stiffness often result in decreased physical activity, which leads to muscle weakness, progressive instability of the joint, and an increased risk of falls, further injuring the knee. Tai Chi improves alignment, optimizes the biomechanical forces on the knee, strengthens the lower limbs, and decreases systemic inflammation. Tai Chi improves balance and decreases the risk of falls and further injury. There is clinical and experimental evidence to suggest that by removing the causes of cell dysregulation, Tai Chi enables the normal healing and repair process to resume.
    Conclusion: Knee OA is a wound that does not heal primarily because repetitive adverse forces on the knee cause synovial macrophages and then local chondrocytes, osteocytes and fibroblasts to dysregulate and stop the normal healing and repair process. Tai Chi mitigates adverse forces on the knee and stabilizes the joint, creating the conditions whereby the normal healing and repair process can resume. Further research is needed.
    Keywords:  Tai Chi; alignment; biomechanics; chronic low-grade inflammation; fibrosis; innate immunity; macrophages; osteoarthritis
    DOI:  https://doi.org/10.3389/fmed.2023.1208326
  46. Biofactors. 2023 Dec 14.
    Melatonin protects Kir2.1 function in an oxidative stress-related model of aging neuroglia.
    Alessia Remigante, Sara Spinelli, Paolo Zuccolini, Paola Gavazzo, Angela Marino, Michael Pusch, Rossana Morabito, Silvia Dossena.
      Melatonin is a pleiotropic biofactor and an effective antioxidant and free radical scavenger and, as such, can be protective in oxidative stress-related brain conditions including epilepsy and aging. To test the potential protective effect of melatonin on brain homeostasis and identify the corresponding molecular targets, we established a new model of oxidative stress-related aging neuroglia represented by U-87 MG cells exposed to D-galactose (D-Gal). This model was characterized by a substantial elevation of markers of oxidative stress, lipid peroxidation, and protein oxidation. The function of the inward rectifying K+ channel Kir2.1, which was identified as the main Kir channel endogenously expressed in these cells, was dramatically impaired. Kir2.1 was unlikely a direct target of oxidative stress, but the loss of function resulted from a reduction of protein abundance, with no alterations in transcript levels and trafficking to the cell surface. Importantly, melatonin reverted these changes. All findings, including the melatonin antioxidant effect, were reproduced in heterologous expression systems. We conclude that the glial Kir2.1 can be a target of oxidative stress and further suggest that inhibition of its function might alter the extracellular K+ buffering in the brain, therefore contributing to neuronal hyperexcitability and epileptogenesis during aging. Melatonin can play a protective role in this context.
    Keywords:  D-galactose; Kir2.1; aging; inward-rectifying potassium channel; melatonin; neuroglia; oxidative stress
    DOI:  https://doi.org/10.1002/biof.2024
  47. Inflammopharmacology. 2023 Dec 12.
    Targeting cardiovascular risk factors with eugenol: an anti-inflammatory perspective.
    Sushma Devi, Samrat Chauhan, Ashi Mannan, Thakur Gurjeet Singh.
      Inflammation is a multifaceted biological reaction to a wide range of stimuli, and it has been linked to the onset and progression of chronic diseases such as heart disease, cancer, and diabetes. Inflammatory markers found in the blood, including C-reactive protein, serum amyloid A, fibrinogen, plasma viscosity, erythrocyte sedimentation rate, interleukin-6, and soluble adhesion molecules (like intercellular adhesion molecule-1 and vascular cell adhesion molecule-1), are risk factors for cardiovascular diseases such as coronary heart disease, stroke, and peripheral arterial disease. These markers play a crucial role in understanding and assessing cardiovascular health. Due to this complicated relationship between inflammation and cardiovascular disease, anti-inflammatory agents of natural origin have been the subject of many preclinical and clinical studies in recent years. Eugenol is a natural phenolic compound found in clove oil, nutmeg oil, cinnamon oil, and bay leaf oil, as well as other essential oils. Eugenol has been shown to have anti-inflammatory properties in many forms of experimental inflammation. It may scavenge free radicals, which contribute to inflammation and tissue damage. Various studies also suggest that eugenol can limit the production of inflammatory mediators such as prostaglandins, cytokines, and chemokines. Animal models of arthritis, colitis, and lung damage, as well as human clinical studies, have shown that eugenol has phenomenal anti-inflammatory properties. These properties suggest that eugenol may be able to reduce the risk of cardiovascular diseases.
    Keywords:  Antioxidant; Calcium channel blocker; Cardiovascular; Eugenol; Hypertension; Inflammation; NF-kB
    DOI:  https://doi.org/10.1007/s10787-023-01392-w
  48. ACS Appl Mater Interfaces. 2023 Dec 11.
    Endothelial Response to the Combined Biomechanics of Vessel Stiffness and Shear Stress Is Regulated via Piezo1.
    Austin Lai, Ying Zhou, Peter Thurgood, Chanly Chheang, Nadia Chandra Sekar, Ngan Nguyen, Karlheinz Peter, Khashayar Khoshmanesh, Sara Baratchi.
      How endothelial cells sense and respond to dynamic changes in their biophysical surroundings as we age is not fully understood. Vascular stiffness is clearly a contributing factor not only in several cardiovascular diseases but also in physiological processes such as aging and vascular dementia. To address this gap, we utilized a microfluidic model to explore how substrate stiffness in the presence of shear stress affects endothelial morphology, senescence, proliferation, and inflammation. We also studied the role of mechanosensitive ion channel Piezo1 in endothelial responses under the combined effect of shear stress and substrate stiffness. To do so, we cultured endothelial cells inside microfluidic channels covered with fibronectin-coated elastomer with elastic moduli of 40 and 200 kPa, respectively, mimicking the stiffness of the vessel walls in young and aged arteries. The endothelial cells were exposed to atheroprotective and atherogenic shear stress levels of 10 and 2 dyn/cm2, respectively. Our findings show that substrate stiffness affects senescence under atheroprotective flow conditions and cytoskeleton remodeling, senescence, and inflammation under atherogenic flow conditions. Additionally, we found that the expression of Piezo1 plays a crucial role in endothelial adaptation to flow and regulation of inflammation under both atheroprotective and atherogenic shear stress levels. However, Piezo1 contribution to endothelial senescence was limited to the soft substrate and atheroprotective shear stress level. Overall, our study characterizes the response of endothelial cells to the combined effect of shear stress and substrate stiffness and reveals a previously unidentified role of Piezo1 in endothelial response to vessel stiffening, which potentially can be therapeutically targeted to alleviate endothelial dysfunction in aging adults.
    Keywords:  Piezo1; mechanotransduction; senescence; shear stress; substrate stiffness
    DOI:  https://doi.org/10.1021/acsami.3c07756
  49. J Cachexia Sarcopenia Muscle. 2023 Dec 12.
    Diet quality is associated with adipose tissue and muscle mass: the Coronary Artery Risk Development in Young Adults (CARDIA) study.
    Masoud Isanejad, Lyn M Steffen, James G Terry, James M Shikany, Xia Zhou, So-YunYi, David R Jacobs, John Jeffrey Carr, Brian T Steffen.
       BACKGROUND: Aging is associated with changes in body composition, and preventing loss of muscle mass and accumulation of excess adipose tissue in middle-aged adults may reduce age-related conditions at older ages. Dietary intake is one lifestyle factor shown to improve or maintain body composition. However, few studies have examined the Healthy Eating Index2015 (HEI2015), a measure of diet quality, and the association with body composition in adult men and women.
    METHODS: Participant data (n = 3017) from the Coronary Artery Risk Development in Young Adults (CARDIA) study were used to examine the associations of the HEI2015 with body composition measures at Year 25 (Y25), including (1) 25 year-change in weight, body mass index (BMI), and waist circumference and (2) a computed tomography (CT) scan at Y25 measured muscle mass, muscle quality (better quality = less lipid within the muscle), and adipose tissue depots visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and adipose within skeletal muscle (intermuscular adipose tissue; IMAT). Dietary intake was assessed by a diet history three times over 20 years, at years 0, 7, and 20. HEI2015, averaged over three exams, was created and categorized into quintiles. Multiple regression analysis evaluated the associations of body composition stratified across quintiles of HEI2015 adjusted for demographic characteristics, energy intake, lifestyle factors, and baseline anthropometric measures as appropriate. Race-sex interaction was tested (Pinteraction  > 0.30).
    RESULTS: Over 25 years of follow-up, averaged HEI2015 was significantly and inversely associated with weight gain (Quintile 1 (Q1) 37.3 lb vs. 32.9 in Q5; Ptrend  = 0.01), change in BMI (Q1 5.8 kg/m2 vs. 5.0 in Q5; Ptrend  = 0.005), and change in waist circumference (Q1 17.5 cm vs. 15.2 cm in Q5; Ptrend  < 0.001). By Y25, HEI2015 was inversely associated with VAT Q1 136.8 cm3 vs. 116.6 in Q5; Ptrend  < 0.001) and IMAT volumes (Q1 9.52 vs. 8.12 cm3 in Q5; Ptrend  < 0.001). Although total muscle volume declined (Ptrend  = 0.03), lean muscle mass volume was similar across quintiles (Ptrend  = 0.55). The IMAT/total muscle mass ratio declined across HEI2015 quintiles (Ptrend  < 0.001). Finally, higher HEI2015 was associated with better muscle quality at Y25 (higher value = less lipid within the muscle; Q1 41.1 vs. 42.2 HU in Q5; Ptrend  = 0.002). HEI2015 was nonlinearly, but inversely, associated with SAT (nonlinear P = 0.011).
    CONCLUSIONS: Improving diet quality in young to middle-aged adults is a recommended strategy to promote better measures of body composition. Our study findings suggest that healthier food choices may influence body composition.
    Keywords:  Diet quality; Intramuscular adipose tissue; Muscle mass; Muscle quality; Visceral adipose tissue
    DOI:  https://doi.org/10.1002/jcsm.13399
  50. Neurobiol Aging. 2023 Nov 25. pii: S0197-4580(23)00271-3. [Epub ahead of print]134 126-134
    Does functional system segregation mediate the effects of lifestyle on cognition in older adults?
    Petar P Raykov, Ethan Knights, Cam-Can, Richard N Henson.
      Healthy aging is typically accompanied by cognitive decline. Previous work has shown that engaging in multiple, non-work activities during midlife can have a protective effect on cognition several decades later, rendering it less dependent on brain structural health; the definition of "cognitive reserve". Other work has shown that increasing age is associated with reduced segregation of large-scale brain functional networks. Here we tested the hypothesis that functional segregation (SyS) mediates this effect of middle-aged lifestyle on late-life cognition. We used fMRI data from three tasks in the CamCAN dataset, together with cognitive data on fluid intelligence, episodic memory, and retrospective lifestyle data from the Lifetime of Experiences Questionnaire (LEQ). In all three tasks, we showed that SyS related to fluid intelligence even after adjusting for the (nonlinear) age effects. However, we found no evidence that SyS in late-life mediated the relationship between non-specific (non-occupation) midlife activities and either measure of cognition in late-life. Thus, the brain correlates of cognitive reserve arising from mid-life activities remain to be discovered.
    Keywords:  Aging; Connectivity; FMRI; Fluid Intelligence; Functional System Segregation; Memory
    DOI:  https://doi.org/10.1016/j.neurobiolaging.2023.11.009
  51. Food Nutr Res. 2023 ;67
    Vitamin D - a scoping review for Nordic nutrition recommendations 2023.
    Magritt Brustad, Haakon E Meyer.
      Vitamin D is an essential nutrient. Its role in calcium and phosphorous metabolism, and in the development and maintenance of a healthy skeleton is well documented. In addition, there is some evidence for vitamin D decreasing total mortality and cancer mortality modestly, but not cancer incidence. Vitamin D is unique, as both diet and sun induced production in skin are sources to this vitamin. Individual vitamin D status is thus a sum of both sun exposure and dietary intakes. The discovery of vitamin D receptors and the activation of biological active vitamin D in numerous tissues and organs in the body has given support to hypothesis on vitamin D having extra-skeletal functions. The scientific literature on vitamin D and several health outcomes is high in numbers and has been increasing exponentially the last two decades. However, despite this large body of scientific publications and improvement in study quality, vitamin D supplementation has not shown to give additional health benefits when status is in sufficient range (i.e. circulating 25 hydroxyvitamin D >50 nmol/L). Well-designed studies on insufficient or deficient individuals are lacking. The totality of evidence does not support that increased intake of vitamin D beyond current recommendation will have additional beneficial health effects.
    Keywords:  NNR23; cholecalciferol; ergocalciferol; recommendations; vitamin D
    DOI:  https://doi.org/10.29219/fnr.v67.10230
  52. Front Physiol. 2023 ;14 1264570
    Roles and regulation of Aquaporin-3 in maintaining the gut health: an updated review.
    Cui Zhu, Xiaoyan Nie, Qi Lu, Yinshan Bai, Zongyong Jiang.
      Aquaporin-3 (AQP3) is a predominant water channel protein expressed in the intestine, and plays important roles in the gut physiology and pathophysiology due to its permeability to water, glycerol and hydrogen peroxide. In this review, we systematically summarized the current understanding of the expression of AQP3 in the intestine of different species, and focused on the potential roles of AQP3 in water transport, different types of diarrhea and constipation, intestinal inflammation, intestinal barrier function, oxidative stress, and autophagy. These updated findings have supported that AQP3 may function as an important target in maintaining gut health of human and animals.
    Keywords:  Aquaporin 3; autophagy; barrier function; gut health; inflammation; oxidative stress
    DOI:  https://doi.org/10.3389/fphys.2023.1264570
  53. Sci Rep. 2023 Dec 07. 13(1): 21602
    Nectin-4 regulates cellular senescence-associated enlargement of cell size.
    Ryoko Katasho, Taiki Nagano, Tetsushi Iwasaki, Shinji Kamada.
      Cellular senescence is defined as irreversible growth arrest induced by various stress, such as DNA damage and oxidative stress. Senescent cells exhibit various characteristic morphological changes including enlarged morphology. In our recent study, we identified Nectin-4 to be upregulated in cellular senescence by comparative transcriptomic analysis. However, there are few reports on the relationship between Nectin-4 and senescence. Therefore, we analyzed the function of Nectin-4 in senescence and its biological significance. When overexpressed with Nectin-4, the cells exhibited the enlarged cell morphology closely resembling senescent cells. In addition, the cell size enlargement during DNA damage-induced senescence was suppressed by knockdown of Nectin-4, while there were no significant changes in senescence induction. These results suggest that Nectin-4 is not involved in the regulation of senescence itself but contributes to the senescence-associated cell size increase. Furthermore, the Nectin-4-dependent cell size increase was found to be mediated by Src family kinase (SFK)/PI3 kinase (PI3K)/Rac1 pathway. To explore the functional consequences of cell size enlargement, we analyzed cell survival in Nectin-4-depleted senescent cells. Single-cell tracking experiments revealed that Nectin-4 knockdown induced apoptosis in senescent cells, and there is a strong positive correlation between cell size and survival rate. These results collectively indicate that Nectin-4 plays a causative role in the senescence-associated cell size enlargement via SFK/PI3K/Rac1, which can contribute to survival of senescent cells.
    DOI:  https://doi.org/10.1038/s41598-023-48890-z
  54. Nutrients. 2023 Nov 29. pii: 4950. [Epub ahead of print]15(23):
    Effects of Dietary Methionine Restriction on Cognition in Mice.
    Hannah Lail, Angela M Mabb, Marise B Parent, Filipe Pinheiro, Desiree Wanders.
      Dietary restriction of the essential amino acid, methionine, has been shown to induce unique metabolic protection. The peripheral benefits of methionine restriction (MR) are well established and include improvements in metabolic, energy, inflammatory, and lifespan parameters in preclinical models. These benefits all occur despite MR increasing energy intake, making MR an attractive dietary intervention for the prevention or reversal of many metabolic and chronic conditions. New and emerging evidence suggests that MR also benefits the brain and promotes cognitive health. Despite widespread interest in MR over the past few decades, many findings are limited in scope, and gaps remain in our understanding of its comprehensive effects on the brain and cognition. This review details the current literature investigating the impact of MR on cognition in various mouse models, highlights some of the key mechanisms responsible for its cognitive benefits, and identifies gaps that should be addressed in MR research moving forward. Overall findings indicate that in animal models, MR is associated with protection against obesity-, age-, and Alzheimer's disease-induced impairments in learning and memory that depend on different brain regions, including the prefrontal cortex, amygdala, and hippocampus. These benefits are likely mediated by increases in fibroblast growth factor 21, alterations in methionine metabolism pathways, reductions in neuroinflammation and central oxidative stress, and potentially alterations in the gut microbiome, mitochondrial function, and synaptic plasticity.
    Keywords:  Alzheimer’s disease; age; behavior; brain; cognition; female; high-fat diet; methionine restriction; obesity; sex
    DOI:  https://doi.org/10.3390/nu15234950
  55. Obes Pillars. 2022 Mar;1 100005
    Nutrition and physical activity: An Obesity Medicine Association (OMA) Clinical Practice Statement 2022.
    Lydia Alexander, Sandra M Christensen, Larry Richardson, Amy Beth Ingersoll, Karli Burridge, Angela Golden, Sara Karjoo, Danielle Cortez, Michael Shelver, Harold Edward Bays.
       Background: This Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) on Nutrition and Physical Activity provides clinicians an overview of nutrition and physical activity principles applicable to the care of patients with increased body fat, especially those with adverse fat mass and adiposopathic metabolic consequences.
    Methods: The scientific information and clinical guidance is based upon referenced evidence and derived from the clinical perspectives of the authors.
    Results: This OMA CPS on Nutrition and Physical Activity provides basic clinical information regarding carbohydrates, proteins, fats (including trans fats, saturated fats, polyunsaturated fats, and monounsaturated fats), general principles of healthful nutrition, nutritional factors associated with improved health outcomes, and food labels. Included are the clinical implications of isocaloric substitution of refined carbohydrates with saturated fats and vice-versa, as well as definitions of low-calorie, very low-calorie, carbohydrate-restricted, and fat-restricted dietary intakes. Specific dietary plans discussed include carbohydrate-restricted diets, fat-restricted diets, very low-calorie diets, the Mediterranean diet, Therapeutic Lifestyle diet, Dietary Approaches to Stop Hypertension (DASH), ketogenic (modified Atkins) diet, Ornish diet, Paleo diet, vegetarian or vegan diet (whole food/plant-based), intermittent fasting/time restricted feeding, and commercial diet programs. This clinical practice statement also examines the health benefits of physical activity and provides practical pre-exercise medical evaluation guidance as well as suggestions regarding types and recommended amounts of dynamic (aerobic) training, resistance (anaerobic) training, leisure time physical activity, and non-exercise activity thermogenesis (NEAT). Additional guidance is provided regarding muscle physiology, exercise prescription, metabolic equivalent tasks (METS), and methods to track physical activity progress.
    Conclusion: This Obesity Medicine Association Clinical Practice Statement on Nutrition and Physical Activity provides clinicians an overview of nutrition and physical activity. Implementation of appropriate nutrition and physical activity in patients with pre-obesity and/or obesity may improve the health of patients, especially those with adverse fat mass and adiposopathic metabolic consequences.
    Keywords:  Clinical practice statement; Nutrition; Obesity; Physical activity
    DOI:  https://doi.org/10.1016/j.obpill.2021.100005
  56. Small Methods. 2023 Dec 10. e2301315
    Imaging Structural and Electrical Changes of Aging Cells Using Scanning Ion Conductance Microscopy.
    Yao Song, Shuting Zhang, Chen Cao, Jia Yan, Mei Li, Xinyu Li, Feng Chen, Ning Gu.
      The local charge density and distribution of extracellular membranes play a crucial role in the various cellular processes, such as regulation and localization of membrane proteins, electrophysiological signal transduction, transcriptional control, cell growth, and cell death. In this study, a novel scanning ion conductance microscopy-based method is employed to extracellular membrane mapping. This method allows to not only visualize the dynamic topography and surface charge distribution around individual cells, but also distinguish the charge difference. To validate the accuracy and effectiveness of this method, the charge density on model sample surfaces are initially manipulated and the charge sensing mechanism using finite element modeling (FEM) is explored subsequently. By applying this method, both the extracellular charge distributions and topography structures of normal and senescent human dental pulp stem cells (hDPSCs) are able to monitor. Interestingly, it is observed that the surface charge became significantly more negative after cellular senescence. This innovative approach enables us to gain valuable insights into surface charge changes during cellular senescence, which can contribute to a better understanding of the underlying mechanisms and potential therapeutic strategies for age-related diseases.
    Keywords:  Scanning ion conductance microscopy; aging cell; extracellular membrane imaging; finite element modeling
    DOI:  https://doi.org/10.1002/smtd.202301315
  57. bioRxiv. 2023 Nov 27. pii: 2023.11.27.568808. [Epub ahead of print]
    Reduced Achilles tendon stiffness in aging persists at matched activations and associates with higher metabolic cost of walking.
    Jason R Franz, Rebecca L Krupenevich, Aubrey J Gray, John A Batsis, Gregory S Sawicki.
      The mechanisms responsible for increased walking metabolic cost among older adults are poorly understood. We recently proposed a theoretical premise by which age-related reductions in Achilles tendon stiffness (k AT ) can disrupt the neuromechanics of calf muscle behavior and contribute to faster rates of oxygen consumption during walking. The purpose of this study was to objectively evaluate this premise. We quantified k AT at a range of matched activations prescribed using electromyographic biofeedback and walking metabolic cost in a group of 15 younger (age: 23±4 yrs) and 15 older adults (age: 72±5 yrs). Older adults averaged 44% less k AT than younger adults at matched triceps surae activations (p=0.046). This effect appeared to arise not only from altered tendon length-tension relations with age, but also from differences in the operating region of those length-tension relations between younger and older adults. Older adults also walked with a 17% higher net metabolic power than younger adults (p=0.017). In addition, we discovered empirical evidence that lesser k AT exacts a metabolic penalty and was positively correlated with higher net metabolic power during walking (r=-0.365, p=0.048). These results pave the way for interventions focused on restoring ankle muscle-tendon unit structural stiffness to improve walking energetics in aging.
    DOI:  https://doi.org/10.1101/2023.11.27.568808
  58. Nat Commun. 2023 Dec 11. 14(1): 8211
    UniKP: a unified framework for the prediction of enzyme kinetic parameters.
    Han Yu, Huaxiang Deng, Jiahui He, Jay D Keasling, Xiaozhou Luo.
      Prediction of enzyme kinetic parameters is essential for designing and optimizing enzymes for various biotechnological and industrial applications, but the limited performance of current prediction tools on diverse tasks hinders their practical applications. Here, we introduce UniKP, a unified framework based on pretrained language models for the prediction of enzyme kinetic parameters, including enzyme turnover number (kcat), Michaelis constant (Km), and catalytic efficiency (kcat / Km), from protein sequences and substrate structures. A two-layer framework derived from UniKP (EF-UniKP) has also been proposed to allow robust kcat prediction in considering environmental factors, including pH and temperature. In addition, four representative re-weighting methods are systematically explored to successfully reduce the prediction error in high-value prediction tasks. We have demonstrated the application of UniKP and EF-UniKP in several enzyme discovery and directed evolution tasks, leading to the identification of new enzymes and enzyme mutants with higher activity. UniKP is a valuable tool for deciphering the mechanisms of enzyme kinetics and enables novel insights into enzyme engineering and their industrial applications.
    DOI:  https://doi.org/10.1038/s41467-023-44113-1
  59. bioRxiv. 2023 Nov 06. pii: 2023.11.06.565847. [Epub ahead of print]
    Methylation of histone H3 lysine 36 is a barrier for therapeutic interventions of head and neck squamous cell carcinoma.
    Lucas D Caeiro, Yuichiro Nakata, Rodrigo L Borges, Liliana Garcia-Martinez, Carolina P Bañuelos, Stephanie Stransky, Ho Lam Chan, John Brabson, Diana Domínguez, Yusheng Zhang, Peter W Lewis, Salvador Aznar-Benitah, Luisa Cimmino, Daniel Bilbao, Simone Sidoli, Ramiro E Verdun, Lluis Morey.
      Approximately 20% of head and neck squamous cell carcinomas (HNSCC) exhibit reduced methylation on lysine 36 of histone H3 (H3K36me) due to mutations in histone methylase NSD1 or a lysine-to-methionine mutation in histone H3 (H3K36M). Whether such alterations of H3K36me can be exploited for therapeutic interventions is still unknown. Here, we show that HNSCC models expressing H3K36M can be divided into two groups: those that display aberrant accumulation of H3K27me3 and those that maintain steady levels of H3K27me3. The first group shows decreased proliferation, genome instability, and increased sensitivity to genotoxic agents, such as PARP1/2 inhibitors. In contrast, the H3K36M HNSCC models with steady H3K27me3 levels do not exhibit these characteristics unless H3K27me3 levels are elevated, either by DNA hypomethylating agents or by inhibiting the H3K27me3 demethylases KDM6A/B. Mechanistically, we found that H3K36M reduces H3K36me by directly impeding the activities of the histone methyltransferase NSD3 and the histone demethylase LSD2. Notably, we found that aberrant H3K27me3 levels induced by H3K36M expression is not a bona fide epigenetic mark in HNSCC since it requires continuous expression of H3K36M to be inherited. Moreover, increased sensitivity of H3K36M HNSCC models to PARP1/2 inhibitors solely depends on the increased H3K27me3 levels. Indeed, aberrantly high H3K27me3 levels decrease BRCA1 and FANCD2-dependent DNA repair, resulting in higher sensitivity to DNA breaks and replication stress. Finally, in support of our in vitro findings, a PARP1/2 inhibitor alone reduce tumor burden in a H3K36M HNSCC xenograft model with elevated H3K27me3, whereas in a H3K36M HNSCC xenograft model with consistent H3K27me3 levels, a combination of PARP1/2 inhibitors and agents that upregulate H3K27me3 proves to be successful. In conclusion, our findings underscore a delicate balance between H3K36 and H3K27 methylation, essential for maintaining genome stability. This equilibrium presents promising therapeutic opportunities for patients with H3K36me-deficient tumors.
    DOI:  https://doi.org/10.1101/2023.11.06.565847
  60. IEEE Trans Ultrason Ferroelectr Freq Control. 2023 Dec 13. PP
    Clinical, Safety and Engineering Perspectives on Wearable Ultrasound Technology: A Review.
    Pengfei Song, Michael Andre, Parag Chitnis, Sheng Xu, Theodore Croy, Keith Wear, Siddhartha Sikdar.
      Wearable ultrasound has the potential to become a disruptive technology enabling new applications not only in traditional clinical settings, but also in settings where ultrasound is not currently used. Understanding the basic engineering principles and limitations of wearable ultrasound is critical for clinicians, scientists, and engineers to advance potential applications and translate the technology from bench to bedside. Wearable ultrasound devices, especially monitoring devices, have the potential to apply acoustic energy to the body for far longer durations than conventional diagnostic ultrasound systems. Thus, bioeffects associated with prolonged acoustic exposure as well as skin health need to be carefully considered for wearable ultrasound devices. This paper reviews emerging clinical applications, safety considerations, and future engineering and clinical research directions for wearable ultrasound technology.
    DOI:  https://doi.org/10.1109/TUFFC.2023.3342150
  61. iScience. 2023 Dec 15. 26(12): 108558
    Epitranscriptome analysis of NAD-capped RNA by spike-in-based normalization and prediction of chronological age.
    Dean Li, Shuwen Ge, Yandong Liu, Miaomiao Pan, Xueting Wang, Guojing Han, Sili Zou, Rui Liu, Kongyan Niu, Chao Zhao, Nan Liu, Lefeng Qu.
      Nicotinamide adenine dinucleotide (NAD) can be used as an initiating nucleotide in RNA transcription to produce NAD-capped RNA (NAD-RNA). RNA modification by NAD that links metabolite with expressed transcript is a poorly studied epitranscriptomic modification. Current NAD-RNA profiling methods involve multi-steps of chemo-enzymatic labeling and affinity-based enrichment, thus presenting a critical analytical challenge to remove unwanted variations, particularly batch effects. Here, we propose a computational framework, enONE, to remove unwanted variations. We demonstrate that designed spike-in RNA, together with modular normalization procedures and evaluation metrics, can mitigate technical noise, empowering quantitative and comparative assessment of NAD-RNA across different datasets. Using enONE and a human aging cohort, we reveal age-associated features of NAD-capping and further develop an accurate RNA-based aging clock that combines signatures from both transcriptome and NAD-modified epitranscriptome. enONE facilitates the discovery of NAD-RNA responsive to physiological changes, laying an important foundation for functional investigations into this modification.
    Keywords:  Computational bioinformatics; Methodology in biological sciences; Sequence analysis; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2023.108558
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