bims-caglex Biomed News
on Cellular aging and life extension
Issue of 2023–12–24
72 papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño
  1. DNA repair-deficient premature aging models display accelerated epigenetic age.
  2. Application potential of senolytics in clinical treatment.
  3. Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming.
  4. Editorial Commentary: Dasatinib With Quercetin Shows Promise in Decreasing Age-Related Senescence in the Rotator Cuff Tendon-Can It Work Elsewhere?
  5. Potential Geroprotectors - From Bench to Clinic.
  6. Design and optimization of piperlongumine analogs as potent senolytics.
  7. Regulation of telomerase towards tumor therapy.
  8. Analysis of epigenetic clocks links yoga, sleep, education, reduced meat intake, coffee, and a SOCS2 gene variant to slower epigenetic aging.
  9. Exploring the anti-aging effects of fisetin in telomerase-deficient progeria mouse model.
  10. Detection and Elimination of Senescent Cells with a Self-Assembled Senescence-Associated β-Galactosidase-Activatable Nanophotosensitizer.
  11. Cellular senescence and kidney aging.
  12. Cells in Atherosclerosis: Focus on Cellular Senescence from Basic Science to Clinical Practice.
  13. Diet and Aging: The Role of Polyphenol-Rich Diets in Slow Down the Shortening of Telomeres: A Review.
  14. Quinolinic acid impairs mitophagy promoting microglia senescence and poor healthspan in C. elegans: a mechanism of impaired aging process.
  15. Age-Associated Changes of Sirtuin 2 Expression in CNS and the Periphery.
  16. Non-Intrinsic, Systemic Mechanisms of Cellular Senescence.
  17. Age-Related Alternative Splicing: Driver or Passenger in the Aging Process?
  18. Biological Age in Congenital Heart Disease-Exploring the Ticking Clock.
  19. New anti-aging strategies: a narrative review.
  20. Cpne7 deficiency induces cellular senescence and premature aging of dental pulp.
  21. Age-related micro-environmental changes as drivers of clonal hematopoiesis.
  22. Olovnikov, Telomeres, and Telomerase. Is It Possible to Prolong a Healthy Life?
  23. Loss of TDP-43 splicing repression occurs early in the aging population and is associated with Alzheimer's disease neuropathologic changes and cognitive decline.
  24. Epigenetic Mechanisms in Hematologic Aging and Premalignant Conditions.
  25. Implications of Senescent T Cells for Cancer Immunotherapy.
  26. Biology of cognitive aging across species.
  27. Long Telomeric Repeat-Containing RNA (TERRA): Biological Functions and Challenges in Vascular Aging and Disease.
  28. Methods for Estimating Personal Disease Risk and Phylogenetic Diversity of Hematopoietic Stem Cells.
  29. Exogenous Nucleotides Ameliorate Age-Related Decline in Testosterone in Male Senescence-Accelerated Mouse Prone-8 (SAMP8) Mice by Modulating the Local Renin-Angiotensin System Antioxidant Pathway.
  30. The epigenetics of frailty.
  31. Reduced Age-Related Gray Matter Loss in the Orbitofrontal Cortex in Long-Term Meditators.
  32. Aging hallmarks of the primate ovary revealed by spatiotemporal transcriptomics.
  33. SIRT5 variants from patients with mitochondrial disease are associated with reduced SIRT5 stability and activity, but not with neuropathology.
  34. DNA methylation as a window into female reproductive aging.
  35. Metabolic pathways in immune senescence and inflammaging: Novel therapeutic strategy for chronic inflammatory lung diseases. An EAACI position paper from the Task Force for Immunopharmacology.
  36. Microsomal triglyceride transfer protein is necessary to maintain lipid homeostasis and retinal function.
  37. Distinct secretomes in p16- and p21- positive senescent cells across tissues.
  38. Aging and Metabolic Reprogramming of Adipose-Derived Stem Cells Affect Molecular Mechanisms Related to Cardiovascular Diseases.
  39. "If I Were in Nature's Place, I Would Do It Like This..." Life and Hypotheses of Alexey Olovnikov.
  40. Arsenic Exposure and Epigenetic Aging: The Association with Cardiovascular Disease and All-Cause Mortality in the Strong Heart Study.
  41. Interplay of body mass index and metabolic syndrome: association with physiological age from midlife to late-life.
  42. Oxidative Stress and the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Pathway in Multiple Sclerosis: Focus on Certain Exogenous and Endogenous Nrf2 Activators and Therapeutic Plasma Exchange Modulation.
  43. PCSK9: an emerging player in cardiometabolic aging and its potential as a therapeutic target and biomarker.
  44. A ketogenic diet reduces age-induced chronic neuroinflammation in mice.
  45. Exploring the Connectivity of Neurodegenerative Diseases: Microglia as the Center.
  46. Telomere length and cancer risk: finding Goldilocks.
  47. Lipoteichoic acid restrains macrophage senescence via β-catenin/FOXO1/REDD1 pathway in age-related osteoporosis.
  48. Adeno-associated virus vectors for retinal gene therapy in basic research and clinical studies.
  49. Mitochondrial DNA Copy Number Variation in Asthma Risk, Severity, and Exacerbations.
  50. Early cerebral amyloid-β accumulation and hypermetabolism are associated with subtle cognitive deficits before accelerated cerebral atrophy.
  51. Adipsin in the pathogenesis of cardiovascular diseases.
  52. PURPL and NEAT1 Long Non-Coding RNAs Are Modulated in Vascular Smooth Muscle Cell Replicative Senescence.
  53. Can CD133 Be Regarded as a Prognostic Biomarker in Oncology: Pros and Cons.
  54. Anti-Osteoarthritis Mechanism of the Nrf2 Signaling Pathway.
  55. Gene-environment interactions for Parkinson's disease.
  56. Epigenetic regulation of drug metabolism in aging: utilizing epigenetics to optimize geriatric pharmacotherapy.
  57. Global quantitative proteomic analysis of aged mouse hippocampus.
  58. Editorial: DNA repair and interventions in aging.
  59. Audiovisual gamma stimulation for the treatment of neurodegeneration.
  60. Exploring the Therapeutic Potential of Gamma-Aminobutyric Acid in Stress and Depressive Disorders through the Gut-Brain Axis.
  61. Crosstalk between Nrf2 signaling pathway and inflammation in ischemic stroke: Mechanisms of action and therapeutic implications.
  62. Quantitative target engagement of RIPK1 in human whole blood via the cellular thermal shift assay for potential pre-clinical and clinical applications.
  63. Recent Developments in Gene Therapy for Neovascular Age-Related Macular Degeneration: A Review.
  64. Diabetes status and cognitive function in middle-aged and older adults in the Canadian longitudinal study on aging.
  65. 17β-Estradiol (E2) Upregulates the ERα/SIRT1/PGC-1α Signaling Pathway and Protects Mitochondrial Function to Prevent Bilateral Oophorectomy (OVX)-Induced Nonalcoholic Fatty Liver Disease (NAFLD).
  66. DNA methylation aging signatures of multiple metals exposure and their mediation effects in metal-associated mortality: Evidence from the Dongfeng-Tongji cohort study.
  67. Retroelement-Age Clocks: Epigenetic Age Captured by Human Endogenous Retrovirus and LINE-1 DNA methylation states.
  68. WWP1 E3 ligase at the crossroads of health and disease.
  69. Microgravity Effects and Aging Physiology: Similar Changes or Common Mechanisms?
  70. The CEPH aging cohort and biobank: a valuable collection of biological samples from exceptionally long-lived French individuals and their offspring for longevity studies.
  71. Ganoderma lucidum methyl ganoderate E extends lifespan and modulates aging-related indicators in Caenorhabditis elegans.
  72. Modeling transcriptional regulation of the cell cycle using a novel cybernetic-inspired approach.
  1. Aging Cell. 2023 Dec 22. e14058
    DNA repair-deficient premature aging models display accelerated epigenetic age.
    Kevin Perez, Alberto Parras, Sara Picó, Cheyenne Rechsteiner, Amin Haghani, Robert Brooke, Calida Mrabti, Lucas Schoenfeldt, Steve Horvath, Alejandro Ocampo.
      Several premature aging mouse models have been developed to study aging and identify interventions that can delay age-related diseases. Yet, it is still unclear whether these models truly recapitulate natural aging. Here, we analyzed DNA methylation in multiple tissues of four previously reported mouse models of premature aging (Ercc1, LAKI, Polg, and Xpg). We estimated DNA methylation (DNAm) age of these samples using the Horvath clock. The most pronounced increase in DNAm age could be observed in Ercc1 mice, a strain which exhibits a deficit in DNA nucleotide excision repair. Similarly, we detected an increase in epigenetic age in fibroblasts isolated from patients with progeroid syndromes associated with mutations in DNA excision repair genes. These findings highlight that mouse models with deficiencies in DNA repair, unlike other premature aging models, display accelerated epigenetic age, suggesting a strong connection between DNA damage and epigenetic dysregulation during aging.
    Keywords:  DNA damage; accelerated aging; epigenetic clock; methylation; progeria
    DOI:  https://doi.org/10.1111/acel.14058
  2. Biogerontology. 2023 Dec 18.
    Application potential of senolytics in clinical treatment.
    Tiantian Li, Shiyuan Li, Kefeng Ma, Jinming Kong.
      Of the factors studied in individual ageing, the accumulation of senescent cells has been considered as an essential cause of organ degeneration to eventually initiate age-related diseases. Cellular senescence is attributed to the accumulation of damage for an inducement in the activation of cell cycle inhibitory pathways, resulting the cell permanently withdraw from the cell proliferation cycle. Further, senescent cells will activate the inflammatory factor secretion pathway to promote the development of various age-related diseases. Senolytics, a small molecule compound, can delay disease development and extend mammalian lifespan. The evidence from multiple trials shows that the targeted killing of senescent cells has a significant clinical application for the treatment of age-related diseases. In addition, senolytics are also significant for the development of ageing research in solid organ transplantation, which can fully develop the potential of elderly organs and reduce the age gap between demand and supply. We conclude that the main characteristics of cellular senescence, the anti-ageing drug senolytics in the treatment of chronic diseases and organ transplantation, and the latest clinical progress of related researches in order to provide a theoretical basis for the prevention and treatment of ageing and related diseases.
    Keywords:  Disease; Organ transplantation; SASP; Senolytics
    DOI:  https://doi.org/10.1007/s10522-023-10084-5
  3. Nat Aging. 2023 Dec 15.
    Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming.
    Andrea Cipriano, Mahdi Moqri, Sun Y Maybury-Lewis, Ryan Rogers-Hammond, Tineke Anna de Jong, Alexander Parker, Sajede Rasouli, Hans Robert Schöler, David A Sinclair, Vittorio Sebastiano.
      Over the past decade, there has been a dramatic increase in efforts to ameliorate aging and the diseases it causes, with transient expression of nuclear reprogramming factors recently emerging as an intriguing approach. Expression of these factors, either systemically or in a tissue-specific manner, has been shown to combat age-related deterioration in mouse and human model systems at the cellular, tissue and organismal level. Here we discuss the current state of epigenetic rejuvenation strategies via partial reprogramming in both mouse and human models. For each classical reprogramming factor, we provide a brief description of its contribution to reprogramming and discuss additional factors or chemical strategies. We discuss what is known regarding chromatin remodeling and the molecular dynamics underlying rejuvenation, and, finally, we consider strategies to improve the practical uses of epigenetic reprogramming to treat aging and age-related diseases, focusing on the open questions and remaining challenges in this emerging field.
    DOI:  https://doi.org/10.1038/s43587-023-00539-2
  4. Arthroscopy. 2024 Jan;pii: S0749-8063(23)00528-5. [Epub ahead of print]40(1): 45-46
    Editorial Commentary: Dasatinib With Quercetin Shows Promise in Decreasing Age-Related Senescence in the Rotator Cuff Tendon-Can It Work Elsewhere?
    F Alan Barber.
      Cellular senescence is a fundamental mechanism seen in all age-related diseases. Human supraspinatus tendon and adjacent bursal specimens evaluated for cellular senescence by immunohistochemistry and gene expression show more senescent cells in older patients. This confirms the observation that older patients are more likely to have rotator cuff pathology, and older age is associated with lower rates of rotator cuff healing and more frequent tendon retears. Senolytic drugs can selectively eliminate senescent cells without a localized or systemic impact. Tendon and bursal specimens co-cultured and then incubated with dasatinib and quercetin for 48 hours show a significant decrease in senescent cells. This suggests that these drugs may slow biological aging in rotator cuff tendons and offer the possibility of a clinically effective treatment for the aging rotator cuff tendon. Moreover, this concept is promising for the development of future effective therapies addressing tissue senescence.
    DOI:  https://doi.org/10.1016/j.arthro.2023.06.038
  5. Biochemistry (Mosc). 2023 Nov;88(11): 1732-1738
    Potential Geroprotectors - From Bench to Clinic.
    Alexey A Moskalev.
      Geroprotectors are substances that slow down aging process and can be used for prevention of age-related diseases. Geroprotectors can improve functioning of various organ systems and enhance their homeostatic capabilities. We have developed a system of criteria for geroprotectors and proposed their classification based on the mechanisms of their action on the aging processes. Geroprotectors are required to reduce mortality, improve human aging biomarkers, have minimal side effects, and enhance quality of life. Additionally, there are approaches based on combining geroprotectors targeted to different targets and mechanisms of aging to achieve maximum effectiveness. Currently, numerous preclinical studies are being conducted to identify new molecular targets and develop new approaches to extend healthy aging, although the number of clinical trials is limited. Geroprotectors have the potential to become a new class of preventive medicines as they prevent onset of certain diseases or slow down their progression.
    Keywords:  aging; biological age; biomarker; criteria; geroprotector
    DOI:  https://doi.org/10.1134/S0006297923110056
  6. Bioorg Med Chem Lett. 2023 Dec 15. pii: S0960-894X(23)00471-7. [Epub ahead of print]98 129593
    Design and optimization of piperlongumine analogs as potent senolytics.
    Xuan Zhang, Yonghan He, Xingui Liu, Xin Zhang, Peizhong Shi, Yingying Wang, Daohong Zhou, Guangrong Zheng.
      Selective removal of senescent cells (SnCs) offers a promising therapeutic strategy to treat chronic and age-related diseases. Our prior investigations led to the discovery of piperlongumine (PL) and its derivatives as senolytic agents. In this study, our medicinal chemistry campaign on both the α,β-unsaturated δ-valerolactam ring and the phenyl ring of PL culminated in the identification of compound 24, which exhibited an impressive 50-fold enhancement in senolytic activity against senescent WI-38 fibroblasts compared to PL.
    Keywords:  Cellular senescence; Piperlongumine; Senescent cells; Senolytics; Structure activity relationship
    DOI:  https://doi.org/10.1016/j.bmcl.2023.129593
  7. Cell Biosci. 2023 Dec 18. 13(1): 228
    Regulation of telomerase towards tumor therapy.
    Siyu Yan, Song Lin, Hongxin Qiu, Xining Wang, Yijun He, Chuanle Wang, Yan Huang.
      Cancer is an aging-related disease, while aging plays an important role in the development process of tumor, thus the two are inextricably associated. Telomere attrition is one of the recognized hallmark events of senescence. Hence, targeting telomerase which could extends telomere sequences to treat tumors is widely favored. Cancer cells rely on high activity of telomerase to maintain a strong proliferative potential. By inhibiting the expression or protein function of telomerase, the growth of cancer cells can be significantly suppressed. In addition, the human immune system itself has a defense system against malignant tumors. However, excessive cell division results in dramatic shortening on telomeres and decline in the function of immune organs that facilitates cancer cell evasion. It has been shown that increasing telomerase activity or telomere length of these immune cells can attenuate senescence, improve cellular viability, and enhance the immunosuppressive microenvironment of tumor. In this paper, we review the telomerase-targeting progress using different anti-tumor strategies from the perspectives of cancer cells and immune cells, respectively, as well as tracking the preclinical and clinical studies of some representative drugs for the prevention or treatment of tumors.
    Keywords:  Immunotherapy; Telomerase; Tumor
    DOI:  https://doi.org/10.1186/s13578-023-01181-6
  8. Geroscience. 2023 Dec 16.
    Analysis of epigenetic clocks links yoga, sleep, education, reduced meat intake, coffee, and a SOCS2 gene variant to slower epigenetic aging.
    Rezvan Noroozi, Joanna Rudnicka, Aleksandra Pisarek, Bożena Wysocka, Aleksander Masny, Michał Boroń, Kamila Migacz-Gruszka, Paulina Pruszkowska-Przybylska, Magdalena Kobus, Dagmara Lisman, Grażyna Zielińska, Aleksandra Iljin, Joanna A Wiktorska, Małgorzata Michalczyk, Piotr Kaczka, Michał Krzysztofik, Aneta Sitek, Andrzej Ossowski, Magdalena Spólnicka, Wojciech Branicki, Ewelina Pośpiech.
      DNA methylation (DNAm) clocks hold promise for measuring biological age, useful for guiding clinical interventions and forensic identification. This study compared the commonly used DNAm clocks, using DNA methylation and SNP data generated from nearly 1000 human blood or buccal swab samples. We evaluated different preprocessing methods for age estimation, investigated the association of epigenetic age acceleration (EAA) with various lifestyle and sociodemographic factors, and undertook a series of novel genome-wide association analyses for different EAA measures to find associated genetic variants. Our results highlighted the Skin&Blood clock with ssNoob normalization as the most accurate predictor of chronological age. We provided novel evidence for an association between the practice of yoga and a reduction in the pace of aging (DunedinPACE). Increased sleep and physical activity were associated with lower mortality risk score (MRS) in our dataset. University degree, vegetable consumption, and coffee intake were associated with reduced levels of epigenetic aging, whereas smoking, higher BMI, meat consumption, and manual occupation correlated well with faster epigenetic aging, with FitAge, GrimAge, and DunedinPACE clocks showing the most robust associations. In addition, we found a novel association signal for SOCS2 rs73218878 (p = 2.87 × 10-8) and accelerated GrimAge. Our study emphasizes the importance of an optimized DNAm analysis workflow for accurate estimation of epigenetic age, which may influence downstream analyses. The results support the influence of genetic background on EAA. The associated SOCS2 is a member of the suppressor of cytokine signaling family known for its role in human longevity. The reported association between various risk factors and EAA has practical implications for the development of health programs to improve quality of life and reduce premature mortality associated with age-related diseases.
    Keywords:  Coffee; DNA methylation age; Epigenetic age acceleration; Epigenetic clock; SOCS2; Yoga
    DOI:  https://doi.org/10.1007/s11357-023-01029-4
  9. PeerJ. 2023 ;11 e16463
    Exploring the anti-aging effects of fisetin in telomerase-deficient progeria mouse model.
    Rui Zhao, Haomeng Kou, Duo Jiang, Feng Wang.
      Aging is a natural and complex process characterized by the gradual deterioration of tissue and physiological functions in the organism over time. Cell senescence, a hallmark of aging, refers to the permanent and irreversible cell cycle arrest of proliferating cells triggered by endogenous stimuli or environmental stresses. Eliminating senescent cells has been shown to extend the healthy lifespan. In this study, we established a progeria mouse model with telomerase deficiency and confirmed the presence of shortened telomere length and increased expression of aging markers p16INK4a and p21CIP1 in the organ tissues of G3 Tert-/- mice. We identified fisetin as a potent senolytic drug capable of reversing premature aging signs in telomerase-deficient mice. Fisetin treatment effectively suppressed the upregulation of aging markers p16INK4a and p21CIP1 and reduced collagen fiber deposition. Furthermore, we observed a significant elevation in the mRNA level of Stc1 in G3Tert-/- mice, which was reduced after fisetin treatment. Stc1 has been implicated in anti-apoptotic processes through the upregulation of the Akt signaling pathway. Our findings reveal that fisetin exerts its anti-aging effect by inhibiting the Akt signaling pathway through the suppression of Stc1 expression, leading to the apoptosis of senescent cells.
    Keywords:  Aging; Fisetin; Senolytics; Telomerase deficient
    DOI:  https://doi.org/10.7717/peerj.16463
  10. J Med Chem. 2023 Dec 19.
    Detection and Elimination of Senescent Cells with a Self-Assembled Senescence-Associated β-Galactosidase-Activatable Nanophotosensitizer.
    Jacky C H Chu, Junlong Xiong, Clarence T T Wong, Shuai Wang, Dick Yan Tam, Alba García-Fernández, Ramón Martínez-Máñez, Dennis K P Ng.
      Senescent cells have become an important therapeutic target for many age-related dysfunctions and diseases. We report herein a novel nanophotosensitizing system that is responsive to the senescence-associated β-galactosidase (β-gal) for selective detection and elimination of these cells. It involves a dimeric zinc(II) phthalocyanine linked to a β-galactose unit via a self-immolative linker. This compound can self-assemble in aqueous media, forming stable nanoscale particles in which the phthalocyanine units are stacked and self-quenched for fluorescence emission and singlet oxygen production. Upon internalization into senescent HeLa cells, these nanoparticles interact with the overproduced senescence-associated β-gal inside the cells to trigger the disassembly process through enzymatic cleavage of the glycosidic bonds, followed by self-immolation to release the photoactive monomeric phthalocyanine units. These senescent cells can then be lit up with fluorescence and eliminated through the photodynamic action upon light irradiation with a half-maximal inhibitory concentration of 0.06 μM.
    DOI:  https://doi.org/10.1021/acs.jmedchem.3c01306
  11. Clin Sci (Lond). 2023 Dec 22. 137(24): 1805-1821
    Cellular senescence and kidney aging.
    Nikolai Rex, Anette Melk, Roland Schmitt.
      Life expectancy is increasing worldwide, and by 2050 the proportion of the world's population over 65 years of age is estimated to surpass 1.5 billion. Kidney aging is associated with molecular and physiological changes that cause a loss of renal function and of regenerative potential. As the aging population grows, it is crucial to understand the mechanisms underlying these changes, as they increase the susceptibility to developing acute kidney injury (AKI) and chronic kidney disease (CKD). Various cellular processes and molecular pathways take part in the complex process of kidney aging. In this review, we will focus on the phenomenon of cellular senescence as one of the involved mechanisms at the crossroad of kidney aging, age-related disease, and CKD. We will highlight experimental and clinical findings about the role of cellular senescence in kidney aging and CKD. In addition, we will review challenges in senescence research and emerging therapeutic aspects. We will highlight the great potential of senolytic strategies for the elimination of harmful senescent cells to promote healthy kidney aging and to avoid age-related disease and CKD. This review aims to give insight into recent discoveries and future developments, providing a comprehensive overview of current knowledge on cellular senescence and anti-senescent therapies in the kidney field.
    Keywords:  Aging kidney; Cellular Senescence; chronic kidney disease; senolysis; senolytic therapy
    DOI:  https://doi.org/10.1042/CS20230140
  12. Int J Mol Sci. 2023 Dec 05. pii: 17129. [Epub ahead of print]24(24):
    Cells in Atherosclerosis: Focus on Cellular Senescence from Basic Science to Clinical Practice.
    Andrea Ágnes Molnár, Dorottya Tímea Pásztor, Zsófia Tarcza, Béla Merkely.
      Aging is a major risk factor of atherosclerosis through different complex pathways including replicative cellular senescence and age-related clonal hematopoiesis. In addition to aging, extracellular stress factors, such as mechanical and oxidative stress, can induce cellular senescence, defined as premature cellular senescence. Senescent cells can accumulate within atherosclerotic plaques over time and contribute to plaque instability. This review summarizes the role of cellular senescence in the complex pathophysiology of atherosclerosis and highlights the most important senotherapeutics tested in cardiovascular studies targeting senescence. Continued bench-to-bedside research in cellular senescence might allow the future implementation of new effective anti-atherosclerotic preventive and treatment strategies in clinical practice.
    Keywords:  atherosclerosis; cellular senescence; inflammation; oxidative stress; senotherapeutics
    DOI:  https://doi.org/10.3390/ijms242417129
  13. Antioxidants (Basel). 2023 Dec 07. pii: 2086. [Epub ahead of print]12(12):
    Diet and Aging: The Role of Polyphenol-Rich Diets in Slow Down the Shortening of Telomeres: A Review.
    Stefania D'Angelo.
      The ends of human chromosomes are defended by DNA-protein complexes named telomeres, which inhibit the chromosomes from fusing with each other and from being known as a double-strand break by DNA reparation proteins. Telomere length is a marker of biological aging, and disfunction of telomeres is related to age-related syndromes. Telomere attrition has been shown to be accelerated by oxidative stress and inflammation. Telomere length has been proven to be positively linked with nutritional status in human and animal scientific research as several nutrients influence it through mechanisms that imitate their function in cellular roles including oxidative stress and inflammation. Data reported in this article support the idea that following a low-in-fat and rich-plant polyphenols food diet seems to be able to slow down the shortening of telomeres.
    Keywords:  Mediterranean diet; aging; antioxidant; longevity; nutrition; oxidative stress; polyphenol; telomere length
    DOI:  https://doi.org/10.3390/antiox12122086
  14. Biol Direct. 2023 Dec 20. 18(1): 86
    Quinolinic acid impairs mitophagy promoting microglia senescence and poor healthspan in C. elegans: a mechanism of impaired aging process.
    Anjila Dongol, Xi Chen, Peng Zheng, Zehra Boz Seyhan, Xu-Feng Huang.
      Senescent microglia are a distinct microglial phenotype present in aging brain that have been implicated in the progression of aging and age-related neurodegenerative diseases. However, the specific mechanisms that trigger microglial senescence are largely unknown. Quinolinic acid (QA) is a cytotoxic metabolite produced upon abnormal activation of microglia. Brain aging and age-related neurodegenerative diseases have an elevated concentration of QA. In the present study, we investigated whether QA promotes aging and aging-related phenotypes in microglia and C. elegans. Here, we demonstrate for the first time that QA, secreted by abnormal microglial stimulation, induces impaired mitophagy by inhibiting mitolysosome formation and consequently promotes the accumulation of damaged mitochondria due to reduced mitochondrial turnover in microglial cells. Defective mitophagy caused by QA drives microglial senescence and poor healthspan in C. elegans. Moreover, oxidative stress can mediate QA-induced mitophagy impairment and senescence in microglial cells. Importantly, we found that restoration of mitophagy by mitophagy inducer, urolithin A, prevents microglial senescence and improves healthspan in C. elegans by promoting mitolysosome formation and rescuing mitochondrial turnover inhibited by QA. Thus, our study indicates that mitolysosome formation impaired by QA is a significant aetiology underlying aging-associated changes. QA-induced mitophagy impairment plays a critical role in neuroinflammation and age-related diseases. Further, our study suggests that mitophagy inducers such as urolithin A may offer a promising anti-aging strategy for the prevention and treatment of neuroinflammation-associated brain aging diseases.
    Keywords:  Aging; Microglia; Mitochondria; Mitolysosome; Mitophagy; Neuroinflammation; Quinolinic acid; Senescence
    DOI:  https://doi.org/10.1186/s13062-023-00445-y
  15. Biology (Basel). 2023 Nov 29. pii: 1476. [Epub ahead of print]12(12):
    Age-Associated Changes of Sirtuin 2 Expression in CNS and the Periphery.
    Maider Garmendia-Berges, Noemi Sola-Sevilla, MCarmen Mera-Delgado, Elena Puerta.
      Sirtuin 2 (SIRT2), one of the seven members of the sirtuin family, has emerged as a potential regulator of aging and age-related pathologies since several studies have demonstrated that it shows age-related changes in humans and different animal models. A detailed analysis of the relevant works published to date addressing this topic shows that the changes that occur in SIRT2 with aging seem to be opposite in the brain and in the periphery. On the one hand, aging induces an increase in SIRT2 levels in the brain, which supports the notion that its pharmacological inhibition is beneficial in different neurodegenerative diseases. However, on the other hand, in the periphery, SIRT2 levels are reduced with aging while keeping its expression is protective against age-related peripheral inflammation, insulin resistance, and cardiovascular diseases. Thus, systemic administration of any known modulator of this enzyme would have conflicting outcomes. This review summarizes the currently available information on changes in SIRT2 expression in aging and the underlying mechanisms affected, with the aim of providing evidence to determine whether its pharmacological modulation could be an effective and safe pharmacological strategy for the treatment of age-related diseases.
    Keywords:  aging; brain; epigenetics; inflammation; neurodegenerative diseases; sirtuin 2
    DOI:  https://doi.org/10.3390/biology12121476
  16. Cells. 2023 Dec 05. pii: 2769. [Epub ahead of print]12(24):
    Non-Intrinsic, Systemic Mechanisms of Cellular Senescence.
    Rachael E Schwartz, Irina M Conboy.
      Cellular senescence is believed to contribute to aging and disease through the activity of secreted factors that promote inflammation, remodel the extracellular matrix, and adversely modify the behavior of non-senescent cells. While the markers and properties of senescent cells are still under investigation, it is postulated that cellular senescence manifests in vivo as the consequence of cellular damage that accumulates and becomes exacerbated with time. Yet, the notions that senescence has a solely intrinsic and time-dependent nature are questioned by the rapid induction of senescence in young mice and young cells in vitro by exposure to blood from aged animals. Here, we review some of the research on the systemically present factors that increase with age and may contribute to extrinsically induced senescence or "bystander senescence". These include proteins, reactive oxygen species, lipids, and nucleic acids, which may be present in individual soluble form, in vesicles, and in non-membranous multi-component macromolecules.
    Keywords:  aging; blood serum and plasma; bystander senescence; cellular senescence; systemic milieu
    DOI:  https://doi.org/10.3390/cells12242769
  17. Cells. 2023 Dec 12. pii: 2819. [Epub ahead of print]12(24):
    Age-Related Alternative Splicing: Driver or Passenger in the Aging Process?
    Marco Baralle, Maurizio Romano.
      Alternative splicing changes are closely linked to aging, though it remains unclear if they are drivers or effects. As organisms age, splicing patterns change, varying gene isoform levels and functions. These changes may contribute to aging alterations rather than just reflect declining RNA quality control. Three main splicing types-intron retention, cassette exons, and cryptic exons-play key roles in age-related complexity. These events modify protein domains and increase nonsense-mediated decay, shifting protein isoform levels and functions. This may potentially drive aging or serve as a biomarker. Fluctuations in splicing factor expression also occur with aging. Somatic mutations in splicing genes can also promote aging and age-related disease. The interplay between splicing and aging has major implications for aging biology, though differentiating correlation and causation remains challenging. Declaring a splicing factor or event as a driver requires comprehensive evaluation of the associated molecular and physiological changes. A greater understanding of how RNA splicing machinery and downstream targets are impacted by aging is essential to conclusively establish the role of splicing in driving aging, representing a promising area with key implications for understanding aging, developing novel therapeutical options, and ultimately leading to an increase in the healthy human lifespan.
    Keywords:  age-associated splicing events; age-related diseases; aging; alternative splicing; molecular aging; senescence; splice variants; splicing factors; splicing regulation; transcriptome changes
    DOI:  https://doi.org/10.3390/cells12242819
  18. J Cardiovasc Dev Dis. 2023 Dec 10. pii: 492. [Epub ahead of print]10(12):
    Biological Age in Congenital Heart Disease-Exploring the Ticking Clock.
    Tijs K Tournoy, Philip Moons, Bo Daelman, Julie De Backer.
      Over the past 50 years, there has been a major shift in age distribution of patients with congenital heart disease (CHD) thanks to significant advancements in medical and surgical treatment. Patients with CHD are, however, never cured and face unique challenges throughout their lives. In this review, we discuss the growing data suggesting accelerated aging in this population. Adults with CHD are more often and at a younger age confronted with age-related cardiovascular complications such as heart failure, arrhythmia, and coronary artery disease. These can be related to the original birth defect, complications of correction, or any residual defects. In addition, and less deductively, more systemic age-related complications are seen earlier, such as renal dysfunction, lung disease, dementia, stroke, and cancer. The occurrence of these complications at a younger age makes it imperative to further map out the aging process in patients across the spectrum of CHD. We review potential feasible markers to determine biological age and provide an overview of the current data. We provide evidence for an unmet need to further examine the aging paradigm as this stresses the higher need for care and follow-up in this unique, newly aging population. We end by exploring potential approaches to improve lifespan care.
    Keywords:  aging; congenital heart disease; epigenetic clock; telomere length
    DOI:  https://doi.org/10.3390/jcdd10120492
  19. Acta Dermatovenerol Alp Pannonica Adriat. 2023 12;32(4): 159-164
    New anti-aging strategies: a narrative review.
    Vana Stojić, Tea Štrbac, Andrija Stanimirović.
      The objective of anti-aging medicine is to decelerate the aging process and mitigate its associated effects, such as susceptibility to cancer, diabetes, and cardiovascular and neurodegenerative diseases. This review provides an overview of the latest advancements in this field, considering both pharmaceutical and non-pharmaceutical approaches. Electronic literature search involved three databases: MEDLINE, Cochrane, and Google Scholar, supplemented by other available literature. Strategies for delaying aging and related diseases comprise pharmaceutical interventions and lifestyle choices. It is crucial for these strategies to be substantiated by research-based evidence. Lifestyle options include fasting, fasting-mimicking, and ketogenic diets. Anti-aging drugs and supplements operate through diverse mechanisms. Calorie restriction mimetics include the activator of AMP-activated protein kinase (metformin) and inhibitor of mTOR (rapamycin), alongside rilmenidine, exhibiting both effects. Rosmarinic acid, a natural product, functions through its anti-glycation properties. Age-related protein crosslinks are acknowledged as a causative factor in age-related diseases. Anti-aging medicine is an evolving field with a multitude of drugs and strategies, necessitating further clinical studies and long-term follow-up based on clinical experience and insights gained from delayed adverse events.
  20. Aging Cell. 2023 Dec 17. e14061
    Cpne7 deficiency induces cellular senescence and premature aging of dental pulp.
    Yoon Seon Lee, Yeoung-Hyun Park, Geumbit Hwang, Hyejin Seo, Si Hyoung Ki, Shengfeng Bai, Chul Son, Seong Min Roh, Su-Jin Park, Dong-Seol Lee, Ji-Hyun Lee, You-Mi Seo, Won Jun Shon, Daehyun Jeon, Mi Jang, Sahng G Kim, Byoung-Moo Seo, Gene Lee, Joo-Cheol Park.
      Once tooth development is complete, odontoblasts and their progenitor cells in the dental pulp play a major role in protecting tooth vitality from external stresses. Hence, understanding the homeostasis of the mature pulp populations is just as crucial as understanding that of the young, developing ones for managing age-related dentinal damage. Here, it is shown that loss of Cpne7 accelerates cellular senescence in odontoblasts due to oxidative stress and DNA damage accumulation. Thus, in Cpne7-null dental pulp, odontoblast survival is impaired, and aberrant dentin is extensively formed. Intraperitoneal or topical application of CPNE7-derived functional peptide, however, alleviates the DNA damage accumulation and rescues the pathologic dentin phenotype. Notably, a healthy dentin-pulp complex lined with metabolically active odontoblasts is observed in 23-month-old Cpne7-overexpressing transgenic mice. Furthermore, physiologic dentin was regenerated in artificial dentinal defects of Cpne7-overexpressing transgenic mice. Taken together, Cpne7 is indispensable for the maintenance and homeostasis of odontoblasts, while promoting odontoblastic differentiation of the progenitor cells. This research thereby introduces its potential in oral disease-targeted applications, especially age-related dental diseases involving dentinal loss.
    Keywords:  Copine7; aging; dental pulp; oxidative stress; senescence; tooth
    DOI:  https://doi.org/10.1111/acel.14061
  21. Curr Opin Hematol. 2023 Dec 18.
    Age-related micro-environmental changes as drivers of clonal hematopoiesis.
    Tal Bacharach, Nathali Kaushansky, Liran I Shlush.
       PURPOSE OF REVIEW: Both aging and reduced diversity at the hematopoietic stem cells (HSCs) level are ubiquitous. What remains unclear is why some individuals develop clonal hematopoiesis (CH), and why does CH due to specific mutations occur in specific individuals. Much like aging, reduced diversity of HSCs is a complex phenotype shaped by numerous factors (germline & environment). The purpose of the current review is to discuss the role of two other age-related ubiquitous processes that might contribute to the dynamics and characteristics of losing HSC diversity and the evolution of CH. These processes have not been reviewed in depth so far and include the accumulation of fatty bone marrow (FBM), and the decline in sex hormones.
    RECENT FINDINGS: Interestingly, sex hormone decline can directly shape HSC function, but also reshape the delicate balance of BM supporting cells, with a shift towards FBM. FBM accumulation can shape the clonal expansion of preleukemic mutations, particularly DNMT3A mutations, through IL-6 mediation. DNMT3A mutations are one of the only preleukemic mutations which is more prevalent in women, and especially in women with early menopause, demonstrating an association between age-related hormone decline and CH evolution, the mechanisms of which are yet to be discovered.
    SUMMARY: Aging is a multifactorial phenotype and the same is true for the aging of the blood system. While many factors which can shape CH have been discussed, we shed more light on FBM and sex hormone decline. Much more is missing: how and should we even try to prevent these phenomena? Why do they occur? and how they are connected to other age-related blood factors?
    DOI:  https://doi.org/10.1097/MOH.0000000000000798
  22. Biochemistry (Mosc). 2023 Nov;88(11): 1704-1718
    Olovnikov, Telomeres, and Telomerase. Is It Possible to Prolong a Healthy Life?
    Yegor E Yegorov.
      The science of telomeres and telomerase has made tremendous progress in recent decades. In this review, we consider it first in a historical context (the Carrel-Hayflick-Olovnikov-Blackburn chain of discoveries) and then review current knowledge on the telomere structure and dynamics in norm and pathology. Central to the review are consequences of the telomere shortening, including telomere position effects, DNA damage signaling, and increased genetic instability. Cell senescence and role of telomere length in its development are discussed separately. Therapeutic aspects and risks of telomere lengthening methods including use of telomerase and other approaches are also discussed.
    Keywords:  Olovnikov; aging; carcinogenesis; cell senescence; genetic instability; inflammatory aging; telomerase; telomere crisis; telomeres
    DOI:  https://doi.org/10.1134/S0006297923110032
  23. Acta Neuropathol. 2023 Dec 22. 147(1): 4
    Loss of TDP-43 splicing repression occurs early in the aging population and is associated with Alzheimer's disease neuropathologic changes and cognitive decline.
    Koping Chang, Jonathan P Ling, Javier Redding-Ochoa, Yang An, Ling Li, Stephanie A Dean, Thomas G Blanchard, Tatiana Pylyukh, Alexander Barrett, Katherine E Irwin, Abhay Moghekar, Susan M Resnick, Philip C Wong, Juan C Troncoso.
      LATE-NC, the neuropathologic changes of limbic-predominant age-related TAR DNA-binding protein 43 kDa (TDP-43) encephalopathy are frequently associated with Alzheimer's disease (AD) and cognitive impairment in older adults. The association of TDP-43 proteinopathy with AD neuropathologic changes (ADNC) and its impact on specific cognitive domains are not fully understood and whether loss of TDP-43 function occurs early in the aging brain remains unknown. Here, using a large set of autopsies from the Baltimore Longitudinal Study of Aging (BLSA) and another younger cohort, we were able to study brains from subjects 21-109 years of age. Examination of these brains show that loss of TDP-43 splicing repression, as judged by TDP-43 nuclear clearance and expression of a cryptic exon in HDGFL2, first occurs during the 6th decade, preceding by a decade the appearance of TDP-43+ neuronal cytoplasmic inclusions (NCIs). We corroborated this observation using a monoclonal antibody to demonstrate a cryptic exon-encoded neoepitope within HDGFL2 in neurons exhibiting nuclear clearance of TDP-43. TDP-43 nuclear clearance is associated with increased burden of tau pathology. Age at death, female sex, high CERAD neuritic plaque score, and high Braak neurofibrillary stage significantly increase the odds of LATE-NC. Faster rates of cognitive decline on verbal memory (California Verbal Learning Test immediate recall), visuospatial ability (Card Rotations Test), mental status (MMSE) and semantic fluency (Category Fluency Test) were associated with LATE-NC. Notably, the effects of LATE-NC on verbal memory and visuospatial ability are independent of ADNC. However, the effects of TDP-43 nuclear clearance in absence of NCI on the longitudinal trajectories and levels of cognitive measures are not significant. These results establish that loss of TDP-43 splicing repression is an early event occurring in the aging population during the development of TDP-43 proteinopathy and is associated with increased tau pathology. Furthermore, LATE-NC correlates with high levels of ADNC but also has an impact on specific memory and visuospatial functions in aging that is independent of AD.
    Keywords:  Cryptic HDGFL2; Cryptic exons; Dementia; LATE-NC; TDP-43 loss-of-function; TDP-43 neuronal inclusions
    DOI:  https://doi.org/10.1007/s00401-023-02653-2
  24. Epigenomes. 2023 Dec 12. pii: 32. [Epub ahead of print]7(4):
    Epigenetic Mechanisms in Hematologic Aging and Premalignant Conditions.
    Bowen Yan, Qingchen Yuan, Olga A Guryanova.
      Hematopoietic stem cells (HSCs) are essential for maintaining overall health by continuously generating blood cells throughout an individual's lifespan. However, as individuals age, the hematopoietic system undergoes significant functional decline, rendering them more susceptible to age-related diseases. Growing research evidence has highlighted the critical role of epigenetic regulation in this age-associated decline. This review aims to provide an overview of the diverse epigenetic mechanisms involved in the regulation of normal HSCs during the aging process and their implications in aging-related diseases. Understanding the intricate interplay of epigenetic mechanisms that contribute to aging-related changes in the hematopoietic system holds great potential for the development of innovative strategies to delay the aging process. In fact, interventions targeting epigenetic modifications have shown promising outcomes in alleviating aging-related phenotypes and extending lifespan in various animal models. Small molecule-based therapies and reprogramming strategies enabling epigenetic rejuvenation have emerged as effective approaches for ameliorating or even reversing aging-related conditions. By acquiring a deeper understanding of these epigenetic mechanisms, it is anticipated that interventions can be devised to prevent or mitigate the rates of hematologic aging and associated diseases later in life. Ultimately, these advancements have the potential to improve overall health and enhance the quality of life in aging individuals.
    Keywords:  aging; epigenetics; hematopoietic stem cells
    DOI:  https://doi.org/10.3390/epigenomes7040032
  25. Cancers (Basel). 2023 Dec 14. pii: 5835. [Epub ahead of print]15(24):
    Implications of Senescent T Cells for Cancer Immunotherapy.
    Tetsuhiro Kasamatsu.
      T-cell senescence is thought to result from the age-related loss of the ability to mount effective responses to pathogens and tumor cells. In addition to aging, T-cell senescence is caused by repeated antigenic stimulation and chronic inflammation. Moreover, we demonstrated that T-cell senescence was induced by treatment with DNA-damaging chemotherapeutic agents. The characteristics of therapy-induced senescent T (TIS-T) cells and general senescent T cells are largely similar. Senescent T cells demonstrate an increase in the senescence-associated beta-galactosidase-positive population, cell cycle arrest, secretion of senescence-associated secretory phenotypic factors, and metabolic reprogramming. Furthermore, senescent T cells downregulate the expression of the co-stimulatory molecules CD27 and CD28 and upregulate natural killer cell-related molecules. Moreover, TIS-T cells showed increased PD-1 expression. However, the loss of proliferative capacity and decreased expression of co-stimulatory molecules associated with T-cell senescence cause a decrease in T-cell immunocompetence. In this review, we discuss the characteristics of senescent T-cells, including therapy-induced senescent T cells.
    Keywords:  PD-1; T-cell senescence; therapy-induced cellular senescence
    DOI:  https://doi.org/10.3390/cancers15245835
  26. Geriatr Gerontol Int. 2023 Dec 21.
    Biology of cognitive aging across species.
    Sho Kakizawa, Joong-Jean Park, Ayako Tonoki.
      Aging is associated with cognitive decline, which can critically affect quality of life. Examining the biology of cognitive aging across species will lead to a better understanding of the fundamental mechanisms involved in this process, and identify potential interventions that could help to improve cognitive function in aging individuals. This minireview aimed to explore the mechanisms and processes involved in cognitive aging across a range of species, from flies to rodents, and covers topics, such as the role of reactive oxygen species and autophagy/mitophagy in cognitive aging. Overall, this literature provides a comprehensive overview of the biology of cognitive aging across species, highlighting the latest research findings and identifying potential avenues for future research. Geriatr Gerontol Int 2023; ••: ••-••.
    Keywords:  Drosophila; cerebellum; cognitive aging; mouse; mushroom body
    DOI:  https://doi.org/10.1111/ggi.14782
  27. Biomedicines. 2023 Dec 03. pii: 3211. [Epub ahead of print]11(12):
    Long Telomeric Repeat-Containing RNA (TERRA): Biological Functions and Challenges in Vascular Aging and Disease.
    Paola Canale, Jonica Campolo, Andrea Borghini, Maria Grazia Andreassi.
      Telomere dysfunction is implicated in vascular aging and shorter leucocyte telomeres are associated with an increased risk of atherosclerosis, myocardial infarction, and heart failure. Another pathophysiological mechanism that explains the causal relationship between telomere shortening and atherosclerosis development focuses on the clonal hematopoiesis of indeterminate potential (CHIP), which represents a new and independent risk factor in atherosclerotic cardiovascular diseases. Since telomere attrition has a central role in driving vascular senescence, understanding telomere biology is essential to modulate the deleterious consequences of vascular aging and its cardiovascular disease-related manifestations. Emerging evidence indicates that a class of long noncoding RNAs transcribed at telomeres, known as TERRA for "TElomeric Repeat-containing RNA", actively participates in the mechanisms regulating telomere maintenance and chromosome end protection. However, the multiple biological functions of TERRA remain to be largely elucidated. In particular, the role of TERRA in vascular biology is surprisingly unknown. In this review, we discuss the current knowledge of TERRA and its roles in telomere biology. Additionally, we outline the pieces of evidence that exist regarding the relationship between TERRA dysregulation and disease. Finally, we speculate on how a comprehensive understanding of TERRA transcription in the cardiovascular system may provide valuable insights into telomere-associated vascular aging, offering great potential for new therapeutic approaches.
    Keywords:  TERRA; cardiovascular disease; clonal hematopoiesis of indeterminate potential vascular aging; telomere
    DOI:  https://doi.org/10.3390/biomedicines11123211
  28. Mol Biol Evol. 2023 Dec 20. pii: msad279. [Epub ahead of print]
    Methods for Estimating Personal Disease Risk and Phylogenetic Diversity of Hematopoietic Stem Cells.
    Jack M Craig, Glenn S Gerhard, Sudip Sharma, Anastasia Yankovskiy, Sayaka Miura, Sudhir Kumar.
      An individual's chronological age does not always correspond to the health of different tissues in their body, especially in cases of disease. Therefore, estimating and contrasting the physiological age of tissues with an individual's chronological age may be a useful tool to diagnose disease and its progression. Here, we present novel metrics to quantify the loss of phylogenetic diversity in hematopoietic stem cells (HSC), which are precursors to most blood cell types and are associated with many blood-related diseases. These metrics showed an excellent correspondence with an age-related increase in blood cancer incidence, enabling a model to estimate the phylogeny-derived age (phyloAge) of HSCs present in an individual. HSC phyloAge was generally older than the chronological age of patients suffering from myeloproliferative neoplasms (MPN). We present a model that relates excess HSC aging with increased MPN risk. It predicted an over 200 times greater risk based on the HSC phylogenies of the youngest MPN patients analyzed. Our new metrics are designed to be robust to sampling biases and do not rely on prior knowledge of driver mutations or physiological assessments. Consequently, they complement conventional biomarker-based methods to estimate physiological age and disease risk.
    Keywords:  Biological age; cancer risk; hematopoietic stem cells; somatic mutations
    DOI:  https://doi.org/10.1093/molbev/msad279
  29. Nutrients. 2023 Dec 17. pii: 5130. [Epub ahead of print]15(24):
    Exogenous Nucleotides Ameliorate Age-Related Decline in Testosterone in Male Senescence-Accelerated Mouse Prone-8 (SAMP8) Mice by Modulating the Local Renin-Angiotensin System Antioxidant Pathway.
    Qianqian Chen, Rui Liu, Chan Wei, Xiujuan Wang, Xin Wu, Rui Fan, Xiaochen Yu, Zhen Li, Ruixue Mao, Jiani Hu, Na Zhu, Xinran Liu, Yong Li, Meihong Xu.
      In older men, an age-related decline in testosterone is closely associated with various adverse health outcomes. With the progression of aging, hyperactivation of the local renin-angiotensin system (RAS) and oxidative stress increase in the testis. The regulation of RAS antioxidants may be a target to delay testicular aging and maintain testosterone levels. Exogenous nucleotides (NTs) have anti-aging potential in several systems, but there are no studies of their effects on the reproductive system. In our study, we examined the effects of exogenous NTs on testosterone synthesis and explored possible mechanisms of action. Therefore, senescence-accelerated mouse prone-8 (SAMP8) mice and senescence-accelerated mouse resistant 1 (SAMR1) were used in the experiment, and they were randomly divided into an NTs free group (NTs-F), a normal control group (control), a low-dose NTs group (NTs-L), a middle-dose NTs (NTs-M), a high-dose NTs group (NTs-H) and SAMR1 groups, and the testis of the mice were collected for testing after 9 months of intervention. The results showed that exogenous NTs could increase the testicular organ index in mice during aging, and delayed the age-associated decline in testosterone levels in SAMP8 male mice, possibly by modulating the local RAS antioxidant pathway and reducing oxidative stress to protect the testis. The present study provides new research clues for the development of preventive and therapeutic strategies for related diseases.
    Keywords:  exogenous nucleotides; oxidative stress; renin–angiotensin system; testosterone
    DOI:  https://doi.org/10.3390/nu15245130
  30. Epigenomics. 2023 Dec 19.
    The epigenetics of frailty.
    Madia Lozupone, Vincenzo Solfrizzi, Rodolfo Sardone, Vittorio Dibello, Fabio Castellana, Roberta Zupo, Luisa Lampignano, Ilaria Bortone, Antonio Daniele, Francesco Panza.
      The conceptual change of frailty, from a physical to a biopsychosocial phenotype, expanded the field of frailty, including social and behavioral domains with critical interaction between different frailty models. Environmental exposures - including physical exercise, psychosocial factors and diet - may play a role in the frailty pathophysiology. Complex underlying mechanisms involve the progressive interactions of genetics with epigenetics and of multimorbidity with environmental factors. Here we review the literature on possible mechanisms explaining the association between epigenetic hallmarks (i.e., global DNA methylation, DNA methylation age acceleration and microRNAs) and frailty, considered as biomarkers of aging. Frailty could be considered the result of environmental epigenetic factors on biological aging, caused by conflicting DNA methylation age and chronological age.
    Keywords:  DNA methylation; diet; epigenetics; frailty; multimorbidity; psychosocial
    DOI:  https://doi.org/10.2217/epi-2023-0279
  31. Brain Sci. 2023 Dec 06. pii: 1677. [Epub ahead of print]13(12):
    Reduced Age-Related Gray Matter Loss in the Orbitofrontal Cortex in Long-Term Meditators.
    Florian Kurth, Sarah Strohmaier, Eileen Luders.
      The orbitofrontal cortex (OFC) is a functionally heterogeneous brain region contributing to mental processes relating to meditation practices. The OFC has been reported to decline in volume with increasing age and differs in volume between meditation practitioners and non-practitioners. We hypothesized that the age-related decline of the OFC is diminished in meditation practitioners. We tested this hypothesis in a sample of 50 long-term meditators and 50 matched controls by correlating chronological age with regional gray matter volumes of the left and right OFC, as well as in seven left and right cytoarchitectonically defined subregions of the OFC (Fo1-Fo7). In both meditators and controls, we observed a negative relationship between age and OFC (sub)volumes, indicating that older participants have smaller OFC volumes. However, in meditators, the age-related decline was less steep compared to controls. These age-related differences reached significance for left and right Fo2, Fo3, Fo4, and Fo7, as well as left Fo5 and right Fo6. Since different subregions of the OFC are associated with distinct brain functions, further investigations are required to explore the functional implications of these findings in the context of meditation and the aging brain.
    Keywords:  age; brain; gray matter; meditation; mindfulness; orbitofrontal cortex
    DOI:  https://doi.org/10.3390/brainsci13121677
  32. Protein Cell. 2023 Dec 21. pii: pwad063. [Epub ahead of print]
    Aging hallmarks of the primate ovary revealed by spatiotemporal transcriptomics.
    Huifen Lu, Ying Jing, Chen Zhang, Shuai Ma, Weiqi Zhang, Daoyuan Huang, Bin Zhang, Yuesheng Zuo, Yingying Qin, Guang-Hui Liu, Yang Yu, Jing Qu, Si Wang.
      The ovary is indispensable for female reproduction, and its age-dependent functional decline is the primary cause of infertility. However, the molecular basis of ovarian aging in higher vertebrates remains poorly understood. Herein, we apply spatiotemporal transcriptomics to benchmark architecture organization as well as cellular and molecular determinants in young primate ovaries and compare these to aged primate ovaries. From a global view, somatic cells within the non-follicle region undergo more pronounced transcriptional fluctuation relative to those in the follicle region, likely constituting a hostile microenvironment that facilitates ovarian aging. Further, we uncovered that inflammation, the senescent associated secretory phenotype (SASP), senescence and fibrosis are the likely primary contributors to ovarian aging (PCOA). Of note, we identified spatial co-localization between a PCOA-featured spot and an unappreciated MT2 (Metallothionein 2) highly expressing spot (MT2high) characterized by high levels of inflammation, potentially serving as an aging hotspot in the primate ovary. Moreover, with advanced age, a subpopulation of MT2high accumulates, likely disseminating and amplifying the senescent signal outward. Our study establishes the first primate spatiotemporal transcriptomic atlas, advancing our understanding of mechanistic determinants underpinning primate ovarian aging and unraveling potential biomarkers and therapeutic targets for aging and age-associated human ovarian disorders.
    Keywords:  aging; inflammation; ovary; primate; senescence; spatial transcriptome
    DOI:  https://doi.org/10.1093/procel/pwad063
  33. bioRxiv. 2023 Dec 08. pii: 2023.12.06.570371. [Epub ahead of print]
    SIRT5 variants from patients with mitochondrial disease are associated with reduced SIRT5 stability and activity, but not with neuropathology.
    Taolin Yuan, Surinder Kumar, Mary Skinner, Ryan Victor-Joseph, Majd Abuaita, Jaap Keijer, Jessica Zhang, Thaddeus J Kunkel, Yanghan Liu, Elyse M Petrunak, Thomas L Saunders, Andrew P Lieberman, Jeanne A Stuckey, Nouri Neamati, Fathiya Al-Murshedi, Majid Alfadhel, Johannes N Spelbrink, Richard Rodenburg, Vincent C J de Boer, David B Lombard.
      SIRT5 is a sirtuin deacylase that represents the major activity responsible for removal of negatively-charged lysine modifications, in the mitochondrial matrix and elsewhere in the cell. In benign cells and mouse models, under basal non-stressed conditions, the phenotypes of SIRT5 deficiency are generally quite subtle. Here, we identify two homozygous SIRT5 variants in human patients suffering from severe mitochondrial disease. Both variants, P114T and L128V, are associated with reduced SIRT5 protein stability and impaired biochemical activity, with no evidence of neomorphic or dominant negative properties. The crystal structure of the P114T enzyme was solved and shows only subtle deviations from wild-type. Via CRISPR-Cas9, we generate a mouse model that recapitulates the human P114T mutation; homozygotes show reduced SIRT5 levels and activity, but no obvious metabolic abnormalities, neuropathology or other gross evidence of severe disease. We conclude that these human SIRT5 variants most likely represent severe hypomorphs, and are likely not the primary pathogenic cause of the neuropathology observed in the patients.
    DOI:  https://doi.org/10.1101/2023.12.06.570371
  34. Epigenomics. 2023 Dec 22.
    DNA methylation as a window into female reproductive aging.
    Anna K Knight, Jessica B Spencer, Alicia K Smith.
      People with ovaries experience reproductive aging as their reproductive function and system declines. This has significant implications for both fertility and long-term health, with people experiencing an increased risk of cardiometabolic disorders after menopause. Reproductive aging can be assessed through markers of ovarian reserve, response to fertility treatment or molecular biomarkers, including DNA methylation. Changes in DNA methylation with age associate with poorer reproductive outcomes, and epigenome-wide studies can provide insight into genes and pathways involved. DNA methylation-based epigenetic clocks can quantify biological age in reproductive tissues and systemically. This review provides an overview of hallmarks and theories of aging in the context of the reproductive system, and then focuses on studies of DNA methylation in reproductive tissues.
    Keywords:  DNA methylation; aging; epigenetic clock; epigenetics; fertility; reproduction
    DOI:  https://doi.org/10.2217/epi-2023-0298
  35. Allergy. 2023 Dec 18.
    Metabolic pathways in immune senescence and inflammaging: Novel therapeutic strategy for chronic inflammatory lung diseases. An EAACI position paper from the Task Force for Immunopharmacology.
    F Roth-Walter, I M Adcock, C Benito-Villalvilla, R Bianchini, L Bjermer, G Caramori, L Cari, K F Chung, Z Diamant, I Eguiluz-Gracia, E F Knol, M Jesenak, F Levi-Schaffer, G Nocentini, L O'Mahony, O Palomares, F Redegeld, M Sokolowska, B C A M Van Esch, C Stellato.
      The accumulation of senescent cells drives inflammaging and increases morbidity of chronic inflammatory lung diseases. Immune responses are built upon dynamic changes in cell metabolism that supply energy and substrates for cell proliferation, differentiation, and activation. Metabolic changes imposed by environmental stress and inflammation on immune cells and tissue microenvironment are thus chiefly involved in the pathophysiology of allergic and other immune-driven diseases. Altered cell metabolism is also a hallmark of cell senescence, a condition characterized by loss of proliferative activity in cells that remain metabolically active. Accelerated senescence can be triggered by acute or chronic stress and inflammatory responses. In contrast, replicative senescence occurs as part of the physiological aging process and has protective roles in cancer surveillance and wound healing. Importantly, cell senescence can also change or hamper response to diverse therapeutic treatments. Understanding the metabolic pathways of senescence in immune and structural cells is therefore critical to detect, prevent, or revert detrimental aspects of senescence-related immunopathology, by developing specific diagnostics and targeted therapies. In this paper, we review the main changes and metabolic alterations occurring in senescent immune cells (macrophages, B cells, T cells). Subsequently, we present the metabolic footprints described in translational studies in patients with chronic asthma and chronic obstructive pulmonary disease (COPD), and review the ongoing preclinical studies and clinical trials of therapeutic approaches aiming at targeting metabolic pathways to antagonize pathological senescence. Because this is a recently emerging field in allergy and clinical immunology, a better understanding of the metabolic profile of the complex landscape of cell senescence is needed. The progress achieved so far is already providing opportunities for new therapies, as well as for strategies aimed at disease prevention and supporting healthy aging.
    Keywords:  cell metabolism; immune senescence; immunometabolism; inflammaging; senolytic drugs; senomorphic drugs
    DOI:  https://doi.org/10.1111/all.15977
  36. bioRxiv. 2023 Dec 06. pii: 2023.12.06.570418. [Epub ahead of print]
    Microsomal triglyceride transfer protein is necessary to maintain lipid homeostasis and retinal function.
    Catharina R Grubaugh, Anuradha Dhingra, Binu Prakash, Diego Montenegro, Janet R Sparrow, Lauren L Daniele, Christine A Curcio, Brent A Bell, M Mahmood Hussain, Kathleen Boesze-Battaglia.
      Lipid processing by the retinal pigment epithelium (RPE) is necessary to maintain retinal health and function. Dysregulation of retinal lipid homeostasis due to normal aging or to age-related disease triggers lipid accumulation within the RPE, on Bruch's membrane (BrM), and in the subretinal space. In its role as a hub for lipid trafficking into and out of the neural retina, the RPE packages a significant amount of lipid into lipid droplets for storage and into apolipoprotein B (apoB)-containing lipoproteins (Blps) for export. Microsomal triglyceride transfer protein (MTP), encoded by the MTTP gene, is essential for Blp assembly. Herein we test the hypothesis that MTP expression in the RPE is essential to maintain lipid balance and retinal function using the newly generated RPEΔMttp mouse model. Using non-invasive ocular imaging, electroretinography, and histochemical and biochemical analyses we show that genetic deletion of Mttp from the RPE results in intracellular lipid accumulation, increased photoreceptor -associated cholesterol deposits and photoreceptor cell death, and loss of rod but not cone function. RPE-specific ablation of Mttp had no significant effect on plasma lipids and lipoproteins. While, apoB was decreased in the RPE, ocular retinoid concentrations remained unchanged. Thus suggesting that RPE MTP is critical for Blp synthesis and assembly but not directly involved in ocular retinoid and plasma lipoprotein metabolism. These studies demonstrate that RPE-specific MTP expression is necessary to establish and maintain retinal lipid homeostasis and visual function.
    DOI:  https://doi.org/10.1101/2023.12.06.570418
  37. bioRxiv. 2023 Dec 05. pii: 2023.12.05.569858. [Epub ahead of print]
    Distinct secretomes in p16- and p21- positive senescent cells across tissues.
    Dominik Saul, Diana Jurk, Madison L Doolittle, Robyn Laura Kosinsky, David G Monroe, Nathan K LeBrasseur, Paul D Robbins, Laura J Niedernhofer, Sundeep Khosla, João F Passos.
      Senescent cells drive age-related tissue dysfunction via the induction of a chronic senescence-associated secretory phenotype (SASP). The cyclin-dependent kinase inhibitors p21 Cip1 and p16 Ink4a have long served as markers of cellular senescence. However, their individual roles remain incompletely elucidated. Thus, we conducted a comprehensive examination of multiple single-cell RNA sequencing (scRNA-seq) datasets spanning both murine and human tissues during aging. Our analysis revealed that p21 Cip1 and p16 Ink4a transcripts demonstrate significant heterogeneity across distinct cell types and tissues, frequently exhibiting a lack of co-expression. Moreover, we identified tissue-specific variations in SASP profiles linked to p21 Cip1 or p16 Ink4a expression. Our study underscores the extraordinary diversity of cellular senescence and the SASP, emphasizing that these phenomena are inherently cell- and tissue-dependent. However, a few SASP factors consistently contribute to a shared "core" SASP. These findings highlight the need for a more nuanced investigation of senescence across a wide array of biological contexts.
    DOI:  https://doi.org/10.1101/2023.12.05.569858
  38. Cells. 2023 Dec 07. pii: 2785. [Epub ahead of print]12(24):
    Aging and Metabolic Reprogramming of Adipose-Derived Stem Cells Affect Molecular Mechanisms Related to Cardiovascular Diseases.
    Paul Holvoet.
      We performed a systematic search of the PubMed database for English-language articles related to the function of adipose-derived stem cells in the pathogenesis of cardiovascular diseases. In preclinical models, adipose-derived stem cells protected arteries and the heart from oxidative stress and inflammation and preserved angiogenesis. However, clinical trials did not reiterate successful treatments with these cells in preclinical models. The low success in patients may be due to aging and metabolic reprogramming associated with the loss of proliferation capacity and increased senescence of stem cells, loss of mitochondrial function, increased oxidative stress and inflammation, and adipogenesis with increased lipid deposition associated with the low potential to induce endothelial cell function and angiogenesis, cardiomyocyte survival, and restore heart function. Then, we identify noncoding RNAs that may be mechanistically related to these dysfunctions of human adipose-derived stem cells. In particular, a decrease in let-7, miR-17-92, miR-21, miR-145, and miR-221 led to the loss of their function with obesity, type 2 diabetes, oxidative stress, and inflammation. An increase in miR-34a, miR-486-5p, and mir-24-3p contributed to the loss of function, with a noteworthy increase in miR-34a with age. In contrast, miR-146a and miR-210 may protect stem cells. However, a systematic analysis of other noncoding RNAs in human adipose-derived stem cells is warranted. Overall, this review gives insight into modes to improve the functionality of human adipose-derived stem cells.
    Keywords:  adipose; atherosclerosis; heart disease; inflammation; oxidative stress; stem cells
    DOI:  https://doi.org/10.3390/cells12242785
  39. Biochemistry (Mosc). 2023 Nov;88(11): 1683-1691
    "If I Were in Nature's Place, I Would Do It Like This..." Life and Hypotheses of Alexey Olovnikov.
    Natalia I Olovnikova, Ivan A Olovnikov, Alla I Kalmykova.
      In this article, we commemorate the life and scientific journey of the brilliant gerontologist-theorist Alexey Olovnikov (1936-2022). In 1971, he published his famous "marginotomy" hypothesis, in which he predicted the replicative shortening of telomeres and its role as a counter of cell divisions and biological age of an organism. This work put forth several remarkable assumptions, including the existence of telomerase, which were confirmed two decades later. Despite this, Alexey Olovnikov moved further in his theoretical studies of aging and proposed a series of new hypotheses that seem no less exotic than the marginotomy hypothesis once appeared. Alexey Olovnikov had an extraordinary way of looking at biological problems and, in addition to aging, authored striking concepts about development, biorhythms, and evolution.
    Keywords:  Olovnikov; aging; chronomeres; marginotomy; printomeres; telomeres
    DOI:  https://doi.org/10.1134/S0006297923110019
  40. Environ Health Perspect. 2023 Dec;131(12): 127016
    Arsenic Exposure and Epigenetic Aging: The Association with Cardiovascular Disease and All-Cause Mortality in the Strong Heart Study.
    Enoch X Jiang, Arce Domingo-Relloso, Ahlam Abuawad, Karin Haack, Maria Tellez-Plaza, M Danielle Fallin, Jason G Umans, Lyle G Best, Ying Zhang, Allison Kupsco, Daniel W Belsky, Shelley A Cole, Ana Navas-Acien.
       BACKGROUND: Inorganic arsenic (As) may increase the risk of cardiovascular disease (CVD) and all-cause mortality through accelerated aging, which can be estimated using epigenetic-based measures.
    OBJECTIVES: We evaluated three DNA methylation-based aging measures (PhenoAge, GrimAge, DunedinPACE) (epigenetic aging measures) as potential mediators of the previously reported association of As exposure with CVD incidence, CVD mortality, and all-cause mortality in the Strong Heart Study (SHS), an epidemiological cohort of American Indian adults.
    METHODS: Blood DNA methylation and urinary As levels were measured in 2,323 SHS participants (41.5% men, mean age of 55 years old). PhenoAge and GrimAge values were calculated using a residual-based method. We tested the association of urinary As with epigenetic aging measures using linear regression, the association of epigenetic aging measures with the three health outcomes using additive hazards models, and the mediation of As-related CVD incidence, CVD mortality, and all-cause mortality by epigenetic aging measures using the product of coefficients method.
    RESULTS: SHS participants with higher vs. lower urinary As levels had similar PhenoAge age, older GrimAge age, and faster DunedinPACE. An interquartile range increase in urinary As was associated with higher of PhenoAge age acceleration [mean difference (95% confidence interval)=0.48 (0.17, 0.80) years], GrimAge age acceleration [0.80 (0.60, 1.00) years], and DunedinPACE [0.011 (0.005, 0.018)], after adjusting for age, sex, center location, genetic components, smoking status, and body mass index. Of the 347 incident CVD events per 100,000 person-years associated with a doubling in As exposure, 21.3% (9.1, 57.1) and 22.6% (9.5, 56.9), were attributable to differences in GrimAge and DunedinPACE, respectively.
    DISCUSSION: Arsenic exposure was associated with older GrimAge and faster DunedinPACE measures of biological age. Furthermore, accelerated biological aging measured from DNA methylation accounted for a relevant fraction of As-associated risk for CVD, CVD mortality, and all-cause mortality in the SHS, supporting the role of As in accelerated aging. Research of the biological underpinnings can contribute to a better understanding of the role of aging in arsenic-related disease. https://doi.org/10.1289/EHP11981.
    DOI:  https://doi.org/10.1289/EHP11981
  41. Geroscience. 2023 Dec 16.
    Interplay of body mass index and metabolic syndrome: association with physiological age from midlife to late-life.
    Peggy Ler, Alexander Ploner, Deborah Finkel, Chandra A Reynolds, Yiqiang Zhan, Juulia Jylhävä, Anna K Dahl Aslan, Ida K Karlsson.
      Obesity and metabolic syndrome (MetS) share common pathophysiological characteristics with aging. To better understand their interplay, we examined how body mass index (BMI) and MetS jointly associate with physiological age, and if the associations changed from midlife to late-life. We used longitudinal data from 1,825 Swedish twins. Physiological age was measured as frailty index (FI) and functional aging index (FAI) and modeled independently in linear mixed-effects models adjusted for chronological age, sex, education, and smoking. We assessed curvilinear associations of BMI and chronological age with physiological age, and interactions between BMI, MetS, and chronological age. We found a significant three-way interaction between BMI, MetS, and chronological age on FI (p-interaction = 0·006), not FAI. Consequently, we stratified FI analyses by age: < 65, 65-85, and ≥ 85 years, and modeled FAI across ages. Except for FI at ages ≥ 85, BMI had U-shaped associations with FI and FAI, where BMI around 26-28 kg/m2 was associated with the lowest physiological age. MetS was associated with higher FI and FAI, except for FI at ages < 65, and modified the BMI-FI association at ages 65-85 (p-interaction = 0·02), whereby the association between higher BMI levels and FI was stronger in individuals with MetS. Age modified the MetS-FI association in ages ≥ 85, such that it was stronger at higher ages (p-interaction = 0·01). Low BMI, high BMI, and metabolic syndrome were associated with higher physiological age, contributing to overall health status among older individuals and potentially accelerating aging.
    Keywords:  Biological age; Frailty index; Metabolic health; Metabolic syndrome; Obesity
    DOI:  https://doi.org/10.1007/s11357-023-01032-9
  42. Int J Mol Sci. 2023 Dec 07. pii: 17223. [Epub ahead of print]24(24):
    Oxidative Stress and the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Pathway in Multiple Sclerosis: Focus on Certain Exogenous and Endogenous Nrf2 Activators and Therapeutic Plasma Exchange Modulation.
    Dimitar Tonev, Albena Momchilova.
      The pathogenesis of multiple sclerosis (MS) suggests that, in genetically susceptible subjects, T lymphocytes undergo activation in the peripheral compartment, pass through the BBB, and cause damage in the CNS. They produce pro-inflammatory cytokines; induce cytotoxic activities in microglia and astrocytes with the accumulation of reactive oxygen species, reactive nitrogen species, and other highly reactive radicals; activate B cells and macrophages and stimulate the complement system. Inflammation and neurodegeneration are involved from the very beginning of the disease. They can both be affected by oxidative stress (OS) with different emphases depending on the time course of MS. Thus, OS initiates and supports inflammatory processes in the active phase, while in the chronic phase it supports neurodegenerative processes. A still unresolved issue in overcoming OS-induced lesions in MS is the insufficient endogenous activation of the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) pathway, which under normal conditions plays an essential role in mitochondria protection, OS, neuroinflammation, and degeneration. Thus, the search for approaches aiming to elevate endogenous Nrf2 activation is capable of protecting the brain against oxidative damage. However, exogenous Nrf2 activators themselves are not without drawbacks, necessitating the search for new non-pharmacological therapeutic approaches to modulate OS. The purpose of the present review is to provide some relevant preclinical and clinical examples, focusing on certain exogenous and endogenous Nrf2 activators and the modulation of therapeutic plasma exchange (TPE). The increased plasma levels of nerve growth factor (NGF) in response to TPE treatment of MS patients suggest their antioxidant potential for endogenous Nrf2 enhancement via NGF/TrkA/PI3K/Akt and NGF/p75NTR/ceramide-PKCζ/CK2 signaling pathways.
    Keywords:  Nuclear Factor Erythroid 2-Related Factor 2 pathway activation; endogenous; exogenous; multiple sclerosis; nerve growth factor; oxidative stress modulation; therapeutic plasma exchange
    DOI:  https://doi.org/10.3390/ijms242417223
  43. Geroscience. 2023 Dec 18.
    PCSK9: an emerging player in cardiometabolic aging and its potential as a therapeutic target and biomarker.
    Anna Csiszar, Stefano Tarantini, Andriy Yabluchanskiy, Zoltan Ungvari.
      Proprotein convertase subtilisin/kexin type 9 (PCSK9), renowned for its pivotal role in low-density lipoprotein (LDL) regulation, has emerged as a compelling regulator of cardiometabolic aging. Beyond its well-established involvement in cholesterol metabolism, PCSK9's multifaceted influence on the aging processes of the cardiovascular and metabolic systems is garnering increasing attention. This review delves into the evolving landscape of PCSK9 in the context of cardiometabolic aging, offering fresh insights into its potential implications. Drawing inspiration from pioneering research conducted by the Pacher laboratory (Arif et al., Geroscience, 2023, PMID: 37726433), we delve into the intricate interplay of PCSK9 within the aging heart and liver, shedding light on its newfound significance. Recent studies underscore PCSK9's pivotal role in liver aging, suggesting intriguing connections between hepatic aging, lipid metabolism, and cardiovascular health. Additionally, we explore the therapeutic potential of PCSK9 as both a target and a biomarker, within the context of age-related cardiovascular disease.
    Keywords:  Aging; Inflammaging; Nonalcoholic fatty liver disease
    DOI:  https://doi.org/10.1007/s11357-023-01003-0
  44. bioRxiv. 2023 Dec 04. pii: 2023.12.01.569598. [Epub ahead of print]
    A ketogenic diet reduces age-induced chronic neuroinflammation in mice.
    Mitsunori Nomura, Natalia Faraj Murad, Sidharth S Madhavan, Brenda Eap, Thelma Y Garcia, Carlos Galicia Aguirre, Eric Verdin, Lisa Ellerby, David Furman, John C Newman.
      Beta-hydroxybutyrate (BHB) is a ketone body synthesized during fasting or strenuous exercise. Our previous study demonstrated that a cyclic ketogenic diet (KD), which induces BHB levels similar to fasting every other week, reduces midlife mortality and improves memory in aging mice. BHB actively regulates gene expression and inflammatory activation through non-energetic signaling pathways. Neither of these activities has been well-characterized in the brain and they may represent mechanisms by which BHB affects brain function during aging. First, we analyzed hepatic gene expression in an aging KD-treated mouse cohort using bulk RNA-seq. In addition to the downregulation of TOR pathway activity, cyclic KD reduces inflammatory gene expression in the liver. We observed via flow cytometry that KD also modulates age-related systemic T cell functions. Next, we investigated whether BHB affects brain cells transcriptionally in vitro . Gene expression analysis in primary human brain cells (microglia, astrocytes, neurons) using RNA-seq shows that BHB causes a mild level of inflammation in all three cell types. However, BHB inhibits the more pronounced LPS-induced inflammatory gene activation in microglia. Furthermore, we confirmed that BHB similarly reduces LPS-induced inflammation in primary mouse microglia and bone marrow-derived macrophages (BMDMs). BHB is recognized as an inhibitor of histone deacetylase (HDAC), an inhibitor of NLRP3 inflammasome, and an agonist of the GPCR Hcar2. Nevertheless, in microglia, BHB's anti-inflammatory effects are independent of these known mechanisms. Finally, we examined the brain gene expression of 12-month-old male mice fed with one-week and one-year cyclic KD. While a one-week KD increases inflammatory signaling, a one-year cyclic KD reduces neuroinflammation induced by aging. In summary, our findings demon-strate that BHB mitigates the microglial response to inflammatory stimuli, like LPS, possibly leading to decreased chronic inflammation in the brain after long-term KD treatment in aging mice.
    DOI:  https://doi.org/10.1101/2023.12.01.569598
  45. J Inflamm Res. 2023 ;16 6107-6121
    Exploring the Connectivity of Neurodegenerative Diseases: Microglia as the Center.
    Yan Wang, Limei Cui, He Zhao, Huhuifen He, Liang Chen, Xicheng Song, Dawei Liu, Jingjing Qiu, Yan Sun.
      Degenerative diseases affect people's life and health and cause a severe social burden. Relevant mechanisms of microglia have been studied, aiming to control and reduce degenerative disease occurrence effectively. This review discussed the specific mechanisms underlying microglia in neurodegenerative diseases, age-related hearing loss, Alzheimer's disease, Parkinson's disease, and peripheral nervous system (PNS) degenerative diseases. It also reviewed the studies of microglia inhibitors (PLX3397/PLX5622) and activators (lipopolysaccharide), and suggested that reducing microglia can effectively curb the genesis and progression of degenerative diseases. Finally, microglial cells' anti-inflammatory and pro-inflammatory dual role was considered the critical communication point in central and peripheral degenerative diseases. Although it is difficult to describe the complex morphological structure of microglia in a unified manner, this does not prevent them from being a target for future treatment of neurodegenerative diseases.
    Keywords:  microglia; neurodegenerative diseases; neuroinflammation
    DOI:  https://doi.org/10.2147/JIR.S440377
  46. Biogerontology. 2023 Dec 18.
    Telomere length and cancer risk: finding Goldilocks.
    Sharon A Savage.
      Telomeres are the nucleoprotein complex at chromosome ends essential in genomic stability. Baseline telomere length (TL) is determined by rare and common germline genetic variants but shortens with age and is susceptible to certain environmental exposures. Cellular senescence or apoptosis are normally triggered when telomeres reach a critically short length, but cancer cells overcome these protective mechanisms and continue to divide despite chromosomal instability. Rare germline variants in telomere maintenance genes cause exceedingly short telomeres for age (< 1st percentile) and the telomere biology disorders, which are associated with elevated risks of bone marrow failure, myelodysplastic syndrome, acute myeloid leukemia, and squamous cell carcinoma of the head/neck and anogenital regions. Long telomeres due to rare germline variants in the same or different telomere maintenance genes are associated with elevated risks of other cancers, such as chronic lymphocytic leukemia or sarcoma. Early epidemiology studies of TL in the general population lacked reproducibility but new methods, including creation of a TL polygenic score using common variants, have found longer telomeres associated with excess risks of renal cell carcinoma, glioma, lung cancer, and others. It has become clear that when it comes to TL and cancer etiology, not too short, not too long, but "just right" telomeres are important in minimizing cancer risk.
    Keywords:  Cancer; Dyskeratosis congenita; Genetic variant; Polygenic inheritance; Polygenic risk score; Telomere; Telomere biology disorder
    DOI:  https://doi.org/10.1007/s10522-023-10080-9
  47. Aging Cell. 2023 Dec 21. e14072
    Lipoteichoic acid restrains macrophage senescence via β-catenin/FOXO1/REDD1 pathway in age-related osteoporosis.
    Weike Cheng, Yong Fu, Zexin Lin, Mouzhang Huang, Yingqi Chen, Yanjun Hu, Qingrong Lin, Bin Yu, Guanqiao Liu.
      Osteoporosis and its related fractures are common causes of morbidity and mortality in older adults, but its underlying molecular and cellular mechanisms remain largely unknown. In this study, we found that lipoteichoic acid (LTA) treatment could ameliorate age-related bone degeneration and attenuate intramedullary macrophage senescence. FOXO1 signaling, which was downregulated and deactivated in aging macrophages, played a key role in the process. Blocking FOXO1 signaling caused decreased REDD1 expression and increased phosphorylation level of mTOR, a major driver of aging, as well as aggravated bone loss and deteriorated macrophage senescence. Moreover, LTA elevated FOXO1 signaling through β-catenin pathway while β-catenin inhibition significantly suppressed FOXO1 signaling, promoted senescence-related protein expression, and accelerated bone degeneration and macrophage senescence. Our findings indicated that β-catenin/FOXO1/REDD1 signaling plays a physiologically significant role that protecting macrophages from senescence during aging.
    Keywords:  FOXO1; REDD1; mTOR; macrophage senescence; osteoporosis; β-Catenin
    DOI:  https://doi.org/10.1111/acel.14072
  48. Front Med (Lausanne). 2023 ;10 1310050
    Adeno-associated virus vectors for retinal gene therapy in basic research and clinical studies.
    Xue Xia, Xinzheng Guo.
      Retinal degenerative diseases, including glaucoma, age-related macular degeneration, diabetic retinopathy, and a broad range of inherited retinal diseases, are leading causes of irreversible vision loss and blindness. Gene therapy is a promising and fast-growing strategy to treat both monogenic and multifactorial retinal disorders. Vectors for gene delivery are crucial for efficient and specific transfer of therapeutic gene(s) into target cells. AAV vectors are ideal for retinal gene therapy due to their inherent advantages in safety, gene expression stability, and amenability for directional engineering. The eye is a highly compartmentalized organ composed of multiple disease-related cell types. To determine a suitable AAV vector for a specific cell type, the route of administration and choice of AAV variant must be considered together. Here, we provide a brief overview of AAV vectors for gene transfer into important ocular cell types, including retinal pigment epithelium cells, photoreceptors, retinal ganglion cells, Müller glial cells, ciliary epithelial cells, trabecular meshwork cells, vascular endothelial cells, and pericytes, via distinct injection methods. By listing suitable AAV vectors in basic research and (pre)clinical studies, we aim to highlight the progress and unmet needs of AAV vectors in retinal gene therapy.
    Keywords:  adeno-associated virus; age-related macular degeneration; diabetic retinopathy; gene therapy; glaucoma; inherited retinal diseases; retina; vector
    DOI:  https://doi.org/10.3389/fmed.2023.1310050
  49. medRxiv. 2023 Dec 05. pii: 2023.12.05.23299392. [Epub ahead of print]
    Mitochondrial DNA Copy Number Variation in Asthma Risk, Severity, and Exacerbations.
    National Heart, Lung, and Blood Institute (NHLBI) Severe Asthma Research Program (SARP)
       Rationale: Although airway oxidative stress and inflammation are central to asthma pathogenesis, there is limited knowledge of the relationship of asthma risk, severity, or exacerbations to mitochondrial dysfunction, which is pivotal to oxidant generation and inflammation.
    Objectives: We investigated whether mitochondrial DNA copy number (mtDNA-CN) as a measure of mitochondrial function is associated with asthma diagnosis, severity, oxidative stress, and exacerbations.
    Methods: We measured mtDNA-CN in blood in two cohorts. In the UK Biobank (UKB), we compared mtDNA-CN in mild and moderate-severe asthmatics to non-asthmatics. In the Severe Asthma Research Program (SARP), we evaluated mtDNA-CN in relation to asthma severity, biomarkers of oxidative stress and inflammation, and exacerbations.
    Measures and Main Results: In UK Biobank, asthmatics ( n = 29,768) have lower mtDNA-CN compared to non-asthmatics ( n = 239,158) (beta, -0.026 [95% CI, -0.038 to -0.014], P = 2.46×10 -5 ). While lower mtDNA-CN is associated with asthma, mtDNA-CN did not differ by asthma severity in either UKB or SARP. Biomarkers of inflammation show that asthmatics have higher white blood cells (WBC), neutrophils, eosinophils, fraction exhaled nitric oxide (F E NO), and lower superoxide dismutase (SOD) than non-asthmatics, confirming greater oxidative stress in asthma. In one year follow-up in SARP, higher mtDNA-CN is associated with reduced risk of three or more exacerbations in the subsequent year (OR 0.352 [95% CI, 0.164 to 0.753], P = 0.007).
    Conclusions: Asthma is characterized by mitochondrial dysfunction. Higher mtDNA-CN identifies an exacerbation-resistant asthma phenotype, suggesting mitochondrial function is important in exacerbation risk.
    DOI:  https://doi.org/10.1101/2023.12.05.23299392
  50. Geroscience. 2023 Dec 16.
    Early cerebral amyloid-β accumulation and hypermetabolism are associated with subtle cognitive deficits before accelerated cerebral atrophy.
    Aftab Bakhtiari, Krisztina Benedek, Ian Law, Birgitte Fagerlund, Erik Lykke Mortensen, Merete Osler, Martin Lauritzen, Henrik B W Larsson, Mark B Vestergaard.
       AIMS: Alzheimer's disease (AD) is characterized by the accumulation of amyloid beta (Aβ) in the brain. The deposition of Aβ is believed to initiate a detrimental cascade, including cerebral hypometabolism, accelerated brain atrophy, and cognitive problems-ultimately resulting in AD. However, the timing and causality of the cascade resulting in AD are not yet fully established. Therefore, we examined whether early Aβ accumulation affects cerebral glucose metabolism, atrophy rate, and age-related cognitive decline before the onset of neurodegenerative disease.
    METHODS: Participants from the Metropolit 1953 Danish Male Birth Cohort underwent brain positron emission tomography (PET) imaging using the radiotracers [11C]Pittsburgh Compound-B (PiB) (N = 70) and [18F]Fluorodeoxyglucose (FDG) (N = 76) to assess cerebral Aβ accumulation and glucose metabolism, respectively. The atrophy rate was calculated from anatomical magnetic resonance imaging (MRI) scans conducted presently and 10 years ago. Cognitive decline was examined from neurophysiological tests conducted presently and ten or 5 years ago.
    RESULTS: Higher Aβ accumulation in AD-critical brain regions correlated with greater visual memory decline (p = 0.023). Aβ accumulation did not correlate with brain atrophy rates. Increased cerebral glucose metabolism in AD-susceptible regions correlated with worse verbal memory performance (p = 0.040).
    CONCLUSIONS: Aβ accumulation in known AD-related areas was associated with subtle cognitive deficits. The association was observed before hypometabolism or accelerated brain atrophy, suggesting that Aβ accumulation is involved early in age-related cognitive dysfunction. The association between hypermetabolism and worse memory performance may be due to early compensatory mechanisms adapting for malfunctioning neurons by increasing metabolism.
    Keywords:  Aging; Amyloid; Atrophy; Cerebral glucose metabolism; Cognition; PET imaging
    DOI:  https://doi.org/10.1007/s11357-023-01031-w
  51. Vascul Pharmacol. 2023 Dec 17. pii: S1537-1891(23)00130-1. [Epub ahead of print]154 107270
    Adipsin in the pathogenesis of cardiovascular diseases.
    Ayobami Dare, Shi-You Chen.
      Adipsin is an adipokine predominantly synthesized in adipose tissues and released into circulation. It is also known as complement factor-D (CFD), acting as the rate-limiting factor in the alternative complement pathway and exerting essential functions on the activation of complement system. The deficiency of CFD in humans is a very rare condition. However, complement overactivation has been implicated in the etiology of numerous disorders, including cardiovascular disease (CVD). Increased circulating level of adipsin has been reported to promote vascular derangements, systemic inflammation, and endothelial dysfunction. Prospective and case-control studies showed that this adipokine is directly associated with all-cause death and rehospitalization in patients with coronary artery disease. Adipsin has also been implicated in pulmonary arterial hypertension, abdominal aortic aneurysm, pre-eclampsia, and type-2 diabetes which is a major risk factor for CVD. Importantly, serum adipsin has been recognized as a unique prognostic marker for assessing cardiovascular diseases. At present, there is paucity of experimental evidence about the precise role of adipsin in the etiology of CVD. However, this mini review provides some insight on the contribution of adipsin in the pathogenesis of CVD and highlights its role on endothelial, smooth muscle and immune cells that mediate cardiovascular functions.
    Keywords:  Adipsin; Cardiovascular disease; Complement factor-D; Endothelial cells; Smooth muscle cells
    DOI:  https://doi.org/10.1016/j.vph.2023.107270
  52. Biomedicines. 2023 Dec 06. pii: 3228. [Epub ahead of print]11(12):
    PURPL and NEAT1 Long Non-Coding RNAs Are Modulated in Vascular Smooth Muscle Cell Replicative Senescence.
    Clara Rossi, Marco Venturin, Jakub Gubala, Angelisa Frasca, Alberto Corsini, Cristina Battaglia, Stefano Bellosta.
      Cellular senescence is characterized by proliferation and migration exhaustion, senescence-associated secretory phenotype (SASP), and oxidative stress. Senescent vascular smooth muscle cells (VSMCs) contribute to cardiovascular diseases and atherosclerotic plaque instability. Since there are no unanimously agreed senescence markers in human VSMCs, to improve our knowledge, we looked for new possible senescence markers. To this end, we first established and characterized a model of replicative senescence (RS) in human aortic VSMCs. Old cells displayed several established senescence-associated markers. They stained positive for the senescence-associated β-galactosidase, showed a deranged proliferation rate, a dramatically reduced expression of PCNA, an altered migratory activity, increased levels of TP53 and cell-cycle inhibitors p21/p16, and accumulated in the G1 phase. Old cells showed an altered cellular and nuclear morphology, downregulation of the expression of LMNB1 and HMGB1, and increased expression of SASP molecules (IL1β, IL6, IL8, and MMP3). In these senescent VSMCs, among a set of 12 manually selected long non-coding RNAs (lncRNAs), we detected significant upregulation of PURPL and NEAT1. We observed also, for the first time, increased levels of RRAD mRNA. The detection of modulated levels of RRAD, PURPL, and NEAT1 during VSMC senescence could be helpful for future studies on potential anti-aging factors.
    Keywords:  NEAT1; PURPL; RRAD; aging; biomarkers; lncRNA; senescence; smooth muscle cells
    DOI:  https://doi.org/10.3390/biomedicines11123228
  53. Int J Mol Sci. 2023 Dec 12. pii: 17398. [Epub ahead of print]24(24):
    Can CD133 Be Regarded as a Prognostic Biomarker in Oncology: Pros and Cons.
    Alisa Gisina, Yan Kim, Konstantin Yarygin, Alexey Lupatov.
      The CD133 cell membrane glycoprotein, also termed prominin-1, is expressed on some of the tumor cells of both solid and blood malignancies. The CD133-positive tumor cells were shown to exhibit higher proliferative activity, greater chemo- and radioresistance, and enhanced tumorigenicity compared to their CD133-negative counterparts. For this reason, CD133 is regarded as a potential prognostic biomarker in oncology. The CD133-positive cells are related to the cancer stem cell subpopulation in many types of cancer. Recent studies demonstrated the involvement of CD133 in the regulation of proliferation, autophagy, and apoptosis in cancer cells. There is also evidence of its participation in the epithelial-mesenchymal transition associated with tumor progression. For a number of malignant tumor types, high CD133 expression is associated with poor prognosis, and the prognostic significance of CD133 has been confirmed in a number of meta-analyses. However, some published papers suggest that CD133 has no prognostic significance or even demonstrate a certain correlation between high CD133 levels and a positive prognosis. This review summarizes and discusses the existing evidence for and against the prognostic significance of CD133 in cancer. We also consider possible reasons for conflicting findings from the studies of the clinical significance of CD133.
    Keywords:  CD133; cancer biomarker; cancer prognosis; cancer stem cells; prominin-1
    DOI:  https://doi.org/10.3390/ijms242417398
  54. Biomedicines. 2023 Nov 29. pii: 3176. [Epub ahead of print]11(12):
    Anti-Osteoarthritis Mechanism of the Nrf2 Signaling Pathway.
    Sarmistha Saha, Nazih Y Rebouh.
      Osteoarthritis (OA) is a chronic degenerative disease and the primary pathogenic consequence of OA is inflammation, which can affect a variety of tissues including the synovial membrane, articular cartilage, and subchondral bone. The development of the intra-articular microenvironment can be significantly influenced by the shift of synovial macrophages between pro-inflammatory and anti-inflammatory phenotypes. By regulating macrophage inflammatory responses, the NF-κB signaling route is essential in the therapy of OA; whereas, the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway appears to manage the relationship between oxidative stress and inflammation. Additionally, it has been demonstrated that under oxidative stress and inflammation, there is a significant interaction between transcriptional pathways involving Nrf2 and NF-κB. Studying how Nrf2 signaling affects inflammation and cellular metabolism may help us understand how to treat OA by reprogramming macrophage behavior because Nrf2 signaling is thought to affect cellular metabolism. The candidates for treating OA by promoting an anti-inflammatory mechanism by activating Nrf2 are also reviewed in this paper.
    Keywords:  Nrf2; inflammation; osteoarthritis
    DOI:  https://doi.org/10.3390/biomedicines11123176
  55. Ann Neurol. 2023 Dec 19.
    Gene-environment interactions for Parkinson's disease.
    Alexandra Reynoso, Roberta Torricelli, Benjamin Meir Jacobs, Jingchunzi Shi, Stella Aslibekyan, Lucy Norcliffe-Kaufmann, Alastair J Noyce, Karl Heilbron.
       OBJECTIVE: Parkinson's disease (PD) is a neurodegenerative disorder with complex aetiology. Multiple genetic and environmental factors have been associated with PD, but most PD risk remains unexplained. The aim of this study was to test for statistical interactions between PD-related genetic and environmental exposures in the 23andMe, Inc. research dataset.
    METHODS: Using a validated PD polygenic risk score (PRS) and common PD-associated variants in the GBA gene, we explored interactions between genetic susceptibility factors and seven life-style and environmental factors: body mass index (BMI), type 2 diabetes (T2D), tobacco use, caffeine consumption, pesticide exposure, head injury, and physical activity (PA).
    RESULTS: We observed that T2D as well as higher BMI, caffeine consumption, and tobacco use were associated with lower odds of PD, while head injury, pesticide exposure, GBA carrier status and PD-PRS were associated with higher odds. No significant association was observed between PA and PD. In interaction analyses, we found statistical evidence for an interaction between polygenic risk of PD and the following environmental/lifestyle factors: T2D (P=6.502x10-8 ), PA (P=8.745x10-5 ), BMI (P=4.314x10-4 ), and tobacco use (P=2.236x10-3 ). While BMI and tobacco use were associated with lower odds of PD regardless of the extent of individual genetic liability, the direction of the relationship between odds of PD and T2D as well as PD and PA, varied depending on PRS.
    INTERPRETATION: We provide preliminary evidence that associations between some environmental and lifestyle factors and PD may be modified by genotype. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/ana.26852
  56. Pharmacogenomics. 2023 Dec 21.
    Epigenetic regulation of drug metabolism in aging: utilizing epigenetics to optimize geriatric pharmacotherapy.
    Sara Abudahab, Patricia W Slattum, Elvin T Price, Joseph L McClay.
      We explore the relationship between epigenetic aging and drug metabolism. We review current evidence for changes in drug metabolism in normal aging, followed by a description of how epigenetic modifications associated with age can regulate the expression and functionality of genes. In particular, we focus on the role of epigenome-wide studies of human and mouse liver in understanding these age-related processes with respect to xenobiotic processing. We highlight genes encoding drug metabolizing enzymes and transporters revealed to be affected by epigenetic aging in these studies. We conclude that substantial evidence exists for epigenetic aging impacting drug metabolism and transport genes, but more work is needed. We further highlight the promise of pharmacoepigenetics applied to enhancing drug safety in older adults.
    Keywords:  DNA methylation; cytochrome P450s; drug metabolism; drug transporters; geriatrics; histone modifications; older adults; pharmacotherapy
    DOI:  https://doi.org/10.2217/pgs-2023-0199
  57. Proteomics. 2023 Dec 19. e2300276
    Global quantitative proteomic analysis of aged mouse hippocampus.
    He Huang, Ashley J van Waardenberg, Mark E Graham, Victor Anggono, Jocelyn Widagdo.
      Understanding the molecular changes associated with the aged brain forms the basis for developing potential strategies for slowing cognitive decline associated with normal aging. Focusing on the hippocampus, a critical brain region involved in learning and memory, we employed tandem mass tag methodology to investigate global proteomic changes that occur in advanced-aged (20-month) versus young (3-month) C57BL/6 male mice. Our analysis revealed the upregulation of 236 proteins in the old hippocampal proteome, including those enriched within several age-related processes, such as the adaptive immune response and molecular metabolic pathways, whereas downregulated proteins (88 in total) are mainly involved in axonogenesis and growth cone-related processes. Categorizing proteins by cell-type enrichment in the brain identified a general upregulation of proteins preferentially expressed in microglia, astrocytes, and oligodendrocytes. In contrast, proteins with neuron-specific expression displayed an overall age-related downregulation. By integrating our proteomic with our previously published transcriptomic data, we discovered a mild but significant positive correlation between mRNA and protein expression changes in the aged hippocampus. Therefore, this proteomic data is a valuable additional resource for further understanding age-related molecular mechanisms.
    Keywords:  aging; cognitive decline; hippocampus; mass-spectrometry; proteomics
    DOI:  https://doi.org/10.1002/pmic.202300276
  58. Front Aging. 2023 ;4 1306463
    Editorial: DNA repair and interventions in aging.
    Robert M Brosh, Alexey Moskalev, Vera Gorbunova.
      
    Keywords:  DNA repair; NAD+; aging; biomarker; cockayne syndrome; epigenetic; mouse model; oxidative stress
    DOI:  https://doi.org/10.3389/fragi.2023.1306463
  59. J Intern Med. 2023 Dec 19.
    Audiovisual gamma stimulation for the treatment of neurodegeneration.
    Cristina Blanco-Duque, Diane Chan, Martin C Kahn, Mitchell H Murdock, Li-Huei Tsai.
      Alzheimer's disease (AD) is the most common type of neurodegenerative disease and a health challenge with major social and economic consequences. In this review, we discuss the therapeutic potential of gamma stimulation in treating AD and delve into the possible mechanisms responsible for its positive effects. Recent studies reveal that it is feasible and safe to induce 40 Hz brain activity in AD patients through a range of 40 Hz multisensory and noninvasive electrical or magnetic stimulation methods. Although research into the clinical potential of these interventions is still in its nascent stages, these studies suggest that 40 Hz stimulation can yield beneficial effects on brain function, disease pathology, and cognitive function in individuals with AD. Specifically, we discuss studies involving 40 Hz light, auditory, and vibrotactile stimulation, as well as noninvasive techniques such as transcranial alternating current stimulation and transcranial magnetic stimulation. The precise mechanisms underpinning the beneficial effects of gamma stimulation in AD are not yet fully elucidated, but preclinical studies have provided relevant insights. We discuss preclinical evidence related to both neuronal and nonneuronal mechanisms that may be involved, touching upon the relevance of interneurons, neuropeptides, and specific synaptic mechanisms in translating gamma stimulation into widespread neuronal activity within the brain. We also explore the roles of microglia, astrocytes, and the vasculature in mediating the beneficial effects of gamma stimulation on brain function. Lastly, we examine upcoming clinical trials and contemplate the potential future applications of gamma stimulation in the management of neurodegenerative disorders.
    Keywords:  Alzheimer's disease; gamma rhythms; neuromodulation; noninvasive brain stimulation; sensory stimulation; therapeutic potential
    DOI:  https://doi.org/10.1111/joim.13755
  60. Biomedicines. 2023 Nov 24. pii: 3128. [Epub ahead of print]11(12):
    Exploring the Therapeutic Potential of Gamma-Aminobutyric Acid in Stress and Depressive Disorders through the Gut-Brain Axis.
    Timur Liwinski, Undine E Lang, Annette B Brühl, Else Schneider.
      Research conducted on individuals with depression reveals that major depressive disorders (MDDs) coincide with diminished levels of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) in the brain, as well as modifications in the subunit composition of the primary receptors (GABAA receptors) responsible for mediating GABAergic inhibition. Furthermore, there is substantial evidence supporting the significant role of GABA in regulating stress within the brain, which is a pivotal vulnerability factor in mood disorders. GABA is readily available and approved as a food supplement in many countries. Although there is substantial evidence indicating that orally ingested GABA may affect GABA receptors in peripheral tissues, there is comparatively less evidence supporting its direct action within the brain. Emerging evidence highlights that oral GABA intake may exert beneficial effects on the brain and psyche through the gut-brain axis. While GABA enjoys wide consumer acceptance in Eastern Asian markets, with many consumers reporting favorable effects on stress regulation, mood, and sleep, rigorous independent research is still largely lacking. Basic research, coupled with initial clinical findings, makes GABA an intriguing neuro-nutritional compound deserving of clinical studies in individuals with depression and other psychological problems.
    Keywords:  enteric nervous system; gut–brain axis; insomnia; microbiome; mood disorder; neurotransmitter; nutraceuticals; nutrition; stress
    DOI:  https://doi.org/10.3390/biomedicines11123128
  61. Exp Neurol. 2023 Dec 17. pii: S0014-4886(23)00340-0. [Epub ahead of print]373 114655
    Crosstalk between Nrf2 signaling pathway and inflammation in ischemic stroke: Mechanisms of action and therapeutic implications.
    Negar Khassafi, Abolfazl Azami Tameh, Hamed Mirzaei, Ali Rafat, Shirin Barati, Negin Khassafi, Zeinab Vahidinia.
      One of the major causes of long-term disability and mortality is ischemic stroke that enjoys limited treatment approaches. On the one hand, oxidative stress, induced by excessive generation of reactive oxygen species (ROS), plays a critical role in post-stroke inflammatory response. Increased ROS generation is one of the basic factors in the progression of stroke-induced neuroinflammation. Moreover, intravenous (IV) thrombolysis using recombinant tissue plasminogen activator (rtPA) as the only medication approved for patients with acute ischemic stroke who suffer from some clinical restrictions it could not cover the complicated episodes that happen after stroke. Thus, identifying novel therapeutic targets is crucial for successful preparation of new medicines. Recent evidence indicates that the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) contributes significantly to regulating the antioxidant production in cytosol, which causes antiinflammatory effects on neurons. New findings have shown a relationship between activation of the Nrf2 and glial cells, nuclear factor kappa B (NF-κB) pathway, the nucleotide-binding domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling, and expression of inflammatory markers, suggesting induction of Nrf2 activation can represent a promising therapeutic alternative as the modulators of Nrf2 dependent pathways for targeting inflammatory responses in neural tissue. Hence, this review addresses the relationship of Nrf2 signaling with inflammation and Nrf2 activators' potential as therapeutic agents. This review helps to improve required knowledge for focused therapy and the creation of modern and improved treatment choices for patients with ischemic stroke.
    Keywords:  Glial cells; Inflammation; Ischemic stroke; Nrf2; Oxidative stress; tBHQ
    DOI:  https://doi.org/10.1016/j.expneurol.2023.114655
  62. SLAS Discov. 2023 Dec 14. pii: S2472-5552(23)00097-7. [Epub ahead of print]
    Quantitative target engagement of RIPK1 in human whole blood via the cellular thermal shift assay for potential pre-clinical and clinical applications.
    Shitalben Patel, Marie Karlsson, Joseph T Klahn, Frank Gambino, Helena Costa, Kathleen A McGuire, Christina K Baumgartner, Jon Williams, Sarah Sandoz, James E Kath.
      The cellular thermal shift assay (CETSA®) is a target engagement method widely used for preclinical characterization of small molecule compounds. CETSA® has been used for semi-quantitative readouts in whole blood with PBMC isolation, and quantitative, plate-based readouts using cell lines. However, there has been no quantitative evaluation of CETSA® in unprocessed human whole blood, which is preferred for clinical applications. Here we report two separate assay formats - Alpha CETSA® and MSD CETSA® - that require less than 100 μL of whole blood per sample without PBMC isolation. We chose RIPK1 as a proof-of-concept target and, by measuring engagement of seven different inhibitors, demonstrate high assay sensitivity and robustness. These quantitative CETSA® platforms enable possible applications in preclinical pharmacokinetic-pharmacodynamic studies, and direct target engagement with small molecules in clinical trials.
    Keywords:  Blood; CETSA; RIPK1; Target engagement
    DOI:  https://doi.org/10.1016/j.slasd.2023.12.007
  63. Biomedicines. 2023 Dec 05. pii: 3221. [Epub ahead of print]11(12):
    Recent Developments in Gene Therapy for Neovascular Age-Related Macular Degeneration: A Review.
    Lucia Finocchio, Marco Zeppieri, Andrea Gabai, Giacomo Toneatto, Leopoldo Spadea, Carlo Salati.
      Age-related macular degeneration (AMD) is a complex and multifactorial disease and a leading cause of irreversible blindness in the elderly population. The anti-vascular endothelial growth factor (anti-VEGF) therapy has revolutionized the management and prognosis of neovascular AMD (nAMD) and is currently the standard of care for this disease. However, patients are required to receive repeated injections, imposing substantial social and economic burdens. The implementation of gene therapy methods to achieve sustained delivery of various therapeutic proteins holds the promise of a single treatment that could ameliorate the treatment challenges associated with chronic intravitreal therapy, and potentially improve visual outcomes. Several early-phase trials are currently underway, evaluating the safety and efficacy of gene therapy for nAMD; however, areas of controversy persist, including the therapeutic target, route of administration, and potential safety issues. In this review, we assess the evolution of gene therapy for nAMD and summarize several preclinical and early-stage clinical trials, exploring challenges and future directions.
    Keywords:  clinical trials; gene therapy; maculopathy; neovascular AMD; target therapy
    DOI:  https://doi.org/10.3390/biomedicines11123221
  64. Front Endocrinol (Lausanne). 2023 ;14 1293988
    Diabetes status and cognitive function in middle-aged and older adults in the Canadian longitudinal study on aging.
    Mohammad Nazmus Sakib, Reza Ramezan, Peter A Hall.
       Objectives: Diabetes is recognized as a significant risk factor for cognitive impairment. However, this association has not been thoroughly examined using large-scale population-based datasets in the Canadian context. The objective of this study was to investigate the potential association between cognitive function and diabetes in a large population-based sample of middle-aged and older Canadians.
    Methods: We utilized baseline data from the Canadian Longitudinal Study on Aging (N=30,097) to test our hypotheses, using five indicators of cognitive function (animal fluency, Stroop interference, reaction time, immediate and delayed memory recall). We conducted multivariate multivariable linear regression and subsequently performed tests for moderation analysis with lifestyle factors and health status.
    Results: The analysis revealed that type 2 diabetes (T2DM) was associated with lower performance on most cognitive tasks, including those assessing executive function (b=0.60, 95% CI 0.31 to 0.90), reaction time (b=16.94, 95% CI 9.18 to 24.70), immediate memory recall (b=-0.10, 95% CI -0.18 to -0.02), and delayed memory recall (b=-0.12, 95% CI -0.21 to -0.02). However, no significant association was observed between other types of diabetes and cognitive performance. Moderation effects were largely null for T2DM, with the exception of alcohol intake for reaction time, and physical activity for animal fluency.
    Conclusions: The study showed that individuals with T2DM exhibit poor performance on tasks that assess executive function, reaction time, and memory. Therefore, optimizing cognitive health among individuals with T2DM should be a priority in primary care. Additionally, further studies should examine this association using longitudinal data.
    Keywords:  CLSA; cognitive function; diabetes; executive function; memory; reaction time
    DOI:  https://doi.org/10.3389/fendo.2023.1293988
  65. Antioxidants (Basel). 2023 Dec 12. pii: 2100. [Epub ahead of print]12(12):
    17β-Estradiol (E2) Upregulates the ERα/SIRT1/PGC-1α Signaling Pathway and Protects Mitochondrial Function to Prevent Bilateral Oophorectomy (OVX)-Induced Nonalcoholic Fatty Liver Disease (NAFLD).
    Ying Tian, Xinyu Hong, Yuan Xie, Zaixin Guo, Qi Yu.
      Premature menopause is associated with an increased prevalence of nonalcoholic fatty liver disease (NAFLD). Menopausal hormone therapy (MHT) has been widely used in clinical practice and has the potential to protect mitochondrial function and alleviate NAFLD. After bilateral oophorectomy (OVX), female rats without 17β-estradiol (E2) intervention developed NAFLD, whereas E2 supplementation was effective in preventing NAFLD in female rats. The altered pathways and cellular events from both comparison pairs, namely, the OVX vs. sham group and the OVX vs. E2 group, were assessed using transcriptomic analysis. KEGG pathways enriched by both transcriptomic and metabolomic analyses strongly suggest that oxidative phosphorylation is a vital pathway that changes during the development of NAFLD and remains unchanged when E2 is applied. Liver tissue from the OVX-induced NAFLD group exhibited increased lipid peroxidation, impaired mitochondria, and downregulated ERα/SIRT1/PGC-1α expression. An in vitro study indicated that the protective effect of E2 treatment on hepatic steatosis could be abolished when ERα or SIRT1 was selectively inhibited. This damage was accompanied by reduced mitochondrial complex activity and increased lipid peroxidation. The current research indicates that E2 upregulates the ERα/SIRT1/PGC-1α signaling pathway and protects mitochondrial function to prevent OVX-induced NAFLD.
    Keywords:  menopausal hormone therapy; mitochondria; nonalcoholic fatty liver disease; oxidative stress; surgical menopause
    DOI:  https://doi.org/10.3390/antiox12122100
  66. J Hazard Mater. 2023 Dec 10. pii: S0304-3894(23)02484-6. [Epub ahead of print]465 133200
    DNA methylation aging signatures of multiple metals exposure and their mediation effects in metal-associated mortality: Evidence from the Dongfeng-Tongji cohort study.
    Chenming Wang, Guorong Zhong, Chenliang Liu, Shiru Hong, Xin Guan, Yang Xiao, Ming Fu, Yuhan Zhou, Yingqian You, Tianhao Wu, Hui Zhao, Yuxi Wang, Shengli Chen, Yichi Zhang, Chaolong Wang, Huan Guo.
      Humans were exposed to multiple metals, but the impact of metals on DNA methylation-age (DNAm-age), a well-recognized aging measure, remains inconclusive. This study included 2942 participants from the Dongfeng-Tongji cohort. We detected their plasma concentrations of 23 metals and determined their genome-wide DNA methylation using the Illumina Human-MethylationEPIC BeadChip. Five DNAm-age acceleration indexes (DAIs), including HannumAge-Accel, HorvathAge-Accel, PhenoAge-Accel, GrimAge-Accel (residual from regressing corresponding DNAm-age on chronological age) and DNAm-mortality score (DNAm-MS), were separately calculated. We found that each 1-unit increase in ln-transformed copper (Cu) was associated with a separate 1.02-, 0.83- and 0.07-unit increase in PhenoAge-Accel, GrimAge-Accel, and DNAm-MS (all FDR<0.05). Each 1-unit increase in ln-transformed nickel (Ni) was associated with a 0.34-year increase in PhenoAge-Accel, while each 1-unit increase in ln-transformed strontium (Sr) was associated with a 0.05-unit increase in DNAm-MS. The Cu, Ni and Sr showed joint positive effects on above three DAIs. PhenoAge-Accel, GrimAge-Accel, and DNAm-MS mediated a separate 6.5%, 12.3%, 6.0% of the positive association between Cu and all-cause mortality; GrimAge-Accel mediated 14.3% of the inverse association of selenium with all-cause mortality. Our findings revealed the effects of Cu, Ni, Sr and their co-exposure on accelerated aging and highlighted mediation roles of DNAm-age on metal-associated mortality.
    Keywords:  All-cause mortality; Biological aging; DNA methylation age; Mediation effect; Metal exposure
    DOI:  https://doi.org/10.1016/j.jhazmat.2023.133200
  67. bioRxiv. 2023 Dec 07. pii: 2023.12.06.570422. [Epub ahead of print]
    Retroelement-Age Clocks: Epigenetic Age Captured by Human Endogenous Retrovirus and LINE-1 DNA methylation states.
    Lishomwa C Ndhlovu, Matthew L Bendall, Varun Dwaraka, Alina Ps Pang, Nicholas Dopkins, Natalia Carreras, Ryan Smith, Douglas F Nixon, Michael J Corley.
      Human endogenous retroviruses (HERVs), the remnants of ancient viral infections embedded within the human genome, and long interspersed nuclear elements 1 (LINE-1), a class of autonomous retrotransposons, are silenced by host epigenetic mechanisms including DNA methylation. The resurrection of particular retroelements has been linked to biological aging. Whether the DNA methylation states of locus specific HERVs and LINEs can be used as a biomarker of chronological age in humans remains unclear. We show that highly predictive epigenetic clocks of chronological age can be constructed from retroelement DNA methylation states in the immune system, across human tissues, and pan-mammalian species. We found retroelement epigenetic clocks were reversed during transient epigenetic reprogramming, accelerated in people living with HIV-1, responsive to antiretroviral therapy, and accurate in estimating long-term culture ages of human brain organoids. Our findings support the hypothesis of epigenetic dysregulation of retroelements as a potential contributor to the biological hallmarks of aging.
    DOI:  https://doi.org/10.1101/2023.12.06.570422
  68. Cell Death Dis. 2023 Dec 21. 14(12): 853
    WWP1 E3 ligase at the crossroads of health and disease.
    Abhayananda Behera, Aramati Bindu Madhava Reddy.
      The E3 ubiquitin ligase WWP1 (WW Domain-containing E3 Ubiquitin Protein Ligase 1) is a member of the HECT (Homologous to the E6-associated protein Carboxyl Terminus) E3 ligase family. It is conserved across several species and plays crucial roles in various physiological processes, including development, cell growth and proliferation, apoptosis, and differentiation. It exerts its functions through ubiquitination or protein-protein interaction with PPXY-containing proteins. WWP1 plays a role in several human diseases, including cardiac conditions, neurodevelopmental, age-associated osteogenic disorders, infectious diseases, and cancers. In solid tumors, WWP1 plays a dual role as both an oncogene and a tumor suppressor, whereas in hematological malignancies such as AML, it is identified as a dedicated oncogene. Importantly, WWP1 inhibition using small molecule inhibitors such as Indole-3-Carbinol (I3C) and Bortezomib or siRNAs leads to significant suppression of cancer growth and healing of bone fractures, suggesting that WWP1 might serve as a potential therapeutic target for several diseases. In this review, we discuss the evolutionary perspective, structure, and functions of WWP1 and its multilevel regulation by various regulators. We also examine its emerging roles in cancer progression and its therapeutic potential. Finally, we highlight WWP1's role in normal physiology, contribution to pathological conditions, and therapeutic potential for cancer and other diseases.
    DOI:  https://doi.org/10.1038/s41419-023-06380-0
  69. Biochemistry (Mosc). 2023 Nov;88(11): 1763-1777
    Microgravity Effects and Aging Physiology: Similar Changes or Common Mechanisms?
    Andrey Yu Ratushnyy, Ludmila B Buravkova.
      Despite the use of countermeasures (including intense physical activity), cosmonauts and astronauts develop muscle atony and atrophy, cardiovascular system failure, osteopenia, etc. All these changes, reminiscent of age-related physiological changes, occur in a healthy person in microgravity quite quickly - within a few months. Adaptation to the lost of gravity leads to the symptoms of aging, which are compensated after returning to Earth. The prospect of interplanetary flights raises the question of gravity thresholds, below which the main physiological systems will decrease their functional potential, similar to aging, and affect life expectancy. An important role in the aging process belongs to the body's cellular reserve - progenitor cells, which are involved in physiological remodeling and regenerative/reparative processes of all physiological systems. With age, progenitor cell count and their regenerative potential decreases. Moreover, their paracrine profile becomes pro-inflammatory during replicative senescence, disrupting tissue homeostasis. Mesenchymal stem/stromal cells (MSCs) are mechanosensitive, and therefore deprivation of gravitational stimulus causes serious changes in their functional status. The review compares the cellular effects of microgravity and changes developing in senescent cells, including stromal precursors.
    Keywords:  aging; cell senescence; mesenchymal stem/stromal cells (MSCs); microgravity
    DOI:  https://doi.org/10.1134/S0006297923110081
  70. Geroscience. 2023 Dec 23.
    The CEPH aging cohort and biobank: a valuable collection of biological samples from exceptionally long-lived French individuals and their offspring for longevity studies.
    Alexandre How-Kit, Mourad Sahbatou, Lise M Hardy, Nicolas P Tessier, Valérie Schiavon, Hélène Le Buanec, Jean-Marc Sebaoun, Hélène Blanché, Jean-François Zagury, Jean-François Deleuze.
      The increasing aging of the human population is currently and for the coming decades a major public health issue in many countries, requiring the implementation of global public health policies promoting healthy and successful aging. Individuals are not equal in the face of aging and some can present exceptional healthspan and/or lifespan, which are notably influenced by both genetic and environmental factors. Research and studies on human aging, healthy aging and longevity should rely in particular on cohorts of long-lived individuals, also including biological samples allowing studies on the biology of aging and longevity. In this manuscript, we provide for the first time a complete description of the CEPH (Centre d'Etude du Polymophisme Humain) Aging cohort, an exceptional cohort recruited during the 90s to 2000s, including more than 1700 French long-lived individuals (≥ 90 years old) born between 1875 and 1916 as well as for some of them their siblings and offspring. Among the participants, 1265 were centenarians, including 255 semi-supercentenarians ([105-110] years old) and 25 supercentenarians (≥ 110 years old). The available anthropometric, epidemiologic and clinical data for the cohort participants are described and especially the collection of blood-derived biological samples associated with the cohort which includes DNA, cryopreserved cells and cell lines, plasma, and serum. This biological collection from the first cohort of centenarians in the world is an inestimable resource for ongoing and future molecular, cellular, and functional studies aimed at deciphering the mechanisms of human (successful) aging and longevity.
    Keywords:  Aging; Biobanks; Biorepository; Blood samples; Centenarians; Cohort study; DNA; Longevity
    DOI:  https://doi.org/10.1007/s11357-023-01037-4
  71. Food Funct. 2023 Dec 18.
    Ganoderma lucidum methyl ganoderate E extends lifespan and modulates aging-related indicators in Caenorhabditis elegans.
    Nkwachukwu Oziamara Okoro, Arome Solomon Odiba, Junjie Han, Patience Ogoamaka Osadebe, Edwin Ogechukwu Omeje, Guiyan Liao, Yichen Liu, Cheng Jin, Wenxia Fang, Hongwei Liu, Bin Wang.
      Methyl Ganoderate E (MGE) is a triterpenoid derived from Ganoderma lucidum (Reishi), an edible mushroom, commonly processed into food forms such as soups, drinks, culinary dishes, and supplements. MGE has been shown to inhibit 3T3-L1 murine adipocyte differentiation when combined with other G. lucidum triterpenes. However, the specific effect of MGE on biological processes remains unknown. In this study, we present the first evidence of MGE's anti-aging effect in Caenorhabditis elegans. Through our screening process using the UPRER regulation ability, we evaluated a library of 74 pure compounds isolated from G. lucidum, and MGE exhibited the most promising results. Subsequent experiments demonstrated that MGE extended the lifespan by 26% at 10 μg ml-1 through daf-16, hsf-1, and skn-1-dependent pathways. MGE also enhanced resistance to various molecular stressors, improved healthspan, increased fertility, and reduced the aggregation of alpha-synuclein and amyloid-beta. Transcriptome data revealed that MGE promoted processes associated with proteolysis and neural activity, while not promoting cell death processes. Collectively, our findings suggest that G. lucidum MGE could be considered as a potential anti-aging intervention, adding to the growing list of such interventions.
    DOI:  https://doi.org/10.1039/d3fo04166b
  72. Biophys J. 2023 Dec 15. pii: S0006-3495(23)04148-6. [Epub ahead of print]
    Modeling transcriptional regulation of the cell cycle using a novel cybernetic-inspired approach.
    Rubesh Raja, Sana Khanum, Lina Aboulmouna, Mano R Maurya, Shakti Gupta, Shankar Subramaniam, Doraiswami Ramkrishna.
      Quantitative understanding of cellular processes, such as cell cycle and differentiation, is impeded by various forms of complexity ranging from myriad molecular players and their multilevel regulatory interactions, cellular evolution with multiple intermediate stages, lack of elucidation of cause-effect relationships among the many system players, and the computational complexity associated with the profusion of variables and parameters. In this paper, we present a modeling framework based on the cybernetic concept that biological regulation is inspired by objectives embedding rational strategies for dimension reduction, process stage specification through the system dynamics, and innovative causal association of regulatory events with the ability to predict the evolution of the dynamical system. The elementary step of the modeling strategy involves stage-specific objective functions that are computationally-determined from experiments, augmented with dynamical network computations involving end point objective functions, mutual information, change point detection, and maximal clique centrality. We demonstrate the power of the method through application to the mammalian cell cycle, which involves thousands of biomolecules engaged in signaling, transcription, and regulation. Starting with a fine-grained transcriptional description obtained from RNA sequencing measurements, we develop an initial model, which is then dynamically modeled using the cybernetic-inspired method (CIM), based on the strategies described above. The CIM is able to distill the most significant interactions from a multitude of possibilities. In addition to capturing the complexity of regulatory processes in a mechanistically causal and stage-specific manner, we identify the functional network modules, including novel cell cycle stages. Our model is able to predict future cell cycles consistent with experimental measurements. We posit that this innovative framework has the promise to extend to the dynamics of other biological processes, with a potential to provide novel mechanistic insights.
    DOI:  https://doi.org/10.1016/j.bpj.2023.12.010
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