bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2023‒10‒29
nineteen papers selected by
Ayesh Seneviratne, Western University
  1. Clonal Hematopoiesis and Inflammation: A Review of Mechanisms and Clinical Implications.
  2. Hematopoietic stem cells through the ages: A lifetime of adaptation to organismal demands.
  3. APOE set the microglia free.
  4. Telomouse-a mouse model with human-length telomeres generated by a single amino acid change in RTEL1.
  5. CD300f immune receptor contributes to healthy aging by regulating inflammaging, metabolism, and cognitive decline.
  6. Providing predictable results and healthy smiles.
  7. Associations of intrinsic capacity, fall risk and frailty in old inpatients.
  8. Clonal haematopoiesis, ageing and kidney disease.
  9. Impact of senolytic treatment on immunity, aging, and disease.
  10. A Narrative Review: The Effect and Importance of Carotenoids on Aging and Aging-Related Diseases.
  11. Temporal dynamics of epigenetic aging and frailty from midlife to old age.
  12. Troubleshooting brain immunohistochemistry.
  13. Unsynchronous conformational transitions induced by the asymmetric adsorption-response of an active diblock copolymer in an inert brush.
  14. Unique Patterns in Amino Acid Sequences of Aging-Related Proteins.
  15. T/myeloid MPAL with biallelic CEBPA mutations.
  16. Akkermansia muciniphila induces slow extramedullary hematopoiesis via cooperative IL-1R/TLR signals.
  17. Cellular senescence in skeletal disease: mechanisms and treatment.
  18. Biological aging in multiple sclerosis.
  19. Vitamin D Improves Cognitive Impairment and Alleviates Ferroptosis via the Nrf2 Signaling Pathway in Aging Mice.
  1. Crit Rev Oncol Hematol. 2023 Oct 23. pii: S1040-8428(23)00275-5. [Epub ahead of print] 104187
    Clonal Hematopoiesis and Inflammation: A Review of Mechanisms and Clinical Implications.
    Daniel I Nathan, Max Dougherty, Manasa Bhatta, John Mascarenhas, Bridget K Marcellino.
      Clonal hematopoiesis (CH) is defined by the presence of somatic mutations in hematopoietic stem and progenitor cells (HSPC). CH is associated primarily with advancing age and confers an elevated risk of progression to overt hematologic malignancy and cardiovascular disease. Increasingly, CH is associated with a wide range of diseases driven by, and sequelae of, inflammation. Accordingly, there is great interest in better understanding the pathophysiologic and clinical relationship between CH, aging, and disease. Both observational and experimental findings support the concept that CH is a potential common denominator in the inflammatory outcomes of aging. However, there is also evidence that local and systemic inflammatory states promote the growth and select for CH clones. In this review, we aim to provide an up-to-date summary of the nature of the relationship between inflammation and CH, which is central to unlocking potential therapeutic opportunities to prevent progression to myeloid malignancy.
    Keywords:  autoimmune disease; cardiovascular disease; clonal hematopoiesis; hematologic malignancy; inflammation; myeloid neoplasm
    DOI:  https://doi.org/10.1016/j.critrevonc.2023.104187
  2. Cell Stem Cell. 2023 Oct 16. pii: S1934-5909(23)00360-0. [Epub ahead of print]
    Hematopoietic stem cells through the ages: A lifetime of adaptation to organismal demands.
    Monica Kasbekar, Carl A Mitchell, Melissa A Proven, Emmanuelle Passegué.
      Hematopoietic stem cells (HSCs), which govern the production of all blood lineages, transition through a series of functional states characterized by expansion during fetal development, functional quiescence in adulthood, and decline upon aging. We describe central features of HSC regulation during ontogeny to contextualize how adaptive responses over the life of the organism ultimately form the basis for HSC functional degradation with age. We particularly focus on the role of cell cycle regulation, inflammatory response pathways, epigenetic changes, and metabolic regulation. We then explore how the knowledge of age-related changes in HSC regulation can inform strategies for the rejuvenation of old HSCs.
    Keywords:  aging; development; epigenetic; hematopoietic stem cells; inflammation; metabolism; niche regulation; quiescence; rejuvenation
    DOI:  https://doi.org/10.1016/j.stem.2023.09.013
  3. Nat Immunol. 2023 Nov;24(11): 1790-1791
    APOE set the microglia free.
    Emile Wogram, Marco Prinz.
      
    DOI:  https://doi.org/10.1038/s41590-023-01651-6
  4. Nat Commun. 2023 Oct 23. 14(1): 6708
    Telomouse-a mouse model with human-length telomeres generated by a single amino acid change in RTEL1.
    Riham Smoom, Catherine Lee May, Vivian Ortiz, Mark Tigue, Hannah M Kolev, Melissa Rowe, Yitzhak Reizel, Ashleigh Morgan, Nachshon Egyes, Dan Lichtental, Emmanuel Skordalakes, Klaus H Kaestner, Yehuda Tzfati.
      Telomeres, the ends of eukaryotic chromosomes, protect genome integrity and enable cell proliferation. Maintaining optimal telomere length in the germline and throughout life limits the risk of cancer and enables healthy aging. Telomeres in the house mouse, Mus musculus, are about five times longer than human telomeres, limiting the use of this common laboratory animal for studying the contribution of telomere biology to aging and cancer. We identified a key amino acid variation in the helicase RTEL1, naturally occurring in the short-telomere mouse species M. spretus. Introducing this variation into M. musculus is sufficient to reduce the telomere length set point in the germline and generate mice with human-length telomeres. While these mice are fertile and appear healthy, the regenerative capacity of their colonic epithelium is compromised. The engineered Telomouse reported here demonstrates a dominant role of RTEL1 in telomere length regulation and provides a unique model for aging and cancer.
    DOI:  https://doi.org/10.1038/s41467-023-42534-6
  5. Cell Rep. 2023 Oct 20. pii: S2211-1247(23)01281-0. [Epub ahead of print]42(10): 113269
    CD300f immune receptor contributes to healthy aging by regulating inflammaging, metabolism, and cognitive decline.
    Frances Evans, Daniela Alí-Ruiz, Natalia Rego, María Luciana Negro-Demontel, Natalia Lago, Fabio Andrés Cawen, Bruno Pannunzio, Paula Sanchez-Molina, Laura Reyes, Andrea Paolino, Jorge Rodríguez-Duarte, Valentina Pérez-Torrado, Almudena Chicote-González, Celia Quijano, Inés Marmisolle, Ana Paula Mulet, Geraldine Schlapp, María Noel Meikle, Mariana Bresque, Martina Crispo, Eduardo Savio, Cristina Malagelada, Carlos Escande, Hugo Peluffo.
      Emerging evidence suggests that immune receptors may participate in many aging-related processes such as energy metabolism, inflammation, and cognitive decline. CD300f, a TREM2-like lipid-sensing immune receptor, is an exceptional receptor as it integrates activating and inhibitory cell-signaling pathways that modulate inflammation, efferocytosis, and microglial metabolic fitness. We hypothesize that CD300f can regulate systemic aging-related processes and ultimately healthy lifespan. We closely followed several cohorts of two strains of CD300f-/- and WT mice of both sexes for 30 months and observed an important reduction in lifespan and healthspan in knockout mice. This was associated with systemic inflammaging, increased cognitive decline, reduced brain glucose uptake observed by 18FDG PET scans, enrichment in microglial aging/neurodegeneration phenotypes, proteostasis alterations, senescence, increased frailty, and sex-dependent systemic metabolic changes. Moreover, the absence of CD300f altered macrophage immunometabolic phenotype. Taken together, we provide strong evidence suggesting that myeloid cell CD300f immune receptor contributes to healthy aging.
    Keywords:  CP: Immunology; CP: Metabolism; DAM; aging; cognitive decline; dementia; glucose metabolism; healthspan; immunometabolism; inflammaging; lifespan; macrophage; microglia; positron emmission tomography; sex differences
    DOI:  https://doi.org/10.1016/j.celrep.2023.113269
  6. Br Dent J. 2023 Oct;235(8): 655
    Providing predictable results and healthy smiles.
      
    DOI:  https://doi.org/10.1038/s41415-023-6485-2
  7. Front Public Health. 2023 ;11 1177812
    Associations of intrinsic capacity, fall risk and frailty in old inpatients.
    Shanshan Shen, Yanhong Xie, Xingkun Zeng, Lingyan Chen, Huilan Guan, Yinghong Yang, Xiushao Wu, Xujiao Chen.
      Introduction: This study explored the associations of intrinsic capacity (IC), fall risk, and frailty in geriatric inpatients.Methods: A total of 703 hospitalized patients aged 75 years or older were recruited for this retrospective observational study from Zhejiang Hospital using a comprehensive geriatric assessment. The IC composite score was constructed from the scores of the Chinese version of the Mini-Mental State Examination, Short Physical Performance Battery, Short Form Mini Nutritional Assessment, 15-item Geriatric Depression Scale, and self-reported hearing and vision impairment. Adverse outcomes were recorded as the fall risk and frailty using the Morse Fall Scale and the Clinical Frailty Scale. Spearman's correlation coefficient analyses and multivariate logistic regression models were used to explore the associations between IC, high fall risk, and frailty.
    Results: Declined IC composite scores were associated with increased risks of falls [odds ratio (OR) = 0.64, 95% confidence interval (CI): 0.57-0.72] and frailty (OR = 0.45, 95%CI: 0.37-0.54) among older hospitalized patients after adjusting for the related potential confounders. In addition, decreased cognitive, vitality, locomotion, and psychological scores were associated with increased adverse health conditions, with ORs ranging from 0.26 to 0.70. Vision impairment was observed to increase the risk of frailty (OR = 0.42, 95%CI: 0.23-0.76) after adjusting for the related potential confounders.
    Discussion: This study indicated that declined IC was associated with fall risk and frailty in older inpatients. Further prospective studies are needed to explore the longitudinal associations between baseline IC and subsequent risk of falls and frailty.
    Keywords:  fall; frailty; hospitalized; intrinsic capacity; older adults
    DOI:  https://doi.org/10.3389/fpubh.2023.1177812
  8. Nat Rev Nephrol. 2023 Oct 26.
    Clonal haematopoiesis, ageing and kidney disease.
    Caitlyn Vlasschaert, Matthew B Lanktree, Michael J Rauh, Tanika N Kelly, Pradeep Natarajan.
      Clonal haematopoiesis of indeterminate potential (CHIP) is a preclinical condition wherein a sizeable proportion of an individual's circulating blood cells are derived from a single mutated haematopoietic stem cell. CHIP occurs frequently with ageing - more than 10% of individuals over 65 years of age are affected - and is associated with an increased risk of disease across several organ systems and premature death. Emerging evidence suggests that CHIP has a role in kidney health, including associations with predisposition to acute kidney injury, impaired recovery from acute kidney injury and kidney function decline, both in the general population and among those with chronic kidney disease. Beyond its direct effect on the kidney, CHIP elevates the susceptibility of individuals to various conditions that can detrimentally affect the kidneys, including cardiovascular disease, obesity and insulin resistance, liver disease, gout, osteoporosis and certain autoimmune diseases. Aberrant pro-inflammatory signalling, telomere attrition and epigenetic ageing are potential causal pathophysiological pathways and mediators that underlie CHIP-related disease risk. Experimental animal models have shown that inhibition of inflammatory cytokine signalling can ameliorate many of the pathological effects of CHIP, and assessment of the efficacy and safety of this class of medications for human CHIP-associated pathology is ongoing.
    DOI:  https://doi.org/10.1038/s41581-023-00778-x
  9. Front Aging. 2023 ;4 1161799
    Impact of senolytic treatment on immunity, aging, and disease.
    Erica C Lorenzo, Blake L Torrance, Laura Haynes.
      Cellular senescence has been implicated in the pathophysiology of many age-related diseases. However, it also plays an important protective role in the context of tumor suppression and wound healing. Reducing senescence burden through treatment with senolytic drugs or the use of genetically targeted models of senescent cell elimination in animals has shown positive results in the context of mitigating disease and age-associated inflammation. Despite positive, albeit heterogenous, outcomes in clinical trials, very little is known about the short-term and long-term immunological consequences of using senolytics as a treatment for age-related conditions. Further, many studies examining cellular senescence and senolytic treatment have been demonstrated in non-infectious disease models. Several recent reports suggest that senescent cell elimination may have benefits in COVID-19 and influenza resolution and disease prognosis. In this review, we discuss the current clinical trials and pre-clinical studies that are exploring the impact of senolytics on cellular immunity. We propose that while eliminating senescent cells may have an acute beneficial impact on primary immune responses, immunological memory may be negatively impacted. Closer investigation of senolytics on immune function and memory generation would provide insight as to whether senolytics could be used to enhance the aging immune system and have potential to be used as therapeutics or prophylactics in populations that are severely and disproportionately affected by infections such as the elderly and immunocompromised.
    Keywords:  D+Q; aging; fisetin; immune cells; immunosenescence; infection; senescence; senolytics
    DOI:  https://doi.org/10.3389/fragi.2023.1161799
  10. Int J Mol Sci. 2023 Oct 15. pii: 15199. [Epub ahead of print]24(20):
    A Narrative Review: The Effect and Importance of Carotenoids on Aging and Aging-Related Diseases.
    Elif Rabia Bakac, Ece Percin, Ayse Gunes-Bayir, Agnes Dadak.
      Aging is generally defined as a time-dependent functional decline that affects most living organisms. The positive increase in life expectancy has brought along aging-related diseases. Oxidative stress caused by the imbalance between pro-oxidants and antioxidants can be given as one of the causes of aging. At the same time, the increase in oxidative stress and reactive oxygen species (ROS) is main reason for the increase in aging-related diseases such as cardiovascular, neurodegenerative, liver, skin, and eye diseases and diabetes. Carotenoids, a natural compound, can be used to change the course of aging and aging-related diseases, thanks to their highly effective oxygen-quenching and ROS-scavenging properties. Therefore, in this narrative review, conducted using the PubMed, ScienceDirect, and Google Scholar databases and complying with the Scale for the Assessment of Narrative Review Articles (SANRA) guidelines, the effects of carotenoids on aging and aging-related diseases were analyzed. Carotenoids are fat-soluble, highly unsaturated pigments that occur naturally in plants, fungi, algae, and photosynthetic bacteria. A large number of works have been conducted on carotenoids in relation to aging and aging-related diseases. Animal and human studies have found that carotenoids can significantly reduce obesity and fatty liver, lower blood sugar, and improve liver fibrosis in cirrhosis, as well as reduce the risk of cardiovascular disease and erythema formation, while also lowering glycated hemoglobin and fasting plasma glucose levels. Carotenoid supplementation may be effective in preventing and delaying aging and aging-related diseases, preventing and treating eye fatigue and dry eye disease, and improving macular function. These pigments can be used to stop, delay, or treat aging-related diseases due to their powerful antioxidant, restorative, anti-proliferative, anti-inflammatory, and anti-aging properties. As an increasingly aging population emerges globally, this review could provide an important prospective contribution to public health.
    Keywords:  aging; aging-related diseases; antioxidant; carotenoids; oxidative stress; pro-oxidant
    DOI:  https://doi.org/10.3390/ijms242015199
  11. J Gerontol A Biol Sci Med Sci. 2023 Oct 27. pii: glad251. [Epub ahead of print]
    Temporal dynamics of epigenetic aging and frailty from midlife to old age.
    Jonathan K L Mak, Ida K Karlsson, Bowen Tang, Yunzhang Wang, Nancy L Pedersen, Sara Hägg, Juulia Jylhävä, Chandra A Reynolds.
      BACKGROUND: DNA methylation-derived epigenetic clocks and frailty are well-established biological age measures capturing different aging processes. However, whether they are dynamically linked to each other across chronological age remains poorly understood.METHODS: This analysis included 1,309 repeated measurements in 524 individuals aged 50 to 90 years from the Swedish Adoption/Twin Study of Aging. Frailty was measured using a validated 42-item frailty index (FI). Five epigenetic clocks were calculated, including four principal component (PC)-based clocks trained on chronological age (PCHorvathAge, PCHannumAge) and aging-related physiological conditions (PCPhenoAge, PCGrimAge), and a pace of aging clock (DunedinPACE). Using dual change score models, we examined the dynamic, bidirectional associations between each of the epigenetic clocks and the FI over age to test for potential causal associations.
    RESULTS: The FI exhibited a nonlinear, accelerated increase across the older adulthood, whereas the epigenetic clocks mostly increased linearly with age. For PCHorvathAge, PCHannumAge, PCPhenoAge, and PCGrimAge, their associations with the FI were primarily due to correlated levels at age 50 but with no evidence of a dynamic longitudinal association. In contrast, we observed a unidirectional association between DunedinPACE and the FI, where a higher DunedinPACE predicted a subsequent increase in the FI, but not vice versa.
    CONCLUSION: Our results highlight a temporal order between epigenetic aging and frailty such that changes in DunedinPACE precede changes in the FI. This potentially suggests that the pace of aging clock can be used as an early marker of the overall physiological decline at system level.
    Keywords:  DNA methylation; dual change score models; epigenetic clock; frailty; longitudinal
    DOI:  https://doi.org/10.1093/gerona/glad251
  12. Lab Anim (NY). 2023 Nov;52(11): 265
    Troubleshooting brain immunohistochemistry.
    Alexandra Le Bras.
      
    DOI:  https://doi.org/10.1038/s41684-023-01276-0
  13. Soft Matter. 2023 Oct 25.
    Unsynchronous conformational transitions induced by the asymmetric adsorption-response of an active diblock copolymer in an inert brush.
    Shuanhu Qi, Shuli Zhao, Zengju Lian.
      To exploit the chemical asymmetry of diblock copolymer chains on the design of high-performance switch sensors, we propose an analytically tractable model system which contains an adsorption-responsive diblock copolymer in an otherwise inert brush, and study its phase transitions by using both analytical theory and self-consistent field calculations. The copolymer chain is chemically asymmetric in the sense that the two blocks assume different adsorption strengths, which is characterized by the defined adsorption ratio. We found that the conformation states, the number of stable phases, and transition types are mainly controlled by the length of each block and the adsorption ratio. In particular, when the length of the ungrafted block is longer than the brush chains, and the adsorption ratio is smaller than a critical value, the copolymer chain shows three thermodynamically stable states, and undergoes two unsynchronous transitions, where the two blocks respond to the adsorption in a different manner, when the adsorption changes from weak to sufficiently strong. For this kind of three-state transition, the transition point, transition barrier, and transition width are evaluated by using the self-consistent field method, and their scaling relationship with respect to the system parameters is extracted, which matches reasonably well with the predictions from the analytical theory. The self-consistent field calculations also indicate that the conformational transitions involved in the three-state transition process are sharp with a low energy barrier, and interestingly, barrier-free transitions are observed. Our finding shows that the three-state transitions not only specify a region where high performance unsynchronous switch sensors can be exploited, but may also provide a useful model understanding the unsynchronous biological processes.
    DOI:  https://doi.org/10.1039/d3sm01040f
  14. Adv Biol (Weinh). 2023 Oct 25. e2300436
    Unique Patterns in Amino Acid Sequences of Aging-Related Proteins.
    Eszter Zita Szatmári, Attila Csordás, Csaba Kerepesi.
      Aging has strong genetic components and the list of genes that may regulate the aging process is collected in the GenAge database. There may be characteristic patterns in the amino acid sequences of aging-related proteins that distinguish them from other proteins and this information will lead to a better understanding of the aging process. To test this hypothesis, human protein sequences are extracted from the UniProt database and the relative frequency of every amino acid residue in aging-related proteins and the remaining proteins is calculated. The main observation is that the mean relative frequency of aspartic acid (D) is consistently higher, while the mean relative frequencies of tryptophan (W) and leucine (L) are consistently lower in aging-related proteins compared to the non-aging-related proteins for the human and four examined model organisms. It is also observed that the mean relative frequency of aspartic acid is higher, while the mean relative frequency of tryptophan is lower in pro-longevity proteins compared to anti-longevity proteins in model organisms. Finally, it is found that aging-related proteins tend to be longer than non-aging-related proteins. It is hoped that this analysis initiates further computational and experimental research to explore the underlying mechanisms of these findings.
    Keywords:  aging; aging-related proteins; amino acid sequence; aspartic acid; tryptophan
    DOI:  https://doi.org/10.1002/adbi.202300436
  15. Blood. 2023 10 26. 142(17): 1500
    T/myeloid MPAL with biallelic CEBPA mutations.
    Mojgan Zarif, Hong Chang.
      
    DOI:  https://doi.org/10.1182/blood.2023021647
  16. EMBO Rep. 2023 Oct 23. e57485
    Akkermansia muciniphila induces slow extramedullary hematopoiesis via cooperative IL-1R/TLR signals.
    Yuxin Wang, Tatsuya Morishima, Maiko Sezaki, Ryo Sato, Gaku Nakato, Shinji Fukuda, Kouji Kobiyama, Ken J Ishii, Yuhua Li, Hitoshi Takizawa.
      Bacterial infections can activate and mobilize hematopoietic stem and progenitor cells (HSPCs) from the bone marrow (BM) to the spleen, a process termed extramedullary hematopoiesis (EMH). Recent studies suggest that commensal bacteria regulate not only the host immune system but also hematopoietic homeostasis. However, the impact of gut microbes on hematopoietic pathology remains unclear. Here, we find that systemic single injections of Akkermansia muciniphila (A. m.), a mucin-degrading bacterium, rapidly activate BM myelopoiesis and slow but long-lasting hepato-splenomegaly, characterized by the expansion and differentiation of functional HSPCs, which we term delayed EMH. Mechanistically, delayed EMH triggered by A. m. is mediated entirely by the MYD88/TRIF innate immune signaling pathway, which persistently stimulates splenic myeloid cells to secrete interleukin (IL)-1α, and in turn, activates IL-1 receptor (IL-1R)-expressing splenic HSPCs. Genetic deletion of Toll-like receptor-2 and -4 (TLR2/4) or IL-1α partially diminishes A. m.-induced delayed EMH, while inhibition of both pathways alleviates splenomegaly and EMH. Our results demonstrate that cooperative IL-1R- and TLR-mediated signals regulate commensal bacteria-driven EMH, which might be relevant for certain autoimmune disorders.
    Keywords:  Akkermansia muciniphila; IL-1; TLR; extramedullary hematopoiesis; hematopoietic stem and progenitor cell
    DOI:  https://doi.org/10.15252/embr.202357485
  17. Cell Mol Biol Lett. 2023 Oct 27. 28(1): 88
    Cellular senescence in skeletal disease: mechanisms and treatment.
    Xu He, Wei Hu, Yuanshu Zhang, Mimi Chen, Yicheng Ding, Huilin Yang, Fan He, Qiaoli Gu, Qin Shi.
      The musculoskeletal system supports the movement of the entire body and provides blood production while acting as an endocrine organ. With aging, the balance of bone homeostasis is disrupted, leading to bone loss and degenerative diseases, such as osteoporosis, osteoarthritis, and intervertebral disc degeneration. Skeletal diseases have a profound impact on the motor and cognitive abilities of the elderly, thus creating a major challenge for both global health and the economy. Cellular senescence is caused by various genotoxic stressors and results in permanent cell cycle arrest, which is considered to be the underlying mechanism of aging. During aging, senescent cells (SnCs) tend to aggregate in the bone and trigger chronic inflammation by releasing senescence-associated secretory phenotypic factors. Multiple signalling pathways are involved in regulating cellular senescence in bone and bone marrow microenvironments. Targeted SnCs alleviate age-related degenerative diseases. However, the association between senescence and age-related diseases remains unclear. This review summarises the fundamental role of senescence in age-related skeletal diseases, highlights the signalling pathways that mediate senescence, and discusses potential therapeutic strategies for targeting SnCs.
    Keywords:  Age-related orthopaedic diseases; Bone marrow; Cellular senescence; Chronic inflammation; Signalling pathways
    DOI:  https://doi.org/10.1186/s11658-023-00501-5
  18. Mult Scler. 2023 Oct 25. 13524585231204122
    Biological aging in multiple sclerosis.
    Yinan Zhang, Jeffrey Atkinson, Christin E Burd, Jennifer Graves, Benjamin M Segal.
      Multiple sclerosis (MS) is most likely to adopt a progressive clinical course during middle age or beyond, and the number of older adults with MS is steadily increasing. Developing new strategies to manage progressive forms of MS, which do not respond to currently available disease-modifying therapies (DMTs), will require a deeper understanding of the mechanisms by which biological aging interacts with pathogenic pathways to propel disability accumulation. In experimental autoimmune encephalomyelitis (EAE), a widely used preclinical mouse model of MS, middle-aged animals experience a more severe and protracted clinical course than their younger counterparts. This exacerbated disease course is accompanied by persistent neuroinflammation. Clinical studies of age-related biomarkers, such as telomere length, senescence markers, and DNA methylation, suggest that biological aging is accelerated in people with MS compared with age- and sex-matched healthy controls. Furthermore, distinguishing biological age from chronological may afford more precision in determining aging effects in MS. Here we review the current literature on aging biology and its impact on MS pathogenesis. Future research on this topic may lead to the development of novel biomarkers and senotherapy agents that slow neurological decline in people with progressive MS by targeting relevant aging-related pathways.
    Keywords:  Animal model; biomarkers; immunology; multiple sclerosis; outcome measurement; progressive
    DOI:  https://doi.org/10.1177/13524585231204122
  19. Int J Mol Sci. 2023 Oct 18. pii: 15315. [Epub ahead of print]24(20):
    Vitamin D Improves Cognitive Impairment and Alleviates Ferroptosis via the Nrf2 Signaling Pathway in Aging Mice.
    Jiaxin Li, Yang Cao, Jie Xu, Jing Li, Chunmei Lv, Qiang Gao, Chi Zhang, Chongfei Jin, Ran Wang, Runsheng Jiao, Hui Zhu.
      Ferroptosis is an iron-dependent mode of cell death associated with the occurrence and development of age-related neurodegenerative diseases. Currently, there are no effective drugs available to prevent or treat these aging-related neurodegenerative diseases. Vitamin D (VD) is an antioxidant and immunomodulator, but its relationship with ferroptosis in aging-related neurodegenerative diseases has not been extensively studied. In this study, we aimed to investigate the role of VD in learning and memory in aging mice. To examine whether VD protects aging hippocampal neurons, we used physiologically active 1,25(OH)2D3. We established aging models in vivo (C57BL/6 mice) and in vitro (HT22 cells) using D-galactose (D-gal). The results demonstrated that VD could improve learning and memory in mice aged via the use of D-gal, and it reduced damage to hippocampal neurons. VD could regulate ferroptosis-related proteins (increasing GPX4 expression and decreasing ACSL4 and ALOX15 protein expression levels), increasing GSH levels, reducing MDA and intracellular and mitochondrial ROS levels, as well as total iron and Fe2+ levels, and improving mitochondrial morphology, thereby alleviating ferroptosis in aging hippocampal neurons. Additionally, VD activated the VDR/Nrf2/HO-1 signaling pathway, thereby inhibiting ferroptosis. Notably, when the VDR was knocked down, VD lost its ability to activate Nrf2. Consequently, inhibiting Nrf2 decreased the protective effect of VD against ferroptosis in aged hippocampal neurons. In summary, VD activates the Nrf2/HO-1 signaling pathway through the VDR, effectively preventing ferroptosis induced by aging in hippocampal neurons.
    Keywords:  aging; ferroptosis; neurodegenerative diseases; vitamin D
    DOI:  https://doi.org/10.3390/ijms242015315
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