bims-longev Biomed News
on Longevity
Issue of 2023–04–09
fourteen papers selected by
Andreea Nitescu
  1. Transcriptomic reprogramming for neuronal age reversal.
  2. Aging: Epigenetic modifications.
  3. The role of transposable elements in aging and cancer.
  4. Epitranscriptomics: new players in an old game.
  5. Mitochondria hormesis delays aging and associated diseases in Caenorhabditis elegans impacting on key ferroptosis players.
  6. Programmed versus non-programmed evolution of aging. What is the evidence?
  7. Age or lifestyle-induced accumulation of genotoxicity is associated with a length-dependent decrease in gene expression.
  8. Adiponectin deficiency accelerates brain aging via mitochondria-associated neuroinflammation.
  9. Anti-inflammaging effects of vitamin D in human gingival fibroblasts with advanced glycation end product stimulation.
  10. Molecular mechanisms of action of metformin: latest advances and therapeutic implications.
  11. The effect of the mindfulness-based interventions on inflammaging: Protocol for a systematic review and meta-analysis.
  12. Aging on the job? The association between occupational characteristics and accelerated biological aging.
  13. Multi-tissue DNA methylation aging clocks for sea lions, walruses and seals.
  14. Proteostasis networks in aging: novel insights from text-mining approaches.
  1. Hum Genet. 2023 Apr 01.
    Transcriptomic reprogramming for neuronal age reversal.
    Alexandru M Plesa, Michael Shadpour, Ed Boyden, George M Church.
      Aging is a progressive multifaceted functional decline of a biological system. Chronic age-related conditions such as neurodegenerative diseases are leading causes of death worldwide, and they are becoming a pressing problem for our society. To address this global challenge, there is a need for novel, safe, and effective rejuvenation therapies aimed at reversing age-related phenotypes and improving human health. With gene expression being a key determinant of cell identity and function, and in light of recent studies reporting rejuvenation effects through genetic perturbations, we propose an age reversal strategy focused on reprogramming the cell transcriptome to a youthful state. To this end, we suggest using transcriptomic data from primary human cells to predict rejuvenation targets and develop high-throughput aging assays, which can be used in large perturbation screens. We propose neural cells as particularly relevant targets for rejuvenation due to substantial impact of neurodegeneration on human frailty. Of all cell types in the brain, we argue that glutamatergic neurons, neuronal stem cells, and oligodendrocytes represent the most impactful and tractable targets. Lastly, we provide experimental designs for anti-aging reprogramming screens that will likely enable the development of neuronal age reversal therapies, which hold promise for dramatically improving human health.
    DOI:  https://doi.org/10.1007/s00439-023-02529-1
  2. Prog Mol Biol Transl Sci. 2023 ;pii: S1877-1173(23)00036-4. [Epub ahead of print]197 171-209
    Aging: Epigenetic modifications.
    Sarita Mishra, Mahima Raval, Akanksha Singh Kachhawaha, Budhi Sagar Tiwari, Anand Krishna Tiwari.
      Aging is one of the most complex and irreversible health conditions characterized by continuous decline in physical/mental activities that eventually poses an increased risk of several diseases and ultimately death. These conditions cannot be ignored by anyone but there are evidences that suggest that exercise, healthy diet and good routines may delay the Aging process significantly. Several studies have demonstrated that Epigenetics plays a key role in Aging and Aging-associated diseases through methylation of DNA, histone modification and non-coding RNA (ncRNA). Comprehension and relevant alterations in these epigenetic modifications can lead to new therapeutic avenues of age-delaying contrivances. These processes affect gene transcription, DNA replication and DNA repair, comprehending epigenetics as a key factor in understanding Aging and developing new avenues for delaying Aging, clinical advancements in ameliorating aging-related diseases and rejuvenating health. In the present article, we have described and advocated the epigenetic role in Aging and associated diseases.
    Keywords:  Age-related diseases; Aging; DNA methylation; Epigenetics; Histone modification; Neurodegenerative diseases; Non-coding RNA
    DOI:  https://doi.org/10.1016/bs.pmbts.2023.02.002
  3. Biogerontology. 2023 Apr 05.
    The role of transposable elements in aging and cancer.
    Pouria Mosaddeghi, Mitra Farahmandnejad, Mohammad M Zarshenas.
      Transposable elements (TEs) constitute a large portion of the human genome. Various mechanisms at the transcription and post-transcription levels developed to suppress TE activity in healthy conditions. However, a growing body of evidence suggests that TE dysregulation is involved in various human diseases, including age-related diseases and cancer. In this review, we explained how sensing TEs by the immune system could induce innate immune responses, chronic inflammation, and following age-related diseases. We also noted that inflammageing and exogenous carcinogens could trigger the upregulation of TEs in precancerous cells. Increased inflammation could enhance epigenetic plasticity and upregulation of early developmental TEs, which rewires the transcriptional networks and gift the survival advantage to the precancerous cells. In addition, upregulated TEs could induce genome instability, activation of oncogenes, or inhibition of tumor suppressors and consequent cancer initiation and progression. So, we suggest that TEs could be considered therapeutic targets in aging and cancer.
    Keywords:  Aging; Cancer; Inflammageing; Transposable elements
    DOI:  https://doi.org/10.1007/s10522-023-10028-z
  4. Biochem Soc Trans. 2023 Apr 04. pii: BST20221417. [Epub ahead of print]
    Epitranscriptomics: new players in an old game.
    Alba Coego, Helena Covelo-Molares, Diana Guallar.
      Ageing is a conserved and unavoidable biological process characterized by progressive decline of physiological functions with time. Despite constituting the greatest risk factor for most human diseases, little is known about the molecular mechanisms driving the ageing process. More than 170 chemical RNA modifications, also known as the epitranscriptome, decorate eukaryotic coding and non-coding RNAs and have emerged as novel regulators of RNA metabolism, modulating RNA stability, translation, splicing or non-coding RNA processing. Studies on short-lived organisms such as yeast or worms connect mutations on RNA modifying enzymes with lifespan changes, and dysregulation of the epitranscriptome has been linked to age-related diseases and ageing hallmarks themselves in mammals. Moreover, transcriptome-wide analyses are starting to reveal changes in messenger RNA modifications in neurodegenerative diseases and in the expression of some RNA modifiers with age. These studies are starting to put the focus on the epitranscriptome as a potential novel regulator of ageing and lifespan, and open new avenues for the identification of targets to treat age-related diseases. In this review, we discuss the connection between RNA modifications and the enzymatic machinery regulating their deposition in coding and non-coding RNAs, and ageing and hypothesize about the potential role of RNA modifications in the regulation of other ncRNAs playing a key role in ageing, such as transposable elements and tRNA fragments. Finally, we reanalyze available datasets of mouse tissues during ageing and report a wide transcriptional dysregulation of proteins involved in the deposition, removal or decoding of several of the best-known RNA modifications.
    Keywords:  5-methylcytosine; N6-methyladenosine; RNA modifications; age-related diseases; ageing hallmarks; epitranscriptome
    DOI:  https://doi.org/10.1042/BST20221417
  5. iScience. 2023 Apr 21. 26(4): 106448
    Mitochondria hormesis delays aging and associated diseases in Caenorhabditis elegans impacting on key ferroptosis players.
    Alfonso Schiavi, Eva Salveridou, Vanessa Brinkmann, Anjumara Shaik, Ralph Menzel, Sumana Kalyanasundaram, Ståle Nygård, Hilde Nilsen, Natascia Ventura.
      Excessive iron accumulation or deficiency leads to a variety of pathologies in humans and developmental arrest in the nematode Caenorhabditis elegans. Instead, sub-lethal iron depletion extends C. elegans lifespan. Hypoxia preconditioning protects against severe hypoxia-induced neuromuscular damage across species but it has low feasible application. In this study, we assessed the potential beneficial effects of genetic and chemical interventions acting via mild iron instead of oxygen depletion. We show that limiting iron availability in C. elegans through frataxin silencing or the iron chelator bipyridine, similar to hypoxia preconditioning, protects against hypoxia-, age-, and proteotoxicity-induced neuromuscular deficits. Mechanistically, our data suggest that the beneficial effects elicited by frataxin silencing are in part mediated by counteracting ferroptosis, a form of non-apoptotic cell death mediated by iron-induced lipid peroxidation. This is achieved by impacting on different key ferroptosis players and likely via gpx-independent redox systems. We thus point to ferroptosis inhibition as a novel potential strategy to promote healthy aging.
    Keywords:  Cell biology; Cellular neuroscience; Cellular physiology
    DOI:  https://doi.org/10.1016/j.isci.2023.106448
  6. Exp Gerontol. 2023 Apr 05. pii: S0531-5565(23)00083-9. [Epub ahead of print]175 112162
    Programmed versus non-programmed evolution of aging. What is the evidence?
    Reinald Pamplona, Mariona Jové, José Gómez, Gustavo Barja.
      The evolutionary meaning and basic molecular mechanisms involved in the determination of longevity remain an unresolved problem. Currently, different theories are on offer in response to these biological traits and to explain the enormous range of longevities observed in the animal kingdom. These theories may be grouped into those that defend non-programmed aging (non-PA) and those that propose the existence of programmed aging (PA). In the present article we examine many observational and experimental data from both the field and from the laboratory and sound reasoning accumulated in recent decades both compatible and not with PA and non-PA evolutionary theories of aging. These analyses are briefly summarized and discussed. Our conclusion is that most of the data favour programmed aging with a possible contribution of non-PA antagonist pleiotropy in various cases.
    Keywords:  Animal longevity; Evolution; Metabolic phenotypes; Pro-longevity dietary interventions; Rate of aging; Signalling pathways
    DOI:  https://doi.org/10.1016/j.exger.2023.112162
  7. iScience. 2023 Apr 21. 26(4): 106368
    Age or lifestyle-induced accumulation of genotoxicity is associated with a length-dependent decrease in gene expression.
    Olga Ibañez-Solé, Irantzu Barrio, Ander Izeta.
      DNA damage has long been advocated as a molecular driver of aging. DNA damage occurs in a stochastic manner, and is therefore more likely to accumulate in longer genes. The length-dependent accumulation of transcription-blocking damage, unlike that of somatic mutations, should be reflected in gene expression datasets of aging. We analyzed gene expression as a function of gene length in several single-cell RNA sequencing datasets of mouse and human aging. We found a pervasive age-associated length-dependent underexpression of genes across species, tissues, and cell types. Furthermore, we observed length-dependent underexpression associated with UV-radiation and smoke exposure, and in progeroid diseases, Cockayne syndrome, and trichothiodystrophy. Finally, we studied published gene sets showing global age-related changes. Genes underexpressed with aging were significantly longer than overexpressed genes. These data highlight a previously undetected hallmark of aging and show that accumulation of genotoxicity in long genes could lead to reduced RNA polymerase II processivity.
    Keywords:  Biological sciences; Molecular Genetics; Molecular biology; Omics; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2023.106368
  8. Immun Ageing. 2023 Apr 01. 20(1): 15
    Adiponectin deficiency accelerates brain aging via mitochondria-associated neuroinflammation.
    Kaiwu He, Lulin Nie, Tahir Ali, Zizhen Liu, Weifen Li, Ruyan Gao, Zena Zhang, Jianjun Liu, Zhongliang Dai, Yongmei Xie, Zaijun Zhang, Gongping Liu, Ming Dong, Zhi-Jian Yu, Shupeng Li, Xifei Yang.
       BACKGROUND: A wide spectrum of changes occurs in the brain with age, from molecular to morphological aspects, and inflammation accompanied by mitochondria dysfunction is one of the significant factors associated with age. Adiponectin (APN), an essential adipokine in glucose and lipid metabolism, is involved in the aging; however, its role in brain aging has not been adequately explored. Here, we aimed to explore the relationship between APN deficiency and brain aging using multiple biochemical and pharmacological methods to probe APN in humans, KO mice, primary microglia, and BV2 cells.
    RESULTS: We found that declining APN levels in aged human subjects correlated with dysregulated cytokine levels, while APN KO mice exhibited accelerated aging accompanied by learning and memory deficits, anxiety-like behaviors, neuroinflammation, and immunosenescence. APN-deficient mice displayed aggravated mitochondrial dysfunction and HDAC1 upregulation. In BV2 cells, the APN receptor agonist AdipoRon alleviated the mitochondrial deficits and aging markers induced by rotenone or antimycin A. HDAC1 antagonism by Compound 60 (Cpd 60) improved mitochondrial dysfunction and age-related inflammation, as validated in D-galactose-treated APN KO mice.
    CONCLUSION: These findings indicate that APN is a critical regulator of brain aging by preventing neuroinflammation associated with mitochondrial impairment via HDAC1 signaling.
    Keywords:  Adiponectin; Aging; BV2 Cells; HDAC1; Mitochondria; Neuroinflammation
    DOI:  https://doi.org/10.1186/s12979-023-00339-7
  9. J Dent Sci. 2023 Apr;18(2): 666-673
    Anti-inflammaging effects of vitamin D in human gingival fibroblasts with advanced glycation end product stimulation.
    Hung-Chieh Lu, Taichen Lin, Min Yee Ng, Chang-Wei Hsieh, Yi-Wen Liao, Chun-Cheng Chen, Cheng-Chia Yu, Chun-Jung Chen.
       Background/purpose: :Both periodontal disease and diabetes mellitus (DM) are long-term inflammatory disorders that are highly prevalent and have a significant health impact. Inflammaging, a state of pre-aging and hyperinflammatory state has been acknowledged for its role in DM patients to have heightened risk of periodontitis. Numerous evidences revealed that inflammaging contributed by cell senescence, acceleration of inflammation and oxidative stress participates in the destruction of periodontium in DM. Abilities of vitamin D in suppressing inflammation and oxidative stress have been revealed in a range of tissues, however in DM's gingival cells, the effect remain undefined.
    Materials and methods: : Under the stimulation of advanced glycation end-products (AGEs), we assessed the cell proliferation in human gingival fibroblast (HGF), IL-6 and IL-8 secretions, cellular senescence expression and generation of reactive oxygen species (ROS) with or without vitamin D intervention. Following that, we examined the expression of Nrf2 and HO-1 to see if vitamin D was able to modulate the anti-oxidant signaling. A knockdown experiment was then conducted to proof the participation of Nrf2 on the secretion of pro-inflammatory IL-6 and IL-8.
    Results: : Following the treatment of vitamin D, AGEs-elicited IL-6 and IL-8 production and cell senescence were dose-dependently repressed. Moreover, vitamin D attenuated AGEs-induced ROS in a dose-dependent pattern. Results from qRT-PCR demonstrated vitamin D reversed the suppression of Nrf2 and HO-1 induced by AGEs. Our findings revealed that the anti-inflammatory and anti-oxidant effect in vitamin D was mediated via the upregulation of Nrf2 expression.
    Conclusion: : These data showed that high levels of AGEs in the gingiva lead to inflammaging reflected by increased pro-inflammatory cytokines, cell senescence expression and oxidative stress. Vitamin D supplementation can reduce oxidative stress and inflammation via the upregulation of Nrf2 signaling and hence, may be a potential approach for treatment of diabetes-associated periodontitis.
    Keywords:  Advanced glycation end products; Periodontitis; Vitamin D
    DOI:  https://doi.org/10.1016/j.jds.2022.10.003
  10. Clin Exp Med. 2023 Apr 04.
    Molecular mechanisms of action of metformin: latest advances and therapeutic implications.
    Hong Zhu, Zhenquan Jia, Yunbo Robert Li, Igor Danelisen.
      Metformin is among the most widely used antidiabetic drugs. Studies over the past few years have identified multiple novel molecular targets and pathways that metformin acts on to exert its beneficial effects in treating type 2 diabetes as well as other disorders involving dysregulated inflammation and redox homeostasis. In this mini-review, we discuss the latest cutting-edge research discoveries on novel molecular targets of metformin in glycemic control, cardiovascular protection, cancer intervention, anti-inflammation, antiaging, and weight control. Identification of these novel targets and pathways not only deepens our understanding of the molecular mechanisms by which metformin exerts diverse beneficial biological effects, but also provides opportunities for developing new mechanistically based drugs for human diseases.
    Keywords:  Cardiovascular disease; Diabetes; Inflammation; Metformin; Mitochondria; Redox signaling
    DOI:  https://doi.org/10.1007/s10238-023-01051-y
  11. PLoS One. 2023 ;18(4): e0284228
    The effect of the mindfulness-based interventions on inflammaging: Protocol for a systematic review and meta-analysis.
    Jing Lv, Haining Peng, Tengbo Yu, Xiaohong Huang.
       BACKGROUND: Inflammaging, a chronic low-grade inflammation, is considered as the basis of age-related diseases. Mindfulness is involved in protecting telomeres, whose shortening causes aging. This paper reports a protocol for the meta-analysis and systematic review to bond the causality between the mindfulness practices and inflammaging responses according to the data collected from the relevant observational studies.
    METHODS AND ANALYSIS: The published studies during 2006-2023 will be identified from PubMed, Web of Science, Cochrane Central Register of Controlled Trials, and ProQuest Dissertation & Theses Global. The retrieved records will be screened independently by two researchers, and the relevant data will be extracted after reaching an agreement. The eligible studies will be analyzed with both of a meta-analysis and a narrative review. The risk of bias will be evaluated according to the Cochrane assessment for risk of biases. In the meta-analysis, random models will be applied to evaluate the effectiveness of mindfulness-based interventions on inflammaging due to the variation among studies. The dppc2 and Cohen's d will be calculated for synthesizing the evidences from the randomized controlled trials and intervention programs without a pretest-posttest design, respectively. The interstudy heterogeneity will be assessed with the Q test and quantified using I2 statistic. The subgroup analyses will be conducted against the categorical moderators and meta-regressions against the continuous ones. A narrative review will be recruited to deepen the understanding of the primary outcomes, in which consequential covariates with limited data in the bulk of reports will be included.
    TRIAL REGISTRATION: PROSPERO registration number CRD42022321766.
    DOI:  https://doi.org/10.1371/journal.pone.0284228
  12. J Gerontol B Psychol Sci Soc Sci. 2023 Apr 02. pii: gbad055. [Epub ahead of print]
    Aging on the job? The association between occupational characteristics and accelerated biological aging.
    Theresa Andrasfay, Jung Ki Kim, Jennifer A Ailshire, Eileen Crimmins.
       OBJECTIVES: There is a common belief that demanding jobs can make workers age faster, but there is little empirical evidence linking occupational characteristics to accelerated biological aging. We examine how occupational categorizations and self-reported working conditions are associated with expanded biological age, which incorporates 22 biomarkers and captures physiologic dysregulation throughout several bodily systems.
    METHODS: Data are from 1,133 participants in the Health and Retirement Study (HRS) who were aged 51-60 and working for pay in the 2010 or 2012 wave and who participated in the 2016 Venous Blood Study (VBS). We estimate associations between occupational category (professional/managerial, sales/clerical, service, and manual) and self-reported working conditions (psychosocial demands, job control, heavy lifting, and working 55 or more hours per week) and expanded biological age.
    RESULTS: Compared to same-age individuals working in professional or managerial positions, those working in service jobs appear 1.65 years older biologically even after adjusting for social and economic characteristics, self-reported working conditions, health insurance, and lifestyle-related risk factors. Low job control is associated with 1.40 years, heavy lifting with 2.08 years, and long working hours with 1.87 years of accelerated biological aging.
    DISCUSSION: Adverse occupational characteristics held at midlife, particularly service work, low job control, heavy lifting, and long work hours, are associated with accelerated biological aging. These findings suggest that work may be important for the overall aging process beyond its associations with specific diseases or risk factors.
    Keywords:  Work-related issues; biomarkers; functional age; psychosocial stress
    DOI:  https://doi.org/10.1093/geronb/gbad055
  13. Commun Biol. 2023 04 01. 6(1): 359
    Multi-tissue DNA methylation aging clocks for sea lions, walruses and seals.
    Todd R Robeck, Amin Haghani, Zhe Fei, Dana M Lindemann, Jennifer Russell, Kelsey E S Herrick, Gisele Montano, Karen J Steinman, Etsuko Katsumata, Joseph A Zoller, Steve Horvath.
      Age determination of wild animals, including pinnipeds, is critical for accurate population assessment and management. For most pinnipeds, current age estimation methodologies utilize tooth or bone sectioning which makes antemortem estimations problematic. We leveraged recent advances in the development of epigenetic age estimators (epigenetic clocks) to develop highly accurate pinniped epigenetic clocks. For clock development, we applied the mammalian methylation array to profile 37,492 cytosine-guanine sites (CpGs) across highly conserved stretches of DNA in blood and skin samples (n = 171) from primarily three pinniped species representing the three phylogenetic families: Otariidae, Phocidae and Odobenidae. We built an elastic net model with Leave-One-Out-Cross Validation (LOOCV) and one with a Leave-One-Species-Out-Cross-Validation (LOSOCV). After identifying the top 30 CpGs, the LOOCV produced a highly correlated (r = 0.95) and accurate (median absolute error = 1.7 years) age estimation clock. The LOSOCV elastic net results indicated that blood and skin clock (r = 0.84) and blood (r = 0.88) pinniped clocks could predict age of animals from pinniped species not used for clock development to within 3.6 and 4.4 years, respectively. These epigenetic clocks provide an improved and relatively non-invasive tool to determine age in skin or blood samples from all pinniped species.
    DOI:  https://doi.org/10.1038/s42003-023-04734-0
  14. Biogerontology. 2023 Apr 01.
    Proteostasis networks in aging: novel insights from text-mining approaches.
    Diogo Neves, Sara Duarte-Pereira, Sérgio Matos, Raquel M Silva.
      Aging is a topic of paramount importance in an increasingly elderly society and has been the focus of extensive research. Protein homeostasis (proteostasis) decline is a hallmark in aging and several age-related diseases, but which specific proteins and mechanisms are involved in proteostasis (de)regulation during the aging process remain largely unknown. Here, we used different text-mining tools complemented with protein-protein interaction data to address this complex topic. Analysis of the integrated protein interaction networks identified novel proteins and pathways associated to proteostasis mechanisms and aging or age-related disorders, indicating that this approach is useful to identify previously unknown links and for retrieving information of potential novel biomarkers or therapeutic targets.
    Keywords:  EGAS; Inflammasome; NAD metabolism; Protein aggregation; Protein–protein interactions
    DOI:  https://doi.org/10.1007/s10522-023-10027-0
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