bims-senagi Biomed News
on Senescence and aging
Issue of 2022–09–04
39 papers selected by
Maria Grazia Vizioli, Mayo Clinic
  1. Cathepsin F is a potential marker for senescent human skin fibroblasts and keratinocytes associated with skin aging.
  2. Nintedanib induces senolytic effect via STAT3 inhibition.
  3. DNA methylation changes and inflammaging in aging-associated diseases.
  4. Cellular senescence and cardiovascular diseases: moving to the "heart" of the problem.
  5. Senescence and cancer - role and therapeutic opportunities.
  6. Senescence plays a role in Myotonic Dystrophy type 1.
  7. Alterations in high-dimensional T-cell profile and gene signature of immune aging in HIV-infected older adults without viremia.
  8. Importance of Bmal1 in Alzheimer's disease and associated aging-related diseases: Mechanisms and interventions.
  9. BID- and BAX-mediated mitochondrial pathway dominates A-1331852-induced apoptosis in senescent A549 cells.
  10. Metformin prevents age-associated ovarian fibrosis by modulating the immune landscape in female mice.
  11. New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary.
  12. Production of MHCII-expressing classical monocytes increases during aging in mice and humans.
  13. Aging is accompanied by T-cell stiffening and reduced interstitial migration through dysfunctional nuclear organization.
  14. Mechanoimmunology: Are inflammatory epigenetic states of macrophages tuned by biophysical factors?
  15. RANKL down-regulates the mast cell proliferation through inducing senescence.
  16. Nanomedicines targeting the Inflammasome as a promising therapeutic approach for cell senescence.
  17. 3-Bromopyruvate, a caloric restriction mimetic, exerts a mitohormetic effect to provide neuroprotection through activation of autophagy in rats during aging.
  18. A senescence stress secretome is a hallmark of therapy-related myeloid neoplasm stromal tissue occurring soon after cytotoxic exposure.
  19. Alzheimer's Amyloid-β Accelerates Cell Senescence and Suppresses the SIRT1/NRF2 Pathway in Human Microglial Cells.
  20. Selenoproteins and the senescence-associated epitranscriptome.
  21. Somatic mutations in single human cardiomyocytes reveal age-associated DNA damage and widespread oxidative genotoxicity.
  22. Loss of seryl-tRNA synthetase (SARS1) causes complex spastic paraplegia and cellular senescence.
  23. Gut metabolite trimethylamine N-oxide induces aging-associated phenotype of midbrain organoids for the induced pluripotent stem cell-based modeling of late-onset disease.
  24. Nicotinamide mononucleotide alleviates osteoblast senescence induction and promotes bone healing in osteoporotic mice.
  25. Deubiquitinating enzyme USP11 promotes renal tubular cell senescence and fibrosis via inhibiting the ubiquitin degradation of TGF-β receptor II.
  26. IgD+ age-associated B cells are the progenitors of the main T-independent B cell response to infection that generates protective Ab and can be induced by an inactivated vaccine in the aged.
  27. Umbilical cord plasma concentrate has beneficial effects on DNA methylation GrimAge and human clinical biomarkers.
  28. Systemic lipolysis promotes physiological fitness in Drosophila melanogaster.
  29. As expected, based on rapamycin-like p53-mediated gerosuppression, mTOR inhibition acts as a checkpoint in p53-mediated tumor suppression.
  30. Alterations in bone metabolites with age in C57BL/6 mice model.
  31. A SPARC-ling link to inflammaging.
  32. Quick course of anti-ageing drug shows success.
  33. Deciphering clock genes as emerging targets against aging.
  34. Menaquinone-7 ameliorates cerebrovascular calcification-associated memory decline in aged mice.
  35. SIRT3 regulates mitochondrial biogenesis in aging-related diseases.
  36. Deconstructing PML-induced premature senescence.
  37. An integrative machine-learning meta-analysis of high-throughput omics data identifies age-specific hallmarks of Alzheimer's disease.
  38. The role of oxidative stress in ovarian aging: a review.
  39. S6 kinase 1 at the central node of cell size and ageing.
  1. Geroscience. 2022 Sep 03.
    Cathepsin F is a potential marker for senescent human skin fibroblasts and keratinocytes associated with skin aging.
    Kento Takaya, Toru Asou, Kazuo Kishi.
      Cellular senescence is characterized by cell cycle arrest and the senescence-associated secretory phenotype (SASP) and can be triggered by a variety of stimuli, including deoxyribonucleic acid (DNA) damage, oxidative stress, and telomere exhaustion. Cellular senescence is associated with skin aging, and identification of specific markers of senescent cells is essential for development of targeted therapies. Cathepsin F (CTSF) has been implicated in dermatitis and various cancers and participates in cell immortalization through its association with Bcl family proteins. It is a candidate therapeutic target to specifically label and eliminate human skin fibroblasts and keratinocytes immortalized by aging and achieve skin rejuvenation. In this study, we investigated whether CTSF is associated with senescence in human fibroblasts and keratinocytes. In senescence models, created using replicative aging, ionizing radiation exposure, and the anticancer drug doxorubicin, various senescence markers were observed, such as senescence-associated β-galactosidase (SA-β-gal) activity, increased SASP gene expression, and decreased uptake of the proliferation marker BrdU. Furthermore, CTSF expression was elevated at the gene and protein levels. In addition, CTSF-positive cells were abundant in aged human epidermis and in some parts of the dermis. In the population of senescent cells with arrested division, the number of CTSF-positive cells was significantly higher than that in the proliferating cell population. These results suggest that CTSF is a candidate for therapeutic modalities targeting aging fibroblasts and keratinocytes.
    Keywords:  Cathepsin; Cellular senescence; Fibroblast; Keratinocytes; Senescence-associated secretory phenotype; Skin aging
    DOI:  https://doi.org/10.1007/s11357-022-00648-7
  2. Cell Death Dis. 2022 Sep 02. 13(9): 760
    Nintedanib induces senolytic effect via STAT3 inhibition.
    Hyun-Ji Cho, Jeong-A Hwang, Eun Jae Yang, Eok-Cheon Kim, Jae-Ryong Kim, Sung Young Kim, Young Zoon Kim, Sang Chul Park, Young-Sam Lee.
      Selective removal of senescent cells, or senolytic therapy, has been proposed to be a potent strategy for overcoming age-related diseases and even for reversing aging. We found that nintedanib, a tyrosine kinase inhibitor, selectively induced the death of primary human dermal fibroblasts undergoing RS. Similar to ABT263, a well-known senolytic agent, nintedanib triggered intrinsic apoptosis in senescent cells. Additionally, at the concentration producing the senolytic effect, nintedanib arrested the cell cycle of nonsenescent cells in the G1 phase without inducing cytotoxicity. Interestingly, the mechanism by which nintedanib activated caspase-9 in the intrinsic apoptotic pathway differed from that of ABT263 apoptosis induction; specifically, nintedanib did not decrease the levels of Bcl-2 family proteins in senescent cells. Moreover, nintedanib suppressed the activation of the JAK2/STAT3 pathway, which caused the drug-induced death of senescent cells. STAT3 knockdown in senescent cells induced caspase activation. Moreover, nintedanib reduced the number of senescence-associated β-galactosidase-positive senescent cells in parallel with a reduction in STAT3 phosphorylation and ameliorated collagen deposition in a mouse model of bleomycin-induced lung fibrosis. Consistently, nintedanib exhibited a senolytic effect through bleomycin-induced senescence of human pulmonary fibroblasts. Overall, we found that nintedanib can be used as a new senolytic agent and that inhibiting STAT3 may be an approach for inducing the selective death of senescent cells. Our findings pave the way for expanding the senolytic toolkit for use in various aging statuses and age-related diseases.
    DOI:  https://doi.org/10.1038/s41419-022-05207-8
  3. Epigenomics. 2022 Aug 31.
    DNA methylation changes and inflammaging in aging-associated diseases.
    Mina Alimohammadi, Shima Makaremi, Ali Rahimi, Vahid Asghariazar, Mahdi Taghadosi, Elham Safarzadeh.
      Aging as an inevitable phenomenon is associated with pervasive changes in physiological functions. There is a relationship between aging and the increase of several chronic diseases. Most age-related disorders are accompanied by an underlying chronic inflammatory state, as demonstrated by local infiltration of inflammatory cells and greater levels of proinflammatory cytokines in the bloodstream. Within inflammaging, many epigenetic events, especially DNA methylation, change. During the aging process, due to aberrations of DNA methylation, biological processes are disrupted, leading to the emergence or progression of a variety of human diseases, including cancer, neurodegenerative disorders, cardiovascular disease and diabetes. The focus of this review is on DNA methylation, which is involved in inflammaging-related activities, and how its dysregulation leads to human disorders.
    Keywords:  DNA methylation; aging; aging-associated diseases; chronic inflammation; epigenetic alteration; inflammaging
    DOI:  https://doi.org/10.2217/epi-2022-0143
  4. Physiol Rev. 2022 Sep 01.
    Cellular senescence and cardiovascular diseases: moving to the "heart" of the problem.
    Konstantinos Evangelou, Panagiotis Vs Vasileiou, Angelos Papaspyropoulos, Orsalia Hazapis, Russell Petty, Marco Demaria, Vassilis G Gorgoulis.
      Cardiovascular diseases (CVDs) constitute the prime cause of global mortality with an immense impact on patient quality of life and disability. Clinical evidence has revealed a strong connection between cellular senescence and worse cardiac outcomes in the majority of CVDs concerning both ischemic and non-ischemic cardiomyopathies. Cellular senescence is characterized by cell cycle arrest accompanied by alterations in several metabolic pathways, resulting in morphological and functional changes. Metabolic rewiring of senescent cells results in marked paracrine activity, through a unique secretome, often exerting deleterious effects on neighboring cells. Here, we recapitulate the hallmarks and key molecular pathways involved in cellular senescence in the cardiac context and summarize the different roles of senescence in the majority of CVDs. In the last few years, the possibility of eliminating senescent cells in various pathological conditions is being increasingly explored, giving rise to the field of senotherapeutics. Therefore, we additionally attempt to clarifythe current state of this field with a focus on cardiac senescence, and discuss the potential of implementing senolytics as atreatment option in heart disease.
    Keywords:  Cardiovascular diseases; cellular senescence; senotherapeutics; stress
    DOI:  https://doi.org/10.1152/physrev.00007.2022
  5. Nat Rev Clin Oncol. 2022 Aug 31.
    Senescence and cancer - role and therapeutic opportunities.
    Clemens A Schmitt, Boshi Wang, Marco Demaria.
      Cellular senescence is a state of stable, terminal cell cycle arrest associated with various macromolecular changes and a hypersecretory, pro-inflammatory phenotype. Entry of cells into senescence can act as a barrier to tumorigenesis and, thus, could in principle constitute a desired outcome for any anticancer therapy. Paradoxically, studies published in the past decade have demonstrated that, in certain conditions and contexts, malignant and non-malignant cells with lastingly persistent senescence can acquire pro-tumorigenic properties. In this Review, we first discuss the major mechanisms involved in the antitumorigenic functions of senescent cells and then consider the cell-intrinsic and cell-extrinsic factors that participate in their switch towards a tumour-promoting role, providing an overview of major translational and emerging clinical findings. Finally, we comprehensively describe various senolytic and senomorphic therapies and their potential to benefit patients with cancer.
    DOI:  https://doi.org/10.1038/s41571-022-00668-4
  6. JCI Insight. 2022 Aug 30. pii: e159357. [Epub ahead of print]
    Senescence plays a role in Myotonic Dystrophy type 1.
    Mikel García-Puga, Ander Saenz-Antoñanzas, Gorka Gerenu, Alex Arrieta, Roberto Fernandez-Torron, Miren Zulaica, Amets Saenz, Joseba Elizazu, Gisela Nogales-Gadea, Shahinaz M Gadalla, Marcos J Araúzo-Bravo, Adolfo Lopez de Munain, Ander Matheu.
      Myotonic dystrophy type 1 (DM1; MIM #160900) is an autosomal dominant disorder, clinically characterized by progressive muscular weakness and multisystem degeneration. The broad phenotypes observed in DM1 patients resemble the appearance of an accelerated aging process. However, the molecular mechanisms underlying these phenotypes remain largely unknown. Transcriptomic analysis of fibroblasts derived from DM1 patients and healthy individuals revealed a decrease in cell cycle activity, cell division, and DNA damage response in DM1, all of which related to the accumulation of cellular senescence. The data from transcriptome analyses were corroborated in human myoblasts and blood samples as well as in mouse and Drosophila models of the disease. Serial passage studies in vitro confirmed the accelerated increase in senescence and the acquisition of a senescence-associated secretory phenotype in DM1 fibroblasts, whereas DM1 Drosophila model showed reduced longevity and impaired locomotor activity. Moreover, functional studies highlighted the impact of BMI1 and downstream p16INK4A/RB and ARF/p53/p21CIP pathways in DM1-associated cellular phenotypes. Importantly, treatment with the senolytic compounds, Quercetin, Dasatinib, or Navitoclax, reversed the accelerated aging phenotypes in both DM1 fibroblasts in vitro and in Drosophila in vivo. Our results identified the accumulation of senescence as part of DM1 pathophysiology and therefore, demonstrated the efficacy of senolytic compounds in the pre-clinical setting.
    Keywords:  Aging; Cell Biology; Cellular senescence; Drug therapy; Neuromuscular disease
    DOI:  https://doi.org/10.1172/jci.insight.159357
  7. Aging Cell. 2022 Aug 29. e13702
    Alterations in high-dimensional T-cell profile and gene signature of immune aging in HIV-infected older adults without viremia.
    Min Sun Shin, Hong-Jai Park, Syim Salahuddin, Ruth R Montgomery, Brinda Emu, Albert C Shaw, Insoo Kang.
      Alterations in the components of the immune system occur with aging. The introduction of combination antiretroviral therapy (ART) has dramatically improved life expectancy in human immunodeficiency virus (HIV) infected individuals by suppressing viral replication and increasing CD4+ T-cell counts. Immunosenescence-like changes, including the expansion of memory CD8+ T cells with senescent features, are reported in young HIV-infected individuals who do not have clinically detectable viremia on ART. However, it is less known whether HIV infection affects the immunosenescent status in older HIV-infected individuals. Here, we addressed this question in older HIV-infected, HIV-uninfected, and frail individuals (all groups age ≥65 years) by examining a set of aging-associated genes in peripheral blood mononuclear cells (PBMCs) as well as by analyzing subsets of CD4+ and CD8+ T cells in depth using high-dimensional CyTOF analysis. Older HIV-infected individuals had increased expression of aging-associated genes such as CX3CR1 in PBMCs which are related to IL-7 receptor low effector memory (IL-7Rαlow EM) CD8+ T cells, a cell population known to expand with age. The subsets of IL-7Rαlow EM CD8+ T cells expressing senescent, cytotoxic, and inflammatory molecules, including CD57, perforin, and CX3CR1, as well as memory CD4+ T cells expressing CD161 and CXCR3, molecules associated with replication-competent HIV-1 harboring cells, were increased in older HIV-infected individuals. Overall, older HIV-infected individuals without detectable viremia on ART had augmented levels of age-associated immune alterations in PBMCs, suggesting that HIV infection has a persistent impact on senescence in older HIV-infected individuals despite the clinically controlled viremia.
    Keywords:  T cells; age; gene expression; human; human immunodeficiency virus (HIV)
    DOI:  https://doi.org/10.1111/acel.13702
  8. Aging Cell. 2022 Sep 03. e13704
    Importance of Bmal1 in Alzheimer's disease and associated aging-related diseases: Mechanisms and interventions.
    Rongping Fan, Xuemin Peng, Lei Xie, Kun Dong, Delin Ma, Weijie Xu, Xiaoli Shi, Shujun Zhang, Juan Chen, Xuefeng Yu, Yan Yang.
      With the aging world population, the prevalence of aging-related disorders is on the rise. Diseases such as Alzheimer's, type 2 diabetes mellitus (T2DM), Parkinson's, atherosclerosis, hypertension, and osteoarthritis are age-related, and most of these diseases are comorbidities or risk factors for AD; however, our understandings of molecular events that regulate the occurrence of these diseases are still not fully understood. Brain and muscle Arnt-like protein-1 (Bmal1) is an irreplaceable clock gene that governs multiple important physiological processes. Continuous research of Bmal1 in AD and associated aging-related diseases is ongoing, and this review picks relevant studies on a detailed account of its role and mechanisms in these diseases. Oxidative stress and inflammation turned out to be common mechanisms by which Bmal1 deficiency promotes AD and associated aging-related diseases, and other Bmal1-dependent mechanisms remain to be identified. Promising therapeutic strategies involved in the regulation of Bmal1 are provided, including melatonin, natural compounds, metformin, d-Ser2-oxyntomodulin, and other interventions, such as exercise, time-restricted feeding, and adiponectin. The establishment of the signaling pathway network for Bmal1 in aging-related diseases will lead to advances in the comprehension of the molecular and cellular mechanisms, shedding light on novel treatments for aging-related diseases and promoting aging-associated brain health.
    Keywords:  ARNTL transcription factors; Alzheimer disease; Parkinson disease; atherosclerosis; diabetes mellitus, type 2; osteoarthritis
    DOI:  https://doi.org/10.1111/acel.13704
  9. Biochem Biophys Res Commun. 2022 Aug 18. pii: S0006-291X(22)01136-6. [Epub ahead of print]627 160-167
    BID- and BAX-mediated mitochondrial pathway dominates A-1331852-induced apoptosis in senescent A549 cells.
    Guihao Wu, Xin Li, Yongtong Zhan, Xuhong Fan, Lingjun Xu, Tongsheng Chen, Xiaoping Wang.
      Recovered senescent tumor cells harbor higher migration and invasion potential, owing to which they play a crucial role in tumor recurrence and drug resistance. The aim of this study was to explore the ability of BH3 mimetics in clearing senescent A549 cells and elucidate their underlying killing mechanism. Doxorubicin-induced cell senescence was determined using augmented senescence-associated beta-galactosidase (SA-β-Gal) staining and increased P16 expression. CCK-8 and crystal violet staining demonstrated that A-1331852, BH3 mimetic, could kill senescent tumor cells without affecting the proliferating cells. A-1331852 induced caspase-dependent senescent cell death accompanied by nuclear concentration, decreased mitochondrial membrane potential, and cleavage of poly (ADP-ribose) polymerase. Most importantly, A-1331852 upregulated the expression of BID and BAX indicating their role in mediating A-1331852-induced apoptosis in senescent A549 cells. The results of fluorescence resonance energy transfer showed that A-1331852 loosened or even released the binding between BCL-xL and tBID, releasing tBID. In addition, A-1331852 also dissociated the binding between BCL-xL and BAX, eventually leading to BAX oligomerization in the mitochondria, and resulting in apoptosis via the mitochondrial pathway. In conclusion, our data demonstrate for the first time that A-1331852 promotes apoptosis of senescent A549 cells by influencing the interaction between BCL-xL and tBID and that between BCL-xL and BAX.
    Keywords:  A-1331852; A549; BAX; BID; Senescence
    DOI:  https://doi.org/10.1016/j.bbrc.2022.08.023
  10. Sci Adv. 2022 Sep 02. 8(35): eabq1475
    Metformin prevents age-associated ovarian fibrosis by modulating the immune landscape in female mice.
    David A Landry, Edward Yakubovich, David P Cook, Sijyl Fasih, Jeremy Upham, Barbara C Vanderhyden.
      Ovarian fibrosis is a pathological condition associated with aging and is responsible for a variety of ovarian dysfunctions. Given the known contributions of tissue fibrosis to tumorigenesis, it is anticipated that ovarian fibrosis may contribute to ovarian cancer risk. We recently reported that diabetic postmenopausal women using metformin had ovarian collagen abundance and organization that were similar to premenopausal ovaries from nondiabetic women. In this study, we investigated the effects of aging and metformin on mouse ovarian fibrosis at a single-cell level. We discovered that metformin treatment prevented age-associated ovarian fibrosis by modulating the proportion of fibroblasts, myofibroblasts, and immune cells. Senescence-associated secretory phenotype (SASP)-producing fibroblasts increased in aged ovaries, and a unique metformin-responsive subpopulation of macrophages emerged in aged mice treated with metformin. The results demonstrate that metformin can modulate specific populations of immune cells and fibroblasts to prevent age-associated ovarian fibrosis and offers a new strategy to prevent ovarian fibrosis.
    DOI:  https://doi.org/10.1126/sciadv.abq1475
  11. Aging (Albany NY). 2022 Aug 29. 14(undefined):
    New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary.
    Tomas Schmauck-Medina, Adrian Molière, Sofie Lautrup, Jianying Zhang, Stefan Chlopicki, Helena Borland Madsen, Shuqin Cao, Casper Soendenbroe, Els Mansell, Mark Bitsch Vestergaard, Zhiquan Li, Yosef Shiloh, Patricia L Opresko, Jean-Marc Egly, Thomas Kirkwood, Eric Verdin, Vilhelm A Bohr, Lynne S Cox, Tinna Stevnsner, Lene Juel Rasmussen, Evandro F Fang.
      Genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, loss of proteostasis, deregulated nutrient-sensing, cellular senescence, stem cell exhaustion, and altered intercellular communication were the original nine hallmarks of ageing proposed by López-Otín and colleagues in 2013. The proposal of these hallmarks of ageing has been instrumental in guiding and pushing forward research on the biology of ageing. In the nearly past 10 years, our in-depth exploration on ageing research has enabled us to formulate new hallmarks of ageing which are compromised autophagy, microbiome disturbance, altered mechanical properties, splicing dysregulation, and inflammation, among other emerging ones. Amalgamation of the 'old' and 'new' hallmarks of ageing may provide a more comprehensive explanation of ageing and age-related diseases, shedding light on interventional and therapeutic studies to achieve healthy, happy, and productive lives in the elderly.
    Keywords:  autophagy; hallmarks of ageing; healthspan; longevity; neurodegeneration
    DOI:  https://doi.org/10.18632/aging.204248
  12. Aging Cell. 2022 Aug 30. e13701
    Production of MHCII-expressing classical monocytes increases during aging in mice and humans.
    Pijus K Barman, Juliana E Shin, Sloan A Lewis, Seokjo Kang, Di Wu, Yizhou Wang, Xiaoming Yang, Prakash S Nagarkatti, Mitzi Nagarkatti, Ilhem Messaoudi, Bérénice A Benayoun, Helen S Goodridge.
      Aging is associated with increased monocyte production and altered monocyte function. Classical monocytes are heterogenous and a shift in their subset composition may underlie some of their apparent functional changes during aging. We have previously shown that mouse granulocyte-monocyte progenitors (GMPs) produce "neutrophil-like" monocytes (NeuMo), whereas monocyte-dendritic cell progenitors (MDPs) produce monocyte-derived dendritic cell (moDC)-producing monocytes (DCMo). Here, we demonstrate that classical monocytes from the bone marrow of old male and female mice have higher expression of DCMo signature genes (H2-Aa, H2-Ab1, H2-Eb1, Cd74), and that more classical monocytes express MHCII and CD74 protein. Moreover, we show that bone marrow MDPs and classical monocytes from old mice yield more moDC. We also demonstrate higher expression of Aw112010 in old monocytes and that Aw112010 lncRNA activity regulates MHCII induction in macrophages, which suggests that elevated Aw112010 levels may underlie increased MHCII expression during monocyte aging. Finally, we show that classical monocyte expression of MHCII is also elevated during healthy aging in humans. Thus, aging-associated changes in monocyte production may underlie altered monocyte function and have implications for aging-associated disorders.
    Keywords:  aging; bone marrow progenitors; monocytes
    DOI:  https://doi.org/10.1111/acel.13701
  13. Immunology. 2022 Aug 04.
    Aging is accompanied by T-cell stiffening and reduced interstitial migration through dysfunctional nuclear organization.
    Blanca González-Bermúdez, Hikaru Kobayashi, Aldo Abarca-Ortega, Miguel Córcoles-Lucas, Mónica González-Sánchez, Mónica De la Fuente, Gustavo V Guinea, Manuel Elices, Gustavo R Plaza.
      Age-associated changes in T-cell function play a central role in immunosenescence. The role of aging in the decreased T-cell repertoire, primarily because of thymic involution, has been extensively studied. However, increasing evidence indicates that aging also modulates the mechanical properties of cells and the internal ordering of diverse cell components. Cellular functions are generally dictated by the biophysical phenotype of cells, which itself is also tightly regulated at the molecular level. Based on previous evidence suggesting that the relative nuclear size contributes to variations of T-cell stiffness, here we examined whether age-associated changes in T-cell migration are dictated by biophysical parameters, in part through nuclear cytoskeleton organization and cell deformability. In this study, we first performed longitudinal analyses of a repertoire of 111 functional, biophysical and biomolecular features of the nucleus and cytoskeleton of mice CD4+ and CD8+ T cells, in both naive and memory state. Focusing on the pairwise correlations, we found that age-related changes in nuclear architecture and internal ordering were correlated with T-cell stiffening and declined interstitial migration. A similarity analysis confirmed that cell-to-cell variation was a direct result of the aging process and we applied regression models to identify biomarkers that can accurately estimate individuals' age. Finally, we propose a biophysical model for a comprehensive understanding of the results: aging involves an evolution of the relative nuclear size, in part through DNA-hypomethylation and nuclear lamin B1, which implies an increased cell stiffness, thus inducing a decline in cell migration.
    Keywords:  CD4 cell; CD8 cell; T cell; aging
    DOI:  https://doi.org/10.1111/imm.13559
  14. APL Bioeng. 2022 Sep;6(3): 031502
    Mechanoimmunology: Are inflammatory epigenetic states of macrophages tuned by biophysical factors?
    Nikhil Jain, Janet M Lord, Viola Vogel.
      Many inflammatory diseases that are responsible for a majority of deaths are still uncurable, in part as the underpinning pathomechanisms and how to combat them is still poorly understood. Tissue-resident macrophages play pivotal roles in the maintenance of tissue homeostasis, but if they gradually convert to proinflammatory phenotypes, or if blood-born proinflammatory macrophages persist long-term after activation, they contribute to chronic inflammation and fibrosis. While biochemical factors and how they regulate the inflammatory transcriptional response of macrophages have been at the forefront of research to identify targets for therapeutic interventions, evidence is increasing that physical factors also tune the macrophage phenotype. Recently, several mechanisms have emerged as to how physical factors impact the mechanobiology of macrophages, from the nuclear translocation of transcription factors to epigenetic modifications, perhaps even DNA methylation. Insight into the mechanobiology of macrophages and associated epigenetic modifications will deliver novel therapeutic options going forward, particularly in the context of increased inflammation with advancing age and age-related diseases. We review here how biophysical factors can co-regulate pro-inflammatory gene expression and epigenetic modifications and identify knowledge gaps that require urgent attention if this therapeutic potential is to be realized.
    DOI:  https://doi.org/10.1063/5.0087699
  15. Cytokine. 2022 Aug 30. pii: S1043-4666(22)00227-7. [Epub ahead of print]159 156018
    RANKL down-regulates the mast cell proliferation through inducing senescence.
    Jin-Ho Lim, Hee-Yun Kim, Ho-Geun Kang, Hyun-Ja Jeong, Hyung-Min Kim.
      An increase in the number of mast cells could contribute to inflammatory diseases and pathologic conditions. A receptor activator of NF-κB ligand (RANKL)/RANK system is one of the key signaling pathways accelerating mast cell-mediated allergic inflammatory reactions. However, the biological functions of RANKL in mast cell proliferation remains to be clarified. The aim of the present study is to clarify the role of RANKL in mast cell proliferation. Surprisingly, RANKL remarkably reduced the proliferation of human mast cell line, HMC-1 cells through the inhibition of murine double minute 2 (MDM2) and Ki-67 mRNA expressions in a dose-dependent manner. RANKL significantly reduced cell viability, whereas it increased cellular senescence via increasing levels of p53, phosphorylated(p)-p53, p21, and p16 and decreasing levels of retinoblastoma protein (pRb) and p-pRb in HMC-1 cells. Even in rat peritoneal mast cells, RANKL induced cellular senescence by increasing filamentous-actin polymerization. In addition, RANKL remarkably reduced thymic stromal lymphopoietin (TSLP)-induced mast cell proliferation via the downregulation of MDM2 and Ki-67. RANKL decreased levels of p-signal transducer and activator of transcription 6 in TSLP-stimulated HMC-1 cells. The mast cell growth factor, interleukin-13 was remarkably down-regulated by treatment with RANKL in TSLP-stimulated HMC-1 cells. Furthermore, RANKL increased the number of senescence-associated β-galactosidase-stained cells and protein levels of p53, p-p53, and p21 in TSLP-stimulated HMC-1 cells. These data suggest that RANKL down-regulates mast cell proliferation by inducing senescence.
    Keywords:  Mast cell; Proliferation; RANKL; Senescence; TSLP
    DOI:  https://doi.org/10.1016/j.cyto.2022.156018
  16. Semin Cancer Biol. 2022 Aug 24. pii: S1044-579X(22)00194-8. [Epub ahead of print]
    Nanomedicines targeting the Inflammasome as a promising therapeutic approach for cell senescence.
    Swati Chaturvedi, Zaiba Naseem, Sherif F El-Khamisy, Muhammad Wahajuddin.
      Technological advancements in the present era have enhanced drug discovery and development. Nanomedicines are valuable pharmacotherapeutic tools against several diseases and disorders including aging related disorders. The mechanistic association between nanomedicines and molecular modulation have been investigated by many researchers. Notwithstanding the availability of tremendous amount of data, role of nanomedicines in aging related disorders intending inflammasome transfiguration have not been thoroughly reviewed till now. In the present review, we discuss the application of nanomedicines in aging related disorders. Further, we highlight the recent updates on modulated upstream and downstream signalling molecules of inflammasome cascade due to nanomedicines. The review will benefit researchers targeting nanomedicines as a therapeutic approach towards treatment age related disorders through inflammasome inflection.
    Keywords:  Nanomedicine; ageing; drug discovery; inflammasome; neurodegeneration
    DOI:  https://doi.org/10.1016/j.semcancer.2022.08.008
  17. Biogerontology. 2022 Sep 01.
    3-Bromopyruvate, a caloric restriction mimetic, exerts a mitohormetic effect to provide neuroprotection through activation of autophagy in rats during aging.
    Jitendra Kumar Arya, Raushan Kumar, Shambhoo Sharan Tripathi, Syed Ibrahim Rizvi.
      In the present study, attempts have been made to evaluate the potential role of 3 Bromopyruvate (3-BP) a glycolytic inhibitor and a caloric restriction mimetic (CRM), to exert neuroprotection in rats during aging through modulation of autophagy. Young male rats (4 months), and naturally aged (22 months) male rats were supplemented with 3-BP (30 mg/kg b.w., orally) for 28 days. Our results demonstrate a significant increase in the antioxidant biomarkers (ferric reducing antioxidant potential level, total thiol, superoxide dismutase, and catalase activities) and a decrease in the level of pro-oxidant biomarkers such as protein carbonyl after 3-BP supplementation in brain tissues. A significant increase in reactive oxygen species (ROS) was observed due to the mitohormetic effect of 3-BP supplementation in the treated rats. Furthermore, the 3-BP treatment also enhanced the activities of electron transport chain complexes I and IV in aged brain mitochondria thus proving its antioxidant potential at the level of mitochondria. Gene expression analysis with reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to assess the expression of autophagy, neuroprotective and aging marker genes. RT-PCR data revealed that 3-BP up-regulated the expression of autophagy markers genes (Beclin-1 and LC3 β), sirtuin-1, and neuronal marker gene (NSE), respectively in the aging brain. The results suggest that 3-BP induces a mitohormetic effect through the elevation of ROS which reinforces defensive mechanism(s) targeted at regulating autophagy. These findings suggest that consistently low-dose 3-BP may be beneficial for neuroprotection during aging and age-related disorders.
    Keywords:  3-Bromopyruvate; Autophagy; Mitohormesis; Neuroprotection; Reactive oxygen species
    DOI:  https://doi.org/10.1007/s10522-022-09988-5
  18. Leukemia. 2022 Aug 29.
    A senescence stress secretome is a hallmark of therapy-related myeloid neoplasm stromal tissue occurring soon after cytotoxic exposure.
    Monika M Kutyna, Chung Hoow Kok, Yoon Lim, Elizabeth Ngoc Hoa Tran, David Campbell, Sharon Paton, Chloe Thompson-Peach, Kelly Lim, Dimitrios Cakouros, Agnes Arthur, Timothy Hughes, Sharad Kumar, Daniel Thomas, Stan Gronthos, Devendra K Hiwase.
      Therapy-related myeloid neoplasm (tMN) is considered a direct consequence of DNA damage in hematopoietic stem cells. Despite increasing recognition that altered stroma can also drive leukemogenesis, the functional biology of the tMN microenvironment remains unknown. We performed multiomic (transcriptome, DNA damage response, cytokine secretome and functional profiling) characterization of bone marrow stromal cells from tMN patients. Critically, we also compared (i) patients with myeloid neoplasm and another cancer but without cytotoxic exposure, (ii) typical primary myeloid neoplasm, and (iii) age-matched controls to decipher the microenvironmental changes induced by cytotoxics vs. neoplasia. Strikingly, tMN exhibited a profoundly senescent phenotype with induction of CDKN1A and β-Galactosidase, defective phenotype, and proliferation. Moreover, tMN stroma showed delayed DNA repair and defective adipogenesis. Despite their dormant state, tMN stromal cells were metabolically highly active with a switch toward glycolysis and secreted multiple pro-inflammatory cytokines indicative of a senescent-secretory phenotype that inhibited adipogenesis. Critically, senolytics not only eliminated dormant cells, but also restored adipogenesis. Finally, sequential patient sampling showed senescence phenotypes are induced within months of cytotoxic exposure, well prior to the onset of secondary cancer. Our data underscores a role of senescence in the pathogenesis of tMN and provide a valuable resource for future therapeutics.
    DOI:  https://doi.org/10.1038/s41375-022-01686-y
  19. Oxid Med Cell Longev. 2022 ;2022 3086010
    Alzheimer's Amyloid-β Accelerates Cell Senescence and Suppresses the SIRT1/NRF2 Pathway in Human Microglial Cells.
    Yuqian An, Yi Li, Yujun Hou, Shichao Huang, Gang Pei.
      Microglia play important roles in maintenance of brain homeostasis, while due to some pathological stimuli in aging-related neurodegenerative diseases including Alzheimer's disease, they are malfunctioning. Here, we demonstrated that amyloid-β (Aβ) accelerated cell senescence characterized by the upregulation of p21 and PAI-1 as well as senescence-associated beta-galactosidase (SA-β-gal) in human microglial cells. Consistently, Aβ induced the senescence-associated mitochondrial dysfunctions such as repression of ATP production, oxygen consumption rate (OCR), and mitochondrial membrane potential and enhancement of ROS production. Furthermore, Aβ was found to significantly suppress mRNA expression and protein level of Sirtuin-1 (SIRT1), a key regulator of senescence, and inhibit mRNA expression and translocation of NRF2, a critical transcription factor in inflammatory responses, leading to impairment of phagocytosis. Rescue of SIRT1, as expected, could counteract the pathological effects of Aβ. In summary, our findings revealed that Aβ accelerates human microglial senescence mainly through its suppression of the SIRT1/NRF2 pathway and suggested that genetic and pharmaceutical rescue of SIRT1 may provide a potential alternative treatment.
    DOI:  https://doi.org/10.1155/2022/3086010
  20. Exp Biol Med (Maywood). 2022 Aug 29. 15353702221116592
    Selenoproteins and the senescence-associated epitranscriptome.
    May Y Lee, Stephen Ojeda-Britez, Dylan Ehrbar, Antonia Samwer, Thomas J Begley, J Andres Melendez.
      Selenium is a naturally found trace element, which provides multiple benefits including antioxidant, anticancer, and antiaging, as well as boosting immunity. One unique feature of selenium is its incorporation as selenocysteine, a rare 21st amino acid, into selenoproteins. Twenty-five human selenoproteins have been discovered, and a majority of these serve as crucial antioxidant enzymes for redox homeostasis. Unlike other amino acids, incorporation of selenocysteine requires a distinctive UGA stop codon recoding mechanism. Although many studies correlating selenium, selenoproteins, aging, and senescence have been performed, it has not yet been explored if the upstream events regulating selenoprotein synthesis play a role in senescence-associated pathologies. The epitranscriptomic writer alkylation repair homolog 8 (ALKBH8) is critical for selenoprotein production, and its deficiency can significantly decrease levels of selenoproteins that are essential for reactive oxygen species (ROS) detoxification, and increase oxidative stress, one of the major drivers of cellular senescence. Here, we review the potential role of epitranscriptomic marks that govern selenocysteine utilization in regulating the senescence program.
    Keywords:  RNA modifications; SASP; Senescence; selenium; selenoproteins
    DOI:  https://doi.org/10.1177/15353702221116592
  21. Nat Aging. 2022 Aug;2(8): 714-725
    Somatic mutations in single human cardiomyocytes reveal age-associated DNA damage and widespread oxidative genotoxicity.
    Sangita Choudhury, August Yue Huang, Junho Kim, Zinan Zhou, Katherine Morillo, Eduardo A Maury, Jessica W Tsai, Michael B Miller, Michael A Lodato, Sarah Araten, Nazia Hilal, Eunjung Alice Lee, Ming Hui Chen, Christopher A Walsh.
      The accumulation of somatic DNA mutations over time is a hallmark of aging in many dividing and nondividing cells but has not been studied in postmitotic human cardiomyocytes. Using single-cell whole-genome sequencing, we identified and characterized the landscape of somatic single-nucleotide variants (sSNVs) in 56 single cardiomyocytes from 12 individuals (aged from 0.4 to 82 years). Cardiomyocyte sSNVs accumulate with age at rates that are faster than in many dividing cell types and nondividing neurons. Cardiomyocyte sSNVs show distinctive mutational signatures that implicate failed nucleotide excision repair and base excision repair of oxidative DNA damage, and defective mismatch repair. Since age-accumulated sSNVs create many damaging mutations that disrupt gene functions, polyploidization in cardiomyocytes may provide a mechanism of genetic compensation to minimize the complete knockout of essential genes during aging. Age-related accumulation of cardiac mutations provides a paradigm to understand the influence of aging on cardiac dysfunction.
    DOI:  https://doi.org/10.1038/s43587-022-00261-5
  22. J Med Genet. 2022 Aug 30. pii: jmedgenet-2022-108529. [Epub ahead of print]
    Loss of seryl-tRNA synthetase (SARS1) causes complex spastic paraplegia and cellular senescence.
    Edgard Verdura, Bruno Senger, Miquel Raspall-Chaure, Agatha Schlüter, Nathalie Launay, Montserrat Ruiz, Carlos Casasnovas, Agustí Rodriguez-Palmero, Alfons Macaya, Hubert Dominique Becker, Aurora Pujol.
       BACKGROUND: Aminoacyl-tRNA synthetases (ARS) are key enzymes catalysing the first reactions in protein synthesis, with increasingly recognised pleiotropic roles in tumourgenesis, angiogenesis, immune response and lifespan. Germline mutations in several ARS genes have been associated with both recessive and dominant neurological diseases. Recently, patients affected with microcephaly, intellectual disability and ataxia harbouring biallelic variants in the seryl-tRNA synthetase encoded by seryl-tRNA synthetase 1 (SARS1) were reported.
    METHODS: We used exome sequencing to identify the causal variant in a patient affected by complex spastic paraplegia with ataxia, intellectual disability, developmental delay and seizures, but without microcephaly. Complementation and serylation assays using patient's fibroblasts and an Saccharomyces cerevisiae model were performed to examine this variant's pathogenicity.
    RESULTS: A de novo splice site deletion in SARS1 was identified in our patient, resulting in a 5-amino acid in-frame insertion near its active site. Complementation assays in S. cerevisiae and serylation assays in both yeast strains and patient fibroblasts proved a loss-of-function, dominant negative effect. Fibroblasts showed an abnormal cell shape, arrested division and increased beta-galactosidase staining along with a senescence-associated secretory phenotype (raised interleukin-6, p21, p16 and p53 levels).
    CONCLUSION: We refine the phenotypic spectrum and modes of inheritance of a newly described, ultrarare neurodevelopmental disorder, while unveiling the role of SARS1 as a regulator of cell growth, division and senescence.
    Keywords:  genetic research; nervous system diseases; neurology; pediatrics; sequence analysis, RNA
    DOI:  https://doi.org/10.1136/jmg-2022-108529
  23. Front Aging Neurosci. 2022 ;14 925227
    Gut metabolite trimethylamine N-oxide induces aging-associated phenotype of midbrain organoids for the induced pluripotent stem cell-based modeling of late-onset disease.
    Youngsun Lee, Ji Su Kang, On-Ju Ham, Mi-Young Son, Mi-Ok Lee.
      Brain organoids are valuable research models for human development and disease since they mimic the various cell compositions and structures of the human brain; however, they have challenges in presenting aging phenotypes for degenerative diseases. This study analyzed the association between aging and the gut metabolite trimethylamine N-oxide (TMAO), which is highly found in the midbrain of elderly and Parkinson's disease (PD) patients. TMAO treatment in midbrain organoid induced aging-associated molecular changes, including increased senescence marker expression (P21, P16), p53 accumulation, and epigenetic alterations. In addition, TMAO-treated midbrain organoids have shown parts of neurodegeneration phenotypes, including impaired brain-derived neurotrophic factor (BDNF) signaling, loss of dopaminergic neurons, astrocyte activation, and neuromelanin accumulation. Moreover, we found TMAO treatment-induced pathophysiological phosphorylation of α-synuclein protein at Ser-129 residues and Tau protein at Ser202/Thr205. These results suggest a role of TMAO in the aging and pathogenesis of the midbrain and provide insight into how intestinal dysfunction increases the risk of PD. Furthermore, this system can be utilized as a novel aging model for induced pluripotent stem cell (iPSC)-based modeling of late-onset diseases.
    Keywords:  TMAO; aging; brain organoid; gut metabolite; midbrain; neurodegenerative disease
    DOI:  https://doi.org/10.3389/fnagi.2022.925227
  24. J Gerontol A Biol Sci Med Sci. 2022 Aug 29. pii: glac175. [Epub ahead of print]
    Nicotinamide mononucleotide alleviates osteoblast senescence induction and promotes bone healing in osteoporotic mice.
    Zu Fu Lu, Liting Jiang, Pooria Lesani, Wen Jie Zhang, Ning Li, Danyang Luo, Yusi Li, Yulin Ye, Ji Bian, Guocheng Wang, Colin R Dunstan, Xin Quan Jiang, Hala Zreiqat.
      Combating the accumulated senescent cells and the healing of osteoporotic bone fracture in the elderly remains a significant challenge. Nicotinamide mononucleotide (NMN), a precursor of NAD +, is an excellent candidate for mitigating aging-related disorders. However, it is unknown if NMN can alleviate senescent cell induction and enhance osteoporotic bone fracture healing. Here we show that NMN treatment partially reverses the effects of tumor necrosis factor-alpha (TNF-α) on human primary osteoblasts (HOBs): senescent cell induction, diminished osteogenic differentiation ability and intracellular NAD + and NADH levels. Mechanistically, NMN restores the mitochondrial dysfunction in HOBs induced by TNF-α evidenced by increased mitochondrial membrane potential and reduced reactive oxidative species and mitochondrial mass. NMN also increases mitophagy activity by down-regulating P62 expression and up-regulating light chain 3B-II (LC3B-II) protein expression. In addition, the cell senescence protective effects of NMN on HOBs are mitigated by a mitophagy inhibitor (Bafilomycin A1). In vivo, NMN supplementation attenuates senescent cell induction in growth plates, partially prevents osteoporosis in an ovariectomized mouse model and accelerates bone healing in osteoporotic mice. We conclude that NMN can be a novel and promising therapeutic candidate to enhance bone fracture healing capacity in the elderly.
    Keywords:  Aging; Bone Regeneration; Osteoporosis; Senescence; bone healing
    DOI:  https://doi.org/10.1093/gerona/glac175
  25. Acta Pharmacol Sin. 2022 Aug 31.
    Deubiquitinating enzyme USP11 promotes renal tubular cell senescence and fibrosis via inhibiting the ubiquitin degradation of TGF-β receptor II.
    Jia-Yun Ni, Xin Wang, Hong-Yan Xie, Ning-Hao Yang, Jing-Yao Li, Xi-Ang Sun, Heng-Jiang Guo, Li Zhou, Wei Zhang, Jun Liu, Li-Min Lu.
      Transforming growth factor-β1 (TGF-β1) is regarded as a key factor in promoting renal fibrosis during chronic kidney disease (CKD). Signaling transduction of TGF-β1 starts with binding to TGF-β type II receptor (Tgfbr2), a constitutively activated kinase that phosphorylates TGF-β type I receptor (Tgfbr1), and then activates downstream Smad2/3 or noncanonical pathways. Previous studies show that cellular senescence is associated with the progression of CKD, and accelerated tubular cell senescence is implicated in promoting renal fibrosis. In the present study we investigated the renal parenchymal cell senescence in fibrosis from the sight of posttranslational regulation and focused on Tgfbr2, the important gatekeeper for TGF-β1 downstream signaling. In mice with unilateral ureteral obstruction (UUO) and folic acid (FA)-induced fibrotic kidneys, we found that Tgfbr2 was markedly elevated without obvious change in its mRNA levels. As an important member of deubiquitinating enzymes, ubiquitin-specific protease 11 (Usp11) was also significantly increased in fibrotic kidneys, and co-distributed with Tgfbr2 in tubular epithelial cells. Pretreatment with Usp11 inhibitor mitoxantrone (MTX, 30 mg · kg-1 · d-1, i.p.) twice a week, for 2 weeks significantly attenuated the elevation of Tgfbr2, activation in downstream senescence-related signaling pathway, as well as renal senescence and fibrosis. In cultured mouse tubular epithelial cells (MTECs), treatment with angiotensin II (Ang-II, 10-7, 10-6 M) dose-dependently elevated both Tgfbr2 and Usp11 levels. Inhibition or knockdown on Usp11 attenuated Ang-II-induced elevation in Tgfbr2 level, and attenuated the activation of downstream senescent-related signaling pathway and as well as cell senescence. We conducted Co-IP experiments, which revealed that Usp11 was able to interact with Tgfbr2, and inhibition of Usp11 increased the ubiquitination of Tgfbr2. Taken together, these results demonstrate that the elevation of Usp11 under pathological condition is implicated in promoting renal fibrosis. Usp11 promotes the development of renal fibrosis by deubiquitinating Tgfbr2, reducing Tgfbr2 ubiquitination degradation, and then facilitating the activation of downstream senescent signaling pathway.
    Keywords:  TGF-β1; Tgfbr2; Usp11; cellular senescence; renal fibrosis; renal tubular epithelial cell
    DOI:  https://doi.org/10.1038/s41401-022-00977-5
  26. Aging Cell. 2022 Sep 02. e13705
    IgD+ age-associated B cells are the progenitors of the main T-independent B cell response to infection that generates protective Ab and can be induced by an inactivated vaccine in the aged.
    Olivia Kugler-Umana, Wenliang Zhang, Yi Kuang, Jialing Liang, Catherine H Castonguay, Susan L Tonkonogy, Ann Marshak-Rothstein, Priyadharshini Devarajan, Susan L Swain.
      Age-associated B cells (ABC) accumulate with age and are associated with autoimmunity and chronic infection. However, their contributions to acute infection in the aged and their developmental pathways are unclear. We find that the response against influenza A virus infection in aged mice is dominated by a Fas+ GL7- effector B cell population we call infection-induced ABC (iABC). Most iABC express IgM and include antibody-secreting cells in the spleen, lung, and bone marrow. We find that in response to influenza, IgD+ CD21- CD23- ABC are the precursors of iABC and become memory B cells. These IgD+ ABC develop in germ-free mice, so are independent of foreign antigen recognition. The response of ABC to influenza infection, resulting in iABC, is T cell independent and requires both extrinsic TLR7 and TLR9 signals. In response to influenza infection, IgD+ ABC can induce a faster recovery of weight and higher total anti-influenza IgG and IgM titers that can neutralize virus. Immunization with whole inactivated virus also generates iABC in aged mice. Thus, in unimmunized aged mice, whose other B and T cell responses have waned, IgD+ ABC are likely the naive B cells with the potential to become Ab-secreting cells and to provide protection from infection in the aged.
    Keywords:  TLR signals; adaptive immunity; age-associated B cells; aging; influenza
    DOI:  https://doi.org/10.1111/acel.13705
  27. Aging Cell. 2022 Sep 02. e13696
    Umbilical cord plasma concentrate has beneficial effects on DNA methylation GrimAge and human clinical biomarkers.
    James Clement, Qi Yan, Megha Agrawal, Ramon E Coronado, John A Sturges, Markus Horvath, Ake T Lu, Robert T Brooke, Steve Horvath.
      Plasma transfusions are standard treatments to replace missing proteins in people with rare genetic diseases. Prior studies have demonstrated that heterochronic parabiosis has beneficial effects on several tissues of old animals receiving young blood. Human clinical trials are currently underway to investigate whether the infusion of plasma or plasma-derived factors from young donors can be used to mitigate human age-related conditions. Here, we use data from a safety study (n = 18, mean age 74) to investigate whether human umbilical cord plasma concentrate (hereinafter Plasma Concentrate) injected weekly (1 ml intramuscular) into elderly human subjects over a 10-week period affects different biomarkers, including epigenetic age measures, standard clinical biomarkers of organ dysfunction, mitochondrial DNA copy number (mtDNA-CN), and leukocyte telomere length. This study shows that treatment with plasma concentrate is safe. More than 20 clinical biomarkers were significantly and beneficially altered following the treatments. For example, creatinine was significantly decreased (p = 0.0039), while estimated glomerular filtration rate (eGFR) was increased (p = 0.0044), indicating the treatment may improve biomarkers of kidney function. Three of four immunoglobulin biomarkers decreased, while telomere length and mtDNA-CN were not significantly affected by the treatment. The treatment reduced DNA methylation-based GrimAge by an average of 0.82 years (p = 0.0093), suggests a reduction in morbidity and mortality risk. By contrast, no significant results could be observed for epigenetic clocks that estimate chronological age. Our results support the view that plasma concentrate contains youth-promoting factors.
    Keywords:  clinical trial; epigenetic clocks; exosome treatment; umbilical cord plasma; young plasma
    DOI:  https://doi.org/10.1111/acel.13696
  28. Aging (Albany NY). 2022 Aug 30. 14(undefined):
    Systemic lipolysis promotes physiological fitness in Drosophila melanogaster.
    Linshan Shang, Elizabeth Aughey, Huiseon Kim, Timothy D Heden, Lu Wang, Charles P Najt, Nicholas Esch, Sophia Brunko, Juan E Abrahante, Marissa Macchietto, Mara T Mashek, Todd Fairbanks, Daniel E L Promislow, Thomas P Neufeld, Douglas G Mashek.
      Since interventions such as caloric restriction or fasting robustly promote lipid catabolism and improve aging-related phenotypical markers, we investigated the direct effect of increased lipid catabolism via overexpression of bmm (brummer, FBgn0036449), the major triglyceride hydrolase in Drosophila, on lifespan and physiological fitness. Comprehensive characterization was carried out using RNA-seq, lipidomics and metabolomics analysis. Global overexpression of bmm strongly promoted numerous markers of physiological fitness, including increased female fecundity, fertility maintenance, preserved locomotion activity, increased mitochondrial biogenesis and oxidative metabolism. Increased bmm robustly upregulated the heat shock protein 70 (Hsp70) family of proteins, which equipped the flies with higher resistance to heat, cold, and ER stress via improved proteostasis. Despite improved physiological fitness, bmm overexpression did not extend lifespan. Taken together, these data show that bmm overexpression has broad beneficial effects on physiological fitness, but these effects did not impact lifespan.
    Keywords:  brummer; lipolysis; physiological fitness; proteostasis; stress resistance
    DOI:  https://doi.org/10.18632/aging.204251
  29. Oncoscience. 2022 ;9 38-41
    As expected, based on rapamycin-like p53-mediated gerosuppression, mTOR inhibition acts as a checkpoint in p53-mediated tumor suppression.
    Mikhail V Blagosklonny.
      
    Keywords:  cancer; geroconversion; hyperfunction theory; p53; senescence; sirolimus
    DOI:  https://doi.org/10.18632/oncoscience.561
  30. Biogerontology. 2022 Sep 02.
    Alterations in bone metabolites with age in C57BL/6 mice model.
    Dhara Patel, Tae Jin Lee, Sandeep Kumar, Sagar Vyavahare, Alison Worth, William D Hill, Mark Hamrick, Carlos M Isales, Rahul S Shinde, Sadanand Fulzele.
      Understanding the pathophysiology behind age-related diseases is an urgent need as the elderly population continues to grow. With age, there is a high risk of musculoskeletal deterioration and associated morbidity and mortality. Although the exact mechanism behind age-related degeneration is unknown, it is well established that alteration in cellular metabolism is one of the important contributing factors. Alteration in signaling pathways with age leads to the accumulation or depletion of several metabolites that play a vital role in musculoskeletal pathophysiology. This study aimed to identify age-related changes in bone tissue metabolites in C57BL/6 mice. We then correlated the differentially expressed metabolites with their functions in bone biology. In both aged males and females, hydroxyproline, glutamine, and alpha-linolenic acid levels were decreased. In aged females, Ornithine (p value = 0.001), L-Proline (p value = 0.008), Uridine (p value = 0.001), Aspartic Acid (p value = 0.004) levels were significantly decreased, and glutamate (p value = 0.002) was elevated. In aged males, N-acetyl-D-glucosamine (pvalue = 0.010), Adrenic acid (pvalue = 0.0099), Arachidonic acid (p value = 0.029) and Allantoin (p value = 0.004) levels were decreased. Metabolic pathway analysis revealed that purine and D-glutamine and D-glutamate metabolism were significantly altered in both sexes, while arginine biosynthesis in females and lipid metabolism in males were highly affected. These differences in metabolic signaling might be one of the reasons for the discrepancy in musculoskeletal disease manifestation between the two sexes. Understanding the role of these metabolites play in the aging bone will allow for new sex-specific targeted therapies against the progression of musculoskeletal diseases.
    Keywords:  Aging; Bone; Gender; Metabolites; Sex
    DOI:  https://doi.org/10.1007/s10522-022-09986-7
  31. Sci Immunol. 2022 Sep 02. 7(75): eade5698
    A SPARC-ling link to inflammaging.
    Jonathan S Maltzman.
      Adipocyte derived SPARC induces pro-inflammatory changes to macrophages, leading to aging that can be reduced by caloric restriction.
    DOI:  https://doi.org/10.1126/sciimmunol.ade5698
  32. Nature. 2022 Aug 31.
    Quick course of anti-ageing drug shows success.
      
    Keywords:  Ageing
    DOI:  https://doi.org/10.1038/d41586-022-02295-6
  33. Ageing Res Rev. 2022 Aug 25. pii: S1568-1637(22)00167-2. [Epub ahead of print]81 101725
    Deciphering clock genes as emerging targets against aging.
    Yanli Zhu, Yanqing Liu, Germaine Escames, Zhi Yang, Huadong Zhao, Lu Qian, Chengxu Xue, Danni Xu, Darío Acuña-Castroviejo, Yang Yang.
      The old people often suffer from circadian rhythm disturbances, which in turn accelerate aging. Many aging-related degenerative diseases such as Alzheimer's disease, Parkinson's disease, and osteoarthritis have an inextricable connection with circadian rhythm. In light of the predominant effects of clock genes on regulating circadian rhythm, we systematically present the elaborate network of roles that clock genes play in aging in this review. First, we briefly introduce the basic background regarding clock genes. Second, we systemically summarize the roles of clock genes in aging and aging-related degenerative diseases. Third, we discuss the relationship between clock genes polymorphisms and aging. In summary, this review is intended to clarify the indispensable roles of clock genes in aging and sheds light on developing clock genes as anti-aging targets.
    Keywords:  Aging; Alzheimer's disease; Clock genes; Genetic polymorphisms; Osteoarthritis; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.arr.2022.101725
  34. Life Sci. 2022 Aug 26. pii: S0024-3205(22)00612-9. [Epub ahead of print]307 120912
    Menaquinone-7 ameliorates cerebrovascular calcification-associated memory decline in aged mice.
    Bombi Lee, Gwang-Muk Choi, Joon-Pyo Hong, Da-Eun Cho, Yoongeun Kim, Mijung Yeom, Jeong Jun Han, Song-Rae Kim, Dae-Hyun Hahm.
      Menaquinone (MK)-7 is a vitamin K2 analog that functions as a cofactor of γ-glutamyl carboxylase involved in the activation of vitamin K (VK)-dependent proteins. The present study aimed to evaluate the effect of MK-7 on memory and cognitive function in aged C57BL/6 mice. Eighteen-month-old mice were raised for a further 4 months, fed on a standard or calcium-rich diet (3 % [w/w]), and were orally given MK-7 (40 and 400 μg/day/mouse) five times per week during the same period. The Morris water maze (MWM) test was performed at 19 and 22 months. The aged mice showed noticeable memory declines in the MWM test at all time points compared with 6-week-old mice, and this memory loss was significantly restored by the daily administration of high-dose MK-7 for 4 months. MK-7 administration also improved micro-computed tomography-based cerebrovascular calcification and aging-associated declines in growth arrest-specific 6, total and carboxylated matrix Gla proteins, and ganglioside levels in the brain of aged mice. It serologically reduced phosphorous levels in the blood, but not the urea, cholesterol, and calcium. Taken together, the long-term administration of MK-7 significantly improved age-related memory and cognitive impairments, possibly through inhibition of cerebrovascular calcification in aged mice, indicating that it can be used to develop new drugs for improving memory and cognitive function in older adults.
    Keywords:  Aging; Cerebrovascular calcification; Matrix Gla proteins; Memory; Menaquinone (MK)-7
    DOI:  https://doi.org/10.1016/j.lfs.2022.120912
  35. J Biomed Res. 2022 Jun 28. 1-12
    SIRT3 regulates mitochondrial biogenesis in aging-related diseases.
    Hong-Yan Li, Zhi-You Cai.
      Sirtuin 3 (SIRT3), the main family member of mitochondrial deacetylase, targets the majority of substrates controlling mitochondrial biogenesis via lysine deacetylation and modulates important cellular functions such as energy metabolism, reactive oxygen species production and clearance, oxidative stress, and aging. Deletion of SIRT3 has a deleterious effect on mitochondrial biogenesis, thus leading to the defect in mitochondrial function and insufficient ATP production. Imbalance of mitochondrial dynamics leads to excessive mitochondrial biogenesis, dampening mitochondrial function. Mitochondrial dysfunction plays an important role in several diseases related to aging, such as cardiovascular disease, cancer and neurodegenerative diseases. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) launches mitochondrial biogenesis through activating nuclear respiratory factors. These factors act on genes, transcribing and translating mitochondrial DNA to generate new mitochondria. PGC1α builds a bridge between SIRT3 and mitochondrial biogenesis. This review described the involvement of SIRT3 and mitochondrial dynamics, particularly mitochondrial biogenesis in aging-related diseases, and further illustrated the role of the signaling events between SIRT3 and mitochondrial biogenesis in the pathological process of aging-related diseases.
    Keywords:  PGC1α; SIRT3; aging-related diseases; mitochondrial biogenesis
    DOI:  https://doi.org/10.7555/JBR.36.20220078
  36. EMBO J. 2022 Sep 01. 41(17): e112081
    Deconstructing PML-induced premature senescence.
    Oliver Bischof, Olivier Kirsh, Mark Pearson, Koji Itahana, Pier Giuseppe Pelicci, Anne Dejean.
      
    DOI:  https://doi.org/10.15252/embj.2022112081
  37. Ageing Res Rev. 2022 Aug 24. pii: S1568-1637(22)00163-5. [Epub ahead of print] 101721
    An integrative machine-learning meta-analysis of high-throughput omics data identifies age-specific hallmarks of Alzheimer's disease.
    Maxim N Shokhirev, Adiv A Johnson.
      Alzheimer's disease (AD) is an incredibly complex and presently incurable age-related brain disorder. To better understand this debilitating disease, we collated and performed a meta-analysis on publicly available RNA-Seq, microarray, proteomics, and microRNA samples derived from AD patients and non-AD controls. 4089 samples originating from brain tissues and blood remained after applying quality filters. Since disease progression in AD correlates with age, we stratified this large dataset into three different age groups: < 75 years, 75-84 years, and ≥ 85 years. The RNA-Seq, microarray, and proteomics datasets were then combined into different integrated datasets. Ensemble machine learning was employed to identify genes and proteins that can accurately classify samples as either AD or control. These predictive inputs were then subjected to network-based enrichment analyses. The ability of genes/proteins associated with different pathways in the Molecular Signatures Database to diagnose AD was also tested. We separately identified microRNAs that can be used to make an AD diagnosis and subjected the predicted gene targets of the most predictive microRNAs to an enrichment analysis. The following key themes emerged from our machine learning and bioinformatics analyses: cell death, cellular senescence, energy metabolism, genomic integrity, glia, immune system, metal ion homeostasis, oxidative stress, proteostasis, and synaptic function. Many of the results demonstrated unique age-specificity. For example, terms highlighting cellular senescence only emerged in the earliest and intermediate age ranges while the majority of results relevant to cell death appeared in the youngest patients. Existing literature corroborates the importance of these hallmarks in AD.
    Keywords:  Alzheimer’s disease; aging; bioinformatics; ensemble learning; machine learning; omics
    DOI:  https://doi.org/10.1016/j.arr.2022.101721
  38. J Ovarian Res. 2022 Sep 01. 15(1): 100
    The role of oxidative stress in ovarian aging: a review.
    Fei Yan, Qi Zhao, Ying Li, Zhibo Zheng, Xinliang Kong, Chang Shu, Yanfeng Liu, Yun Shi.
      Ovarian aging refers to the process by which ovarian function declines until eventual failure. The pathogenesis of ovarian aging is complex and diverse; oxidative stress (OS) is considered to be a key factor. This review focuses on the fact that OS status accelerates the ovarian aging process by promoting apoptosis, inflammation, mitochondrial damage, telomere shortening and biomacromolecular damage. Current evidence suggests that aging, smoking, high-sugar diets, pressure, superovulation, chemotherapeutic agents and industrial pollutants can be factors that accelerate ovarian aging by exacerbating OS status. In addition, we review the role of nuclear factor E2-related factor 2 (Nrf2), Sirtuin (Sirt), mitogen-activated protein kinase (MAPK), protein kinase B (AKT), Forkhead box O (FoxO) and Klotho signaling pathways during the process of ovarian aging. We also explore the role of antioxidant therapies such as melatonin, vitamins, stem cell therapies, antioxidant monomers and Traditional Chinese Medicine (TCM), and investigate the roles of these supplements with respect to the reduction of OS and the improvement of ovarian function. This review provides a rationale for antioxidant therapy to improve ovarian aging.
    Keywords:  Antioxidant; Apoptosis; Cigarette smoking; Inflammation; Melatonin; Nuclear factor E2-related factor 2; Ovarian aging; Oxidative stress; Vitamin C
    DOI:  https://doi.org/10.1186/s13048-022-01032-x
  39. Front Cell Dev Biol. 2022 ;10 949196
    S6 kinase 1 at the central node of cell size and ageing.
    Stefano Fumagalli, Mario Pende.
      Genetic evidence in living organisms from yeast to plants and animals, including humans, unquestionably identifies the Target Of Rapamycin kinase (TOR or mTOR for mammalian/mechanistic) signal transduction pathway as a master regulator of growth through the control of cell size and cell number. Among the mTOR targets, the activation of p70 S6 kinase 1 (S6K1) is exquisitely sensitive to nutrient availability and rapamycin inhibition. Of note, in vivo analysis of mutant flies and mice reveals that S6K1 predominantly regulates cell size versus cell proliferation. Here we review the putative mechanisms of S6K1 action on cell size by considering the main functional categories of S6K1 targets: substrates involved in nucleic acid and protein synthesis, fat mass accumulation, retrograde control of insulin action, senescence program and cytoskeleton organization. We discuss how S6K1 may be involved in the observed interconnection between cell size, regenerative and ageing responses.
    Keywords:  ageing; growth; mTOR; nutrition; senescence; signal transduction
    DOI:  https://doi.org/10.3389/fcell.2022.949196
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