bims-senagi 2021-05-09 papers

bims-senagi

Biomed News

on Senescence and aging

Issue of 2021–05–09
twenty-six papers selected by
Maria Grazia Vizioli, Mayo Clinic

Microphthalmia-Associated Transcription Factor in Senescence and Age-Related Diseases.
Redd1 knockdown prevents doxorubicin-induced cardiac senescence.
Vascular Senescence: A Potential Bridge Between Physiological Aging and Neurogenic Decline.
Short and dysfunctional telomeres protect from allergen-induced airway inflammation.
Senescence mechanisms and targets in the heart.
Gain of PITRM1 peptidase in cortical neurons affords protection of mitochondrial and synaptic function in an advanced age mouse model of Alzheimer's disease.
Prohibitin depletion extends lifespan of a TORC2/SGK-1 mutant through autophagy and the mitochondrial UPR.
Acceleration of ageing via disturbing mTOR-regulated proteostasis by a new ageing-associated gene PC4.
MiR-34a suppression targets Nampt to ameliorate bone marrow mesenchymal stem cell senescence by regulating NAD+-Sirt1 pathway.
Aging-dependent mitochondrial dysfunction mediated by ceramide signaling inhibits antitumor T cell response.
Overexpression of TNFα induces senescence, autophagy and mitochondrial dysfunctions in melanoma cells.
Nicotinamide provides neuroprotection in glaucoma by protecting against mitochondrial and metabolic dysfunction.
Lipoxin A4 Restores Septic Renal Function via Blocking Crosstalk Between Inflammation and Premature Senescence.
BRAFV600E-induced senescence drives Langerhans cell histiocytosis pathophysiology.
Downregulation of DUOX1 function contributes to aging-related impairment of innate airway injury responses and accelerated senile emphysema.
Microglial MT1 activation inhibits LPS-induced neuroinflammation via regulation of metabolic reprogramming.
The impact of aging on innate and adaptive immunity in the human female genital tract.
TIRR inhibits the 53BP1-p53 complex to alter cell-fate programs.
Common genetic associations between age-related diseases.
Nicotinamide improves NAD+ levels to protect against acetaminophen-induced acute liver injury in mice.
Whole-genome sequencing analysis of semi-supercentenarians.
Galectin-1 ameliorates perioperative neurocognitive disorders in aged mice.
Mitochondria ensure immune surveillance by retro-communication with the nucleus.
Effect of longevity genetic variants on the molecular aging rate.
B7-H3 suppresses doxorubicin-induced senescence-like growth arrest in colorectal cancer through the AKT/TM4SF1/SIRT1 pathway.
Melatonin delays ovarian aging in mice by slowing down the exhaustion of ovarian reserve.

Gerontology. 2021 May 03. 1-10

Microphthalmia-Associated Transcription Factor in Senescence and Age-Related Diseases.

Jian Zhang, Yi Mou, Hui Gong, Honghan Chen, Hengyi Xiao.

  Although microphthalmia-associated transcription factor (MITF) has been known for decades as a key regulator for melanocytic differentiation, recent studies expanded its other roles in multiple biological processes. Among these newfound roles, the relationship between MITF and aging is attractive; however, the underlying mechanism remains elusive. Here, we review the documented cues that highlight the implication of MITF in the aging process and particularly discuss the possible mechanisms underlying the participation of MITF in cellular senescence. First, it summarizes the association of MITF with melanocytic senescence, including the roles of MITF in cell cycle regulation, DNA damage repair, oxidative stress response, and the generation of senescence-associated secretory phenotype. Then, it collects the information involving MITF-related senescent changes in nonmelanocytes, such as retinal pigment epithelium cells, osteoclasts, and cardiomyocytes. This review may deepen the understanding of MITF function and be helpful to develop new strategies for improving geriatric health.

Keywords:  Degenerative diseases; Melanocyte; Microphthalmia-associated transcription factor; Senescence

DOI:  https://doi.org/10.1159/000515525
Aging (Albany NY). 2021 May 06. 13

Redd1 knockdown prevents doxorubicin-induced cardiac senescence.

Pianpian Huang, Lijuan Bai, Lihua Liu, Jun Fu, Kefei Wu, Hongxia Liu, Yun Liu, Benming Qi, Benling Qi.

  Regulated in development and DNA damage response-1 (Redd1) is a stress-response gene that is transcriptionally induced by diverse stressful stimuli to influence cellular growth and survival. Although evidence suggests that aging may drive Redd1 expression in skeletal muscles, the expression patterns and functions of Redd1 in senescent cardiomyocytes remain unspecified. To address this issue, in vitro and in vivo models of cardiomyocyte senescence were established by administration of doxorubicin (Dox). Redd1 overexpression and knockdown was achieved in cultured H9c2 cardiomyocytes and mouse tissues using, respectively, lentivirals and adeno-associated virus 9 (AAV9) vectors. In the hearts of both aged (24 months old) and Dox-treated mice, as well as in Dox-exposed H9c2 cardiomyocytes, high Redd1 expression accompanied the increase in both cellular senescence markers (p16INK4a and p21) and pro-inflammatory cytokine expression indicative of a stress-associated secretory phenotype (SASP). Notably, Redd1 overexpression accentuated, whereas Redd1 silencing markedly attenuated, Dox-induced cardiomyocyte senescence features both in vitro and in vivo. Notably, AAV9-shRNA-mediated Redd1 silencing significantly alleviated Dox-induced cardiac dysfunction. Moreover, through pharmacological inhibition, immunofluorescence, and western blotting, signaling pathway analyses indicated that Redd1 promotes cardiomyocyte senescence as a downstream effector of p38 MAPK to promote NF-kB signaling via p65 phosphorylation and nuclear translocation.

Keywords:  NF-κB; cardiomyocyte senescence; doxorubicin; p38 MAPK; redd1

DOI:  https://doi.org/10.18632/aging.202972
Front Neurosci. 2021 ;15 666881

Vascular Senescence: A Potential Bridge Between Physiological Aging and Neurogenic Decline.

Sara Rojas-Vázquez, Laura Blasco-Chamarro, Irene López-Fabuel, Ramón Martínez-Máñez, Isabel Fariñas.

  The adult mammalian brain contains distinct neurogenic niches harboring populations of neural stem cells (NSCs) with the capacity to sustain the generation of specific subtypes of neurons during the lifetime. However, their ability to produce new progeny declines with age. The microenvironment of these specialized niches provides multiple cellular and molecular signals that condition NSC behavior and potential. Among the different niche components, vasculature has gained increasing interest over the years due to its undeniable role in NSC regulation and its therapeutic potential for neurogenesis enhancement. NSCs are uniquely positioned to receive both locally secreted factors and adhesion-mediated signals derived from vascular elements. Furthermore, studies of parabiosis indicate that NSCs are also exposed to blood-borne factors, sensing and responding to the systemic circulation. Both structural and functional alterations occur in vasculature with age at the cellular level that can affect the proper extrinsic regulation of NSCs. Additionally, blood exchange experiments in heterochronic parabionts have revealed that age-associated changes in blood composition also contribute to adult neurogenesis impairment in the elderly. Although the mechanisms of vascular- or blood-derived signaling in aging are still not fully understood, a general feature of organismal aging is the accumulation of senescent cells, which act as sources of inflammatory and other detrimental signals that can negatively impact on neighboring cells. This review focuses on the interactions between vascular senescence, circulating pro-senescence factors and the decrease in NSC potential during aging. Understanding the mechanisms of NSC dynamics in the aging brain could lead to new therapeutic approaches, potentially include senolysis, to target age-dependent brain decline.

Keywords:  adult neural stem cell; endothelial cell senescence; neurogenic niche; parabiosis; senescence-associated secretory phenotype

DOI:  https://doi.org/10.3389/fnins.2021.666881
Aging Cell. 2021 May 04. e13352

Short and dysfunctional telomeres protect from allergen-induced airway inflammation.

Sergio Piñeiro-Hermida, Paula Martínez, Maria A Blasco.

  Asthma is a chronic inflammatory disease affecting 300 million people worldwide. As telomere shortening is a well-established hallmark of aging and that asthma incidence decreases with age, here we aimed to study the role of short telomeres in asthma pathobiology. To this end, wild-type and telomerase-deficient mice with short telomeres (third-generation (G3 Tert-/- mice)) were challenged with intranasal house dust mite (HDM) extract. We also challenged with HDM wild-type mice in which we induced a telomere dysfunction by the administration of 6-thio-2´-deoxyguanosine (6-thio-dG). Following HDM exposure, G3 Tert-/- and 6-thio-dG treated mice exhibited attenuated eosinophil counts and presence of hematopoietic stem cells in the bone marrow, as well as lower levels of IgE and circulating eosinophils. Accordingly, both G3 Tert-/- and 6-thio-dG treated wild-type mice displayed reduced airway hyperresponsiveness (AHR), as indicated by decreased airway remodeling and allergic airway inflammation markers in the lung. Furthermore, G3 Tert-/- and 6-thio-dG treated mice showed lower differentiation of Club cells, attenuating goblet cell hyperplasia. Club cells of G3 Tert-/- and 6-thio-dG treated mice displayed increased DNA damage and senescence and reduced proliferation. Thus, short/dysfunctional telomeres play a protective role in murine asthma by impeding both AHR and mucus secretion after HDM exposure. Therefore, our findings imply that telomeres play a relevant role in allergen-induced airway inflammation.

Keywords:  6-thio-dG; allergy; house dust mite (HDM); telomerase; telomeres

DOI:  https://doi.org/10.1111/acel.13352
Cardiovasc Res. 2021 May 07. pii: cvab161. [Epub ahead of print]

Senescence mechanisms and targets in the heart.

Maggie S Chen, Richard T Lee, Jessica C Garbern.

Cellular senescence is a state of irreversible cell cycle arrest associated with ageing. Senescence of different cardiac cell types can direct the pathophysiology of cardiovascular diseases such as atherosclerosis, myocardial infarction, and cardiac fibrosis. While age-related telomere shortening represents a major cause of replicative senescence, the senescent state can also be induced by oxidative stress, metabolic dysfunction, and epigenetic regulation, among other stressors. It is critical that we understand the molecular pathways that lead to cellular senescence and the consequences of cellular senescence in order to develop new therapeutic approaches to treat cardiovascular disease. In this review, we discuss molecular mechanisms of cellular senescence, explore how cellular senescence of different cardiac cell types (including cardiomyocytes, cardiac endothelial cells, cardiac fibroblasts, vascular smooth muscle cells, valve interstitial cells) can lead to cardiovascular disease, and highlight potential therapeutic approaches that target molecular mechanisms of cellular senescence to prevent or treat cardiovascular disease.

DOI: https://doi.org/10.1093/cvr/cvab161
Aging Cell. 2021 May 05. e13368

Gain of PITRM1 peptidase in cortical neurons affords protection of mitochondrial and synaptic function in an advanced age mouse model of Alzheimer's disease.

Fang Du, Qing Yu, Shijun Yan, Zhihua Zhang, Jhansi Rani Vangavaragu, Doris Chen, Shi Fang Yan, Shirley ShiDu Yan.

  Mitochondrial dysfunction is one of the early pathological features of Alzheimer's disease (AD). Accumulation of cerebral and mitochondrial Aβ links to mitochondrial and synaptic toxicity. We have previously demonstrated the mechanism by which presequence peptidase (PITRM1)-mediated clearance of mitochondrial Aβ contributes to mitochondrial and cerebral amyloid pathology and mitochondrial and synaptic stress in adult transgenic AD mice overexpressing Aβ up to 12 months old. Here, we investigate the effect of PITRM1 in an advanced age AD mouse model (up to 19-24 months) to address the fundamental unexplored question of whether restoration/gain of PITRM1 function protects against mitochondrial and synaptic dysfunction associated with Aβ accumulation and whether this protection is maintained even at later ages featuring profound amyloid pathology and synaptic failure. Using newly developed aged PITRM1/Aβ-producing AD mice, we first uncovered reduction in PITRM1 expression in AD-affected cortex of AD mice at 19-24 months of age. Increasing neuronal PITRM1 activity/expression re-established mitochondrial respiration, suppressed reactive oxygen species, improved synaptic function, and reduced loss of synapses even at advanced ages (up to 19-24 months). Notably, loss of PITRM1 proteolytic activity resulted in Aβ accumulation and failure to rescue mitochondrial and synaptic function, suggesting that PITRM1 activity is required for the degradation and clearance of mitochondrial Aβ and Aβ deposition. These data indicate that augmenting PITRM1 function results in persistent life-long protection against Aβ toxicity in an AD mouse model. Therefore, augmenting PITRM1 function may enhance Aβ clearance in mitochondria, thereby maintaining mitochondrial integrity and ultimately slowing the progression of AD.

Keywords:  amyloid pathology; mitochondria-related proinflammation; mitochondrial Aβ clearance; mitochondrial proteolysis; synaptic rescue

DOI:  https://doi.org/10.1111/acel.13368
Aging Cell. 2021 May 03. e13359

Prohibitin depletion extends lifespan of a TORC2/SGK-1 mutant through autophagy and the mitochondrial UPR.

Patricia de la Cruz-Ruiz, Blanca Hernando-Rodríguez, Mercedes M Pérez-Jiménez, María Jesús Rodríguez-Palero, Manuel D Martínez-Bueno, Antoni Pla, Roxani Gatsi, Marta Artal-Sanz.

  Mitochondrial prohibitins (PHB) are highly conserved proteins with a peculiar effect on lifespan. While PHB depletion shortens lifespan of wild-type animals, it enhances longevity of a plethora of metabolically compromised mutants, including target of rapamycin complex 2 (TORC2) mutants sgk-1 and rict-1. Here, we show that sgk-1 mutants have impaired mitochondrial homeostasis, lipogenesis and yolk formation, plausibly due to alterations in membrane lipid and sterol homeostasis. Remarkably, all these features are suppressed by PHB depletion. Our analysis shows the requirement of SRBP1/SBP-1 for the lifespan extension of sgk-1 mutants and the further extension conferred by PHB depletion. Moreover, although the mitochondrial unfolded protein response (UPRmt ) and autophagy are induced in sgk-1 mutants and upon PHB depletion, they are dispensable for lifespan. However, the enhanced longevity caused by PHB depletion in sgk-1 mutants requires both, the UPRmt and autophagy, but not mitophagy. We hypothesize that UPRmt induction upon PHB depletion extends lifespan of sgk-1 mutants through autophagy and probably modulation of lipid metabolism.

Keywords:  SGK-1; UPRmt; autophagy; lipogenesis; mitochondria; prohibitin

DOI:  https://doi.org/10.1111/acel.13359
Aging Cell. 2021 May 06. e13370

Acceleration of ageing via disturbing mTOR-regulated proteostasis by a new ageing-associated gene PC4.

Long Chen, Fengying Liao, Jie Wu, Ziwen Wang, Zhongyong Jiang, Chi Zhang, Peng Luo, Le Ma, Qiang Gong, Yang Wang, Qing Wang, Min Luo, Zeyu Yang, Shiqian Han, Chunmeng Shi.

  Research on ageing-associated genes is important for investigating ageing and anti-ageing strategies. Here, we firstly reported that the human positive cofactor 4 (PC4), a multifunctional and highly conserved nucleoprotein, is accumulated and activated during ageing and causes global accelerated ageing process by disrupting proteostasis. Mechanistically, PC4 interacts with Sin3-HDAC complex and inhibits its deacetylated activity, leads to hyper-acetylation of the histones at the promoters of mTOR-related genes and causes mTOR signalling activation. Accordingly, mTOR activation causes excessive protein synthesis, resulting in impaired proteostasis and accelerated senescence. These results reveal a new biological function of PC4 in vivo, recognizes PC4 as a new ageing-associated gene and provides a genetically engineered mouse model to simulate natural ageing. More importantly, our findings also indicate that PC4 is involved in histone acetylation and serves as a potential target to improve proteostasis and delay ageing.

Keywords:  PC4; ageing; mTOR; protein synthesis; proteostasis

DOI:  https://doi.org/10.1111/acel.13370
Stem Cell Res Ther. 2021 May 06. 12(1): 271

MiR-34a suppression targets Nampt to ameliorate bone marrow mesenchymal stem cell senescence by regulating NAD+-Sirt1 pathway.

Chenchen Pi, Cao Ma, Huan Wang, Hui Sun, Xiao Yu, Xingyu Gao, Yue Yang, Yanan Sun, Haiying Zhang, Yingai Shi, Yan Li, Yulin Li, Xu He.

   BACKGROUND: Expansion-mediated replicative senescence and age-related natural senescence have adverse effects on mesenchymal stem cell (MSC) regenerative capability and functionality, thus severely impairing the extensive applications of MSC-based therapies. Emerging evidences suggest that microRNA-34a (miR-34a) has been implicated in the process of MSC senescence; however, the molecular mechanisms with regard to how miR-34a influencing MSC senescence remain largely undetermined.
METHODS: MiR-34a expression in MSCs was evaluated utilizing RT-qPCR. The functional effects of miR-34a exerting on MSC senescence were investigated via gene manipulation. Relevant gene and protein expression levels were analyzed by RT-qPCR and western blot. Luciferase reporter assays were applied to confirm that Nampt is a direct target of miR-34a. The underlying regulatory mechanism of miR-34a targeting Nampt in MSC senescence was further explored by measuring intracellular NAD+ content, NAD+/NADH ratio and Sirt1 activity.
RESULTS: In contrast to Nampt expression, miR-34a expression incremented in senescent MSCs. MiR-34a overexpression in young MSCs resulted in senescence-associated characteristics as displayed by senescence-like morphology, prolonged cell proliferation, declined osteogenic differentiation potency, heightened senescence-associated-β-galactosidase activity, and upregulated expression levels of the senescence-associated factors. Conversely, miR-34a suppression in replicative senescent and natural senescent MSCs contributed to diminished senescence-related phenotypic features. We identified Nampt as a direct target gene of miR-34a. In addition, miR-34a repletion resulted in prominent reductions in Nampt expression levels, NAD+ content, NAD+/NADH ratio, and Sirt1 activity, whereas anti-miR-34a treatment exerted the opposite effects. Furthermore, miR-34a-mediated MSC senescence was evidently rescued following the co-treatment with Nampt overexpression.
CONCLUSION: This study identifies a significant role of miR-34a playing in MSC replicative senescence and natural senescence via targeting Nampt and further mediating by NAD+-Sirt1 pathway, carrying great implications for optimal strategies for MSC therapeutic applications.

Keywords:  Mesenchymal stem cell; Nampt; Regulation; Senescence; miR-34a; miRNA

DOI:  https://doi.org/10.1186/s13287-021-02339-0
Cell Rep. 2021 May 04. pii: S2211-1247(21)00407-1. [Epub ahead of print]35(5): 109076

Aging-dependent mitochondrial dysfunction mediated by ceramide signaling inhibits antitumor T cell response.

Silvia Vaena, Paramita Chakraborty, Han Gyul Lee, Alhaji H Janneh, Mohamed Faisal Kassir, Gyda Beeson, Zachariah Hedley, Ahmet Yalcinkaya, M Hanief Sofi, Hong Li, Monica L Husby, Robert V Stahelin, Xue-Zhong Yu, Shikhar Mehrotra, Besim Ogretmen.

  We lack a mechanistic understanding of aging-mediated changes in mitochondrial bioenergetics and lipid metabolism that affect T cell function. The bioactive sphingolipid ceramide, induced by aging stress, mediates mitophagy and cell death; however, the aging-related roles of ceramide metabolism in regulating T cell function remain unknown. Here, we show that activated T cells isolated from aging mice have elevated C14/C16 ceramide accumulation in mitochondria, generated by ceramide synthase 6, leading to mitophagy/mitochondrial dysfunction. Mechanistically, aging-dependent mitochondrial ceramide inhibits protein kinase A, leading to mitophagy in activated T cells. This aging/ceramide-dependent mitophagy attenuates the antitumor functions of T cells in vitro and in vivo. Also, inhibition of ceramide metabolism or PKA activation by genetic and pharmacologic means prevents mitophagy and restores the central memory phenotype in aging T cells. Thus, these studies help explain the mechanisms behind aging-related dysregulation of T cells' antitumor activity, which can be restored by inhibiting ceramide-dependent mitophagy.

Keywords:  CerS6; PKA; SS SphK2; T cell; aging; immunotherapy; lipid signaling; melanoma; mitophagy; sphingolipids and ceramide

DOI:  https://doi.org/10.1016/j.celrep.2021.109076
BMC Cancer. 2021 May 06. 21(1): 507

Overexpression of TNFα induces senescence, autophagy and mitochondrial dysfunctions in melanoma cells.

Silvia Tyciakova, Valeria Valova, Barbora Svitkova, Miroslava Matuskova.

   BACKGROUND: Tumor necrosis factor alpha (TNFα) is a pleiotropic cytokine with both anti-tumorigenic and pro-tumorigenic activity, affecting tumor cell biology, the balance between cell survival and death. The final effect of TNFα is dependent on the type of malignant cells, with the potential to arrest cancer progression.
METHODS: In order to explain the diverse cellular response to TNFα, we engineered melanoma and colorectal carcinoma cell lines stably overexpressing this cytokine.
RESULTS: Under the TNFα overexpression, significant upregulation of two genes was observed: proinflammatory cytokine IL6 gene in melanoma cells A375 and gene for pro-apoptotic ligand TRAIL in colorectal carcinoma cells HT29, both mediated by TNFα/TNFR1 signaling. Malignant melanoma line A375 displayed also increased autophagy on day 3, followed by premature senescence on day 6. Both processes seem to be interconnected, following earlier apoptosis induction and deregulation of mitochondrial functions. We documented altered mitochondrial status, lowered ATP production, lowered mitochondrial mass, and changes in mitochondrial morphology (shortened and condensed mitochondria) both in melanoma and colorectal carcinoma cells. Overexpression of TNFα was not linked with significant affection of the subpopulation of cancer stem-like cells in vitro. However, we could demonstrate a decrease in aldehyde dehydrogenase (ALDH) activity up to 50%, which is associated with to the stemness phenotype.
CONCLUSIONS: Our in vitro study of direct TNFα influence demonstrates two distinct outcomes in tumor cells of different origin, in non-epithelial malignant melanoma cells of neural crest origin, and in colorectal carcinoma cells derived from the epithelium.

Keywords:  Aldehyde dehydrogenase activity; Autophagy; Cancer stem cell-related markers; Melanoma; Mitochondrial status; Senescence; TNFα

DOI:  https://doi.org/10.1186/s12885-021-08237-1
Redox Biol. 2021 Apr 24. pii: S2213-2317(21)00136-1. [Epub ahead of print]43 101988

Nicotinamide provides neuroprotection in glaucoma by protecting against mitochondrial and metabolic dysfunction.

James R Tribble, Amin Otmani, Shanshan Sun, Sevannah A Ellis, Gloria Cimaglia, Rupali Vohra, Melissa Jöe, Emma Lardner, Abinaya P Venkataraman, Alberto Domínguez-Vicent, Eirini Kokkali, Seungsoo Rho, Gauti Jóhannesson, Robert W Burgess, Peter G Fuerst, Rune Brautaset, Miriam Kolko, James E Morgan, Jonathan G Crowston, Marcela Votruba, Pete A Williams.

  Nicotinamide adenine dinucleotide (NAD) is a REDOX cofactor and metabolite essential for neuronal survival. Glaucoma is a common neurodegenerative disease in which neuronal levels of NAD decline. We assess the effects of nicotinamide (a precursor to NAD) on retinal ganglion cells (the affected neuron in glaucoma) in normal physiological conditions and across a range of glaucoma relevant insults including mitochondrial stress and axon degenerative insults. We demonstrate retinal ganglion cell somal, axonal, and dendritic neuroprotection by nicotinamide in rodent models which represent isolated ocular hypertensive, axon degenerative, and mitochondrial degenerative insults. We performed metabolomics enriched for small molecular weight metabolites for the retina, optic nerve, and superior colliculus which demonstrates that ocular hypertension induces widespread metabolic disruption, including consistent changes to α-ketoglutaric acid, creatine/creatinine, homocysteine, and glycerophosphocholine. This metabolic disruption is prevented by nicotinamide. Nicotinamide provides further neuroprotective effects by increasing oxidative phosphorylation, buffering and preventing metabolic stress, and increasing mitochondrial size and motility whilst simultaneously dampening action potential firing frequency. These data support continued determination of the utility of long-term nicotinamide treatment as a neuroprotective therapy for human glaucoma.

Keywords:  Glaucoma; Metabolism; Metabolomics; Mitochondria; Nicotinamide; Retina; Retinal ganglion cell

DOI:  https://doi.org/10.1016/j.redox.2021.101988
Front Immunol. 2021 ;12 637753

Lipoxin A4 Restores Septic Renal Function via Blocking Crosstalk Between Inflammation and Premature Senescence.

Chaojin Chen, Rongzong Qiu, Jing Yang, Qian Zhang, Guoliang Sun, Xiaofeng Gao, Ziqing Hei, Haocong Ji.

  Acute kidney injury (AKI) occurs in half of patients with septic shock, resulting in unacceptably high mortality. However, effective preventive treatments are still lacking. We hypothesized that pretreatment with lipoxin A4 (LXA4), known to promote inflammation resolution, may attenuate septic AKI via blocking crosstalk between inflammation and cellular senescence. In this study, rats developed AKI following cecal ligation and puncture (CLP), as evidenced by a dynamic increase in serum creatinine, blood urea nitrogen, urinary kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, and pathological injury, accompanied by increased levels of inflammation (IL-6, TNF-α, and HMGB1) and tubular cell senescence. While, on the one hand, inhibition of senescence with rapamycin restored renal function and attenuated septic inflammatory response, on the other hand, LXA4 administration inhibited renal inflammation and tubular epithelial cell senescence after CLP. Ultimately, pretreatment with LXA4 significantly restored renal function and increased the survival rate of rats after CLP. Furthermore, LXA4 inhibited NF-κB-mediated inflammatory response and the p53/p21 senescence pathway in vivo and in vitro. However, the effect was reversed by PPAR-γ siRNA and antagonist. These results indicated that LXA4 exerted its renoprotective effects by blocking the crosstalk between inflammation and premature senescence in a PPAR-γ-dependent manner. Our findings also suggested that premature senescence plays a critical role in septic AKI and that inhibition of the crosstalk between inflammation and premature senescence may represent a new and major mechanism through which LXA4 attenuates septic AKI.

Keywords:  acute kidney injury; cellular senescence; inflammation resolution; lipoxin A4; sepsis

DOI:  https://doi.org/10.3389/fimmu.2021.637753
Nat Med. 2021 May 06.

BRAFV600E-induced senescence drives Langerhans cell histiocytosis pathophysiology.

Camille Bigenwald, Jessica Le Berichel, C Matthias Wilk, Rikhia Chakraborty, Steven T Chen, Alexandra Tabachnikova, Rebecca Mancusi, Harshal Abhyankar, Maria Casanova-Acebes, Ilaria Laface, Guray Akturk, Jenielle Jobson, Zoi Karoulia, Jerome C Martin, John Grout, Anahita Rafiei, Howard Lin, Markus G Manz, Alessia Baccarini, Poulikos I Poulikakos, Brian D Brown, Sacha Gnjatic, Amaia Lujambio, Kenneth L McClain, Jennifer Picarsic, Carl E Allen, Miriam Merad.

Langerhans cell histiocytosis (LCH) is a potentially fatal condition characterized by granulomatous lesions with characteristic clonal mononuclear phagocytes (MNPs) harboring activating somatic mutations in mitogen-activated protein kinase (MAPK) pathway genes, most notably BRAFV600E. We recently discovered that the BRAFV600E mutation can also affect multipotent hematopoietic progenitor cells (HPCs) in multisystem LCH disease. How the BRAFV600E mutation in HPCs leads to LCH is not known. Here we show that enforced expression of the BRAFV600E mutation in early mouse and human multipotent HPCs induced a senescence program that led to HPC growth arrest, apoptosis resistance and a senescence-associated secretory phenotype (SASP). SASP, in turn, promoted HPC skewing toward the MNP lineage, leading to the accumulation of senescent MNPs in tissue and the formation of LCH lesions. Accordingly, elimination of senescent cells using INK-ATTAC transgenic mice, as well as pharmacologic blockade of SASP, improved LCH disease in mice. These results identify senescent cells as a new target for the treatment of LCH.

DOI: https://doi.org/10.1038/s41591-021-01304-x
Am J Physiol Lung Cell Mol Physiol. 2021 May 05.

Downregulation of DUOX1 function contributes to aging-related impairment of innate airway injury responses and accelerated senile emphysema.

Caspar Schiffers, Lennart K A Lundblad, Milena Hristova, Aida Habibovic, Christopher M Dustin, Nirav Daphtary, Minara Aliyeva, David J Seward, Yvonne M W Janssen-Heininger, Emiel F M Wouters, Niki L Reynaert, Albert van der Vliet.

  Aging is associated with a gradual loss of lung function due to increased cellular senescence, decreased regenerative capacity and impaired innate host defense. One important aspect of innate airway epithelial host defense to non-microbial triggers is the secretion of alarmins such as IL-33 and activation of type 2 inflammation, which were previously found to depend on activation of the NADPH oxidase (NOX) homolog DUOX1, and redox-dependent signaling pathways that promote alarmin secretion. Here, we demonstrate that normal aging of C57BL/6J mice resulted in markedly decreased lung innate epithelial type 2 responses to exogenous triggers such as the airborne allergen, D. pteronyssinus, which was associated with marked downregulation of DUOX1, as well as DUOX1-mediated redox-dependent signaling. DUOX1-deficiency was also found to accelerate age-related airspace enlargement and decline in lung function, but did not consistently affect other features of lung aging such as senescence-associated inflammation. Intriguingly, observations of age-related DUOX1 downregulation and enhanced airspace enlargement due to DUOX1 deficiency in C57BL/6J mice, which lack a functional mitochondrial nicotinamide nucleotide transhydrogenase (NNT), were much less dramatic in C57BL/6NJ mice with normal NNT function, although the latter mice also displayed impaired innate epithelial injury responses with advancing age. Overall, our findings indicate a marked aging-dependent decline in (DUOX1-dependent) innate airway injury responses to external non-microbial triggers, but the impact of aging on DUOX1 downregulation and its significance for age-related senile emphysema development was variable between different C57BL6 substrains, possibly related to metabolic alterations due to differences in NNT function.

Keywords:  Aging; Emphysema; Epithelium; NADPH oxidase

DOI:  https://doi.org/10.1152/ajplung.00021.2021
Aging Cell. 2021 May 08. e13375

Microglial MT1 activation inhibits LPS-induced neuroinflammation via regulation of metabolic reprogramming.

Chao Gu, Fen Wang, Yu-Ting Zhang, Shi-Zhuang Wei, Jun-Yi Liu, Hong-Yang Sun, Guang-Hui Wang, Chun-Feng Liu.

  Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Although its pathogenesis remains unclear, a number of studies indicate that microglia-mediated neuroinflammation makes a great contribution to the pathogenesis of PD. Melatonin receptor 1 (MT1) is widely expressed in glia cells and neurons in substantia nigra (SN). Neuronal MT1 is a neuroprotective factor, but it remains largely unknown whether dysfunction of microglial MT1 is involved in the PD pathogenesis. Here, we found that MT1 was reduced in microglia of SN in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. Microglial MT1 activation dramatically inhibited lipopolysaccharide (LPS)-induced neuroinflammation, whereas loss of microglial MT1 aggravated it. Metabolic reprogramming of microglia was found to contribute to the anti-inflammatory effects of MT1 activation. LPS-induced excessive aerobic glycolysis and impaired oxidative phosphorylation (OXPHOS) could be reversed by microglial MT1 activation. MT1 positively regulated pyruvate dehydrogenase alpha 1 (PDHA1) expression to enhance OXPHOS and suppress aerobic glycolysis. Furthermore, in LPS-treated microglia, MT1 activation decreased the toxicity of conditioned media to the dopaminergic (DA) cell line MES23.5. Most importantly, the anti-inflammatory effects of MT1 activation were observed in LPS-stimulated mouse model. In general, our study demonstrates that MT1 activation inhibits LPS-induced microglial activation through regulating its metabolic reprogramming, which provides a mechanistic insight for microglial MT1 in anti-inflammation.

Keywords:  DA neurons; MT1; PDHA1; Parkinson’s disease; microglia; neuroinflammation

DOI:  https://doi.org/10.1111/acel.13375
Aging Cell. 2021 May 05. e13361

The impact of aging on innate and adaptive immunity in the human female genital tract.

Marta Rodriguez-Garcia, Mickey V Patel, Zheng Shen, Charles R Wira.

  Mucosal tissues in the human female reproductive tract (FRT) are primary sites for both gynecological cancers and infections by a spectrum of sexually transmitted pathogens, including human immunodeficiency virus (HIV), that compromise women's health. While the regulation of innate and adaptive immune protection in the FRT by hormonal cyclic changes across the menstrual cycle and pregnancy are being intensely studied, little to nothing is known about the alterations in mucosal immune protection that occur throughout the FRT as women age following menopause. The immune system in the FRT has two key functions: defense against pathogens and reproduction. After menopause, natural reproductive function ends, and therefore, two overlapping processes contribute to alterations in immune protection in aging women: menopause and immunosenescence. The goal of this review is to summarize the multiple immune changes that occur in the FRT with aging, including the impact on the function of epithelial cells, immune cells, and stromal fibroblasts. These studies indicate that major aspects of innate and adaptive immunity in the FRT are compromised in a site-specific manner in the FRT as women age. Further, at some FRT sites, immunological compensation occurs. Overall, alterations in mucosal immune protection contribute to the increased risk of sexually transmitted infections (STI), urogenital infections, and gynecological cancers. Further studies are essential to provide a foundation for the development of novel therapeutic interventions to restore immune protection and reverse conditions that threaten women's lives as they age.

Keywords:  Dendritic cells; TGFβ; epithelial cells; female reproductive tract; fibroblasts; menopause; resident memory T cells; sex hormones; sexually transmitted infections

DOI:  https://doi.org/10.1111/acel.13361
Mol Cell. 2021 Apr 29. pii: S1097-2765(21)00234-3. [Epub ahead of print]

TIRR inhibits the 53BP1-p53 complex to alter cell-fate programs.

Nishita Parnandi, Veronica Rendo, Gaofeng Cui, Maria Victoria Botuyan, Michaela Remisova, Huy Nguyen, Pascal Drané, Rameen Beroukhim, Matthias Altmeyer, Georges Mer, Dipanjan Chowdhury.

  53BP1 influences genome stability via two independent mechanisms: (1) regulating DNA double-strand break (DSB) repair and (2) enhancing p53 activity. We discovered a protein, Tudor-interacting repair regulator (TIRR), that associates with the 53BP1 Tudor domain and prevents its recruitment to DSBs. Here, we elucidate how TIRR affects 53BP1 function beyond its recruitment to DSBs and biochemically links the two distinct roles of 53BP1. Loss of TIRR causes an aberrant increase in the gene transactivation function of p53, affecting several p53-mediated cell-fate programs. TIRR inhibits the complex formation between the Tudor domain of 53BP1 and a dimethylated form of p53 (K382me2) that is poised for transcriptional activation of its target genes. TIRR mRNA expression levels negatively correlate with the expression of key p53 target genes in breast and prostate cancers. Further, TIRR loss is selectively not tolerated in p53-proficient tumors. Therefore, we establish that TIRR is an important inhibitor of the 53BP1-p53 complex.

Keywords:  53BP1; NMR; TIRR; Tudor; cancer; cell fate; p53; senescence; survival; transcription factor

DOI:  https://doi.org/10.1016/j.molcel.2021.03.039
Nat Aging. 2021 Apr;1(4): 400-412

Common genetic associations between age-related diseases.

Handan Melike Dönertaş, Daniel K Fabian, Matías Fuentealba Valenzuela, Linda Partridge, Janet M Thornton.

  Age is a common risk factor in many diseases, but the molecular basis for this relationship is elusive. In this study we identified 4 disease clusters from 116 diseases in the UK Biobank data, defined by their age-of-onset profiles, and found that diseases with the same onset profile are genetically more similar, suggesting a common etiology. This similarity was not explained by disease categories, co-occurrences or disease cause-effect relationships. Two of the four disease clusters had an increased risk of occurrence from age 20 and 40 years respectively. They both showed an association with known aging-related genes, yet differed in functional enrichment and evolutionary profiles. Moreover, they both had age-related expression and methylation changes. We also tested mutation accumulation and antagonistic pleiotropy theories of aging and found support for both.

Keywords:  Aging; GWAS; UK Biobank; age-related disease; antagonistic pleiotropy; mutation accumulation

DOI:  https://doi.org/10.1038/s43587-021-00051-5
Hum Exp Toxicol. 2021 May 05. 9603271211014573

Nicotinamide improves NAD+ levels to protect against acetaminophen-induced acute liver injury in mice.

J Xu, L Zhang, R Jiang, K Hu, D Hu, C Liao, S Jiang, Y Yang, J Huang, L Tang, L Li.

  Acetaminophen (APAP) overdose causes acute liver injury (ALI). Nicotinamide adenine dinucleotide (NAD) is an essential coenzyme, and NAD+ is oxidized type which synthesized from nicotinamide (NAM). The present study aimed to investigate the role of NAD+ in ALI and protective property of NAM. The mice were subjected to different doses APAP. After 8 hours, the serum activities of alaninetransaminase (ALT) and aspartate aminotransferase (AST), the hepatic NAD+ level and nicotinamide phosphoribosyltransferase (NAMPT) expression were determined. Then, the mice were pretreated with NAM (800 mg/kg), the hepatoprotective effects and the key antioxidative molecules were evaluated. Our findings indicated that APAP resulted in remarkable NAD+ depletion in a dose-dependent manner accompanied by NAMPT downregulation, and NAM pretreatment significantly elevated the NAD+ decline due to upregulation of NAMPT. Moreover, the downregulated Kelch-like ECH-associated protein-1 (Keap1), upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) and its translocation activation after NAM administration were confirmed, which were in accordance with improved superoxide dismutase (SOD) and glutathione (GSH) levels. Finally, NAM dramatically exhibited hepatoprotective effects by reducing the liver index and necrotic area. This study has suggested that APAP impairs liver NAD+ level and NAM is able to improve hepatic NAD+ to activate antioxidant pathway against APAP-induced ALI.

Keywords:  Nicotinamide; acetaminophen; acute liver injury; antioxidant; nicotinamide adenine dinucleotide

DOI:  https://doi.org/10.1177/09603271211014573
Elife. 2021 May 04. pii: e57849. [Epub ahead of print]10

Whole-genome sequencing analysis of semi-supercentenarians.

Paolo Garagnani, Julien Marquis, Massimo Delledonne, Chiara Pirazzini, Elena Marasco, Katarzyna Malgorzata Kwiatkowska, Vincenzo Iannuzzi, Maria Giulia Bacalini, Armand Valsesia, Jerome Carayol, Frederic Raymond, Alberto Ferrarini, Luciano Xumerle, Sebastiano Collino, Daniela Mari, Beatrice Arosio, Martina Casati, Evelyn Ferri, Daniela Monti, Benedetta Nacmias, Sandro Sorbi, Donata Luiselli, Davide Pettener, Gastone Castellani, Claudia Sala, Giuseppe Passarino, Francesco De Rango, Patrizia D'Aquila, Luca Bertamini, Nicola Martinelli, Domenico Girelli, Oliviero Olivieri, Cristina Giuliani, Patrick Descombes, Claudio Franceschi.

  Extreme longevity is the paradigm of healthy aging as individuals who reached the extreme decades of human life avoided or largely postponed all major age-related diseases. In this study, we sequenced at high coverage (90X) the whole genome of 81 semi-supercentenarians and supercentenarians [105+/110+] (mean age: 106.6 ± 1.6) and of 36 healthy unrelated geographically matched controls (mean age 68.0 ± 5.9) recruited in Italy. The results showed that 105+/110+ are characterized by a peculiar genetic background associated with efficient DNA repair mechanisms, as evidenced by both germline data (common and rare variants) and somatic mutations patterns (lower mutation load if compared to younger healthy controls). Results were replicated in a second independent cohort of 333 Italian centenarians and 358 geographically matched controls. The genetics of 105+/110+ identified DNA repair and clonal haematopoiesis as crucial players for healthy aging and for the protection from cardiovascular events.

Keywords:  ageing; clonal hematopoiesis; genetics; genomics; geroscience; human; longevity; semi-supercentenarians; sequencing

DOI:  https://doi.org/10.7554/eLife.57849
CNS Neurosci Ther. 2021 May 04.

Galectin-1 ameliorates perioperative neurocognitive disorders in aged mice.

Zhiwen Shen, Hui Xu, Wen Song, Chuwen Hu, Mingyan Guo, Jinfeng Li, Junhua Li.

   INTRODUCTION: The incidence of perioperative neurocognitive disorders (PND) is higher in the elderly patients undergoing surgery. Microglia activation-mediated neuroinflammation is one of the hallmarks of PND. Galectin-1 has been identified as a pivotal modulator in the central nervous system (CNS), while the role of galectin-1 in PND induced by microglia-mediated neuroinflammation is still undetermined.
METHODS: An exploratory laparotomy model anesthetized with isoflurane was employed to investigate the role of galectin-1 on PND in aged mice. Open field test and Morris water maze were used to test the cognitive function 3- or 7-days post-surgery. The activation of microglia in the hippocampus of aged mice was tested by immunohistochemistry. Western blot, enzyme-linked immunosorbent assay (ELISA), and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to elucidate the underlying mechanisms.
RESULTS: Galectin-1 attenuated the cognitive dysfunction induced by surgery in aged mice and inhibited microglial activity. Moreover, galectin-1 decreased the expression level of inflammatory proteins (interleukin-1β, interleukin-6, and tumor necrosis factor-α), and prevented neuronal loss in the hippocampus. Galectin-1 inhibited the inflammation of BV2 microglial cells induced by lipopolysaccharide via decreasing the translocation of NF-κB p65 and c-Jun, while this kind of inhibition was rescued when overexpressing IRAK1.
CONCLUSION: Our findings provide evidence that galectin-1 may inhibit IRAK1 expression, thus suppressing inflammatory response, inhibiting neuroinflammation, and improving ensuing cognitive dysfunction. Collectively, these findings unveil that galectin-1 may elicit protective effects on surgery-induced neuroinflammation and neurocognitive disorders.

Keywords:  IRAK1; galectin-1; microglia activation; neuroinflammation; perioperative neurocognitive disorders

DOI:  https://doi.org/10.1111/cns.13645
Cell Metab. 2021 May 04. pii: S1550-4131(21)00179-0. [Epub ahead of print]33(5): 853-855

Mitochondria ensure immune surveillance by retro-communication with the nucleus.

Manuel Rigon, Amelia R Townley, Michelangelo Campanella.

Mitochondria cover several functions within the cell, including an influence on the transcription of nuclear genes. Recent work by Tigano et al. (2021) in Nature has identified a pathway of mitochondrial retrograde communication in which the nucleus senses aberrations in the mtDNA to drive the innate immune response.

DOI: https://doi.org/10.1016/j.cmet.2021.04.013
Geroscience. 2021 May 04.

Effect of longevity genetic variants on the molecular aging rate.

Anastasia Gurinovich, Zeyuan Song, William Zhang, Anthony Federico, Stefano Monti, Stacy L Andersen, Lori L Jennings, David J Glass, Nir Barzilai, Sofiya Millman, Thomas T Perls, Paola Sebastiani.

  We conducted a genome-wide association study of 1320 centenarians from the New England Centenarian Study (median age = 104 years) and 2899 unrelated controls using >9 M genetic variants imputed to the HRC panel of ~65,000 haplotypes. The genetic variants with the most significant associations were correlated to 4131 proteins that were profiled in the serum of a subset of 224 study participants using a SOMAscan array. The genetic associations were replicated in a genome-wide association study of 480 centenarians and ~800 controls of Ashkenazi Jewish descent. The proteomic associations were replicated in a proteomic scan of approximately 1000 Ashkenazi Jewish participants from a third cohort. The analysis replicated a protein signature associated with APOE genotypes and confirmed strong overexpression of BIRC2 (p < 5E-16) and under-expression of APOB in carriers of the APOE2 allele (p < 0.05). The analysis also discovered and replicated associations between longevity variants and slower changes of protein biomarkers of aging, including a novel protein signature of rs2184061 (CDKN2A/CDKN2B in chromosome 9) that suggests a genetic regulation of GDF15. The analyses showed that longevity variants correlate with proteome signatures that could be manipulated to discover healthy-aging targets.

Keywords:  Extreme human longevity; Genetic variants; Molecular aging rate; SOMAscan array

DOI:  https://doi.org/10.1007/s11357-021-00376-4
Cell Death Dis. 2021 May 06. 12(5): 453

B7-H3 suppresses doxorubicin-induced senescence-like growth arrest in colorectal cancer through the AKT/TM4SF1/SIRT1 pathway.

Ruoqin Wang, Linqing Sun, Suhua Xia, Hongya Wu, Yanchao Ma, Shenghua Zhan, Guangbo Zhang, Xueguang Zhang, Tongguo Shi, Weichang Chen.

Emerging evidence suggests that cellular senescence induced by chemotherapy has been recognized as a new weapon for cancer therapy. This study aimed to research novel functions of B7-H3 in cellular senescence induced by a low dose of doxorubicin (DOX) in colorectal cancer (CRC). Here, our results demonstrated that B7-H3 knockdown promoted, while B7-H3 overexpression inhibited, DOX-induced cellular senescence. B7-H3 knockdown dramatically enhanced the growth arrest of CRC cells after low-dose DOX treatment, but B7-H3 overexpression had the opposite effect. By RNA-seq analysis and western blot, we showed that B7-H3 prevented cellular senescence and growth arrest through the AKT/TM4SF1/SIRT1 pathway. Blocking the AKT/TM4SF1/SIRT1 pathway dramatically reversed B7-H3-induced resistance to cellular senescence. More importantly, B7-H3 inhibited DOX-induced cellular senescence of CRC cells in vivo. Therefore, targeting B7-H3 or the B7-H3/AKT/TM4SF1/SIRT1 pathway might be a new strategy for promoting cellular senescence-like growth arrest during drug treatment in CRC.

DOI: https://doi.org/10.1038/s41419-021-03736-2
Commun Biol. 2021 May 06. 4(1): 534

Melatonin delays ovarian aging in mice by slowing down the exhaustion of ovarian reserve.

Chan Yang, Qinghua Liu, Yingjun Chen, Xiaodong Wang, Zaohong Ran, Fang Fang, Jiajun Xiong, Guoshi Liu, Xiang Li, Liguo Yang, Changjiu He.

Studies have shown that melatonin (MLT) can delay ovarian aging, but the mechanism has not been fully elucidated. Here we show that granulosa cells isolated from mice follicles can synthesize MLT; the addition of MLT in ovary culture system inhibited follicle activation and growth; In vivo experiments indicated that injections of MLT to mice during the follicle activation phase can reduce the number of activated follicles by inhibiting the PI3K-AKT-FOXO3 pathway; during the early follicle growth phase, MLT administration suppressed follicle growth and atresia, and multiple pathways involved in folliculogenesis, including PI3K-AKT, were suppressed; MLT deficiency in mice increased follicle activation and atresia, and eventually accelerated age-related fertility decline; finally, we demonstrated that prolonged high-dose MLT intake had no obvious adverse effect. This study presents more insight into the roles of MLT in reproductive regulation that endogenous MLT delays ovarian aging by inhibiting follicle activation, growth and atresia.

DOI: https://doi.org/10.1038/s42003-021-02042-z