bims-senagi Biomed News
on Senescence and aging
Issue of 2021‒07‒11
thirty-four papers selected by
Maria Grazia Vizioli
Mayo Clinic

  1. Cancer Lett. 2021 Jul 05. pii: S0304-3835(21)00327-X. [Epub ahead of print]
      Cellular senescence is a stress response that imposes a growth arrest on cancer and nonmalignant cells during cancer therapy. By secreting a plethora of proinflammatory factors collectively termed the senescence-associated secretory phenotype (SASP), therapy-induced senescent cells can promote tumorigenesis. Moreover, the SASP from senescent cells is also able to drive therapy resistance and mediate many adverse effects of cancer therapy. Because senescent cell production often occurs during cancer therapy, it is important to carefully consider these potential detrimental effects. Senotherapy, which refers to selective removal of senescent cells, has been proposed as a promising adjuvant approach to eliminate the adverse effects of senescent cells. Thus, in this review we summarize in detail the mechanisms by which senescent cells contribute to tumorigenesis and therapeutic resistance. Also, we thoroughly discuss the potential strategies regarding how to effectively circumvent the undesirable effects of therapy-induced senescent cells.
    Keywords:  Cancer therapy; Cellular senescence; SASP; Senolysis; Senotherapy
  2. Oxid Med Cell Longev. 2021 ;2021 5546711
      Vascular endothelial cell senescence is involved in human aging and age-related vascular disorders. Guidance receptor UNC5B is implicated in oxidative stress and angiogenesis. Nonetheless, little is known about the role of UNC5B in endothelial cell senescence. Here, we cultured primary human umbilical vein endothelial cells to young and senescent phases. Subsequently, the expression of UNC5B was identified in replicative senescent cells, and then, its effect on endothelial cell senescence was confirmed by UNC5B-overexpressing lentiviral vectors and RNA interference. Overexpression of UNC5B in young endothelial cells significantly increased senescence-associated β-galactosidase-positive cells, upregulated the mRNAs expression of the senescence-associated secretory phenotype genes, reduced total cell number, and inhibited the potential for cell proliferation. Furthermore, overexpression of UNC5B promoted the generation of intracellular reactive oxygen species (ROS) and activated the P53 pathway. Besides, overexpression of UNC5B disturbed endothelial function by inhibiting cell migration and tube formation. Nevertheless, silencing UNC5B generated conflicting outcomes. Blocking ROS production or inhibiting the function of P53 rescued endothelial cell senescence induced by UNC5B. These findings suggest that UNC5B promotes endothelial cell senescence, potentially by activating the ROS-P53 pathway. Therefore, inhibiting UNC5B might reduce endothelial cell senescence and hinder age-related vascular disorders.
  3. Front Physiol. 2021 ;12 693067
      Cellular senescence is a stable form of cell cycle arrest in response to various stressors. While it serves as an endogenous pro-resolving mechanism, detrimental effects ensue when it is dysregulated. In this review, we introduce recent advances for cellular senescence and inflammaging, the underlying mechanisms for the reduction of nicotinamide adenine dinucleotide in tissues during aging, new knowledge learned from p16 reporter mice, and the development of machine learning algorithms in cellular senescence. We focus on pathobiological insights underlying cellular senescence of the vascular endothelium, a critical interface between blood and all tissues. Common causes and hallmarks of endothelial senescence are highlighted as well as recent advances in endothelial senescence. The regulation of cellular senescence involves multiple mechanistic layers involving chromatin, DNA, RNA, and protein levels. New targets are discussed including the roles of long noncoding RNAs in regulating endothelial cellular senescence. Emerging small molecules are highlighted that have anti-aging or anti-senescence effects in age-related diseases and impact homeostatic control of the vascular endothelium. Lastly, challenges and future directions are discussed including heterogeneity of endothelial cells and endothelial senescence, senescent markers and detection of senescent endothelial cells, evolutionary differences for immune surveillance in mice and humans, and long noncoding RNAs as therapeutic targets in attenuating cellular senescence. Accumulating studies indicate that cellular senescence is reversible. A better understanding of endothelial cellular senescence through lifestyle and pharmacological interventions holds promise to foster a new frontier in the management of cardiovascular disease risk.
    Keywords:  DNA damage; SASP; anti-senescent therapies; cellular senescence; long noncoding RNAs; vascular endothelium
  4. Methods Mol Biol. 2021 ;2366 193-212
      Therapy-induced senescence (TIS or therapy-induced premature senescence) is a key cellular program triggered in the course of cancer radiotherapy and chemotherapy with genotoxic drugs, both in cancer cells and in normal cells, whose activation critically affects the outcome of cancer therapy. Drug-induced senescent cells undergo a permanent cell cycle arrest, acquire distinctive morphological and biochemical alterations, and an enhanced secretory ability, referred to as senescence-associated secretory phenotype (SASP). The transcription factor NF-κB acts as a master regulator of the SASP, driving the expression of senescence-associated secretome components.Here we describe protocols for the establishment of a tetracycline-regulated cell system for the investigation of the role of NF-κB in TIS. We also describe protocols routinely used in our laboratory, to investigate TIS in this Tet-On inducible expression system. Finally, we describe techniques for the validation of TIS induction.
    Keywords:  BrdU; Conditioned medium; DNA damage foci; IκBαM; NF-κB; SA-beta-gal; SASP; Tet-On system; Therapy-induced senescence
  5. Head Neck. 2021 Jul 06.
      Senescence is a common denominator in wound healing, fibrosis, and cancer. Although, senescence is transiently antifibrotic, when prolonged, promotes fibrosis and malignant transformation. Eligible studies indexed in MEDLINE, Embase and Web of Science were searched to understand the role of cellular senescence in the pathogenesis of oral submucous fibrosis (OSF) and its malignant transformation. The senescence-associated secretory phenotype (SASP) components like IL-1, IL-6, and GRO-α induce double-strand DNA breaks in keratinocytes and drive genetic instability. SASP derived from myofibroblasts induces epithelial-mesenchymal transition in OSF and facilitates cancer progression. The use of senolytics has been shown to eliminate senescent cells from the areas of fibrosis, thereby preventing malignancy. Naturally occurring agents such as apigenin and kaempferol inhibit SASP. Mechanistic insight into the emerging role of senescence in the pathogenesis of OSF and modalities to inhibit senescence-associated antiapoptotic pathways as a supplementary therapy to prevent malignant transformation of OSF is underlined.
    Keywords:  cellular senescence; myofibroblasts; oral cancer; oral submucous fibrosis; senescence-associated secretory phenotype
  6. Front Immunol. 2021 ;12 700790
      In this review, we examine senescent cells and the overlap between the direct biological impact of senescence and the indirect impact senescence has via its effects on other cell types, particularly the macrophage. The canonical roles of macrophages in cell clearance and in other physiological functions are discussed with reference to their functions in diseases of the kidney and other organs. We also explore the translational potential of different approaches based around the macrophage in future interventions to target senescent cells, with the goal of preventing or reversing pathologies driven or contributed to in part by senescent cell load in vivo.
    Keywords:  ageing; fibrosis; immunevasion; immunoageing; macrophage; senescence; senescence-associated secretory phenotype; senolytic
  7. Cell Tissue Res. 2021 Jul 05.
      Estrogens play multiple roles in maintaining skeletal homeostasis by regulating many physiological processes in bone cells. Recently, cellular senescence in bone cells, especially in osteocytes, has been demonstrated to be a pivotal factor in bone loss. However, whether and how estrogen mediates cellular senescence in bone cells remains unknown. Here, we show that estrogen is negatively correlated with p53-related cellular senescence, primarily through the regulation of p53 protein levels, both in vivo and in vitro. Further study confirmed that estrogen attenuated the nuclear import of p53 and accelerated p53 degradation in osteocyte-like MLO-Y4 cells and osteoblastic MC3T3-E1 cells. A screen of p53-related ubiquitinating/deubiquitinating enzymes indicated that estrogen induced the degradation of p53 through the regulation of Usp10, a deubiquitinase that is directly linked to p53. Usp10 inhibition attenuated H2O2-induced senescence in MLO-Y4 cells, as indicated by p53/p21 quantification, a senescence-associated β-galactosidase (SA-β-gal) assay, and p53 localization visualization with a confocal microscope. Usp10 overexpression abolished the estrogen-mediated regulation of p53 and the downstream transcriptional gene p21. The injection of ovariectomized (OVX) mice with Spautin-1, a Usp10 inhibitor, inhibited the expression of p53 and the transcription of downstream senescence markers, as well as promoted bone mass recovery. Taken together, our study unveils the regulatory function of estrogen in the prevention of cellular senescence through the regulation of Usp10, thereby accelerating the degradation of senescent factor p53 and inhibiting its nuclear import.
    Keywords:  Bone cells; Cellular senescence; Estrogen; Usp10; p53
  8. Neurobiol Aging. 2021 Jun 10. pii: S0197-4580(21)00192-5. [Epub ahead of print]106 26-36
      Identification of molecules and molecular pathways that can ameliorate aging-associated decline in cognitive function is crucial. Here we report that the protein levels of transcription factor EB (TFEB) were markedly reduced in both the cytosolic and nuclear fractions of the frontal cortex and hippocampus at 18-months of age relative to 6 months in the normal male wild-type mice. In the transgenic mice with ectopic expression of flag-TFEB in neurons, we observed that the levels of actin-normalized PGC1α and mtTFA were significantly increased in both the cortex and the hippocampus. Additionally, we confirmed increased mitochondria numbers in the flag-TFEB mice by transmission electron microscopy. Most importantly, TFEB expression in the 18-month-old transgenic mice mitigated markers of senescence including P16INK4a, γ-H2AX, and lamin B1, and improved memory skills implying that TFEB may exert an anti-aging effect by modulating neuronal senescence. Taken together these data strongly support that TFEB can be a useful therapeutic target for brain senescent cells to help overcome the age-related issues in cognition and possibly, achieve healthy aging.
    Keywords:  Aging; Lamin B1; Learning and memory; Mitochondria; P16INK4a; PGC1-α; Senescence; TFEB; mtTFA; γ-H2AX
  9. Mech Ageing Dev. 2021 Jul 05. pii: S0047-6374(21)00112-3. [Epub ahead of print] 111540
      Ageing is the biggest risk factor for impaired cardiovascular health, with cardiovascular disease being the cause of death in 40% of individuals over 65 years old. Ageing is associated with an increased prevalence of atherosclerosis, coronary artery stenosis and subsequent myocardial infarction, thoracic aortic aneurysm, valvular heart disease and heart failure. An accumulation of senescence and increased inflammation, caused by the senescence-associated secretory phenotype, have been implicated in the aetiology and progression of these age-associated diseases. Recently it has been demonstrated that compounds targeting components of anti-apoptotic pathways expressed by senescent cells can preferentially induce senescence cells to apoptosis and have been termed senolytics. In this review, we discuss the evidence demonstrating that senescence contributes to cardiovascular disease, with a particular focus on studies that indicate the promise of senotherapy. Based on these data we suggest novel indications for senolytics as a treatment of cardiovascular diseases which have yet to be studied in the context of senotherapy. Finally, while the potential benefits are encouraging, several complications may result from senolytic treatment. We, therefore, consider these challenges in the context of the cardiovascular system.
    Keywords:  Ageing; atherosclerosis; cardiovascular; heart failure; inflammation; remodelling; senescence; senolytic
  10. J Am Heart Assoc. 2021 Jul 06. e020712
      Background Chronic inflammation through cellular senescence, known as the senescence-associated secretory phenotype, is a mechanism of various organ diseases, including atherosclerosis. Particularly, ionizing radiation (IR) contributes to cellular senescence by causing DNA damage. Although previous clinical studies have demonstrated that radiotherapy causes atherosclerosis as a long-term side effect, the detailed mechanism is unclear. This study was conducted to investigate the relationship between radiation-induced atherosclerosis and senescence-associated secretory phenotype in murine carotid arteries. Methods and Results Partial ligation of the left carotid artery branches in 9-week-old male apolipoprotein E-deficient mice was performed to induce atherosclerosis. The mice received total body irradiation at a dose of 6 Gy using gamma rays at 2 weeks post operation. We compared the samples collected 4 weeks after IR with unirradiated control samples. The IR and control groups presented pathologically progressive lesions in 90.9% and 72.3% of mice, respectively. Plaque volume, macrophage accumulation, and phenotype switching of vascular smooth muscle cells were advanced in the IR group. Irradiated samples showed increased persistent DNA damage response (53BP1 [p53 binding protein 1]), upregulated cyclin-dependent kinase inhibitors (p16INK4a and p21), and elevated inflammatory chemokines expression (monocyte chemotactic protein-1, keratinocyte-derived chemokine, and macrophage inflammatory protein 2). Conclusions IR promoted plaque growth in murine carotid arteries. Our findings support the possibility that senescence-associated secretory phenotype aggravates atherogenesis in irradiated artery. This mice model might contribute to mechanism elucidation of radiation-induced atherosclerosis.
    Keywords:  DNA damage; atherosclerosis; carotid artery stenosis; cellular senescence; irradiation
  11. Cell Rep. 2021 Jul 06. pii: S2211-1247(21)00710-5. [Epub ahead of print]36(1): 109334
      Persistent senescent cells (SCs) are known to underlie aging-related chronic disorders, but it is now recognized that SCs may be at the center of tissue remodeling events, namely during development or organ repair. In this study, we show that two distinct senescence profiles are induced in the context of a spinal cord injury between the regenerative zebrafish and the scarring mouse. Whereas induced SCs in zebrafish are progressively cleared out, they accumulate over time in mice. Depletion of SCs in spinal-cord-injured mice, with different senolytic drugs, improves locomotor, sensory, and bladder functions. This functional recovery is associated with improved myelin sparing, reduced fibrotic scar, and attenuated inflammation, which correlate with a decreased secretion of pro-fibrotic and pro-inflammatory factors. Targeting SCs is a promising therapeutic strategy not only for spinal cord injuries but potentially for other organs that lack regenerative competence.
  12. Autoimmun Rev. 2021 Jul 05. pii: S1568-9972(21)00166-X. [Epub ahead of print] 102893
      The number of elderly multiple sclerosis (MS) patients is growing, mainly due to the increase in the life expectancy of the general population and the availability of effective disease-modifying treatments. However, current treatments reduce the frequency of relapses and slow the progression of the disease, but they cannot stop the disability accumulation associated with disease progression. One possible explanation is the impact of immunosenescence, which is associated with the accumulation of unusual immune cell subsets that are thought to have a role in the development of an early ageing process in autoimmunity. Here, we provide a recent overview of how senescence affects immune cell function and how it is involved in the pathogenesis of autoimmune diseases, particularly MS. Numerous studies have demonstrated age-related immune changes in experimental autoimmune encephalomyelitis models, and the premature onset of immunosenescence has been demonstrated in MS patients. Therefore, potential therapeutic strategies based on rejuvenating the immune system have been proposed. Senolytics and regenerative strategies using haematopoietic stem cells, therapies based on rejuvenating oligodendrocyte precursor cells, microglia and monocytes, thymus cells and senescent B and T cells are capable of reversing the process of immunosenescence and could have a beneficial impact on the progression of MS.
    Keywords:  Ageing; Autoimmunity; Immunosenescence; Multiple sclerosis
  13. Dev Cell. 2021 Jun 28. pii: S1534-5807(21)00516-5. [Epub ahead of print]
      Aneuploidy, an unbalanced number of chromosomes, is highly deleterious at the cellular level and leads to senescence, a stress-induced response characterized by permanent cell-cycle arrest and a well-defined associated secretory phenotype. Here, we use a Drosophila epithelial model to delineate the pathway that leads to the induction of senescence as a consequence of the acquisition of an aneuploid karyotype. Whereas aneuploidy induces, as a result of gene dosage imbalance, proteotoxic stress and activation of the major protein quality control mechanisms, near-saturation functioning of autophagy leads to compromised mitophagy, accumulation of dysfunctional mitochondria, and the production of radical oxygen species (ROS). We uncovered a role of c-Jun N-terminal kinase (JNK) in driving senescence as a consequence of dysfunctional mitochondria and ROS. We show that activation of the major protein quality control mechanisms and mitophagy dampens the deleterious effects of aneuploidy, and we identify a role of senescence in proteostasis and compensatory proliferation for tissue repair.
    Keywords:  Drosophila; aneuploidy; autophagy; chromosomal instability; mitochondrial dysfunction; mitophagy; proteotoxic stress; senescence; tissue repair
  14. 3 Biotech. 2021 Jul;11(7): 338
      Metal oxide nanoparticles are known to exhibit unique properties such as catalyzing the neutralization of superoxide anions, hydroxyl radicals, hydrogen peroxides and behave as antioxidant enzymes. Oxidative stress, damage and chronic inflammation are major causes and consequences of aging and age-associated disorders. With the increasing popularity of metal oxide nanoparticles, they have been applied in various age-related pathologies using their antioxidant property. Metal oxide nanoparticles have been used as diagnostic, therapeutic, and as theranostics. This review summarizes the applications of metal oxide nanoparticles in aging and age-associated disorders such as cardiovascular diseases, diabetes, cancer, neurodegenerative disorders. Oxidative stress plays a central role in the activation of inflammatory pathways, disturbing the mitochondrial function, decreasing the telomere length and leading the cell towards senescence or death. Oxidative damage is the common pathway in the progression of aging and related diseases. Metal oxide nanoparticles scavenge or precisely detect the generated reactive oxygen species, hence applied in both diagnostics and therapeutics.
    Keywords:  Aging; Inflammation; Metal oxide nanoparticles; Nanozymes; Oxidative stress
  15. Aging Cell. 2021 Jul 06. e13381
      Transcriptome-based drug screening is emerging as a powerful tool to identify geroprotective compounds to intervene in age-related disease. We hypothesized that, by mimicking the transcriptional signature of the highly conserved longevity intervention of FOXO3 (daf-16 in worms) overexpression, we could identify and repurpose compounds with similar downstream effects to increase longevity. Our in silico screen, utilizing the LINCS transcriptome database of genetic and compound interventions, identified several FDA-approved compounds that activate FOXO downstream targets in mammalian cells. These included the neuromuscular blocker atracurium, which also robustly extends both lifespan and healthspan in Caenorhabditis elegans. This longevity is dependent on both daf-16 signaling and inhibition of the neuromuscular acetylcholine receptor subunit unc-38. We found unc-38 RNAi to improve healthspan, lifespan, and stimulate DAF-16 nuclear localization, similar to atracurium treatment. Finally, using RNA-seq transcriptomics, we identify atracurium activation of DAF-16 downstream effectors. Together, these data demonstrate the capacity to mimic genetic lifespan interventions with drugs, and in doing so, reveal that the neuromuscular acetylcholine receptor regulates the highly conserved FOXO/DAF-16 longevity pathway.
    Keywords:  DAF-16; FOXO; acetylcholine; aging; atracurium; longevity; neuromuscular junction
  16. Aging (Albany NY). 2021 Jul 08. 13
      Idiopathic pulmonary fibrosis (IPF) is an age-related disorder that carries a universally poor prognosis and is thought to arise from repetitive micro injuries to the alveolar epithelium. To date, a major factor limiting our understanding of IPF is a deficiency of disease models, particularly in vitro models that can recapitulate the full complement of molecular attributes in the human condition. In this study, we aimed to develop a model that more closely resembles the aberrant IPF lung epithelium. By exposing mouse alveolar epithelial cells to repeated, low doses of bleomycin, instead of usual one-time exposures, we uncovered changes strikingly similar to those in the IPF lung epithelium. This included the acquisition of multiple phenotypic and functional characteristics of senescent cells and the adoption of previously described changes in mitochondrial homeostasis, including alterations in redox balance, energy production and activity of the mitochondrial unfolded protein response. We also uncovered dramatic changes in cellular metabolism and detected a profound loss of proteostasis, as characterized by the accumulation of cytoplasmic protein aggregates, dysregulated expression of chaperone proteins and decreased activity of the ubiquitin proteasome system. In summary, we describe an in vitro model that closely resembles the aberrant lung epithelium in IPF. We propose that this simple yet powerful tool could help uncover new biological mechanisms and assist in developing new pharmacological tools to treat the disease.
    Keywords:  IPF; aging; epithelial cells; mitochondria; proteostasis
  17. J Biol Chem. 2021 Jun 30. pii: S0021-9258(21)00729-8. [Epub ahead of print] 100929
      The NAD+-dependent deacetylase Sirt1 has been implicated in the prevention of many age-related diseases, including cancer, type 2 diabetes, and cardiovascular disease. Resveratrol, a plant polyphenol, exhibits anti-aging, anti-tumor, and vascular protection effects by activating Sirt1. However, the molecular mechanism of Sirt1 activation as induced by resveratrol remains unclear. By knockdown/rescue experiments, flurometric Sirt1 activity assay, immunoprecipitation and pull-down assays, we identify here that the tumor suppressor LKB1 (liver kinase B1) as a direct activator of Sirt1 elicited by resveratrol. Resveratrol promotes the binding between LKB1 and Sirt1, which we first reported, and this binding leads to LKB1-mediated phosphorylation of Sirt1 at three different serine residues in the C-terminus of Sirt1. Mechanistically, LKB1-mediated phosphorylation increases intramolecular interactions in Sirt1, such as the binding of the C-terminus to the deacetylase core domain, thereby eliminating DBC1 (Deleted in Breast Cancer 1, Sirt1 endogenous inhibitor) inhibition and promoting Sirt1-substrate interaction. Functionally, LKB1-dependent Sirt1 activation increases mitochondrial biogenesis and respiration through deacetylation and activation of the transcriptional co-activator PGC-1α. These results identify Sirt1 as a context-dependent target of LKB1 and suggest that a resveratrol-stimulated LKB1-Sirt1 pathway plays a vital role in mitochondrial metabolism, a key physiological process contributes to numerous age-related diseases.
    Keywords:  LKB1; Sirt1; deacetylation; mitochondria; phosphorylation
  18. J Hepatocell Carcinoma. 2021 ;8 685-699
      Purpose: Cancer stem cells (CSCs) have been considered involving in tumorigenesis, local recurrence, and therapeutic drug resistance of hepatocellular carcinoma (HCC). To investigate novel and effective methods for targeting hepatic CSCs is crucial for a permanent cure of liver cancer.Methods: The expression level of SIRT1 was detected in CSCs of HCC tissues and cancer cell lines. Expression of CSC markers, the self-renewal and tumorigenic ability of liver CSCs were analyzed with SIRT1 inhibition. Cellular senescence-related markers were used to detect CSCs senescence after inhibition of SIRT1.
    Results: SIRT1 was highly expressed in CSCs of HCC cell lines and human HCC tissues. In vitro study revealed that decreasing of SIRT1 level significantly downregulated the stemness-associated genes of liver CSCs and reduced the CSC stemness properties. Also, downregulated SIRT1 suppressed liver CSCs proliferation by decreasing their self-renewal abilities. Furthermore, CSCs with decreased SIRT1 expression showed limited tumorigenicity and formed smaller HCC tumor in vivo. And SIRT1 decreased CSCs became more susceptible to chemotherapeutic drugs. Mechanistically, SIRT1 decreased CSCs became senescence through the activation of p53-p21 and p16 pathway. The data further indicated that the tumor formed from SIRT1-knockdown CSCs exhibited higher senescence-associated β-galactosidase (SA-β-Gal) activity but lower proliferative capacity.
    Conclusion: Taken together, these findings pointed that induction of senescence in liver CSCs is an effective tumor suppression method for HCC, and SIRT1 may be served as a promising target for HCC treatment.
    Keywords:  SIRT1; cellular senescence; hepatocellular carcinoma; liver cancer stem cells; self-renewal; stemness
  19. Geroscience. 2021 Jul 09.
      Advanced age is associated with a decline in response to stress. This contributes to the establishment of chronic inflammation, one of the hallmarks of aging and age-related disease. Heat shock proteins (HSP) are determinants of life span, and their progressive malfunction leads to age-related pathology. To discuss the function of HSP on age-related chronic inflammation and illness. An updated review of literature and discussion of relevant work on the topic of HSP in normal aging and chronic inflammatory pathology was performed. HSP contribute to inflamm-aging. They also play a key role in age-associated pathology linked to chronic inflammation such as autoimmune disorders, neurological disease, cardiovascular disorder, and cancer. HSP may be targeted for control of their effects related to age and chronic inflammation. Research on HSP functions in age-linked chronic inflammatory disorders provides an opportunity to improve health span and delay age-related chronic disorders.
    Keywords:  Age; Chronic; Disease; HSP; Inflammation; Therapy
  20. Front Cell Dev Biol. 2020 ;8 597993
      Secretory pathway calcium ATPase 1 (SPCA1) is a calcium pump localized specifically to the Golgi. Its effects on UVA-induced senescence have never been examined. In our study, expression of SPCA1 was increased in UVA-irradiated human dermal fibroblasts (HDFs) by activating mitogen-activated protein kinase (MAPK) and its downstream transcription factor, c-jun. Dual-luciferase reporter and chromatin immunoprecipitation assays revealed that c-jun regulated SPCA1 by binding to its promoter. Furthermore, downregulating SPCA1 with siRNA transfection aggravated UVA-induced senescence due to an elevation of intracellular calcium concentrations and a subsequent increase in reactive oxygen species (ROS) and MAPK activity. In contrast, overexpression of SPCA1 reduced calcium overload, consequently lowering the ROS level and suppressing MAPK activation. This alleviated the cellular senescence caused by UVA irradiation. These results indicated that SPCA1 might exert a protective effect on UVA-induced senescence in HDFs via forming a negative feedback loop. Specifically, activation of MAPK/c-jun triggered by UVA transcriptionally upregulated SPCA1. In turn, the increased SPCA1 lowered the intracellular Ca2+ level, probably through pumping Ca2+ into the Golgi, leading to a reduction of ROS, eventually decreasing MAPK activity and diminishing UVA-induced senescence.
    Keywords:  MAPK pathway; ROS; SPCA1; UVA; intracellular calcium concentration; negative feedback
  21. Aging Cell. 2021 Jul 03. e13419
      Sirtuin1 (SIRT1) and Sirtuin3 (SIRT3) protects cardiac function against ischemia/reperfusion (I/R) injury. Mitochondria are critical in response to myocardial I/R injury as disturbance of mitochondrial dynamics contributes to cardiac dysfunction. It is hypothesized that SIRT1 and SIRT3 are critical components to maintaining mitochondria homeostasis especially mitochondrial dynamics to exert cardioprotective actions under I/R stress. The results demonstrated that deficiency of SIRT1 and SIRT3 in aged (24-26 months) mice hearts led to the exacerbated cardiac dysfunction in terms of cardiac systolic dysfunction, cardiomyocytes contractile defection, and abnormal cardiomyocyte calcium flux during I/R stress. Moreover, the deletion of SIRT1 or SIRT3 in young (4-6 months) mice hearts impair cardiomyocyte contractility and shows aging-like cardiac dysfunction upon I/R stress, indicating the crucial role of SIRT1 and SIRT3 in protecting myocardial contractility from I/R injury. The biochemical and seahorse analysis showed that the deficiency of SIRT1/SIRT3 leads to the inactivation of AMPK and alterations in mitochondrial oxidative phosphorylation (OXPHOS) that causes impaired mitochondrial respiration in response to I/R stress. Furthermore, the remodeling of the mitochondria network goes together with hypoxic stress, and mitochondria undergo the processes of fusion with the increasing elongated branches during hypoxia. The transmission electron microscope data showed that cardiac SIRT1/SIRT3 deficiency in aging alters mitochondrial morphology characterized by the impairment of mitochondria fusion under I/R stress. Thus, the age-related deficiency of SIRT1/SIRT3 in the heart affects mitochondrial dynamics and respiration function that resulting in the impaired contractile function of cardiomyocytes in response to I/R.
    Keywords:  SIRT1; SIRT3; aging; ischemia/reperfusion; mitochondria fission and fusion
  22. Front Cell Neurosci. 2021 ;15 652111
      Neuroinflammation and the tissue-resident innate immune cells, the microglia, respond and contribute to neurodegenerative pathology. Although microglia have been the focus of work linking neuroinflammation and associated dementias like Alzheimer's Disease, the inflammatory milieu of brain is a conglomerate of cross-talk amongst microglia, systemic immune cells and soluble mediators like cytokines. Age-related changes in the inflammatory profile at the levels of both the brain and periphery are largely orchestrated by immune system cells. Strong evidence indicates that both innate and adaptive immune cells, the latter including T cells and B cells, contribute to chronic neuroinflammation and thus dementia. Neurodegenerative hallmarks coupled with more traditional immune system stimuli like infection or injury likely combine to trigger and maintain persistent microglial and thus brain inflammation. This review summarizes age-related changes in immune cell function, with special emphasis on lymphocytes as a source of inflammation, and discusses how such changes may potentiate both systemic and central nervous system inflammation to culminate in dementia. We recap the understudied area of AD-associated changes in systemic lymphocytes in greater detail to provide a unifying perspective of inflammation-fueled dementia, with an eye toward evidence of two-way communication between the brain parenchyma and blood immune cells. We focused our review on human subjects studies, adding key data from animal models as relevant.
    Keywords:  CD4; CD8; T cells; Th17; Treg; monocytes; neuroimmunology; neuroinflammation
  23. Food Funct. 2021 Jul 05.
      Pathological myocardial hypertrophy, which lacks effective prevention and treatment strategies, makes the elderly susceptible to various cardiovascular diseases. Based on the beneficial attributes of lactoferrin in aging-related diseases, we aimed to investigate whether lactoferrin could exert protection against aging-related cardiac hypertrophy and further explore the underlying mechanisms. Here, we assessed the effects of lactoferrin on myocardial pathology, apoptotic proteins, mitochondrial morphology, kinetics, autophagy, and aging-related markers, including lipofuscin deposition, overloaded iron, and oxidative stress, which are known to destabilize the mitochondrial-lysosomal axis in aged mice. Upon the administration of lactoferrin, aged hearts showed amelioration of pathological cardiac hypertrophy, which was associated with decreased apoptosis, improved morphology, rearrangement of mitochondrial dynamics, increased lysosome-dependent autophagy, and inhibition of factors detrimental to the mitochondrial-lysosomal axis. In conclusion, lactoferrin ameliorated pathological cardiac hypertrophy, potentially by improving the mitochondrial quality related to mitochondrial dynamics and the mitochondrial-lysosomal axis, thus reducing mitochondria-dependent apoptosis, which is the pivotal factor for cardiac hypertrophy in aged mice.
  24. J Neuroinflammation. 2021 Jul 06. 18(1): 153
      BACKGROUND: Neuroinflammation is a major driver of age-related brain degeneration and concomitant functional impairment. In patients with Alzheimer's disease, the most common form of age-related dementia, factors that enhance neuroinflammation may exacerbate disease progression, in part by impairing the glymphatic system responsible for clearance of pathogenic beta-amyloid. Inflammatory bowel diseases (IBDs) induce neuroinflammation and exacerbate cognitive impairment in the elderly. The NACHT-LRR and pyrin (PYD) domain-containing protein 3 (NLRP3) inflammasome has been implicated in neuroinflammation. Therefore, we examined if the NLRP3 inflammasome contributes to glymphatic dysfunction and cognitive impairment in an aging mouse model of IBD.METHODS: Sixteen-month-old C57BL/6J and NLRP3 knockout (KO) mice received 1% wt/vol dextran sodium sulfate (DSS) in drinking water to model IBD. Colitis induction was confirmed by histopathology. Exploratory behavior was examined in the open field, associative memory by the novel-object recognition and Morris water maze tests, glymphatic clearance by in vivo two-photon imaging, and neuroinflammation by immunofluorescence and western blotting detection of inflammatory markers.
    RESULTS: Administration of DSS induced colitis, impaired spatial and recognition memory, activated microglia, and increased A1-like astrocyte numbers. In addition, DSS treatment impaired glymphatic clearance, aggravated amyloid plaque accumulation, and induced neuronal loss in the cortex and hippocampus. These neurodegenerative responses were associated with increased NLRP3 inflammasome expression and accumulation of gut-derived T lymphocytes along meningeal lymphatic vessels. Conversely, NLRP3 depletion protected against cognitive dysfunction, neuroinflammation, and neurological damage induced by DSS.
    CONCLUSIONS: Colitis can exacerbate age-related neuropathology, while suppression of NLRP3 inflammasome activity may protect against these deleterious effects of colitis.
    Keywords:  Cognition; Glymphatic clearance; Inflammatory bowel disease; NLRP3 inflammasome; T cell
  25. Oxid Med Cell Longev. 2021 ;2021 6673343
      The oxysterol 27-hydroxycholesterol (27HC) is the first identified endogenous selective estrogen receptor modulator (SERM), which like endogenous estrogen 17β-estradiol (E2) induces the proliferation of estrogen receptor- (ER-) positive breast cancer cells in vitro. However, 27HC differs from E2 in that it shows adverse effects in the nervous system. Our previous study confirmed that 27HC could induce neural senescence by activating phosphorylated signal transducer and activator of transcription, which E2 could not. The purpose of the present study is to investigate whether STAT3 acetylation was involved in 27HC-induced neural senescence. Microglia (BV2 cells) and rat pheochromocytoma cells (PC12 cells) were used in vitro to explore the effect of resveratrol (REV) on 27HC-induced neural senescence. Senescence-associated β-galactosidase (SA-β-Gal) staining was performed using an SA-β-Gal Staining Kit in cells and zebrafish larvae. Zebrafish were used in vivo to assess the effect of 27HC on locomotor behavior and aging. We found that 27HC could induce senescence in neural cells, and REV, which has been employed as a Sirtuin-1 (SIRT1) agonist, could attenuate 27HC-induced senescence by inhibiting STAT3 signaling via SIRT1. Moreover, in the zebrafish model, REV attenuated 27HC-induced locomotor behavior disorder and aging in the spinal cord of zebrafish larvae, which was also associated with the activation of SIRT1-mediated STAT3 signaling. Our findings unveiled a novel mechanism by which REV alleviates 27HC-induced senescence in neural cells and affects zebrafish locomotor behavior by activating SIRT1-mediated STAT3 signaling.
  26. Nat Aging. 2021 Jan;1(1): 29-35
      Aging has largely been defined by analog measures of organ and organismal dysfunction. This has led to the characterization of aging processes at the molecular and cellular levels that underlie these gradual changes. However, current knowledge does not fully explain the growing body of data emerging from large epidemiological, systems biology, and single cell studies of entire organisms pointing to varied rates of aging between individuals (different functionality and lifespan), across lifespan (asynchronous aging), and within an organism at the tissue and organ levels (aging mosaicism). Here we consider these inhomogeneities in the broader context of the rate of aging and from the perspective of underlying cellular changes. These changes reflect genetic, environmental, and stochastic factors that cells integrate to adopt new homeostatic, albeit less functional, states, such as cellular senescence. In this sense, cellular aging can be viewed, at least in part, as a quantal process we refer to as "digital aging". Nevertheless, analog declines of tissue dysfunction and organ failure with age could be the sum of underlying digital events. Importantly, cellular aging, digital or otherwise, is not uniform across time or space within the organism or between organisms of the same species. Certain tissues may exhibit earliest signs of cellular aging, acting as drivers for organismal aging as signals from those driver cells within those tissues may accelerate the aging of other cells locally or even systemically. Advanced methodologies at the systems level and at the single cell level are likely to continue to refine our understanding to the processes of how cells and tissues age and how the integration of those processes leads to the complexities of individual, organismal aging.
  27. Aging Cell. 2021 Jul 09. e13427
      Osteoarthritis (OA), the most prevalent joint disease, is a major cause of disability worldwide. Growth hormone (GH) has been suggested to play significant roles in maintaining articular chondrocyte function and ultimately articular cartilage (AC) homeostasis. In humans, the age-associated decline in GH levels was hypothesized to play a role in the etiology of OA. We studied the impact of adult-onset isolated GH deficiency (AOiGHD) on the life span and skeletal integrity including the AC, in 23- to 30-month-old male and female mice on C57/BL6 genetic background. Reductions in GH during adulthood were associated with extended life span and reductions in body temperature in female mice only. However, end-of-life pathology revealed high levels of lymphomas in both sexes, independent of GH status. Skeletal characterization revealed increases in OA severity in AOiGHD mice, evidenced by AC degradation in both femur and tibia, and significantly increased osteophyte formation in AOiGHD females. AOiGHD males showed significant increases in the thickness of the synovial lining cell layer that was associated with increased markers of inflammation (IL-6, iNOS). Furthermore, male AOiGHD showed significant increases in matrix metalloproteinase-13 (MMP-13), p16, and β-galactosidase immunoreactivity in the AC as compared to controls, indicating increased cell senescence. In conclusion, while the life span of AOiGHD females increased, their health span was compromised by high-grade lymphomas and the development of severe OA. In contrast, AOiGHD males, which did not show extended life span, showed an overall low grade of lymphomas but exhibited significantly decreased health span, evidenced by increased OA severity.
    Keywords:  articular cartilage; growth hormone; health span; life span; osteoarthritis; osteophyte; subchondral bone
  28. Sci Rep. 2021 Jul 07. 11(1): 14059
      Regenerative medicine applications require cells that are not inflicted with senescence after in vitro culture for an optimal in vivo outcome. Methods to overcome replicative senescence include genomic modifications which have their own disadvantages. We have evaluated a three-dimensional (3D) thermo-reversible gelation polymer (TGP) matrix environment for its capabilities to reverse cellular senescence. The expression of senescence-associated beta-galactosidase (SA-βgal) by human chondrocytes from osteoarthritis-affected cartilage tissue, grown in a conventional two-dimensional (2D) monolayer culture versus in 3D-TGP were compared. In 2D, the cells de-differentiated into fibroblasts, expressed higher SA-βgal and started degenerating at 25 days. SA-βgal levels decreased when the chondrocytes were transferred from the 2D to the 3D-TGP culture, with cells exhibiting a tissue-like growth until 42-45 days. Other senescence associated markers such as p16INK4a and p21 were also expressed only in 2D cultured cells but not in 3D-TGP tissue engineered cartilage. This is a first-of-its-kind report of a chemically synthesized and reproducible in vitro environment yielding an advantageous reversal of aging of human chondrocytes without any genomic modifications. The method is worth consideration as an optimal method for growing cells for regenerative medicine applications.
  29. Nat Cell Biol. 2021 Jul 08.
      Tissue turnover requires activation and lineage commitment of tissue-resident stem cells (SCs). These processes are impacted by ageing, but the mechanisms remain unclear. Here, we addressed the mechanisms of ageing in murine hair follicle SCs (HFSCs) and observed a widespread reduction in chromatin accessibility in aged HFSCs, particularly at key self-renewal and differentiation genes, characterized by bivalent promoters occupied by active and repressive chromatin marks. Consistent with this, aged HFSCs showed reduced ability to activate bivalent genes for efficient self-renewal and differentiation. These defects were niche dependent as the transplantation of aged HFSCs into young recipients or synthetic niches restored SC functions. Mechanistically, the aged HFSC niche displayed widespread alterations in extracellular matrix composition and mechanics, resulting in mechanical stress and concomitant transcriptional repression to silence promoters. As a consequence, increasing basement membrane stiffness recapitulated age-related SC changes. These data identify niche mechanics as a central regulator of chromatin state, which, when altered, leads to age-dependent SC exhaustion.
  30. iScience. 2021 Jul 23. 24(7): 102703
      Lifespan is limited both by intrinsic decline in vigor with age and by accumulation of external insults. There exists a general picture of the deficits of aging, one that is reflected in a pattern of age-correlated changes in gene expression conserved across species. Here, however, by comparing gene expression profiling of Drosophila raised either conventionally, or free of bacteria, we show that ∼70% of these conserved, age-associated changes in gene expression fail to occur in germ-free flies. Among the processes that fail to show time-dependent change under germ-free conditions are two aging features that are observed across phylogeny, declining expression of stress response genes and increasing expression of innate immune genes. These comprise adaptive strategies the organism uses to respond to bacteria, rather than being inevitable components of age-dependent decline. Changes in other processes are independent of the microbiome and can serve as autonomous markers of aging of the individual.
    Keywords:  Biological sciences; microbiology; microbiome; physiology
  31. J Cell Mol Med. 2021 Jul 06.
      Ageing is a crucial risk factor for the development of age-related cardiovascular diseases. Therefore, the molecular mechanisms of ageing and novel anti-ageing interventions need to be deeply studied. Alginate oligosaccharide (AOS) possesses high pharmacological activities and beneficial effects. Our study was undertaken to investigate whether AOS could be used as an anti-ageing drug to alleviate cardiac ageing. D-galactose (D-gal)-induced C57BL/6J ageing mice were established by subcutaneous injection of D-gal (200 mg·kg-1 ·d-1 ) for 8 weeks. AOS (50, 100 and 150 mg·kg-1 ·d-1 ) were administrated intragastrically for the last 4 weeks. As a result, AOS prevented cardiac dysfunction in D-gal-induced ageing mice, including partially preserved ejection fraction (EF%) and fractional shortening (FS%). AOS inhibited D-gal-induced up-regulation of natriuretic peptides A (ANP), brain natriuretic peptide (BNP) and ageing markers p53 and p21 in a dose-dependent manner. To further explore the potential mechanisms contributing to the anti-ageing protective effect of AOS, the age-related mitochondrial compromise was analysed. Our data indicated that AOS alleviated D-gal-induced cardiac ageing by improving mitochondrial biogenesis, maintaining the mitochondrial integrity and enhancing the efficient removal of impaired mitochondria. AOS also decreased the ROS production and oxidative stress status, which, in turn, further inhibiting cardiac mitochondria from being destroyed. Together, these results demonstrate that AOS may be an effective therapeutic agent to alleviate cardiac ageing.
    Keywords:  D-galactose; alginate oligosaccharide; cardiac ageing; mitochondria; oxidative stress
  32. Front Cell Dev Biol. 2021 ;9 656549
      Background: Senescence is involved in many complications of pregnancy. However, whether senescent changes are also associated with missed miscarriage has not been fully investigated.Methods: The levels of p16, p21, and γH2AX, markers of senescence, were measured in placentas collected from women with missed miscarriage by immunohistochemistry and Western blotting. Levels of misfolded proteins in missed miscarriage placentas or normal first-trimester placenta that had been treated with H2O2 (100 μM) or extracellular vesicles (EVs) collected from missed miscarriage placental explant culture were measured by fluorescent compound, thioflavin-T. The production of reactive oxygen species (ROS) by missed miscarriage placentas was measured by CellROX® Deep Red.
    Results: Increased levels of p16, p21, and γH2AX were presented in missed miscarriage placentas compared to controls. Increased levels of misfolded proteins were shown in missed miscarriage placentas, but not in EVs that were collected from missed miscarriage placentas. The ROS production was significantly increased in missed miscarriage placental explant cultures. Increased levels of misfolded proteins were seen in the normal first-trimester placenta that had been treated with H2O2 compared to untreated.
    Conclusion: Our data demonstrate that there are increases in senescence and endoplasmic reticulum stress and ROS production in missed miscarriage placenta. Oxidative stress and an accumulation of misfolded proteins in missed miscarriage placentas may contribute to the changes of senescence and endoplasmic reticulum stress seen in missed miscarriage placentas.
    Keywords:  endoplasmic reticulum stress; extracellular vesicles; miRNA sequence; miscarriage; misfolded proteins; placenta; senescence
  33. Exp Gerontol. 2021 Jul 02. pii: S0531-5565(21)00247-3. [Epub ahead of print] 111465
      Human biological aging from maturity to senescence is associated with a gradual loss of muscle mass and neuromuscular function. It is not until very old age (>80 years) however, that these changes often manifest into functional impairments. A driving factor underlying the age-related loss of muscle mass and function is the reduction in the number and quality of motor units (MUs). A MU consists of a single motoneuron, located either in the spinal cord or the brain stem, and all of the muscle fibres it innervates via its peripheral axon. Throughout the adult lifespan, MUs are slowly, but progressively lost. The compensatory process of collateral reinnervation attempts to recapture orphaned muscle fibres following the death of a motoneuron. Whereas this process helps mitigate loss of muscle mass during the latter decades of adult aging, the neuromuscular system has fewer and larger MUs, which have lower quality connections between the axon terminal and innervated muscle fibres. Whether this process of MU death and degradation can be attenuated with habitual physical activity has been a challenging question of great interest. This review focuses on age-related alterations of the human neuromuscular system, with an emphasis on the MU, and presents findings on the potential protective effects of lifelong physical activity. Although there is some discrepancy across studies of masters athletes, if one considers all experimental limitations as well as the available literature in animals, there is compelling evidence of a protective effect of chronic physical training on human MUs. Our tenet is that high-levels of physical activity can mitigate the natural trajectory of loss of quantity and quality of MUs in old age.
    Keywords:  Atrophy; Masters athletes; Motor unit; Muscle; Neuroprotection; Physical activity; Sarcopenia; Training