bims-senagi Biomed News
on Senescence and aging
Issue of 2020‒11‒22
twenty-two papers selected by
Maria Grazia Vizioli
Mayo Clinic

  1. Nat Metab. 2020 Nov;2(11): 1265-1283
      Declining tissue nicotinamide adenine dinucleotide (NAD) levels are linked to ageing and its associated diseases. However, the mechanism for this decline is unclear. Here, we show that pro-inflammatory M1-like macrophages, but not naive or M2 macrophages, accumulate in metabolic tissues, including visceral white adipose tissue and liver, during ageing and acute responses to inflammation. These M1-like macrophages express high levels of the NAD-consuming enzyme CD38 and have enhanced CD38-dependent NADase activity, thereby reducing tissue NAD levels. We also find that senescent cells progressively accumulate in visceral white adipose tissue and liver during ageing and that inflammatory cytokines secreted by senescent cells (the senescence-associated secretory phenotype, SASP) induce macrophages to proliferate and express CD38. These results uncover a new causal link among resident tissue macrophages, cellular senescence and tissue NAD decline during ageing and offer novel therapeutic opportunities to maintain NAD levels during ageing.
  2. Nat Metab. 2020 Nov;2(11): 1284-1304
      Decreased NAD+ levels have been shown to contribute to metabolic dysfunction during aging. NAD+ decline can be partially prevented by knockout of the enzyme CD38. However, it is not known how CD38 is regulated during aging, and how its ecto-enzymatic activity impacts NAD+ homeostasis. Here we show that an increase in CD38 in white adipose tissue (WAT) and the liver during aging is mediated by accumulation of CD38+ immune cells. Inflammation increases CD38 and decreases NAD+. In addition, senescent cells and their secreted signals promote accumulation of CD38+ cells in WAT, and ablation of senescent cells or their secretory phenotype decreases CD38, partially reversing NAD+ decline. Finally, blocking the ecto-enzymatic activity of CD38 can increase NAD+ through a nicotinamide mononucleotide (NMN)-dependent process. Our findings demonstrate that senescence-induced inflammation promotes accumulation of CD38 in immune cells that, through its ecto-enzymatic activity, decreases levels of NMN and NAD+.
  3. Aging Cell. 2020 Nov 21. e13267
      Aging leads to a number of disorders caused by cellular senescence, tissue damage, and organ dysfunction. It has been reported that anti-inflammatory and insulin-sensitizing compounds delay, or reverse, the aging process and prevent metabolic disorders, neurodegenerative disease, and muscle atrophy, improving healthspan and extending lifespan. Here we investigated the effects of PPARγ agonists in preventing aging and increasing longevity, given their known properties in lowering inflammation and decreasing glycemia. Our molecular and physiological studies show that long-term treatment of mice at 14 months of age with low doses of the PPARγ ligand rosiglitazone (Rosi) improved glucose metabolism and mitochondrial functionality. These effects were associated with decreased inflammation and reduced tissue atrophy, improved cognitive function, and diminished anxiety- and depression-like conditions, without any adverse effects on cardiac and skeletal functionality. Furthermore, Rosi treatment of mice started when they were 14 months old was associated with lifespan extension. A retrospective analysis of the effects of the PPARγ agonist pioglitazone (Pio) on longevity showed decreased mortality in patients receiving Pio compared to those receiving a PPARγ-independent insulin secretagogue glimepiride. Taken together, these data suggest the possibility of using PPARγ agonists to promote healthy aging and extend lifespan.
    Keywords:  PPARγ; adipose tissue; aging; metabolism; rosiglitazone
  4. Exp Gerontol. 2020 Nov 12. pii: S0531-5565(20)30501-5. [Epub ahead of print] 111153
      We previously reported that 2,4-dihydroxyphenyl-benzo[d]thiazole (MHY553) is a PPARα agonist, which has been shown to inhibit tyrosinase activity in murine melanocyte and alleviate hepatic steatosis in aged rats. This study investigated the effects of MHY553 on the age-related occurrence of inflammatory responses via the molecular modulation of the nuclear factor-κB (NF-κB) signaling pathway in the skin of aged rats and skin fibroblast cells. Moreover, we investigated the antioxidant effect of MHY553 via in vitro assays of reactive oxygen species (ROS) and peroxynitrite (ONOO-) scavenging activities. We also scrutinized the ability of MHY553 as a PPARα activator in aged rat skin and H2O2-induced Hs27 fibroblast cells. In vivo experiments were performed in young, aged, and MHY553-fed aged rats (3 mg or 5 mg∙kg -1∙day -1 for 4 weeks). MHY553 dose-dependently scavenged ROS and ONOO-. Furthermore, we found that MHY553 suppressed the NF-κB transcription factor and downregulated mitogen-activated protein kinase (MAPK)/activator protein-1 (AP-1) signaling. MHY553 also inhibited the expression of pro-inflammatory cytokines including COX-2, iNOS, IL-1β, and IL-6. Our findings indicate the MHY553 scavenges ROS/reactive nitrogen species and inhibits inflammatory cytokines through PPARα activation in the skin. Thus, these results suggest that MHY553 may be of therapeutic interest for protecting skin from oxidative stress-induced damage and intrinsic aging.
    Keywords:  Aged skin; Anti-inflammation; Antioxidant; Benzothiazole scaffold; PPARα agonist
  5. Aging (Albany NY). 2020 Nov 18. 12
      INTRODUCTION: Aging is characterized by the progressive loss of physiological capacity. At the cellular level, two key hallmarks of the aging process include telomere length (TL) shortening and cellular senescence. Repeated intermittent hyperoxic exposures, using certain hyperbaric oxygen therapy (HBOT) protocols, can induce regenerative effects which normally occur during hypoxia. The aim of the current study was to evaluate whether HBOT affects TL and senescent cell concentrations in a normal, non-pathological, aging adult population.METHODS: Thirty-five healthy independently living adults, aged 64 and older, were enrolled to receive 60 daily HBOT exposures. Whole blood samples were collected at baseline, at the 30th and 60th session, and 1-2 weeks following the last HBOT session. Peripheral blood mononuclear cells (PBMCs) telomeres length and senescence were assessed.
    RESULTS: Telomeres length of T helper, T cytotoxic, natural killer and B cells increased significantly by over 20% following HBOT. The most significant change was noticed in B cells which increased at the 30th session, 60th session and post HBOT by 25.68%±40.42 (p=0.007), 29.39%±23.39 (p=0.0001) and 37.63%±52.73 (p=0.007), respectively. There was a significant decrease in the number of senescent T helpers by -37.30%±33.04 post-HBOT (P<0.0001). T-cytotoxic senescent cell percentages decreased significantly by -10.96%±12.59 (p=0.0004) post-HBOT. In conclusion, the study indicates that HBOT may induce significant senolytic effects including significantly increasing telomere length and clearance of senescent cells in the aging populations.
    Keywords:  aging; hyperbaric oxygen; length; senescence; telomere
  6. Geroscience. 2020 Nov 15.
      Our recent study has established that young blood factors are not causal, nor necessary, for the systemic rejuvenation of mammalian tissues. Instead, a procedure referred to as neutral blood exchange (NBE) that resets signaling milieu to a pro-regenerative state through dilution of old plasma, enhanced the health and repair of the muscle and liver, and promoted better hippocampal neurogenesis in 2-year-old mice (Mehdipour et al., Aging 12:8790-8819, 2020). Here we expand the rejuvenative phenotypes of NBE, focusing on the brain. Namely, our results demonstrate that old mice perform much better in novel object and novel texture (whisker discrimination) tests after a single NBE, which is accompanied by reduced neuroinflammation (less-activated CD68+ microglia). Evidence against attenuation/dilution of peripheral senescence-associated secretory phenotype (SASP) as the main mechanism behind NBE was that the senolytic ABT 263 had limited effects on neuroinflammation and did not enhance hippocampal neurogenesis in the old mice. Interestingly, peripherally acting ABT 263 and NBE both diminished SA-βGal signal in the old brain, demonstrating that peripheral senescence propagates to the brain, but NBE was more robustly rejuvenative than ABT 263, suggesting that rejuvenation was not simply by reducing senescence. Explaining the mechanism of the positive effects of NBE on the brain, our comparative proteomics analysis demonstrated that dilution of old blood plasma yields an increase in the determinants of brain maintenance and repair in mice and in people. These findings confirm the paradigm of rejuvenation through dilution of age-elevated systemic factors and extrapolate it to brain health and function.
    Keywords:  Memory and Cognition; Neuroinflammation; Neutral blood exchange; Plasma dilution; Rejuvenation; Senolytics
  7. Elife. 2020 Nov 19. pii: e61073. [Epub ahead of print]9
      Older age is a strong shared risk factor for many chronic diseases and there is increasing interest in identifying aging biomarkers. Here a proteomic analysis of 1301 plasma proteins was conducted in 997 individuals between 21 and 102 years of age. We identified 651 proteins associated with age (506 over-represented, 145 underrepresented with age) was identified. Mediation analysis suggested a role for partial cis-epigenetic control of protein expression with age. Of the age-associated proteins, 33.5% and 45.3%, were associated with mortality and multimorbidity, respectively. There was enrichment of proteins associated with inflammation and extracellular matrix as well as senescence-associated secretory proteins. A 76-protein proteomic age signature predicted accumulation of chronic diseases and all-cause mortality. These data support the premise of proteomic biomarkers to monitor aging trajectories and to identify individuals at higher risk for disease to be targeted for in depth diagnostic procedures and early interventions.
    Keywords:  computational biology; epidemiology; global health; human; systems biology
  8. Aging (Albany NY). 2020 Nov 16. 12
      Aging is defined as a time-dependent functional decline that occurs in many physiological systems. This decline is the primary risk factor for prominent human pathologies such as cancer, metabolic disorders, cardiovascular disorders, and neurodegenerative diseases. Aging and age-related diseases have multiple causes. Parabiosis experiments, in which the circulatory systems of young and old mice were surgically joined, revealed that young plasma counteracts aging and rejuvenates organs in old mice, suggesting the existence of rejuvenating factors that become less abundant with aging. Diverse approaches have identified a large number of plasma proteins whose levels differ significantly between young and old mice, as well as numerous rejuvenating factors that reverse aged-related impairments in multiple tissues. These observations suggest that increasing the levels of key rejuvenating factors could promote restorative biological processes or inhibit pathological degeneration. Inspired by such findings, several companies have begun selling "young blood transfusions," and others have tested young plasma as a treatment for Alzheimer's disease. Here, we summarize the current findings regarding rejuvenating factors.
    Keywords:  aging; plasma proteins; rejuvenation; young blood
  9. Nat Rev Rheumatol. 2020 Nov 18.
      The development of osteoarthritis (OA) correlates with a rise in the number of senescent cells in joint tissues, and the senescence-associated secretory phenotype (SASP) has been implicated in cartilage degradation and OA. Age-related mitochondrial dysfunction and associated oxidative stress might induce senescence in joint tissue cells. However, senescence is not the only driver of OA, and the mechanisms by which senescent cells contribute to disease progression are not fully understood. Furthermore, it remains uncertain which joint cells and SASP-factors contribute to the OA phenotype. Research in the field has looked at developing therapeutics (namely senolytics and senomorphics) that eliminate or alter senescent cells to stop disease progression and pathogenesis. A better understanding of how senescence contributes to joint dysfunction may enhance the effectiveness of these approaches and provide relief for patients with OA.
  10. FEBS J. 2020 Nov 17.
      Cellular senescence, a stable cell division arrest caused by severe damage and stress, is a hallmark of aging in vertebrates including humans. With progressing age, senescent cells accumulate in a variety of mammalian tissues, where they contribute to tissue aging, identifying cellular senescence as a major target to delay or prevent aging. There is an increasing demand for the discovery of new classes of small molecules which would either avoid or postpone cellular senescence by selectively eliminating senescent cells from the body (i.e. "senolytics") or inactivating/switching damage-inducing properties of senescent cells (i.e. "senostatics/senomorphics"), such as the senescence-associated secretory phenotype. Whereas compounds with senolytic or senostatic activity have already been described, their efficacy and specificity has not been fully established for clinical use yet. Here, we review mechanisms of senescence that are related to mitochondria and their inter-organelle communication, and the involvement of proteostasis networks and metabolic control in the senescent phenotype. These cellular functions are associated with cellular senescence in in vitro and in vivo models but have not been fully exploited for the search of new compounds to counteract senescence yet. Therefore, we explore possibilities to target these mechanisms as new opportunities to selectively eliminate and/or disable senescent cells with the aim of tissue rejuvenation. We assume that this research will provide new compounds from the chemical space which act as mimetics of caloric restriction, modulators of calcium signaling and mitochondrial physiology, or as proteostasis optimizers, bearing the potential to counteract cellular senescence, thereby allowing healthy aging.
    Keywords:  Autophagy; RNA modification; calcium signaling homeostasis; caloric restriction(CR) mimetic; interorganellar connectivity; lysosome; mitochondria; mitophagy; proteostasis; senescence; translational control
  11. Curr Mol Med. 2020 Nov 12.
      BACKGROUND: Cellular senescence is a state of stable growth arrest triggered by mitogenic and metabolic stressors. Ageing and a high-fat diet (HFD) are proven inducers of senescence in various organs, presenting a challenge for ageing populations worldwide. Our previous study demonstrated that ROS scavenger N-acetylcysteine (NAC) can improve insulin resistance(IR) and chronic inflammation in diet-induced obesity mice, an effect better achieved through early intervention. We herein investigate whether NAC can improve cellular senescence in a diet-induced obesity mouse model, and whether a legacy effect is presented with early intervention.MATERIALS AND METHODS: For a twelve-month treatment course, all C57B/L6 mice were fed a chow diet (CD), high-fat high sucrose diet (HFD), CD+NAC1-12 (NAC intervention 1st-12th month), HFD+NAC1-12, and HFD+NAC1-6 (NAC intervention 1st-6th month). Statical analysis was used to analyze the different of markers of cellular senescence and inflammation.
    RESULTS: Throughout the study, the HFD group exhibited significantly increased body weight (BW) and body fat, markers of senescence, decreased motor activity (MA) and impaired glucose tolerance. Compared to the HFD group, the HFD+NAC1-12 group exhibited increased MA, decreased BW and body fat, improved glucose tolerance, and decreased senescence markers. The HFD+NAC1-6 group showed similar effects to the HFD+NAC1-12 group, despite discontinuing NAC for6 months. Our study showed that NAC significantly increased MA in the both HFD+NAC1-12 and HFD+NAC1-6 groups, and improved HFD-induced mitochondrial and intracellular ROS expression, DNA and protein oxidative damage, and adipose tissue inflammation.
    CONCLUSION: Legacy effect was indeed presented in HFD-induced cellular senescence with NAC intervention, with possible mechanisms being persistently increased motor activity and anti-oxidative stress effects.
    Keywords:  Cellular senescence; N-acetylcysteine; insulin resistance; legacy effect; obesity; type 2 diabetes
  12. Aging Cell. 2020 Nov 17. e13278
      Advancing maternal age causes a progressive reduction in fertility. The decline in developmental competence of the oocyte with age is likely to be a consequence of multiple contributory factors. Loss of epigenetic quality of the oocyte could impair early developmental events or programme adverse outcomes in offspring that manifest only later in life. Here, we undertake joint profiling of the transcriptome and DNA methylome of individual oocytes from reproductively young and old mice undergoing natural ovulation. We find reduced complexity as well as increased variance in the transcriptome of oocytes from aged females. This transcriptome heterogeneity is reflected in the identification of discrete sub-populations. Oocytes with a transcriptome characteristic of immature chromatin configuration (NSN) clustered into two groups: one with reduced developmental competence, as indicated by lower expression of maternal effect genes, and one with a young-like transcriptome. Oocytes from older females had on average reduced CpG methylation, but the characteristic bimodal methylation landscape of the oocyte was preserved. Germline differentially methylated regions of imprinted genes were appropriately methylated irrespective of age. For the majority of differentially expressed transcripts, the absence of correlated methylation changes suggests a post-transcriptional basis for most age-related effects on the transcriptome. However, we did find differences in gene body methylation at which there were corresponding changes in gene expression, indicating age-related effects on transcription that translate into methylation differences. Interestingly, oocytes varied in expression and methylation of these genes, which could contribute to variable competence of oocytes or penetrance of maternal age-related phenotypes in offspring.
    Keywords:  DNA methylation; advanced maternal age; chromatin; epigenetics; gene expression; oocytes; single-cell genomics
  13. Front Immunol. 2020 ;11 579220
      Old individuals are more susceptible to various infections due to immunological changes that occur during the aging process. These changes named collectively as "immunosenescence" include decreases in both the innate and adaptive immune responses in addition to the exacerbated production of inflammatory cytokines. This scenario of immunological dysfunction and its relationship with disease development in older people has been widely studied, especially in infections that can be fatal, such as influenza and, more recently, COVID-19. In the current scenario of SARS-CoV-2 infection, many mechanisms of disease pathogenesis in old individuals have been proposed. To better understand the dynamics of COVID-19 in this group, aspects related to immunological senescence must be well elucidated. In this article, we discuss the main mechanisms involved in immunosenescence and their possible correlations with the susceptibility of individuals of advanced age to SARS-CoV-2 infection and the more severe conditions of the disease.
    Keywords:  COVID-19; SARS-CoV-2; aging; coronavirus; immunosenescence; inflammaging
  14. Ageing Res Rev. 2020 Nov 12. pii: S1568-1637(20)30348-2. [Epub ahead of print] 101213
      Numerous systemic vascular dysfunction that leads to age-related diseases is highly associated with endothelial cell senescence; thus, identifying consensus features of endothelial cell senescence is crucial in understanding the mechanisms and identifying potential therapeutic targets. Here, by utilizing a total of 8 screened studies from four different origins, we have successfully obtained common features in both gene and pathway level via sophisticated machine learning algorithms. A total of 400 differentially expressed genes (DEGs) were newly discovered with meta-analysis when compared to the usage of individual studies. The generated parsimonious model established 36 genes and 50 pathways features with non-zero coefficient, suggesting remarkable association of phosphoglycerate dehydrogenase and serine biosynthesis pathway with endothelial cellular senescence. For the cross-validation process to measure model performance of 36 deduced features, leave-one-study-out cross-validation (LOSOCV) was employed, resulting in an overall area under the receiver operating characteristic (AUROC) of 0.983 (95 % CI, 0.952-1.000) showing excellent discriminative performance. Moreover, pathway-level analysis was performed by Pathifier algorithm, obtaining a total of 698 pathway deregulation scores from the 10,416 merged genes. In this process, high dimensional data was eventually narrowed down to 50 core pathways with AUROC value of 0.980 (95 % CI, 0.943, 1.000). The robust model with high performance underscores the merit of utilizing sophisticated meta-analysis in finding consensus features of endothelial cell senescence, which may lead to the development of therapeutic targets and advanced understanding of vascular dysfunction pathogenesis with further elucidation.
    Keywords:  Cardiovascular disease; Endothelial senescence; Meta-analysis; Vascular dysfunction
  15. Cardiovasc Res. 2020 Nov 03. pii: cvaa318. [Epub ahead of print]
      This review seeks to provide an update of the mechanisms of vascular cell senescence, from newly identified molecules to arterial ageing phenotypes, and finally to present a computational approach to connect these selected proteins in biological networks. We will discuss current key signalling and gene expression pathways by which these focus proteins and networks drive normal and accelerated vascular ageing. We also review the possibility that senolytic drugs, designed to restore normal cell differentiation and function, could effectively treat multiple age-related vascular diseases. Finally, we discuss how cell senescence is both a cause and a consequence of vascular ageing because of the possible feedback controls between identified networks.
    Keywords:  Epigenetics; Protein network; Senescence; Senolytic drugs; Vascular ageing
  16. Cancer Res. 2020 Nov 20. pii: canres.1088.2020. [Epub ahead of print]
      Bone marrow adipocytes (BMAd) have recently been implicated in accelerating bone metastatic cancers such as acute myelogenous leukemia and breast cancer. Importantly, bone marrow adipose tissue (BMAT) expands with aging and obesity - two key risk factors in multiple myeloma disease prevalence - suggesting that BMAd may influence and be influenced by myeloma cells in the marrow. Here we provide evidence that reciprocal interactions and cross-regulation of myeloma cells and BMAd play a role in multiple myeloma pathogenesis and treatment response. Bone marrow biopsies from MM patients revealed significant loss of BMAT with myeloma cell infiltration of the marrow, whereas BMAT was restored after treatment for multiple myeloma. Myeloma cells reduced BMAT in different pre-clinical murine models of multiple myeloma and in vitro using myeloma cell-adipocyte co-cultures. In addition, multiple myeloma cells altered adipocyte gene expression and cytokine secretory profiles, which were also associated with bioenergetic changes and induction of a senescent-like phenotype. In vivo, senescence markers were also increased in the bone marrow of tumor-burdened mice. BMAd, in turn, provided resistance to dexamethasone-induced cell cycle arrest and apoptosis, illuminating a new possible driver of myeloma cell evolution in a drug resistant clone. Our findings reveal that bi-directional interactions between BMAd and myeloma cells have significant implications for the pathogenesis and treatment of multiple myeloma. Targeting senescence in the bone marrow adipocyte or other bone marrow cells may represent a novel therapeutic approach for treatment of multiple myeloma.
  17. Cancer Discov. 2020 Nov 20.
      Timp1 status in Pten-null prostate cancer cells dictated whether senescence was detrimental in vivo.
  18. Theranostics. 2020 ;10(26): 11976-11997
      Rapid increase in aging populations is an urgent problem because older adults are more likely to suffer from disabilities and age-related diseases (ARDs), burdening healthcare systems and society in general. ARDs are characterized by the progressive deterioration of tissues and organs over time, eventually leading to tissue and organ failure. To date, there are no effective interventions to prevent the progression of ARDs. Hence, there is an urgent need for new treatment strategies. Ferroptosis, an iron-dependent cell death, is linked to normal development and homeostasis. Accumulating evidence, however, has highlighted crucial roles for ferroptosis in ARDs, including neurodegenerative and cardiovascular diseases. In this review, we a) summarize initiation, regulatory mechanisms, and molecular signaling pathways involved in ferroptosis, b) discuss the direct and indirect involvement of the activation and/or inhibition of ferroptosis in the pathogenesis of some important diseases, and c) highlight therapeutic targets relevant for ARDs.
    Keywords:  age-related diseases; ferroptosis; iron; lipid peroxidation; reactive oxygen species
  19. Cell Rep Med. 2020 May 19. 1(2): 100020
      Pancreatic adenocarcinomas (PDACs) are scarcely vascularized and thus virtually insensitive to chemotherapy and immunotherapy. In a recent issue of Cell, Lowe and collaborators1 have demonstrated that senescence induction by MEK plus CDK4/CDK6 inhibitors favors PDAC revascularization coupled to infiltration by therapeutically actionable CD8+ T cells.
  20. Front Immunol. 2020 ;11 575764
      Invariant natural killer T (iNKT) cells represent a subclass of T cells possessing a restricted repertoire of T cell receptors enabling them to recognize lipid derived ligands. iNKT cells are continuously generated in thymus and differentiate into three main subpopulations: iNKT1, iNKT2, and iNKT17 cells. We investigated the transcriptomes of these subsets comparing cells isolated from young adult (6-10 weeks old) and aged BALB/c mice (25-30 weeks of age) in order to identify genes subject to an age-related regulation of expression. These time points were selected to take into consideration the consequences of thymic involution that radically alter the existing micro-milieu. Significant differences were detected in the expression of histone genes affecting all iNKT subsets. Also the proliferative capacity of iNKT cells decreased substantially upon aging. Several genes were identified as possible candidates causing significant age-dependent changes in iNKT cell generation and/or function such as genes coding for granzyme A, ZO-1, EZH2, SOX4, IGF1 receptor, FLT4, and CD25. Moreover, we provide evidence that IL2 differentially affects homeostasis of iNKT subsets with iNKT17 cells engaging a unique mechanism to respond to IL2 by initiating a slow rate of proliferation.
    Keywords:  IL2; aging; invariant natural killer T cells; thymus; transcriptome