bims-senagi Biomed News
on Senescence and aging
Issue of 2021‒11‒14
28 papers selected by
Maria Grazia Vizioli
Mayo Clinic

  1. Mech Ageing Dev. 2021 Nov 03. pii: S0047-6374(21)00167-6. [Epub ahead of print]200 111595
      Cellular senescence is a state of cell cycle arrest induced by several forms of metabolic stress. Senescent cells accumulate with advancing age and have a distinctive phenotype, characterized by profound chromatin alterations and a robust senescence-associated secretory phenotype (SASP) that exerts negative effects on tissue health, both locally and systemically. In preclinical models, pharmacological agents that eliminate senescent cells (senotherapeutics) restore health and youthful properties in multiple tissues. To date, however, very little is understood about the vulnerability of terminally-differentiated skeletal muscle fibers and the resident mononuclear cells that populate the interstitial microenvironment of skeletal muscle to senescence, and their contribution to the onset and progression of skeletal muscle loss and dysfunction with aging. Scientific advances in these areas have the potential to highlight new therapeutic approaches to optimize late-life muscle health. To this end, this review highlights the current evidence and the key questions that need to be addressed to advance the field's understanding of cellular senescence as a mediator of skeletal muscle aging and the potential for emerging senescent cell-targeting therapies to counter age-related deficits in muscle mass, strength, and function.
    Keywords:  Fibroadipogenic progenitor cells; Muscle fiber; Sarcopenia; Satellite cells; Senescence-associated secretory phenotype; Senolytics
  2. Front Cardiovasc Med. 2021 ;8 763930
      Overlapping risks for cancer and cardiovascular diseases (CVD), the two leading causes of mortality worldwide, suggest a shared biology between these diseases. The role of senescence in the development of cancer and CVD has been established. However, its role as the intersection between these diseases remains unclear. Senescence was originally characterized by an irreversible cell cycle arrest after a high number of divisions, namely replicative senescence (RS). However, it is becoming clear that senescence can also be instigated by cellular stress, so-called stress-induced premature senescence (SIPS). Telomere shortening is a hallmark of RS. The contribution of telomere DNA damage and subsequent DNA damage response/repair to SIPS has also been suggested. Although cellular senescence can mediate cell cycle arrest, senescent cells can also remain metabolically active and secrete cytokines, chemokines, growth factors, and reactive oxygen species (ROS), so-called senescence-associated secretory phenotype (SASP). The involvement of SASP in both cancer and CVD has been established. In patients with cancer or CVD, SASP is induced by various stressors including cancer treatments, pro-inflammatory cytokines, and ROS. Therefore, SASP can be the intersection between cancer and CVD. Importantly, the conventional concept of senescence as the mediator of cell cycle arrest has been challenged, as it was recently reported that chemotherapy-induced senescence can reprogram senescent cancer cells to acquire "stemness" (SAS: senescence-associated stemness). SAS allows senescent cancer cells to escape cell cycle arrest with strongly enhanced clonogenic growth capacity. SAS supports senescent cells to promote both cancer and CVD, particularly in highly stressful conditions such as cancer treatments, myocardial infarction, and heart failure. As therapeutic advances have increased overlapping risk factors for cancer and CVD, to further understand their interaction may provide better prevention, earlier detection, and safer treatment. Thus, it is critical to study the mechanisms by which these senescence pathways (SAS/SASP) are induced and regulated in both cancer and CVD.
    Keywords:  SASP; cancer; cardiovascular disease; replicative senescence (RS); senescence associated secretory phenotype; stress-induced premature senescence (SIPS)
  3. MedComm (Beijing). 2021 Jun;2(2): 279-287
      Alveolar epithelial cells (ACEs) gradually senescent as aging, which is one of the main causes of respiratory defense and function decline. Investigating the mechanisms of ACE senescence is important for understanding how the human respiratory system works. NAD+ is reported to reduce during the aging process. Supplementing NAD+ intermediates can activate sirtuin deacylases (SIRT1-SIRT7), which regulates the benefits of exercise and dietary restriction, reduce the level of intracellular oxidative stress, and improve mitochondrial function, thereby reversing cell senescence. We showed that nicotinamide mononucleotide (NMN) could effectively mitigate age-associated physiological decline in the lung of 8-10 months old C57BL/6 mice and bleomycin-induced pulmonary fibrosis in young mice of 6-8 weeks. Besides, the treatment of primary ACEs with NMN can markedly ameliorate cell senescence phenotype in vitro. These findings to improve the respiratory system function and reduce the incidence and mortality from respiratory diseases in the elderly are of great significance.
    Keywords:  NAD+; aging; alveolar epithelial cells; nicotinamide mononucleotide; senescence
  4. Elife. 2021 Nov 10. pii: e72449. [Epub ahead of print]10
      Cellular senescence is a highly complex and programmed cellular state with diverse and, at times, conflicting physiological and pathological roles across the lifespan of an organism. Initially considered a cell culture artifact, senescence evolved from an age-related circumstance to an intricate cellular defense mechanism in response to stress, implicated in a wide spectrum of biological processes like tissue remodelling, injury and cancer. The development of new tools to study senescence in vivo paved the way to uncover its functional roles in various frameworks, which are sometimes hard to reconcile. Here, we review the functional impact of senescent cells on different organismal contexts. We provide updated insights on the role of senescent cells in tissue repair and regeneration, in which they essentially modulate the levels of fibrosis and inflammation, discussing how "time" seems to be the key maestro of their effects. Finally, we overview the current clinical research landscape to target senescent cells and contemplate its repercussions on this fast-evolving field.
    Keywords:  cell biology; pathophysiology; senescence; senotherapies; time; tissue remodelling
  5. Exp Gerontol. 2021 Nov 03. pii: S0531-5565(21)00398-3. [Epub ahead of print]156 111616
      Osteoarthritis (OA) is an age-related disease, which is mainly treated with oral, topical, and/or intra-articular options to relieve symptoms and lack of specific treatment measures. Fibroblasts (FLS) are crucial cells in joint inflammation and destruction. Cellular senescence plays an important role during OA pathogenesis and senescent cells exhibit cell-cycle arrest and senescence-associated secretory phenotype (SASP). SRY-related HMG-box 4 (SOX4) is a contributing factor during many developmental processes and is elevated in inflamed synovium than in noninflamed synovium from arthritis patients. This study was designed to investigate whether SOX4 participate in the pathogenesis of OA by affecting FLS senescence and explore the internal mechanism. Firstly, we found that FLS cells exhibited more cellular senescence in OA compared with control group. We also verified the role of reactive oxygen species (ROS)/TGF-β signal in the induction of OA-FLS senescence. During the exploration of SOX4 in cell senescence, the results indicated that SOX4 activation promotes cell senescence and SASP of OA-FLS. Apart from that, we also confirmed that SOX4, regulated by ROS/TGF-β signal, was critical transcription factor associated with OA-FLS senescence. Therefore, SOX4 is likely to be a novel therapeutic target and early diagnostic marker during OA pathogenesis.
    Keywords:  Fibroblast; Osteoarthritis; ROS/TGF-β; SOX4; Senescence
  6. Br J Dermatol. 2021 Nov 13.
      Senescent cells accumulate in several tissues during ageing, including the skin, and contribute to the functional decline of the skin via the senescence-associated secretory phenotypes (SASPs) 1 . Due to the potential negative effects of SASPs during the ageing process, drugs that selectively target senescent cells or SASPs represent an important therapeutic strategy to delay skin ageing. The selective induction of cell death specifically to kill senescent cells using drugs, referred to as senolytics, is a main approach to achieve this strategy 2 .
  7. Aging Cell. 2021 Nov 11. e13512
      Inflammaging, characterized by an increase in low-grade chronic inflammation with age, is a hallmark of aging and is strongly associated with various age-related diseases, including chronic liver disease (CLD) and hepatocellular carcinoma (HCC). Because necroptosis is a cell death pathway that induces inflammation through the release of DAMPs, we tested the hypothesis that age-associated increase in necroptosis contributes to chronic inflammation in aging liver. Phosphorylation of MLKL and MLKL oligomers, markers of necroptosis, as well as phosphorylation of RIPK3 and RIPK1 were significantly upregulated in the livers of old mice relative to young mice and this increase occurred in the later half of life (i.e., after 18 months of age). Markers of M1 macrophages, expression of pro-inflammatory cytokines (TNFα, IL6 and IL1β), and markers of fibrosis were all significantly upregulated in the liver with age and the change in necroptosis paralleled the changes in inflammation and fibrosis. Hepatocytes and liver macrophages isolated from old mice showed elevated levels of necroptosis markers as well as increased expression of pro-inflammatory cytokines relative to young mice. Short-term treatment with the necroptosis inhibitor, necrostatin-1s (Nec-1s), reduced necroptosis, markers of M1 macrophages, fibrosis, and cell senescence as well as reducing the expression of pro-inflammatory cytokines in the livers of old mice. Thus, our data show for the first time that liver aging is associated with increased necroptosis and necroptosis contributes to chronic inflammation in the liver, which in turn appears to contribute to liver fibrosis and possibly CLD.
    Keywords:  aging; fibrosis; inflammation; liver; necroptosis; necrostatin-1s
  8. FASEB J. 2021 Dec;35(12): e21991
      Mitochondria are intimately connected to cell fate and function. Here, we review how these intracellular organelles participate in the induction and maintenance of the senescent state. In particular, we discuss how alterations in mitochondrial metabolism, quality control and dynamics are all involved in various aspects of cellular senescence. Together, these observations suggest that mitochondria are active participants and are mechanistically linked to the unique biology of senescence. We further describe how these insights can be potentially exploited for therapeutic benefit.
    Keywords:  aging; metabolism; mitophagy; reactive oxygen species; senolytic
  9. Int J Mol Sci. 2021 Oct 27. pii: 11619. [Epub ahead of print]22(21):
      Several investigations on senescence and its causative role in aging have underscored the importance of developing senotherapeutics, a field focused on killing senescent cells and/or preventing their accumulation within tissues. Using polyphenols in counteracting senescence may facilitate the development of senotherapeutics given their presence in the human diet, their confirmed tolerability and absence of severe side effects, and their role in preventing senescence and inducing the death of senescent cells. Against that background, we evaluated the effect of piceatannol, a natural polyphenol, on the senescence of mesenchymal stromal cells (MSCs), which play a key role in the body's homeostasis. Among our results, piceatannol reduced the number of senescent cells both after genotoxic stress that induced acute senescence and in senescent replicative cultures. Such senotherapeutics activity, moreover, promoted the recovery of cell proliferation and the stemness properties of MSCs. Altogether, our findings demonstrate piceatannol's effectiveness in counteracting senescence by targeting its associated pathways and detecting and affecting P53-dependent and P53-independent senescence. Our study thus suggests that, given piceatannol's various mechanisms to accomplish its pleiotropic activities, it may be able to counteract any senescent phenotypes.
    Keywords:  mesenchymal stem cells; polyphenols; senescence; senolytics
  10. Front Pharmacol. 2021 ;12 758792
      Hyperglycemia-induced endothelial cell senescence has been widely reported to be involved in the pathogenesis of type 2 diabetes mellitus‒accelerated atherosclerosis. Thus, understanding the underlying mechanisms and identifying potential therapeutic targets for endothelial cell senescence are valuable for attenuating atherosclerosis progression. C1q/tumor necrosis factor-related protein 9 (CTRP9), an emerging potential cardiokine, exerts a significant protective effect with respect to atherosclerosis, particularly in endothelial cells. However, the exact mechanism by which CTRP9 prevents endothelial cells from hyperglycemia-induced senescence remains unclear. This study aimed to investigate the effects of CTRP9 on hyperglycemia-induced endothelial cell senescence and atherosclerotic plaque formation in diabetic apolipoprotein E knockout (ApoE KO) mice. Human umbilical vein endothelial cells (HUVECs) were cultured in normal glucose (5.5 mM) and high glucose (40 mM) with or without recombinant human CTRP9 protein (3 μg/ml) for 48 h. Purified lentiviruses overexpressing CTRP9 (Lv-CTRP9) and control vectors containing green fluorescent protein (Lv-GFP) were injected via the tail vein into streptozotocin-induced diabetic ApoE KO mice. Results revealed that exposure of HUVECs to HG significantly increased the expression of Krüppel-like factor 4 (KLF4) and cyclin-dependent kinase inhibitor p21 (p21) and decreased that of telomerase reverse transcriptase (TERT). Treatment with recombinant human CTRP9 protein protected HUVECs from HG-induced premature senescence and dysfunction. CTRP9 promoted the phosphorylation of AMP-activated kinase (AMPK), attenuated the expression of KLF4 and p21 induced by HG, and increased the expression of TERT in HUVECs. Furthermore, in the background of AMPKα knockdown or KLF4 activation, the protective effects of CTRP9 were abolished. In-vivo experiments showed that the overexpression of CTRP9 inhibited vascular senescence and reduced atherosclerotic plaque formation in ApoE KO mice with diabetes. In conclusion, we demonstrate that KLF4 upregulation plays a crucial role in HG-induced endothelial senescence. This anti-atherosclerotic effect of CTRP9 may be partly attributed to the inhibition of HG-induced endothelial senescence through an AMPKα/KLF4-dependent mechanism, suggesting that CTRP9 could benefit further therapeutic approaches for type 2 diabetes mellitus‒accelerated atherosclerosis.
    Keywords:  AMPK; CTRP9; KLF4; atherosclerosis; hyperglycemia; senescence
  11. Oncogene. 2021 Nov 12.
      Oncogene induced senescence is a tumor suppressing defense mechanism, in which the cell cycle-dependent protein kinase (CDK) inhibitor p16INK4A (encoded by the CDKN2A gene) plays a key role. We previously reported that a transcriptional co-activator chromodomain helicase DNA binding protein 7 (CHD7) mediates oncogenic ras-induced senescence by inducing transcription of the p16INK4A gene. In the current study, we identified myeloid zinc finger 1 (MZF1) as the transcriptional factor that recruits CHD7 to the p16INK4A promoter, where it mediates oncogenic ras-induced p16INK4A transcription and senescence through CHD7, in primary human cells from multiple origins. Moreover, the expression of MZF1 is induced by oncogenic ras in senescent cells through the c-Jun and Ets1 transcriptional factors upon their activation by the Ras-Raf-1-MEK-ERK signaling pathway. In non-small cell lung cancer (NSCLC) and pancreatic adenocarcinoma (PAAD) where activating ras mutations occur frequently, reduced MZF1 expression is observed in tumors, as compared to corresponding normal tissues, and correlates with poor patient survival. Analysis of single cell RNA-sequencing data from PAAD patients revealed that among the tumor cells with normal RB expression levels, those with reduced levels of MZF1 are more likely to express lower p16INK4A levels. These findings have identified novel signaling components in the pathway that mediates induction of the p16INK4A tumor suppressor and the senescence response, and suggested that MZF1 is a potential tumor suppressor in at least some cancer types, the loss of which contributes to the inactivation of the p16INK4A/RB pathway and disruption of senescence in tumor cells with intact RB.
  12. Int J Mol Sci. 2021 Nov 04. pii: 11967. [Epub ahead of print]22(21):
      Ischemic stroke is one of the leading causes of death, and even timely treatment can result in severe disabilities. Reperfusion of the ischemic stroke region and restoration of the blood supply often lead to a series of cellular and biochemical consequences, including generation of reactive oxygen species (ROS), expression of inflammatory cytokines, inflammation, and cerebral cell damage, which is collectively called cerebral ischemia-reperfusion (IR) injury. Since ROS and inflammatory cytokines are involved in cerebral IR injury, injury could involve cellular senescence. Thus, we investigated whether senolytic therapy that eliminates senescent cells could be an effective treatment for cerebral IR injury. To determine whether IR induces neural cell senescence in vitro, astrocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). OGD/R induced astrocyte senescence and senescent cells in OGD/R-injured astrocytes were effectively eliminated in vitro by ABT263, a senolytic agent. IR in rats with intraluminal middle cerebral artery occlusion induced cellular senescence in the ischemic region. The senescent cells in IR-injured rats were effectively eliminated by intravenous injections of ABT263. Importantly, ABT263 treatment significantly reduced the infarct volume and improved neurological function in behavioral tests. This study demonstrated, for the first time, that senolytic therapy has therapeutic potential for cerebral IR injury.
    Keywords:  ABT263; astrocyte; inflammation; ischemia-reperfusion injury; ischemic stroke; senescence; senolytic therapy
  13. Cell Mol Neurobiol. 2021 Nov 12.
      Cell senescence is the growth arrest caused by the accumulation of irreparable cell damage, which is involved in physiological and pathological processes and regulated by the post-transcriptional level. This regulation is performed by transcriptional regulators and driven by aging-related small RNAs, long non-coding RNAs, and RNA-binding proteins. N6-methyladenosine (m6A) is the most common chemical modification in eukaryotic mRNA, which can enhance or reduce the binding of transcriptional regulators. Increasing studies have confirmed the crucial role of m6A in controlling mRNA in various physiological processes. Remarkably, recent reports have indicated that abnormal methylation of m6A-related RNA may affect cell senescence. In this review, we clarified the association between m6A modification and cell senescence and analyzed the limitations of the current research.
    Keywords:  Cell senescence; N6-methyladenosine methylation; mRNAs
  14. J Med Chem. 2021 Nov 09.
      Cellular senescence, a process that arrests the cell cycle, is a cellular response mechanism for various stresses and is implicated in aging and various age-related diseases. However, the understanding of senescence in living organisms is insufficient, largely due to the scarcity of sensitive tools for the detection of cellular senescence in vivo. Herein, we describe the development of a self-immobilizing near-infrared (NIR) fluorogenic probe that can be activated by senescence-associated β-galactosidase (SA-β-Gal), the most widely used senescence marker. The NIR signal is turned on only in the presence of SA-β-Gal, and the fluorescence signal is retained to the site of activation via in situ labeling, significantly enhancing the sensitivity of the probe. We demonstrate its efficient noninvasive imaging of senescence in mice xenograft models.
  15. Ageing Res Rev. 2021 Nov 09. pii: S1568-1637(21)00257-9. [Epub ahead of print] 101510
      Iron is indispensable for normal body functions across species because of its critical roles in red blood cell function and many essential proteins and enzymes required for numerous physiological processes. Regulation of iron homeostasis is an intricate process involving multiple modulators at the systemic, cellular, and molecular levels. Interestingly, emerging evidence has demonstrated that many modulators of iron homeostasis contribute to organismal aging and longevity. On the other hand, the age-related dysregulation of iron homeostasis is often associated with multiple age-related pathologies including bone resorption and neurodegenerative diseases such as Alzheimer's disease. Thus, a thorough understanding on the interconnections between systemic and cellular iron balance and organismal aging may help decipher the etiologies of multiple age-related diseases, which could ultimately lead to developing therapeutic strategies to delay aging and treat various age-related diseases. Here we present the current understanding on the mechanisms of iron homeostasis. We also discuss the impacts of aging on iron homeostatic processes and how dysregulated iron metabolism may affect aging and organismal longevity.
    Keywords:  C. elegans; Drosophila; Iron; aging; homeostasis; human diseases; longevity
  16. Gut Microbes. 2021 Jan-Dec;13(1):13(1): 1994835
      Identifying ways to deal with the challenges presented by aging is an urgent task, as we are facing an aging society. External factors such as diet, exercise and drug therapy have proven to be major elements in controlling healthy aging and prolonging life expectancy. More recently, the intestinal microbiota has also become a key factor in the anti-aging process. As the intestinal microbiota changes with aging, an imbalance in intestinal microorganisms can lead to many age-related degenerative diseases and unhealthy aging. This paper reviews recent research progress on the relationship between intestinal microorganisms and anti-aging effects, focusing on the changes and beneficial effects of intestinal microorganisms under dietary intervention, exercise and drug intervention. In addition, bacteriotherapy has been used to prevent frailty and unhealthy aging. Most of these anti-aging approaches improve the aging process and age-related diseases by regulating the homeostasis of intestinal flora and promoting a healthy intestinal environment. Intervention practices based on intestinal microorganisms show great potential in the field of anti-aging medicine.
    Keywords:  Intestinal microbiota; aging; bacteriotherapy; dietary intervention; drugs; exercise
  17. Int J Mol Sci. 2021 Oct 25. pii: 11487. [Epub ahead of print]22(21):
      Aging is the major risk factor for cardiovascular disease, which is the leading cause of mortality worldwide among aging populations. Cisd2 is a prolongevity gene that mediates lifespan in mammals. Previously, our investigations revealed that a persistently high level of Cisd2 expression in mice is able to prevent age-associated cardiac dysfunction. This study was designed to apply a genetic approach that induces cardiac-specific Cisd2 overexpression (Cisd2 icOE) at a late-life stage, namely a time point immediately preceding the onset of old age, and evaluate the translational potential of this approach. Several discoveries are pinpointed. Firstly, Cisd2 is downregulated in the aging heart. This decrease in Cisd2 leads to cardiac dysfunction and impairs electromechanical performance. Intriguingly, Cisd2 icOE prevents an exacerbation of age-associated electromechanical dysfunction. Secondly, Cisd2 icOE ameliorates cardiac fibrosis and improves the integrity of the intercalated discs, thereby reversing various structural abnormalities. Finally, Cisd2 icOE reverses the transcriptomic profile of the aging heart, changing it from an older-age pattern to a younger pattern. Intriguingly, Cisd2 icOE modulates a number of aging-related pathways, namely the sirtuin signaling, autophagy, and senescence pathways, to bring about rejuvenation of the heart as it enters old age. Our findings highlight Cisd2 as a novel molecular target for developing therapies targeting cardiac aging.
    Keywords:  Cisd2; cardiac aging; cardiac rejuvenation; inducible cardiac-specific overexpression
  18. Cancer Med. 2021 Nov 11.
      Inhibition of CDK4/6 slows the cell cycle and induces senescence in breast cancer cells. However, senescent cancer cells promote invasion and metastasis. Several drugs reportedly target senescent cells, including ABT-263 (navitoclax). We examined the effects of the CDK4/6 inhibitor abemaciclib and ABT-263 on two human breast cancer cell lines. The abemaciclib and ABT-263 combination additively decreased the viability of MDA-MB-231 cells, but not MCF-7 cells. Also, the combination therapy-induced caspase-dependent apoptosis in MDA-MB-231 cells. Combination therapy with abemaciclib and ABT-737, an ABT-263 analog, significantly suppressed the in vivo growth of MDA-MB-231 with transient body-weight loss. Given that p16Ink4a and p21Cip1/Waf1 are key factors in senescence and that both cell lines were negative for p16, the role of p21 in apoptosis of treated breast cancer cells was investigated. Although abemaciclib increased the cytoplasmic p21 level in both cell lines as a hallmark of senescence, the abemaciclib and ABT-263 combination decreased it only in MDA-MB-231 cells. This decrease of p21 expression was relieved by caspase inhibition, and p21 was colocalized with caspase-3 in the cytoplasm of MDA-MB-231 cells. Alternatively, small interfering RNA-mediated knockdown of p21 rendered caspase-3-negative MCF-7 cells susceptible to abemaciclib and ABT-263, as well as TNF-related apoptosis-inducing ligand. Furthermore, a clinical database analysis showed that p21high breast cancer patients had a poorer prognosis compared to p21low patients. These results suggest that cytoplasmic p21 plays a protective role in apoptosis of CDK4/6 inhibitor-induced senescent breast cancer cells.
    Keywords:  ABT-263; abemaciclib; breast cancer; p21; senescence
  19. Mech Ageing Dev. 2021 Nov 09. pii: S0047-6374(21)00170-6. [Epub ahead of print]200 111598
      Aging is characterized by several physiological changes in the human body, such as the remodeling/redistribution of body fat, highlighted by the increase in fat in the abdominal region due to reduced fat in the peripheral limbs. Abdominal fat is related to metabolic complications and an increased risk for developing diseases such as obesity, type 2 diabetes mellitus, and hypertension. Understanding this process is crucial for developing new therapeutic strategies able to mitigate its impact. This redistribution of fat has been associated with lower activation of brown adipose tissue over the years of life. Brown adipose tissue differs from white adipose tissue, mainly because it produces heat, increasing energy expenditure. Current evidence points to morphological and functional changes in mitochondria during aging, a key mechanism for understanding the dysmetabolic and pro-inflammatory phenotype associated with senescence. Therefore, this minireview will focus on how aging-induced mitochondrial changes are involved in the remodeling/redistribution of body fat.
    Keywords:  Aging; Fat redistribution; Mitochondria; Senescence
  20. Aging Cell. 2021 Nov 09. e13513
      Oxidative stress caused by excess reactive oxygen species (ROS) accelerates telomere erosion and mitochondrial injury, leading to impaired cellular functions and cell death. Whether oxidative stress-mediated telomere erosion induces mitochondrial injury, or vice versa, in human T cells-the major effectors of host adaptive immunity against infection and malignancy-is poorly understood due to the pleiotropic effects of ROS. Here we employed a novel chemoptogenetic tool that selectively produces a single oxygen (1 O2 ) only at telomeres or mitochondria in Jurkat T cells. We found that targeted 1 O2 production at telomeres triggered not only telomeric DNA damage but also mitochondrial dysfunction, resulting in T cell apoptotic death. Conversely, targeted 1 O2 formation at mitochondria induced not only mitochondrial injury but also telomeric DNA damage, leading to cellular crisis and apoptosis. Targeted oxidative stress at either telomeres or mitochondria increased ROS production, whereas blocking ROS formation during oxidative stress reversed the telomeric injury, mitochondrial dysfunction, and cellular apoptosis. Notably, the X-ray repair cross-complementing protein 1 (XRCC1) in the base excision repair (BER) pathway and multiple mitochondrial proteins in other cellular pathways were dysregulated by the targeted oxidative stress. By confining singlet 1 O2 formation to a single organelle, this study suggests that oxidative stress induces dual injury in T cells via crosstalk between telomeres and mitochondria. Further identification of these oxidation pathways may offer a novel approach to preserve mitochondrial functions, protect telomere integrity, and maintain T cell survival, which can be exploited to combat various immune aging-associated diseases.
    Keywords:  DNA damage and repair; T cell senescence; mitochondria; oxidative stress; telomeres
  21. Cell Death Discov. 2021 Nov 12. 7(1): 349
      The role of cellular senescence in radiation-induced pulmonary fibrosis (RIPF) and the underlying mechanisms are unknown. We isolated radiation-induced senescent tdTOMp16 positive mesenchymal stem cells, established their absence of cell division, then measured levels of irradiation-induced expression of biomarkers of senescence by RNA-seq analysis. We identified a Log2 6.17-fold upregulation of tyrosine kinase Fgr, which was a potent inducer of biomarkers of fibrosis in target cells in non-contact co-cultures. Inhibition of Fgr by shRNA knockdown did not block radiation-induced senescence in vitro; however, both shRNA knockdown, or addition of a specific small-molecule inhibitor of Fgr, TL02-59, abrogated senescent cell induction of profibrotic genes in transwell-separated target cells. Single-cell RNA-seq (scRNAseq) analysis of mouse lungs at day 150 after 20 Gy thoracic irradiation revealed upregulation of Fgr in senescent neutrophils, and macrophages before detection of lung fibrosis. Thus, upregulated Fgr in radiation-induced senescent cells mediates RIPF and is a potential therapeutic target for the prevention of this radiation late effect.
  22. Metabolism. 2021 Oct 28. pii: S0026-0495(21)00223-7. [Epub ahead of print]126 154923
      More than a century after discovering NAD+, information is still evolving on the role of this molecule in health and diseases. The biological functions of NAD+ and NAD+ precursors encompass pathways in cellular energetics, inflammation, metabolism, and cell survival. Several metabolic and neurological diseases exhibit reduced tissue NAD+ levels. Significantly reduced levels of NAD+ are also associated with aging, and enhancing NAD+ levels improved healthspan and lifespan in animal models. Recent studies suggest a causal link between senescence, age-associated reduction in tissue NAD+ and enzymatic degradation of NAD+. Furthermore, the discovery of transporters and receptors involved in NAD+ precursor (nicotinic acid, or niacin, nicotinamide, and nicotinamide riboside) metabolism allowed for a better understanding of their role in cellular homeostasis including signaling functions that are independent of their functions in redox reactions. We also review studies that demonstrate that the functional effect of niacin is partially due to the activation of its cell surface receptor, GPR109a. Based on the recent progress in understanding the mechanism and function of NAD+ and NAD+ precursors in cell metabolism, new strategies are evolving to exploit these molecules' pharmacological potential in the maintenance of metabolic balance.
    Keywords:  NAD; Niacin; Niacin receptor; Nicotinamide adenine mononucleotide; Nicotinamide riboside
  23. iScience. 2021 Nov 19. 24(11): 103250
      Aging is the prime risk factor for the development of type 2 diabetes. We investigated the role of the interleukin-1 (IL-1) system on insulin secretion in aged mice. During aging, expression of the protective IL-1 receptor antagonist decreased in islets, whereas IL-1beta gene expression increased specifically in the CD45 + islet immune cell fraction. One-year-old mice with a whole-body knockout of IL-1beta had higher insulin secretion in vivo and in isolated islets, along with enhanced proliferation marker Ki67 and elevated size and number of islets. Myeloid cell-specific IL-1beta knockout preserved glucose-stimulated insulin secretion during aging, whereas it declined in control mice. Isolated islets from aged myeloIL-1beta ko mice secreted more insulin along with increased expression of Ins2, Kir6.2, and of the cell-cycle gene E2f1. IL-1beta treatment of isolated islets reduced E2f1, Ins2, and Kir6.2 expression in beta cells. We conclude that IL-1beta contributes the age-associated decline of beta cell function.
    Keywords:  Cell biology; Cellular physiology; Physiology
  24. Front Cell Dev Biol. 2021 ;9 733945
      Disrupted myelin and impaired myelin repair have been observed in the brains of patients and various mouse models of Alzheimer's disease (AD). Clemastine, an H1-antihistamine, shows the capability to induce oligodendrocyte precursor cell (OPC) differentiation and myelin formation under different neuropathological conditions featuring demyelination via the antagonism of M1 muscarinic receptor. In this study, we investigated if aged APPSwe/PS1dE9 mice, a model of AD, can benefit from chronic clemastine treatment. We found the treatment reduced brain amyloid-beta deposition and rescued the short-term memory deficit of the mice. The densities of OPCs, oligodendrocytes, and myelin were enhanced upon the treatment, whereas the levels of degraded MBP were reduced, a marker for degenerated myelin. In addition, we also suggest the role of clemastine in preventing OPCs from entering the state of cellular senescence, which was shown recently as an essential causal factor in AD pathogenesis. Thus, clemastine exhibits therapeutic potential in AD via preventing senescence of OPCs.
    Keywords:  Alzheimer’s disease; cellular senescence; clemastine; myelin; oligodendrocyte precursor cells; oligodendrocytes
  25. Aging Cell. 2021 Nov 09. e13508
      An increasing number of men are fathering children at an older age than in the past. While advanced maternal age has long been recognized as a risk factor for adverse reproductive outcomes, the influence of paternal age on reproduction is incompletely comprehended. Herein, we found that miR-125a-5p was upregulated in the sperm of aging males and was related to inferior sperm DNA integrity as an adverse predictor. Moreover, we demonstrated that miR-125a-5p suppressed mitochondrial function and increased cellular DNA damage in GC2 cells. We also found that miR-125a-5p perturbed embryo development at specific morula/blastocyst stages. Mechanistically, we confirmed that miR-125a-5p disturbed the mitochondrial function by targeting Rbm38 and activating the p53 damage response pathway, and induced a developmental delay in a p21-dependent manner. Our study revealed an important role of miR-125a-5p in sperm function and early embryo development of aging males, and provided a fresh view to comprehend the aging process in sperm.
    Keywords:  DNA damage; Rbm38; male aging; miRNA; sperm
  26. Nat Commun. 2021 Nov 09. 12(1): 6463
      Diet composition, calories, and fasting times contribute to the maintenance of health. However, the impact of very low-calorie intake (VLCI) achieved with either standard laboratory chow (SD) or a plant-based fasting mimicking diet (FMD) is not fully understood. Here, using middle-aged male mice we show that 5 months of short 4:10 VLCI cycles lead to decreases in both fat and lean mass, accompanied by improved physical performance and glucoregulation, and greater metabolic flexibility independent of diet composition. A long-lasting metabolomic reprograming in serum and liver is observed in mice on VLCI cycles with SD, but not FMD. Further, when challenged with an obesogenic diet, cycles of VLCI do not prevent diet-induced obesity nor do they elicit a long-lasting metabolic memory, despite achieving modest metabolic flexibility. Our results highlight the importance of diet composition in mediating the metabolic benefits of short cycles of VLCI.
  27. Cell Rep. 2021 Nov 09. pii: S2211-1247(21)01460-1. [Epub ahead of print]37(6): 109981
      Memory T cells exhibit considerable diversity that determines their ability to be protective. Here, we examine whether changes in T cell heterogeneity contribute to the age-associated failure of immune memory. By screening for age-dependent T cell-surface markers, we identify CD4 and CD8 memory T cell subsets that are unrelated to previously defined subsets of central and effector memory cells. Memory T cells expressing the ecto-5'-nucleotidase CD73 constitute a functionally distinct subset of memory T cells that declines with age. They resemble long-lived, polyfunctional memory cells but are also poised to display effector functions and to develop into cells resembling tissue-resident memory T cells (TRMs). Upstream regulators of differential chromatin accessibility and transcriptomes include transcription factors that facilitate CD73 expression and regulate TRM differentiation. CD73 is not just a surrogate marker of these regulatory networks but is directly involved in T cell survival.
    Keywords:  CD73; RUNX; T cell differentiation; adenosine; aging; heterogeneity; immunosenescence; memory T cell; tissue-residing memory T cells
  28. Cell Rep. 2021 Nov 09. pii: S2211-1247(21)01456-X. [Epub ahead of print]37(6): 109977
      Tumor necrosis factor (TNF) is a key driver of several inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis, in which affected tissues show an interferon-stimulated gene signature. Here, we demonstrate that TNF triggers a type-I interferon response that is dependent on the cyclic guanosine monophosphate-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. We show that TNF inhibits PINK1-mediated mitophagy and leads to altered mitochondrial function and to an increase in cytosolic mtDNA levels. Using cGAS-chromatin immunoprecipitation (ChIP), we demonstrate that cytosolic mtDNA binds to cGAS after TNF treatment. Furthermore, TNF induces a cGAS-STING-dependent transcriptional response that mimics that of macrophages from rheumatoid arthritis patients. Finally, in an inflammatory arthritis mouse model, cGAS deficiency blocked interferon responses and reduced inflammatory cell infiltration and joint swelling. These findings elucidate a molecular mechanism linking TNF to type-I interferon signaling and suggest a potential benefit for therapeutic targeting of cGAS/STING in TNF-driven diseases.
    Keywords:  ISG; STING; TNF; arthritis; autoimmune; cGAS; interferon; mitophagy; mtDNA