bims-senagi Biomed News
on Senescence and aging
Issue of 2021‒02‒21
twenty-five papers selected by
Maria Grazia Vizioli
Mayo Clinic


  1. Genes Dev. 2021 Feb 18.
      Senescence is a key barrier to neoplastic transformation. To identify senescence regulators relevant to cancer, we screened a genome-wide shRNA library. Here, we describe exportin 7 (XPO7) as a novel regulator of senescence and validate its function in telomere-induced, replicative, and oncogene-induced senescence (OIS). XPO7 is a bidirectional transporter that regulates the nuclear-cytoplasmic shuttling of a broad range of substrates. Depletion of XPO7 results in reduced levels of TCF3 and an impaired induction of the cyclin-dependent kinase inhibitor p21CIP1 during OIS. Deletion of XPO7 correlates with poorer overall survival in several cancer types. Moreover, depletion of XPO7 alleviated OIS and increased tumor formation in a mouse model of liver cancer. Our results suggest that XPO7 is a novel tumor suppressor that regulates p21CIP1 expression to control senescence and tumorigenesis.
    Keywords:  TCF3; XPO7; functional screen; p21CIP1; senescence; tumor suppressor
    DOI:  https://doi.org/10.1101/gad.343269.120
  2. Sci Transl Med. 2021 Jan 27. pii: eaaz8697. [Epub ahead of print]13(578):
      Stem cell senescence increases alongside the progressive functional declines that characterize aging. The effects of extracellular vesicles (EVs) are now attracting intense interest in the context of aging and age-related diseases. Here, we demonstrate that neonatal umbilical cord (UC) is a source of EVs derived from mesenchymal stem cells (MSC-EVs). These UC-produced MSC-EVs (UC-EVs) contain abundant anti-aging signals and rejuvenate senescing adult bone marrow-derived MSCs (AB-MSCs). UC-EV-rejuvenated AB-MSCs exhibited alleviated aging phenotypes and increased self-renewal capacity and telomere length. Mechanistically, UC-EVs rejuvenate AB-MSCs at least partially by transferring proliferating cell nuclear antigen (PCNA) into recipient AB-MSCs. When tested in therapeutic context, UC-EV-triggered rejuvenation enhanced the regenerative capacities of AB-MSCs in bone formation, wound healing, and angiogenesis. Intravenously injected UC-EVs conferred anti-aging phenotypes including decreased bone and kidney degeneration in aged mice. Our findings reveal that UC-EVs are of high translational value in anti-aging intervention.
    DOI:  https://doi.org/10.1126/scitranslmed.aaz8697
  3. Aging (Albany NY). 2021 Feb 12. 13
      Senescent cells produce chronic inflammation that contributes to the diseases and debilities of aging. How this process is orchestrated in epithelial cells, the origin of human carcinomas, is poorly understood. We used human normal oral keratinocytes (NOKs) to elucidate senescence programs in a prototype primary mucosal epithelial cell that senesces spontaneously. While NOKs exhibit several typical facets of senescence, they also display distinct characteristics. These include expression of p21WAF1/CIP1 at early passages, making this common marker of senescence unreliable in NOKs. Transcriptome analysis by RNA-seq revealed specific commonalities with and differences from cancer cells, explicating the tumor avoidance role of senescence. Repression of DNA repair genes that correlated with downregulation of E2F1 mRNA and protein was observed for two donors; a divergent result was seen for the third. Using proteomic profiling of soluble (non-vesicular) and extracellular vesicle (EV) associated secretions, we propose additions to the senescence associated secretory phenotype, including HSP60, which localizes to the surface of EVs. Finally, EVs from senescent NOKs activate interferon pathway signaling in THP-1 monocytes in a STING-dependent manner and associate with mitochondrial and nuclear DNA. Our results highlight senescence changes in epithelial cells and how they might contribute to chronic inflammation and age-related diseases.
    Keywords:  carcinoma; cellular senescence; extracellular vesicles; inflammation; keratinocytes
    DOI:  https://doi.org/10.18632/aging.202658
  4. Ageing Res Rev. 2021 Feb 10. pii: S1568-1637(21)00027-1. [Epub ahead of print]67 101280
      Aging is a progressive degenerative process involving a chronic low-grade inflammation and the accumulation of senescent cells. One major issue is to reveal the mechanisms which promote the deposition of pro-inflammatory senescent cells within tissues. The accumulation involves mechanisms which increase cellular senescence as well as those inhibiting the clearance of senescent cells from tissues. It is known that a persistent inflammatory state evokes a compensatory immunosuppression which inhibits pro-inflammatory processes by impairing the functions of effector immune cells, e.g., macrophages, T cells and natural killer (NK) cells. Unfortunately, these cells are indispensable for immune surveillance and the subsequent clearance of senescent cells, i.e., the inflammation-induced counteracting immunosuppression prevents the cleansing of host tissues. Moreover, senescent cells can also repress their own clearance by expressing inhibitors of immune surveillance and releasing the ligands of NKG2D receptors which impair their surveillance by NK and cytotoxic CD8+ T cells. It seems that cellular senescence and immunosuppression establish a feed-forward process which promotes the aging process and age-related diseases. I will examine in detail the immunosuppressive mechanisms which impair the surveillance and clearance of pro-inflammatory senescent cells with aging. In addition, I will discuss several therapeutic strategies to halt the degenerative feed-forward circuit associated with the aging process and age-related diseases.
    Keywords:  Ageing; Alzheimer’s; Anti-inflammatory; Immunometabolism; Immunosenescence; Inflammaging; SASP
    DOI:  https://doi.org/10.1016/j.arr.2021.101280
  5. Stem Cells Int. 2021 ;2021 6638249
      The elderly population is prone to tendinopathy due to aging-related tendon changes such as cellular senescence and a decreased ability to modulate inflammation. Aging can render tendon stem/progenitor cells (TSCs) into premature senescence. We investigated the effects of rapamycin, a specific mTOR inhibitor, on the senescence of TSCs. We first showed that after treatment with bleomycin in vitro, rat patellar TSCs (PTSCs) underwent senescence, characterized by morphological alterations, induction of senescence-associated β-galactosidase (SA-β-gal) activity, and an increase in p53, p21, and p62 protein expression. Senescence of PTSCs was also characterized by the elevated expression of MMP-13 and TNF-α genes, both of which are molecular hallmarks of chronic tendinopathy. We then showed that rapamycin treatment was able to reverse the above senescent phenotypes and increase autophagy in the senescent PTSCs. The activation of autophagy and senescence rescue was, at least partly, due to the translocation of HMGB1 from the nucleus to the cytosol that functions as an autophagy promoter. By reducing TSC senescence, rapamycin may be used as a therapeutic to inhibit tendinopathy development in the aging population by promoting autophagy.
    DOI:  https://doi.org/10.1155/2021/6638249
  6. Exp Anim. 2021 Feb 15.
      Long-term administration of D-galactose induces oxidative stress and accelerates normal age-related changes. Hence, the D-galactose-treated rodent model has been widely used for aging research. In this study, we examined the immunological characteristics, especially CD4+ T-cell subset composition, of D-galactose-induced aging model mice to evaluate the model's utility in immunosenescence studies. The spleens of aging model mice subjected to repeated subcutaneous injections of D-galactose exhibited significant increases in T cells with the memory phenotype (CD62Llow CD44high) and individual T-cell subsets (Th1, Th2, Th17 and Treg). Furthermore, cells with the phenotype of T follicular helper (Tfh) cells were spontaneously increased. The features of T-cell subset composition in D-galactose-treated mice were in close agreement with those observed in normal aged mice and appeared to mimic the currently known normal aging processes associated with T-cell homeostasis. Our results suggest that D-galactose-induced aging models would be useful for immunosenescence studies focusing on T-cell homeostasis and give valuable insight into age-related immune system dysregulation.
    Keywords:  D-galactose; T-cell subsets; aging model; immunosenescence
    DOI:  https://doi.org/10.1538/expanim.20-0095
  7. Pharmacol Ther. 2021 Feb 12. pii: S0163-7258(21)00018-8. [Epub ahead of print] 107817
      Cellular senescence constitutes a permanent state of cell cycle arrest in proliferative cells induced by different stresses. The exploration of tumor pathogenesis and therapies has been a research hotspot in recent years. Cellular senescence is a significant mechanism to prevent the proliferation of potential tumor cells, but it can also promote tumor growth. Increasing evidence suggests that cellular senescence is involved in the pathogenesis and development of hematological malignancies, including leukemia, myelodysplastic syndrome (MDS) and multiple myeloma (MM). Cellular senescence is associated with functional decline of hematopoietic stem cells (HSCs) and increased risk of hematological malignancies. Moreover, the bone marrow (BM) microenvironment has a crucial regulatory effect in the process of these diseases. The senescence-associated secretory phenotype (SASP) in the BM microenvironment establishes a protumor environment that supports the proliferation and survival of tumor cells. Therefore, a series of therapeutic strategies targeting cellular senescence have been gradually developed, including the induction of cellular senescence and elimination of senescent cells. This review systematically summarizes the emerging information describing the roles of cellular senescence in tumorigenesis and potential clinical applications, which may be beneficial for designing rational therapeutic strategies for various hematopoietic malignancies.
    Keywords:  Bone marrow (BM) microenvironment; Cellular senescence; Hematological malignancies; Hematopoietic stem cell (HSC); Senescence-associated secretory phenotype (SASP)
    DOI:  https://doi.org/10.1016/j.pharmthera.2021.107817
  8. Front Immunol. 2020 ;11 616949
      The immune system is a tightly regulated network which allows the development of defense mechanisms against foreign antigens and tolerance toward self-antigens. Regulatory T cells (Treg) contribute to immune homeostasis by maintaining unresponsiveness to self-antigens and suppressing exaggerated immune responses. Dysregulation of any of these processes can lead to serious consequences. Classically, Treg cell functions have been described in CD4+ T cells, but other immune cells also harbour the capacity to modulate immune responses. Regulatory functions have been described for different CD8+ T cell subsets, as well as other T cells such as γδT cells or NKT cells. In this review we describe the diverse populations of Treg cells and their role in different scenarios. Special attention is paid to the aging process, which is characterized by an altered composition of immune cells. Treg cells can contribute to the development of various age-related diseases but they are poorly characterized in aged individuals. The huge diversity of cells that display immune modulatory functions and the lack of universal markers to identify Treg make the expanding field of Treg research complex and challenging. There are still many open questions that need to be answered to solve the enigma of regulatory T cells.
    Keywords:  aging; autoimmunity; diversity; immune homeostasis; inflammation; regulatory T cells
    DOI:  https://doi.org/10.3389/fimmu.2020.616949
  9. Front Aging Neurosci. 2021 ;13 573966
      Senescence-accelerated mouse prone 8 (SAMP8) is an animal model of age-related central nervous system (CNS) disorders. Although SAMP8 shows deficits in learning, memory, and emotion, its motor coordination has not been clarified. We have recently reported that DGKγ-regulated PKCγ activity is important for cerebellar motor coordination. However, involvement of the functional correlation between the kinases in age-related motor dyscoordination still remains unknown. Therefore, we have investigated the motor coordination in SAMP8 and involvement of the functional correlation between DGKγ and PKCγ in the age-related motor dyscoordination. Although 6 weeks old SAMP8 showed equivalent motor coordination with control mice (SAMR1) in the rotarod test, 24 weeks old SAMP8 exhibited significantly less latency in the rotarod test and more frequent slips in the beam test compared to the age-matched SAMR1. Furthermore, 24 weeks old SAMP8 showed the higher locomotor activity in open field test and Y-maze test. Western blotting revealed that DGKγ expression decreased in the cerebellum of 24 weeks old SAMP8, while PKCγ was upregulated. These results suggest that SAMP8 is a useful model of age-related motor dysfunction and that the DGKγ-regulated PKCγ activity is involved in the age-related motor dyscoordination.
    Keywords:  DGKγ; PKCγ; SAMP8; functional correlation; motor coordination
    DOI:  https://doi.org/10.3389/fnagi.2021.573966
  10. Front Cell Dev Biol. 2020 ;8 626011
      The antidiabetic drug metformin exerts pleiotropic effects on multiple organs, including the cardiovascular system. Evidence has shown that metformin improves healthspan and lifespan in male mice, yet its lifespan lengthening effect in females remains elusive. We herein demonstrated that metformin fails to extend the lifespan in female mice. Compared to 2-month-old young controls, 20-month-old female mice showed a spectrum of degenerative cardiac phenotypes alongside significant alterations in the extracellular matrix composition. Despite lowered reactive oxygen species production, long-term metformin treatment did not improve cardiac function in the aged female mice. In contrast, RNA sequencing analyses demonstrated that metformin treatment elevated the extracellular matrix-related gene while lowering oxidative phosphorylation-related gene expression in the heart. In addition, metformin treatment induced metabolic reprogramming that suppressed mitochondrial respiration but activated glycolysis (i.e., Warburg effect) in cultured primary cardiomyocytes and macrophages, thereby sustaining an inflammatory status and lowering ATP production. These findings suggest the unexpected detrimental effects of metformin on the regulation of cardiac homeostasis and longevity in female mice, reinforcing the significance of comprehensive testing prior to the translation of metformin-based novel therapies.
    Keywords:  ECM—extracellular matrix; heart aging; inflammation; longevity; metformin; mitochondrion
    DOI:  https://doi.org/10.3389/fcell.2020.626011
  11. Am J Physiol Endocrinol Metab. 2021 Feb 15.
      1,25(OH)2D3 have been demonstrated to exert direct actions on male reproductive system in humans or in animals. With age, renal synthesis of 1,25(OH)2D3 declines significantly, and vitamin D supplementation has been found to alleviate the manifestations of male reproductive aging. Therefore, the relationship between 1,25(OH)2D3 and male reproductive aging needs further study. Methods and results: To determine whether 1,25(OH)2D3 deficiency accelerates male reproductive senescence in aging mice, wild-type and 1α(OH)ase-/- male mice fed a rescue diet after weaning, and the reproductive phenotypes were evaluated at 12-18 month of age. We demonstrated that 1,25(OH)2D3 deficiency accelerated male reproductive senescence, representing lower fertility efficiency and gonadal hormone levels, reducing cell proliferation, increasing cell apoptosis, cellular senescence and the senescence-associated secretory phenotype (SASP). We confirmed that the increased oxidative stress and DNA damage detected in 1α(OH)ase-/- mice resulted in accelerated reproductive senescence in reproductive system, since exogenous antioxidant PQQ supplementation could largely rescue reproductive aging phenotype. We further validated the antioxidant effect of 1,25(OH)2D3 in aging wild-type mice and senescent Leydig cells by treated 18-month-old wild-type male mice or TM3 cells with 1,25(OH)2D3 or vehicle. We assessed the differential gene expression between grouped senescent TM3 cells using RNA-Seq, and verified 1,25(OH)2D3 exerted an antioxidant role by acting NF-kappaB/SOD. Conclusions: This study suggests that 1,25(OH)2D3 deficiency accelerates male reproductive senescence in aging mice by increasing oxidative stress and 1,25(OH)2D3 plays a role in alleviating oxidative stress via NF-kappaB/SOD signaling pathway.
    Keywords:  1,25(OH)2D3; NF-kappaB/SOD signaling pathway; aging mice; male reproductive senescence; oxidative stress
    DOI:  https://doi.org/10.1152/ajpendo.00531.2020
  12. Curr Mol Med. 2021 Feb 17.
      The aging process deteriorates organs' function at different levels, causing its progressive decline to resist stress, damage, and disease. In addition to alterations in metabolic control and gene expression, the rate of aging has been connected with the generation of high amounts of Reactive Oxygen Species (ROS). The essential perspective in free radical biology is that reactive oxygen species (ROS) and free radicals are toxic, mostly cause direct biological damage to targets, and are thus a major cause of oxidative stress. Different enzymatic and non-enzymatic compounds in the cells have roles in neutralizing this toxicity. Oxidative damage in aging is mostly high in particular molecular targets, such as mitochondrial DNA and aconitase, and oxidative stress in mitochondria can cause tissue aging across intrinsic apoptosis. Mitochondria's function and morphology are impaired through aging, following a decrease in the membrane potential by an increase in peroxide generation and size of the organelles. Telomeres may be the significant trigger of replicative senescence. Oxidative stress accelerates telomere loss, whereas antioxidants slow it down. Oxidative stress is a crucial modulator of telomere shortening, and that telomere-driven replicative senescence is mainly a stress response. The age-linked mitochondrial DNA mutation and protein dysfunction aggregate in some organs like the brain and skeletal muscle, thus contributing considerably to these post-mitotic tissues' aging. The aging process is mostly due to accumulated damage done by harmful species in some macromolecules such proteins, DNA, and lipids. The degradation of non-functional, oxidized proteins is a crucial part of the antioxidant defenses of cells, in which the clearance of these proteins occurs through autophagy in the cells, which is known as mitophagy for mitochondria.
    Keywords:  Aging; Senescence; Mitochondrial dysfunction; Reactive oxygen species
    DOI:  https://doi.org/10.2174/1566524021666210218112616
  13. Cell Death Dis. 2021 Feb 16. 12(2): 190
      Although aging is a major risk factor for most types of cancers, it is barely studied in this context. The transmembrane protein PLA2R1 (phospholipase A2 receptor) promotes cellular senescence, which can inhibit oncogene-induced tumor initiation. Functions and mechanisms of action of PLA2R1 during aging are largely unknown. In this study, we observed that old Pla2r1 knockout mice were more prone to spontaneously develop a wide spectrum of tumors compared to control littermates. Consistently, these knockout mice displayed increased Parp1, a master regulator of DNA damage repair, and decreased DNA damage, correlating with large human dataset analysis. Forced PLA2R1 expression in normal human cells decreased PARP1 expression, induced DNA damage and subsequent senescence, while the constitutive expression of PARP1 rescued cells from these PLA2R1-induced effects. Mechanistically, PARP1 expression is repressed by a ROS (reactive oxygen species)-Rb-dependent mechanism upon PLA2R1 expression. In conclusion, our results suggest that PLA2R1 suppresses aging-induced tumors by repressing PARP1, via a ROS-Rb signaling axis, and inducing DNA damage and its tumor suppressive responses.
    DOI:  https://doi.org/10.1038/s41419-021-03468-3
  14. Front Cell Dev Biol. 2021 ;9 623175
      During vertebrate embryonic development, cellular senescence occurs at multiple locations. To date, it has been accepted that when there has been induction of senescence in an embryonic tissue, β-galactosidase activity is detectable at a pH as high as 6.0, and this has been extensively used as a marker of cellular senescence in vivo in both whole-mount and cryosections. Such senescence-associated β-galactosidase (SA-β-GAL) labeling appears enhanced in degenerating regions of the vertebrate embryo that are also affected by programmed cell death. In this sense, there is a strong SA-β-GAL signal which overlaps with the pattern of cell death in the interdigital tissue of the developing limbs, and indeed, many of the labeled cells detected go on to subsequently undergo apoptosis. However, it has been reported that β-GAL activity at pH 6.0 is also enhanced in healthy neurons, and some retinal neurons are strongly labeled with this histochemical technique when they begin to differentiate during early embryonic development. These labeled early post-mitotic neurons also express other senescence markers such as p21. Therefore, the reliability of this histochemical technique in studying senescence in cells such as neurons that undergo prolonged and irreversible cell-cycle arrest is questionable because it is also expressed in healthy post-mitotic cells. The identification of new biomarkers of cellular senescence would, in combination with established markers, increase the specificity and efficiency of detecting cellular senescence in embryonic and healthy mature tissues.
    Keywords:  cell death; cell senescence; development; histochemistry; limb; retina
    DOI:  https://doi.org/10.3389/fcell.2021.623175
  15. Front Pharmacol. 2020 ;11 585821
      Sirtuins are NAD+ dependent histone deacetylases (HDAC) that play a pivotal role in neuroprotection and cellular senescence. SIRT1-7 are different homologs from sirtuins. They play a prominent role in many aspects of physiology and regulate crucial proteins. Modulation of sirtuins can thus be utilized as a therapeutic target for metabolic disorders. Neurological diseases have distinct clinical manifestations but are mainly age-associated and due to loss of protein homeostasis. Sirtuins mediate several life extension pathways and brain functions that may allow therapeutic intervention for age-related diseases. There is compelling evidence to support the fact that SIRT1 and SIRT2 are shuttled between the nucleus and cytoplasm and perform context-dependent functions in neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). In this review, we highlight the regulation of SIRT1 and SIRT2 in various neurological diseases. This study explores the various modulators that regulate the activity of SIRT1 and SIRT2, which may further assist in the treatment of neurodegenerative disease. Moreover, we analyze the structure and function of various small molecules that have potential significance in modulating sirtuins, as well as the technologies that advance the targeted therapy of neurodegenerative disease.
    Keywords:  SIRT1; SIRT2; modulators; neurodegenerative diseases; neuroprotective mechanism; resveratrol; selective pockets, sir reals
    DOI:  https://doi.org/10.3389/fphar.2020.585821
  16. J Transl Med. 2021 Feb 16. 19(1): 71
      Skeletal muscle aging is associated with a decline in motor function and loss of muscle mass- a condition known as sarcopenia. The underlying mechanisms that drive this pathology are associated with a failure in energy generation in skeletal muscle, either from age-related decline in mitochondrial function, or from disuse. To an extent, lifelong exercise is efficacious in preserving the energetic properties of skeletal muscle and thus may delay the onset of sarcopenia. This review discusses the cellular and molecular changes in skeletal muscle mitochondria during the aging process and how different exercise modalities work to reverse these changes. A key factor that will be described is the efficiency of mitochondrial coupling-ATP production relative to O2 uptake in myocytes and how that efficiency is a main driver for age-associated decline in skeletal muscle function. With that, we postulate the most effective exercise modality and protocol for reversing the molecular hallmarks of skeletal muscle aging and staving off sarcopenia. Two other concepts pertinent to mitochondrial efficiency in exercise-trained skeletal muscle will be integrated in this review, including- mitophagy, the removal of dysfunctional mitochondrial via autophagy, as well as the implications of muscle fiber type changes with sarcopenia on mitochondrial function.
    Keywords:  Aging; Exercise; Mitochondria; Skeletal muscle
    DOI:  https://doi.org/10.1186/s12967-021-02737-1
  17. Exp Ther Med. 2021 Mar;21(3): 238
      Glucocorticoid-induced osteoporosis is characterized by osteoblastic cell and microarchitecture dysfunction, as well as a loss of bone mass. Cell senescence contributes to the pathological process of osteoporosis and sodium hydrosulfide (NaHS) regulates the potent protective effects through delaying cell senescence. The aim of the present study was to investigate whether senescence could contribute to dexamethasone (Dex)-induced osteoblast impairment and to examine the effect of NaHS on Dex-induced cell senescence and damage. It was found that the levels of the senescence-associated markers, p53 and p21, were markedly increased in osteoblasts exposed to Dex. A p53 inhibitor reversed Dex-induced osteoblast injury, a process that was mitigated by NaHS administration through alleviating osteoblastic cell senescence. MicroRNA (miR)-22 blocked the impact of NaHS on Dex-induced osteoblast damage and senescence through targeting the regulation of Sirtuin 1 (sirt1) expression, as shown by the decreased cell viability and alkaline phosphatase activity, as well as an increased expression of p53 and p21. It was revealed that the sirt1 gene was the target of miR-22 in osteoblastic MC3T3-E1 cells through combining the results of dual luciferase reporter assays and reverse transcription-quantitative PCR, as well as western blot analyses. Silencing of sirt1 abolished the protective effect of NaHS against Dex-associated osteoblast senescence and injury. Taken together, the present study showed that NaHS prevents Dex-induced cell senescence and damage through targeting the miR-22/sirt1 pathway in osteoblastic MC3T3-E1 cells.
    Keywords:  Sirtuin 1; dexamethasone; microRNA-22; osteoblasts; senescence; sodium hydrosulfide
    DOI:  https://doi.org/10.3892/etm.2021.9669
  18. FEBS J. 2021 Feb 16.
      The adaptive immune system has the enormous challenge to protect the host through the generation and differentiation of pathogen-specific short-lived effector T cells while in parallel developing long-lived memory cells to control future encounters with the same pathogen. A complex regulatory network is needed to preserve a population of naïve cells over lifetime that exhibit sufficient diversity of antigen receptors to respond to new antigens, while also sustaining immune memory. In parallel, cells need to maintain their proliferative potential and the plasticity to differentiate into different functional lineages. Initial signs of waning immune competence emerge after 50 years of age, with increasing clinical relevance in the 7th -10th decade of life. Morbidity and mortality from infections increase, as drastically exemplified by the current COVID-19 pandemic. Many vaccines, such as for the influenza virus, are poorly effective to generate protective immunity in older individuals. Age-associated changes occur at the level of the T cell population as well as the functionality of its cellular constituents. The system highly relies on the self-renewal of naïve and memory T cells, which is robust but eventually fails. Genetic and epigenetic modifications contribute to functional differences in responsiveness and differentiation potential. To some extent, these changes arise from defective maintenance; to some, they represent successful, but not universally beneficial adaptations to the aging host. Interventions that can compensate for the age-related defects and improve immune responses in older adults are increasingly within reach.
    Keywords:  Immunosenescence; T cell aging; T cell differentiation; T cell homeostasis; adaptive immunity; cellular senescence
    DOI:  https://doi.org/10.1111/febs.15770
  19. Aging (Albany NY). 2021 Feb 11. 13
      Inappropriate activation or overactivation of cyclic GMP-AMP synthase (cGAS) by double-stranded deoxyribonucleic acid (dsDNA) initiates a regulatory signaling cascade triggering a variety of inflammatory responses, which are a great threat to human health. This study focused on identifying the role of cGAS in atherosclerosis and its potential mechanisms. The relationship between cGAS and atherosclerosis was identified in an ApoE -/- mouse model. Meanwhile, RNA sequencing (RNA-seq) analysis of the underlying mechanisms of atherosclerosis in RAW264.7 macrophages treated with cGAS inhibition was conducted. Results showed that cGAS was positively correlated with atherosclerotic plaque area, and was mainly distributed in macrophages. RNA-seq analysis revealed that inflammatory response, immune response and cytokine-cytokine receptor interaction may play important roles in the development of atherosclerosis. Real-time quantitative polymerase chain reaction (RT-qPCR) results showed that the expression of the pro-inflammatory factors, signal transducer and activator of transcription (Stat), interferon regulatory factor (Irf), toll-like receptors (Tlrs), and type I interferons (Ifns) were synergistically reduced when cGAS was inhibited. Furthermore, cGAS inhibition significantly inhibited RAW264.7 macrophage M1 polarization. These results demonstrate that cGAS may contribute to the development of atherosclerosis through synergistic inflammatory signaling of TLRs, STAT/IRF as well as IFNs, leading to macrophage M1 polarization.
    Keywords:  M1 polarization; RNA-seq; atherosclerosis; cGAS; synergistic inflammatory signaling
    DOI:  https://doi.org/10.18632/aging.202491
  20. Mol Cell. 2021 Feb 18. pii: S1097-2765(21)00044-7. [Epub ahead of print]81(4): 739-755.e7
      Cyclic GMP-AMP synthase (cGAS) recognition of cytosolic DNA is critical for the immune response to cancer and pathogen infection. Here, we discover that cGAS-DNA phase separation is required to resist negative regulation and allow efficient sensing of immunostimulatory DNA. We map the molecular determinants of cGAS condensate formation and demonstrate that phase separation functions to limit activity of the cytosolic exonuclease TREX1. Mechanistically, phase separation forms a selective environment that suppresses TREX1 catalytic function and restricts DNA degradation to an outer shell at the droplet periphery. We identify a TREX1 mutation associated with the severe autoimmune disease Aicardi-Goutières syndrome that increases penetration of TREX1 into the repressive droplet interior and specifically impairs degradation of phase-separated DNA. Our results define a critical function of cGAS-DNA phase separation and reveal a molecular mechanism that balances cytosolic DNA degradation and innate immune activation.
    Keywords:  TREX1; cGAS; innate immunity; phase separation
    DOI:  https://doi.org/10.1016/j.molcel.2021.01.024
  21. Cell Rep. 2021 Jan 26. pii: S2211-1247(20)31663-6. [Epub ahead of print]34(4): 108674
      Naive and memory T cells are maintained in a quiescent state, yet capable of rapid response and differentiation to antigen challenge via molecular mechanisms that are not fully understood. In naive cells, the deletion of Foxo1 following thymic development results in the increased expression of multiple AP-1 family members, rendering T cells less able to respond to antigenic challenge. Similarly, in the absence of FOXO1, post-infection memory T cells exhibit the characteristics of extended activation and senescence. Age-based analysis of human peripheral T cells reveals that levels of FOXO1 and its downstream target, TCF7, are inversely related to host age, whereas the opposite is found for AP-1 factors. These characteristics of aging also correlate with the formation of T cells manifesting features of cellular senescence. Our work illustrates a role for FOXO1 in the active maintenance of stem-like properties in T cells at the timescales of acute infection and organismal life span.
    Keywords:  AP-1; CD8; FOXO1; T cells; aging; effector; immune senescence; memory; multipotency; quiescence
    DOI:  https://doi.org/10.1016/j.celrep.2020.108674
  22. Cell Rep. 2021 Feb 16. pii: S2211-1247(21)00026-7. [Epub ahead of print]34(7): 108713
      AMP-activated protein kinase (AMPK) is an energy sensor that plays roles in multiple biological processes beyond metabolism. Several studies have suggested that AMPK is involved in the DNA damage response (DDR), but the mechanisms remain unclear. Herein, we demonstrate that AMPK promotes classic non-homologous end joining (c-NHEJ) in double-strand break (DSB) repair through recruiting a key chromatin-based mediator named p53-binding protein 1 (53BP1), which facilitates the end joining of distal DNA ends during DDR. We find that the interaction of AMPK and 53BP1 spatially occurs under DSB stress. In the context of DSBs, AMPK directly phosphorylates 53BP1 at Ser1317 and promotes 53BP1 recruitment during DDR for an efficient c-NHEJ, thus maintaining genomic stability and diversity of the immune repertoire. Taken together, our study demonstrates that AMPK is a regulator of 53BP1 and controls c-NHEJ choice by phospho-regulation.
    Keywords:  53BP1; AMPK; DNA double-strand break repair; genomic stability; phosphorylation
    DOI:  https://doi.org/10.1016/j.celrep.2021.108713
  23. Biochem J. 2021 Feb 19. pii: BCJ20200676. [Epub ahead of print]
      Abnormal lipid accumulation is associated to the development of metabolic diseases such as hepatic steatosis and lipid storage diseases. Pharmacological agents that can attenuate lipid accumulation therefore have therapeutic potentials for these diseases. Resveratrol (RSV), a natural active substance found in fruits and nuts, has been reported to effectively reduce the intracellular lipid accumulation, but the underlying mechanisms of RSV remain elusive. Here, we show that RSV triggers an endoplasmic reticulum (ER)- Ca2+ signaling that activates transcriptional factor EB (TFEB), a master transcriptional regulator of autophagic and lysosomal biogenesis. Moreover, RSV activates protein phosphatase 2A (PP2A), which binds and dephosphorylates TFEB, promoting its nuclear translocation and the expression of TFEB target genes required for autophagosome and lysosomal biogenesis. Notably, genetic inhibition of TFEB significantly ameliorates RSV-mediated lipid clearance. Taken together, these data link RSV-induced ER calcium signaling, PP2A and TFEB activation to promote autophagy and lysosomal function, by which RSV may trigger a cellular self-defense mechanism that effectively mitigate lipid accumulation commonly associated with many metabolic diseases.
    Keywords:  Lysosome; PP2A; Resveratrol; TFEB
    DOI:  https://doi.org/10.1042/BCJ20200676
  24. Proc Natl Acad Sci U S A. 2021 Feb 23. pii: e1921481118. [Epub ahead of print]118(8):
      Behaviors that rely on the hippocampus are particularly susceptible to chronological aging, with many aged animals (including humans) maintaining cognition at a young adult-like level, but many others the same age showing marked impairments. It is unclear whether the ability to maintain cognition over time is attributable to brain maintenance, sufficient cognitive reserve, compensatory changes in network function, or some combination thereof. While network dysfunction within the hippocampal circuit of aged, learning-impaired animals is well-documented, its neurobiological substrates remain elusive. Here we show that the synaptic architecture of hippocampal regions CA1 and CA3 is maintained in a young adult-like state in aged rats that performed comparably to their young adult counterparts in both trace eyeblink conditioning and Morris water maze learning. In contrast, among learning-impaired, but equally aged rats, we found that a redistribution of synaptic weights amplifies the influence of autoassociational connections among CA3 pyramidal neurons, yet reduces the synaptic input onto these same neurons from the dentate gyrus. Notably, synapses within hippocampal region CA1 showed no group differences regardless of cognitive ability. Taking the data together, we find the imbalanced synaptic weights within hippocampal CA3 provide a substrate that can explain the abnormal firing characteristics of both CA3 and CA1 pyramidal neurons in aged, learning-impaired rats. Furthermore, our work provides some clarity with regard to how some animals cognitively age successfully, while others' lifespans outlast their "mindspans."
    Keywords:  aging; cognition; hippocampus; synapse
    DOI:  https://doi.org/10.1073/pnas.1921481118