bims-senagi Biomed News
on Senescence and aging
Issue of 2021–05–02
twenty-one papers selected by
Maria Grazia Vizioli, Mayo Clinic
  1. The long non-coding RNA MIR31HG regulates the senescence associated secretory phenotype.
  2. Algorithmic assessment of cellular senescence in experimental and clinical specimens.
  3. Nicotinamide Phosphoribosyltransferase as a Key Molecule of the Aging/Senescence Process.
  4. Coordinate regulation of the senescent state by selective autophagy.
  5. Cellular Senescence and Inflammaging in the Skin Microenvironment.
  6. Loss of p16: A Bouncer of the Immunological Surveillance?
  7. Sir4 Deficiency Reverses Cell Senescence by Sub-Telomere Recombination.
  8. Interferon Regulatory Factor 7 impairs cellular metabolism with age in adipose-derived stromal cells.
  9. Cellular pyrimidine imbalance triggers mitochondrial DNA-dependent innate immunity.
  10. Phosphorylation of cGAS by CDK1 impairs self-DNA sensing in mitosis.
  11. TMPRSS11a is a novel age-altered, tissue specific regulator of migration and wound healing.
  12. Frataxin deficiency promotes endothelial senescence in pulmonary hypertension.
  13. Role of MicroRNA-145 in DNA Damage Signalling and Senescence in Vascular Smooth Muscle Cells of Type 2 Diabetic Patients.
  14. Human Prostate Epithelial Cells Activate the AIM2 Inflammasome upon Cellular Senescence: Role of POP3 Protein in Aging-Related Prostatic Inflammation.
  15. Evolving concepts in NAD+ metabolism.
  16. Senescent Microglia: The Key to the Ageing Brain?
  17. Shikimic acid protects skin cells from UV-induced senescence through activation of the NAD+-dependent deacetylase SIRT1.
  18. Advances in Understanding of the Role of Lipid Metabolism in Aging.
  19. Adiponectin preserves metabolic fitness during aging.
  20. Cytosolic DNA sensing by cGAS: regulation, function, and human diseases.
  21. The central role of DNA damage in the ageing process.
  1. Nat Commun. 2021 04 28. 12(1): 2459
    The long non-coding RNA MIR31HG regulates the senescence associated secretory phenotype.
    Marta Montes, Michal Lubas, Frederic S Arendrup, Bettina Mentz, Neha Rohatgi, Sarunas Tumas, Lea M Harder, Anders J Skanderup, Jens S Andersen, Anders H Lund.
      Oncogene-induced senescence provides a barrier against malignant transformation. However, it can also promote cancer through the secretion of a plethora of factors released by senescent cells, called the senescence associated secretory phenotype (SASP). We have previously shown that in proliferating cells, nuclear lncRNA MIR31HG inhibits p16/CDKN2A expression through interaction with polycomb repressor complexes and that during BRAF-induced senescence, MIR31HG is overexpressed and translocates to the cytoplasm. Here, we show that MIR31HG regulates the expression and secretion of a subset of SASP components during BRAF-induced senescence. The SASP secreted from senescent cells depleted for MIR31HG fails to induce paracrine invasion without affecting the growth inhibitory effect. Mechanistically, MIR31HG interacts with YBX1 facilitating its phosphorylation at serine 102 (p-YBX1S102) by the kinase RSK. p-YBX1S102 induces IL1A translation which activates the transcription of the other SASP mRNAs. Our results suggest a dual role for MIR31HG in senescence depending on its localization and points to the lncRNA as a potential therapeutic target in the treatment of senescence-related pathologies.
    DOI:  https://doi.org/10.1038/s41467-021-22746-4
  2. Nat Protoc. 2021 Apr 28.
    Algorithmic assessment of cellular senescence in experimental and clinical specimens.
    J Kohli, B Wang, S M Brandenburg, N Basisty, K Evangelou, M Varela-Eirin, J Campisi, B Schilling, V Gorgoulis, M Demaria.
      The development of genetic tools allowed for the validation of the pro-aging and pro-disease functions of senescent cells in vivo. These discoveries prompted the development of senotherapies-pharmaceutical interventions aimed at interfering with the detrimental effect of senescent cells-that are now entering the clinical stage. However, unequivocal identification and examination of cellular senescence remains highly difficult because of the lack of universal and specific markers. Here, to overcome the limitation of measuring individual markers, we describe a detailed two-phase algorithmic assessment to quantify various senescence-associated parameters in the same specimen. In the first phase, we combine the measurement of lysosomal and proliferative features with the expression of general senescence-associated genes to validate the presence of senescent cells. In the second phase we measure the levels of pro-inflammatory markers for specification of the type of senescence. The protocol can help graduate-level basic scientists to improve the characterization of senescence-associated phenotypes and the identification of specific senescent subtypes. Moreover, it can serve as an important tool for the clinical validation of the role of senescent cells and the effectiveness of anti-senescence therapies.
    DOI:  https://doi.org/10.1038/s41596-021-00505-5
  3. Int J Mol Sci. 2021 Apr 02. pii: 3709. [Epub ahead of print]22(7):
    Nicotinamide Phosphoribosyltransferase as a Key Molecule of the Aging/Senescence Process.
    Fiqri D Khaidizar, Yasumasa Bessho, Yasukazu Nakahata.
      Aging is a phenomenon underlined by complex molecular and biochemical changes that occur over time. One of the metabolites that is gaining strong research interest is nicotinamide adenine dinucleotide, NAD+, whose cellular level has been shown to decrease with age in various tissues of model animals and humans. Administration of NAD+ precursors, nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), to supplement NAD+ production through the NAD+ salvage pathway has been demonstrated to slow down aging processes in mice. Therefore, NAD+ is a critical metabolite now understood to mitigate age-related tissue function decline and prevent age-related diseases in aging animals. In human clinical trials, administration of NAD+ precursors to the elderly is being used to address systemic age-associated physiological decline. Among NAD+ biosynthesis pathways in mammals, the NAD+ salvage pathway is the dominant pathway in most of tissues, and NAMPT is the rate limiting enzyme of this pathway. However, only a few activators of NAMPT, which are supposed to increase NAD+, have been developed so far. In this review, we will focus on the importance of NAD+ and the possible application of an activator of NAMPT to promote successive aging.
    Keywords:  IRW; NAD+; NAMPT; NMN; NMNH; NR; P7C3; PNGL; SBI-797812; aging/senescence
    DOI:  https://doi.org/10.3390/ijms22073709
  4. Dev Cell. 2021 Apr 27. pii: S1534-5807(21)00317-8. [Epub ahead of print]
    Coordinate regulation of the senescent state by selective autophagy.
    Yeonghyeon Lee, Jaejin Kim, Mi-Sung Kim, Yoojin Kwon, Sanghee Shin, Hyerim Yi, Hyeonkyeong Kim, Moon Jong Chang, Chong Bum Chang, Seung-Baik Kang, V Narry Kim, Jin-Hong Kim, Jong-Seo Kim, Stephen J Elledge, Chanhee Kang.
      Cellular senescence is a complex stress response implicated in aging. Autophagy can suppress senescence but is counterintuitively necessary for full senescence. Although its anti-senescence role is well described, to what extent autophagy contributes to senescence establishment and the underlying mechanisms is poorly understood. Here, we show that selective autophagy of multiple regulatory components coordinates the homeostatic state of senescence. We combined a proteomic analysis of autophagy components with protein stability profiling, identifying autophagy substrate proteins involved in several senescence-related processes. Selective autophagy of KEAP1 promoted redox homeostasis during senescence. Furthermore, selective autophagy limited translational machinery components to ameliorate senescence-associated proteotoxic stress. Lastly, selective autophagy of TNIP1 enhanced senescence-associated inflammation. These selective autophagy networks appear to operate in vivo senescence during human osteoarthritis. Our data highlight a caretaker role of autophagy in the stress support network of senescence through regulated protein stability and unravel the intertwined relationship between two important age-related processes.
    Keywords:  aging; autophagy; cellular senescence; inflammation; oxidative stress; proteostasis; regulated protein stability; selective autophagy; stress response
    DOI:  https://doi.org/10.1016/j.devcel.2021.04.008
  5. Int J Mol Sci. 2021 Apr 08. pii: 3849. [Epub ahead of print]22(8):
    Cellular Senescence and Inflammaging in the Skin Microenvironment.
    Young In Lee, Sooyeon Choi, Won Seok Roh, Ju Hee Lee, Tae-Gyun Kim.
      Cellular senescence and aging result in a reduced ability to manage persistent types of inflammation. Thus, the chronic low-level inflammation associated with aging phenotype is called "inflammaging". Inflammaging is not only related with age-associated chronic systemic diseases such as cardiovascular disease and diabetes, but also skin aging. As the largest organ of the body, skin is continuously exposed to external stressors such as UV radiation, air particulate matter, and human microbiome. In this review article, we present mechanisms for accumulation of senescence cells in different compartments of the skin based on cell types, and their association with skin resident immune cells to describe changes in cutaneous immunity during the aging process.
    Keywords:  fibroblasts; immune cells; inflammaging; keratinocytes; melanocytes; senescence; skin
    DOI:  https://doi.org/10.3390/ijms22083849
  6. Life (Basel). 2021 Apr 02. pii: 309. [Epub ahead of print]11(4):
    Loss of p16: A Bouncer of the Immunological Surveillance?
    Kelly E Leon, Naveen Kumar Tangudu, Katherine M Aird, Raquel Buj.
      p16INK4A (hereafter called p16) is an important tumor suppressor protein frequently suppressed in human cancer and highly upregulated in many types of senescence. Although its role as a cell cycle regulator is very well delineated, little is known about its other non-cell cycle-related roles. Importantly, recent correlative studies suggest that p16 may be a regulator of tissue immunological surveillance through the transcriptional regulation of different chemokines, interleukins and other factors secreted as part of the senescence-associated secretory phenotype (SASP). Here, we summarize the current evidence supporting the hypothesis that p16 is a regulator of tumor immunity.
    Keywords:  cell-cycle; chemotherapy resistance; melanoma; pancreatic adenocarcinoma; senescence; senescence-associated secretory phenotype (SASP); tumor infiltration
    DOI:  https://doi.org/10.3390/life11040309
  7. Cells. 2021 Apr 01. pii: 778. [Epub ahead of print]10(4):
    Sir4 Deficiency Reverses Cell Senescence by Sub-Telomere Recombination.
    Jun Liu, Xiaojing Hong, Lihui Wang, Chao-Ya Liang, Jun-Ping Liu.
      Telomere shortening results in cellular senescence and the regulatory mechanisms remain unclear. Here, we report that the sub-telomere regions facilitate telomere lengthening by homologous recombination, thereby attenuating senescence in yeast Saccharomyces cerevisiae. The telomere protein complex Sir3/4 represses, whereas Rif1 promotes, the sub-telomere Y' element recombination. Genetic disruption of SIR4 increases Y' element abundance and rescues telomere-shortening-induced senescence in a Rad51-dependent manner, indicating a sub-telomere regulatory switch in regulating organismal senescence by DNA recombination. Inhibition of the sub-telomere recombination requires Sir4 binding to perinuclear protein Mps3 for telomere perinuclear localization and transcriptional repression of the telomeric repeat-containing RNA TERRA. Furthermore, Sir4 repression of Y' element recombination is negatively regulated by Rif1 that mediates senescence-evasion induced by Sir4 deficiency. Thus, our results demonstrate a dual opposing control mechanism of sub-telomeric Y' element recombination by Sir3/4 and Rif1 in the regulation of telomere shortening and cell senescence.
    Keywords:  Rif1; Sir4; cell senescence; senescence regulation; sub-telomeres; telomere binding protein; yeast
    DOI:  https://doi.org/10.3390/cells10040778
  8. J Cell Sci. 2021 Apr 30. pii: jcs.256230. [Epub ahead of print]
    Interferon Regulatory Factor 7 impairs cellular metabolism with age in adipose-derived stromal cells.
    Alice Nodari, Ilaria Scambi, Daniele Peroni, Elisa Calabria, Donatella Benati, Silvia Mannucci, Marcello Manfredi, Andrea Frontini, Silvia Visonà, Andrea Bozzato, Andrea Sbarbati, Federico Schena, Emilio Marengo, Mauro Krampera, Mirco Galiè.
      Dysregulated immunity and widespread metabolic dysfunctions are the most relevant hallmarks of the passing time over the adult life and their combination at midlife is strongly related to increased vulnerability to diseases. However, their causal connection remains largely unclear. Combining multi-omics and functional analyses on adipose derived stromal cells established from young (1 month) and midlife (12 months) mice we show that the increase of Interferon Regulatory Factor 7 (IRF7) over the adult life drives major metabolic changes, which includes impaired mitochondrial function, altered amino acid biogenesis and reduced expression of genes involved in branched chain amino acid (BCAA) degradation. Our results draw a new paradigm of aging as the 'sterile' activation of a cell-autonomous pathway of self-defense and identify a crucial mediator of this pathway, IRF7, as driver of metabolic dysfunction with age.
    Keywords:  Aging; Branched chain amino acid degradation; Cellular metabolism; IFN signaling; Interferon regulatory factor 7; Mitochondria
    DOI:  https://doi.org/10.1242/jcs.256230
  9. Nat Metab. 2021 Apr 26.
    Cellular pyrimidine imbalance triggers mitochondrial DNA-dependent innate immunity.
    Hans-Georg Sprenger, Thomas MacVicar, Amir Bahat, Kai Uwe Fiedler, Steffen Hermans, Denise Ehrentraut, Katharina Ried, Dusanka Milenkovic, Nina Bonekamp, Nils-Göran Larsson, Hendrik Nolte, Patrick Giavalisco, Thomas Langer.
      Cytosolic mitochondrial DNA (mtDNA) elicits a type I interferon response, but signals triggering the release of mtDNA from mitochondria remain enigmatic. Here, we show that mtDNA-dependent immune signalling via the cyclic GMP-AMP synthase‒stimulator of interferon genes‒TANK-binding kinase 1 (cGAS-STING-TBK1) pathway is under metabolic control and is induced by cellular pyrimidine deficiency. The mitochondrial protease YME1L preserves pyrimidine pools by supporting de novo nucleotide synthesis and by proteolysis of the pyrimidine nucleotide carrier SLC25A33. Deficiency of YME1L causes inflammation in mouse retinas and in cultured cells. It drives the release of mtDNA and a cGAS-STING-TBK1-dependent inflammatory response, which requires SLC25A33 and is suppressed upon replenishment of cellular pyrimidine pools. Overexpression of SLC25A33 is sufficient to induce immune signalling by mtDNA. Similarly, depletion of cytosolic nucleotides upon inhibition of de novo pyrimidine synthesis triggers mtDNA-dependent immune responses in wild-type cells. Our results thus identify mtDNA release and innate immune signalling as a metabolic response to cellular pyrimidine deficiencies.
    DOI:  https://doi.org/10.1038/s42255-021-00385-9
  10. Cell Discov. 2020 Apr 28. 6(1): 26
    Phosphorylation of cGAS by CDK1 impairs self-DNA sensing in mitosis.
    Li Zhong, Ming-Ming Hu, Li-Jun Bian, Ying Liu, Qiang Chen, Hong-Bing Shu.
      The cyclic GMP-AMP synthase (cGAS) is a widely used DNA sensor, which detects cytosolic DNA species without a preference of self or non-self microbial DNA in interphase to initiate innate immune response. How cGAS is regulated to avoid self-DNA sensing upon nuclear envelope breakdown (NEBD) during mitosis remains enigmatic. Here we show that cGAS is mostly localized in the cytoplasm in interphase and rapidly translocated to chromosomes upon NEBD in mitosis. The major mitotic kinase CDK1-cyclin B complex phosphorylates human cGAS at S305 or mouse cGAS at S291, which inhibits its ability to synthesize cGAMP upon mitotic entry. The type 1 phosphatase PP1 dephosphorylates cGAS upon mitotic exit to enable its DNA sensing ability. Our findings reveal a mechanism on how the DNA sensor cGAS is post-translationally regulated by cell cycle-dependent enzymes to ensure its proper activation for host defense of cytosolic DNA in interphase and inert to self-DNA in mitosis.
    DOI:  https://doi.org/10.1038/s41421-020-0162-2
  11. FASEB J. 2021 May;35(5): e21597
    TMPRSS11a is a novel age-altered, tissue specific regulator of migration and wound healing.
    Christian Fernandez, Andres Burgos, Diego Morales, Roberto Rosales-Rojas, Javiera Canelo, Ariela Vergara-Jaque, Gabriel Viliod Vieira, Rodrigo Alberto Alves da Silva, Katiuchia Uzzun Sales, Michael J Conboy, Eun Ji Bae, Kang-Sik Park, Vicente A Torres, Mauricio Garrido, Oscar Cerda, Irina M Conboy, Mónica Cáceres.
      Aging is a gradual biological process characterized by a decrease in cellular and organism functions. Aging-related processes involve changes in the expression and activity of several proteins. Here, we identified the transmembrane protease serine 11a (TMPRSS11a) as a new age-specific protein that plays an important role in skin wound healing. TMPRSS11a levels increased with age in rodent and human skin and gingival samples. Strikingly, overexpression of TMPRSS11a decreased cell migration and spreading, and inducing cellular senescence. Mass spectrometry, bioinformatics, and functional analyses revealed that TMPRSS11a interacts with integrin β1 through an RGD sequence contained within the C-terminal domain and that this motif was relevant for cell migration. Moreover, TMPRSS11a was associated with cellular senescence, as shown by overexpression and downregulation experiments. In agreement with tissue-specific expression of TMPRSS11a, shRNA-mediated downregulation of this protein improved wound healing in the skin, but not in the skeletal muscle of old mice, where TMPRSS11a is undetectable. Collectively, these findings indicate that TMPRSS11a is a tissue-specific factor relevant for wound healing, which becomes elevated with aging, promoting cellular senescence and inhibiting cell migration and skin repair.
    Keywords:  RGD motif; aging; beta1 integrin; cell migration
    DOI:  https://doi.org/10.1096/fj.202002253RRR
  12. J Clin Invest. 2021 Apr 27. pii: 136459. [Epub ahead of print]
    Frataxin deficiency promotes endothelial senescence in pulmonary hypertension.
    Miranda K Culley, Jingsi Zhao, Yi Yin Tai, Ying Tang, Dror Perk, Vinny Negi, Qiujun Yu, Chen-Shan C Woodcock, Adam Handen, Gil Speyer, Seungchan Kim, Yen-Chun Lai, Taijyu Satoh, Annie Mm Watson, Yassmin Al Aaraj, John Sembrat, Mauricio Rojas, Dmitry Goncharov, Elena A Goncharova, Omar F Khan, Daniel G Anderson, James E Dahlman, Aditi U Gurkar, Robert Lafyatis, Ahmed U Fayyaz, Margaret M Redfield, Mark T Gladwin, Marlene Rabinovitch, Mingxia Gu, Thomas Bertero, Stephen Y Chan.
      The dynamic regulation of endothelial pathophenotypes in pulmonary hypertension (PH) remains undefined. Cellular senescence is linked to PH with intracardiac shunts; however, its regulation across PH subtypes is unknown. Since endothelial deficiency of iron-sulfur (Fe-S) clusters is pathogenic in PH, we hypothesized that a Fe-S biogenesis protein, frataxin (FXN), controls endothelial senescence. An endothelial subpopulation in rodent and patient lungs across PH subtypes exhibited reduced FXN and elevated senescence. In vitro, hypoxic and inflammatory FXN deficiency abrogated activity of endothelial Fe-S-containing polymerases, promoting replication stress, DNA damage response, and senescence. This was also observed in stem cell-derived endothelial cells from Friedreich's ataxia (FRDA), a genetic disease of FXN deficiency, ataxia, and cardiomyopathy, often with PH. In vivo, FXN deficiency-dependent senescence drove vessel inflammation, remodeling, and PH, while pharmacologic removal of senescent cells in Fxn-deficient rodents ameliorated PH. These data offer a model of endothelial biology in PH, where FXN deficiency generates a senescent endothelial subpopulation, promoting vascular inflammatory and proliferative signals in other cells to drive disease. These findings also establish an endothelial etiology for PH in FRDA and left heart disease and support therapeutic development of senolytic drugs, reversing effects of Fe-S deficiency across PH subtypes.
    Keywords:  Cardiovascular disease; Endothelial cells; Hypertension; Pulmonology; Vascular Biology
    DOI:  https://doi.org/10.1172/JCI136459
  13. Cells. 2021 Apr 16. pii: 919. [Epub ahead of print]10(4):
    Role of MicroRNA-145 in DNA Damage Signalling and Senescence in Vascular Smooth Muscle Cells of Type 2 Diabetic Patients.
    Karen E Hemmings, Kirsten Riches-Suman, Marc A Bailey, David J O'Regan, Neil A Turner, Karen E Porter.
      Increased cardiovascular morbidity and mortality in individuals with type 2 diabetes (T2DM) is a significant clinical problem. Despite advancements in achieving good glycaemic control, this patient population remains susceptible to macrovascular complications. We previously discovered that vascular smooth muscle cells (SMC) cultured from T2DM patients exhibit persistent phenotypic aberrancies distinct from those of individuals without a diagnosis of T2DM. Notably, persistently elevated expression levels of microRNA-145 co-exist with characteristics consistent with aging, DNA damage and senescence. We hypothesised that increased expression of microRNA-145 plays a functional role in DNA damage signalling and subsequent cellular senescence specifically in SMC cultured from the vasculature of T2DM patients. In this study, markers of DNA damage and senescence were unambiguously and permanently elevated in native T2DM versus non-diabetic (ND)-SMC. Exposure of ND cells to the DNA-damaging agent etoposide inflicted a senescent phenotype, increased expression of apical kinases of the DNA damage pathway and elevated expression levels of microRNA-145. Overexpression of microRNA-145 in ND-SMC revealed evidence of functional links between them; notably increased secretion of senescence-associated cytokines and chronic activation of stress-activated intracellular signalling pathways, particularly the mitogen-activated protein kinase, p38α. Exposure to conditioned media from microRNA-145 overexpressing cells resulted in chronic p38α signalling in naïve cells, evidencing a paracrine induction and reinforcement of cell senescence. We conclude that targeting of microRNA-145 may provide a route to novel interventions to eliminate DNA-damaged and senescent cells in the vasculature and to this end further detailed studies are warranted.
    Keywords:  DNA damage; microRNA; microRNA-145; saphenous vein; senescence; smooth muscle cells; type 2 diabetes
    DOI:  https://doi.org/10.3390/cells10040919
  14. Life (Basel). 2021 Apr 20. pii: 366. [Epub ahead of print]11(4):
    Human Prostate Epithelial Cells Activate the AIM2 Inflammasome upon Cellular Senescence: Role of POP3 Protein in Aging-Related Prostatic Inflammation.
    Ravichandran Panchanathan, Vaikundamoorthy Ramalingam, Hongzhu Liu, Divaker Choubey.
      Increased levels of type I (T1) interferon (IFN)-inducible POP3 protein in myeloid cells inhibit activation of the AIM2 inflammasome and production of IL-1β and IL-18 proinflammatory cytokines. The AIM2 mRNA levels were significantly higher in benign prostate hyperplasia (BPH) than the normal prostate. Further, human normal prostate epithelial cells (PrECs), upon becoming senescent, activated an inflammasome. Because in aging related BPH senescent PrECs accumulate, we investigated the role of POP3 and AIM2 proteins in pre-senescent and senescent PrECs. Here we report that the basal levels of the POP3 mRNA and protein were lower in senescent (versus young or old) PrECs that exhibited activation of the T1 IFN response. Further, treatment of PrECs and a BPH cell line (BPH-1) that expresses the androgen receptor (AR) with the male sex hormone dihydrotestosterone (DHT) increased the basal levels of POP3 mRNA and protein, but not AIM2, and inhibited activation of the AIM2 inflammasome. Of interest, a stable knockdown of POP3 protein expression in the BPH-1 cell line increased cytosolic DNA-induced activation of AIM2 inflammasome. These observations suggest a potential role of POP3 protein in aging-related prostatic inflammation.
    Keywords:  AIM2 inflammasome; POP3; inflammation; prostate; senescence
    DOI:  https://doi.org/10.3390/life11040366
  15. Cell Metab. 2021 Apr 22. pii: S1550-4131(21)00169-8. [Epub ahead of print]
    Evolving concepts in NAD+ metabolism.
    Claudia C S Chini, Julianna D Zeidler, Sonu Kashyap, Gina Warner, Eduardo Nunes Chini.
      NAD(H) and NADP(H) have traditionally been viewed as co-factors (or co-enzymes) involved in a myriad of oxidation-reduction reactions including the electron transport in the mitochondria. However, NAD pathway metabolites have many other important functions, including roles in signaling pathways, post-translational modifications, epigenetic changes, and regulation of RNA stability and function via NAD-capping of RNA. Non-oxidative reactions ultimately lead to the net catabolism of these nucleotides, indicating that NAD metabolism is an extremely dynamic process. In fact, recent studies have clearly demonstrated that NAD has a half-life in the order of minutes in some tissues. Several evolving concepts on the metabolism, transport, and roles of these NAD pathway metabolites in disease states such as cancer, neurodegeneration, and aging have emerged in just the last few years. In this perspective, we discuss key recent discoveries and changing concepts in NAD metabolism and biology that are reshaping the field. In addition, we will pose some open questions in NAD biology, including why NAD metabolism is so fast and dynamic in some tissues, how NAD and its precursors are transported to cells and organelles, and how NAD metabolism is integrated with inflammation and senescence. Resolving these questions will lead to significant advancements in the field.
    Keywords:  NAD pathway metabolites; NAD(+); aging; disease; humans; mitochondria; transport; vitamin B3
    DOI:  https://doi.org/10.1016/j.cmet.2021.04.003
  16. Int J Mol Sci. 2021 Apr 22. pii: 4402. [Epub ahead of print]22(9):
    Senescent Microglia: The Key to the Ageing Brain?
    Eleanor K Greenwood, David R Brown.
      Ageing represents the single biggest risk factor for development of neurodegenerative disease. Despite being such long-lived cells, microglia have been relatively understudied for their role in the ageing process. Reliably identifying aged microglia has proven challenging, not least due to the diversity of cell populations, and the limitations of available models, further complicated by differences between human and rodent cells. Consequently, the literature contains multiple descriptions and categorisations of microglia with neurotoxic phenotypes, including senescence, without any unifying markers. The role of microglia in brain homeostasis, particularly iron storage and metabolism, may provide a key to reliable identification.
    Keywords:  Senescence Associated Secretory Phenotype; ageing; iron; microglia; neurodegeneration; senescence
    DOI:  https://doi.org/10.3390/ijms22094402
  17. Aging (Albany NY). 2021 04 26. 13
    Shikimic acid protects skin cells from UV-induced senescence through activation of the NAD+-dependent deacetylase SIRT1.
    Alfredo Martínez-Gutiérrez, Irene Fernández-Duran, Anna Marazuela-Duque, Nicolás G Simonet, Ibraheem Yousef, Immaculada Martínez-Rovira, Josefina Martínez-Hoyos, Alejandro Vaquero.
      UV radiation is one of the main contributors to skin photoaging by promoting the accumulation of cellular senescence, which in turn induces a proinflammatory and tissue-degrading state that favors skin aging. The members of the sirtuin family of NAD+-dependent enzymes play an anti-senescence role and their activation suggests a promising approach for preventing UV-induced senescence in the treatment of skin aging. A two-step screening designed to identify compounds able to protect cells from UV-induced senescence through sirtuin activation identified shikimic acid (SA), a metabolic intermediate in many organisms, as a bona-fide candidate. The protective effects of SA against senescence were dependent on specific activation of SIRT1 as the effect was abrogated by the SIRT1 inhibitor EX-527. Upon UV irradiation SA induced S-phase accumulation and a decrease in p16INK4A expression but did not protect against DNA damage or increased polyploidies. In contrast, SA reverted misfolded protein accumulation upon senescence, an effect that was abrogated by EX-527. Consistently, SA induced an increase in the levels of the chaperone BiP, resulting in a downregulation of unfolded protein response (UPR) signaling and UPR-dependent autophagy, avoiding their abnormal hyperactivation during senescence. SA did not directly activate SIRT1 in vitro, suggesting that SIRT1 is a downstream effector of SA signaling specifically in the response to cellular senescence. Our study not only uncovers a shikimic acid/SIRT1 signaling pathway that prevents cellular senescence, but also reinforces the role of sirtuins as key regulators of cell proteostasis.
    Keywords:  SIRT1; UV irradiation; human dermal fibroblasts; senescence; shikimic acid
    DOI:  https://doi.org/10.18632/aging.203010
  18. Cells. 2021 Apr 13. pii: 880. [Epub ahead of print]10(4):
    Advances in Understanding of the Role of Lipid Metabolism in Aging.
    Ki Wung Chung.
      During aging, body adiposity increases with changes in the metabolism of lipids and their metabolite levels. Considering lipid metabolism, excess adiposity with increased lipotoxicity leads to various age-related diseases, including cardiovascular disease, cancer, arthritis, type 2 diabetes, and Alzheimer's disease. However, the multifaceted nature and complexities of lipid metabolism make it difficult to delineate its exact mechanism and role during aging. With advances in genetic engineering techniques, recent studies have demonstrated that changes in lipid metabolism are associated with aging and age-related diseases. Lipid accumulation and impaired fatty acid utilization in organs are associated with pathophysiological phenotypes of aging. Changes in adipokine levels contribute to aging by modulating changes in systemic metabolism and inflammation. Advances in lipidomic techniques have identified changes in lipid profiles that are associated with aging. Although it remains unclear how lipid metabolism is regulated during aging, or how lipid metabolites impact aging, evidence suggests a dynamic role for lipid metabolism and its metabolites as active participants of signaling pathways and regulators of gene expression. This review describes recent advances in our understanding of lipid metabolism in aging, including established findings and recent approaches.
    Keywords:  age-related diseases; aging; lipid metabolism
    DOI:  https://doi.org/10.3390/cells10040880
  19. Elife. 2021 Apr 27. pii: e65108. [Epub ahead of print]10
    Adiponectin preserves metabolic fitness during aging.
    Na Li, Shangang Zhao, Zhuzhen Zhang, Yi Zhu, Christy M Gliniak, Lavanya Vishvanath, Yu A An, May-Yun Wang, Yingfeng Deng, Qingzhang Zhu, Bo Shan, Amber Sherwood, Toshiharu Onodera, Orhan K Oz, Ruth Gordillo, Rana K Gupta, Ming Liu, Tamas L Horvath, Vishwa Deep Dixit, Philipp E Scherer.
      Adiponectin is essential for the regulation of tissue substrate utilization and systemic insulin sensitivity. Clinical studies have suggested a positive association of circulating adiponectin with healthspan and lifespan. However, the direct effects of adiponectin on promoting healthspan and lifespan remain unexplored. Here, we are using an adiponectin null mouse and a transgenic adiponectin overexpression model. We directly assessed the effects of circulating adiponectin on the aging process and found that adiponectin null mice display exacerbated age-related glucose and lipid metabolism disorders. Moreover, adiponectin null mice have a significantly shortened lifespan on both chow and high-fat diet (HFD). In contrast, a transgenic mouse model with elevated circulating adiponectin levels has a dramatically improved systemic insulin sensitivity, reduced age-related tissue inflammation and fibrosis, and a prolonged healthspan and median lifespan. These results support a role of adiponectin as an essential regulator for healthspan and lifespan.
    Keywords:  cell biology; mouse
    DOI:  https://doi.org/10.7554/eLife.65108
  20. Signal Transduct Target Ther. 2021 Apr 30. 6(1): 170
    Cytosolic DNA sensing by cGAS: regulation, function, and human diseases.
    Le Yu, Pengda Liu.
      Sensing invasive cytosolic DNA is an integral component of innate immunity. cGAS was identified in 2013 as the major cytosolic DNA sensor that binds dsDNA to catalyze the synthesis of a special asymmetric cyclic-dinucleotide, 2'3'-cGAMP, as the secondary messenger to bind and activate STING for subsequent production of type I interferons and other immune-modulatory genes. Hyperactivation of cGAS signaling contributes to autoimmune diseases but serves as an adjuvant for anticancer immune therapy. On the other hand, inactivation of cGAS signaling causes deficiency to sense and clear the viral and bacterial infection and creates a tumor-prone immune microenvironment to facilitate tumor evasion of immune surveillance. Thus, cGAS activation is tightly controlled. In this review, we summarize up-to-date multilayers of regulatory mechanisms governing cGAS activation, including cGAS pre- and post-translational regulations, cGAS-binding proteins, and additional cGAS regulators such as ions and small molecules. We will also reveal the pathophysiological function of cGAS and its product cGAMP in human diseases. We hope to provide an up-to-date review for recent research advances of cGAS biology and cGAS-targeted therapies for human diseases.
    DOI:  https://doi.org/10.1038/s41392-021-00554-y
  21. Nature. 2021 Apr;592(7856): 695-703
    The central role of DNA damage in the ageing process.
    Björn Schumacher, Joris Pothof, Jan Vijg, Jan H J Hoeijmakers.
      Ageing is a complex, multifaceted process leading to widespread functional decline that affects every organ and tissue, but it remains unknown whether ageing has a unifying causal mechanism or is grounded in multiple sources. Phenotypically, the ageing process is associated with a wide variety of features at the molecular, cellular and physiological level-for example, genomic and epigenomic alterations, loss of proteostasis, declining overall cellular and subcellular function and deregulation of signalling systems. However, the relative importance, mechanistic interrelationships and hierarchical order of these features of ageing have not been clarified. Here we synthesize accumulating evidence that DNA damage affects most, if not all, aspects of the ageing phenotype, making it a potentially unifying cause of ageing. Targeting DNA damage and its mechanistic links with the ageing phenotype will provide a logical rationale for developing unified interventions to counteract age-related dysfunction and disease.
    DOI:  https://doi.org/10.1038/s41586-021-03307-7
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