bims-senagi Biomed News
on Senescence and aging
Issue of 2021–04–04
23 papers selected by
Maria Grazia Vizioli, Mayo Clinic
  1. m6A-independent genome-wide METTL3 and METTL14 redistribution drives the senescence-associated secretory phenotype.
  2. A decrease in NAD+ contributes to the loss of osteoprogenitors and bone mass with aging.
  3. Therapy-Induced Senescence: Opportunities to Improve Anti-Cancer Therapy.
  4. Hypoxia-inducible factor-2α mediates senescence-associated intrinsic mechanisms of age-related bone loss.
  5. Chemoinformatic Screening for the Selection of Potential Senolytic Compounds from Natural Products.
  6. Senolytics: targeting senescent cells for age-associated diseases.
  7. Transcriptomic Analysis of Cellular Senescence: One Step Closer to Senescence Atlas.
  8. Declined miR-181a-5p expression is associated with impaired natural killer cell development and function with aging.
  9. Human skin aging is associated with increased expression of the histone variant H2A.J in the epidermis.
  10. Biological functions of therapy-induced senescence in cancer.
  11. Transcriptome and lipidome profile of human mesenchymal stem cells with reduced senescence and increased trilineage differentiation ability upon drug treatment.
  12. Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and lifespan in mice.
  13. 17-a-estradiol late in life extends lifespan in aging UM-HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex.
  14. Skeletal muscle transcriptome in healthy aging.
  15. Understanding the Potential Role of Sirtuin 2 on Aging: Consequences of SIRT2.3 Overexpression in Senescence.
  16. Reprogramming lipid metabolism prevents effector T cell senescence and enhances tumor immunotherapy.
  17. JNK signaling prevents biliary cyst formation through a CASPASE-8-dependent function of RIPK1 during aging.
  18. Selenium supplementation inhibits IGF-1 signaling and confers methionine restriction-like healthspan benefits to mice.
  19. cGAS-STING cytosolic DNA sensing pathway is suppressed by JAK2-STAT3 in tumor cells.
  20. Targeting the Mitochondria-Proteostasis Axis to Delay Aging.
  21. Telomere Length and Oxidative Stress and Its Relation with Metabolic Syndrome Components in the Aging.
  22. Olfactory perception of food abundance regulates dietary restriction-mediated longevity via a brain-to-gut signal.
  23. Inactivating histone deacetylase HDA promotes longevity by mobilizing trehalose metabolism.
  1. Nat Cell Biol. 2021 Apr 01.
    m6A-independent genome-wide METTL3 and METTL14 redistribution drives the senescence-associated secretory phenotype.
    Pingyu Liu, Fuming Li, Jianhuang Lin, Takeshi Fukumoto, Timothy Nacarelli, Xue Hao, Andrew V Kossenkov, M Celeste Simon, Rugang Zhang.
      Methyltransferase-like 3 (METTL3) and 14 (METTL14) are core subunits of the methyltransferase complex that catalyses messenger RNA N6-methyladenosine (m6A) modification. Despite the expanding list of m6A-dependent functions of the methyltransferase complex, the m6A-independent function of the METTL3 and METTL14 complex remains poorly understood. Here we show that genome-wide redistribution of METTL3 and METTL14 transcriptionally drives the senescence-associated secretory phenotype (SASP) in an m6A-independent manner. METTL14 is redistributed to the enhancers, whereas METTL3 is localized to the pre-existing NF-κB sites within the promoters of SASP genes during senescence. METTL3 and METTL14 are necessary for SASP. However, SASP is not regulated by m6A mRNA modification. METTL3 and METTL14 are required for both the tumour-promoting and immune-surveillance functions of senescent cells, which are mediated by SASP in vivo in mouse models. In summary, our results report an m6A-independent function of the METTL3 and METTL14 complex in transcriptionally promoting SASP during senescence.
    DOI:  https://doi.org/10.1038/s41556-021-00656-3
  2. NPJ Aging Mech Dis. 2021 Apr 01. 7(1): 8
    A decrease in NAD+ contributes to the loss of osteoprogenitors and bone mass with aging.
    Ha-Neui Kim, Filipa Ponte, Aaron Warren, Rebecca Ring, Srividhya Iyer, Li Han, Maria Almeida.
      Age-related osteoporosis is caused by a deficit in osteoblasts, the cells that secrete bone matrix. The number of osteoblast progenitors also declines with age associated with increased markers of cell senescence. The forkhead box O (FoxO) transcription factors attenuate Wnt/β-catenin signaling and the proliferation of osteoprogenitors, thereby decreasing bone formation. The NAD+-dependent Sirtuin1 (Sirt1) deacetylates FoxOs and β-catenin in osteoblast progenitors and, thereby, increases bone mass. However, it remains unknown whether the Sirt1/FoxO/β-catenin pathway is dysregulated with age in osteoblast progenitors. We found decreased levels of NAD+ in osteoblast progenitor cultures from old mice, associated with increased acetylation of FoxO1 and markers of cell senescence. The NAD+ precursor nicotinamide riboside (NR) abrogated FoxO1 and β-catenin acetylation and several marker of cellular senescence, and increased the osteoblastogenic capacity of cells from old mice. Consistent with these effects, NR administration to C57BL/6 mice counteracted the loss of bone mass with aging. Attenuation of NAD+ levels in osteoprogenitor cultures from young mice inhibited osteoblastogenesis in a FoxO-dependent manner. In addition, mice with decreased NAD+ in cells of the osteoblast lineage lost bone mass at a young age. Together, these findings suggest that the decrease in bone formation with old age is due, at least in part, to a decrease in NAD+ and dysregulated Sirt1/FoxO/β-catenin pathway in osteoblast progenitors. NAD+ repletion, therefore, represents a rational therapeutic approach to skeletal involution.
    DOI:  https://doi.org/10.1038/s41514-021-00058-7
  3. J Natl Cancer Inst. 2021 Apr 01. pii: djab064. [Epub ahead of print]
    Therapy-Induced Senescence: Opportunities to Improve Anti-Cancer Therapy.
    Pataje G Prasanna, Deborah E Citrin, Jeffrey Hildesheim, Mansoor M Ahmed, Sundar Venkatachalam, Gabriela Riscuta, Dan Xi, Guangrong Zheng, Jan van Deursen, Jorg Goronzy, Stephen J Kron, Mitchell S Anscher, Norman E Sharpless, Judith Campisi, Stephen L Brown, Laura J Niedernhofer, Ana O'Loghlen, Alexandros G Georgakilas, Francois Paris, David Gius, David A Gewirtz, Clemens A Schmitt, Mohamed E Abazeed, James L Kirkland, Ann Richmond, Paul B Romesser, Scott W Lowe, Jesus Gil, Marc S Mendonca, Sandeep Burma, Daohong Zhou, C Norman Coleman.
      Cellular senescence is an essential tumor suppressive mechanism that prevents the propagation of oncogenically activated, genetically unstable, and/or damaged cells. Induction of tumor cell senescence is also one of the underlying mechanisms by which cancer therapies exert antitumor activity. However, an increasing body of evidence from preclinical studies demonstrates that radiation and chemotherapy cause accumulation of senescent cells (SnCs) both in tumor and normal tissue. SnCs in tumors can, paradoxically, promote tumor relapse, metastasis, and resistance to therapy, in part, through expression of the senescence-associated secretory phenotype. In addition, SnCs in normal tissue can contribute to certain radiation- and chemotherapy-induced side effects. Because of its multiple roles, cellular senescence could serve as an important target in the fight against cancer. This commentary provides a summary of the discussion at the National Cancer Institute Workshop on Radiation, Senescence, and Cancer (August 10-11, 2020, National Cancer Institute, Bethesda, MD) regarding the current status of senescence research, heterogeneity of therapy-induced senescence, current status of senotherapeutics and molecular biomarkers, a concept of "one-two punch" cancer therapy (consisting of therapeutics to induce tumor cell senescence followed by selective clearance of SnCs), and its integration with personalized adaptive tumor therapy. It also identifies key knowledge gaps and outlines future directions in this emerging field to improve treatment outcomes for cancer patients.
    Keywords:  "One-Two Punch" Cancer Therapy; Aging; Cancer; Cancer Therapy; Radiation; Radiation Therapy; Senescence; Senolytics; Senomorphics; Senotherapeutics; Therapy-Induced Senescence
    DOI:  https://doi.org/10.1093/jnci/djab064
  4. Exp Mol Med. 2021 Apr 02.
    Hypoxia-inducible factor-2α mediates senescence-associated intrinsic mechanisms of age-related bone loss.
    Sun Young Lee, Ka Hyon Park, Gyuseok Lee, Su-Jin Kim, Won-Hyun Song, Seung-Hee Kwon, Jeong-Tae Koh, Yun Hyun Huh, Je-Hwang Ryu.
      Aging is associated with cellular senescence followed by bone loss leading to bone fragility in humans. However, the regulators associated with cellular senescence in aged bones need to be identified. Hypoxia-inducible factor (HIF)-2α regulates bone remodeling via the differentiation of osteoblasts and osteoclasts. Here, we report that HIF-2α expression was highly upregulated in aged bones. HIF-2α depletion in male mice reversed age-induced bone loss, as evidenced by an increase in the number of osteoblasts and a decrease in the number of osteoclasts. In an in vitro model of doxorubicin-mediated senescence, the expression of Hif-2α and p21, a senescence marker gene, was enhanced, and osteoblastic differentiation of primary mouse calvarial preosteoblast cells was inhibited. Inhibition of senescence-induced upregulation of HIF-2α expression during matrix maturation, but not during the proliferation stage of osteoblast differentiation, reversed the age-related decrease in Runx2 and Ocn expression. However, HIF-2α knockdown did not affect p21 expression or senescence progression, indicating that HIF-2α expression upregulation in senescent osteoblasts may be a result of aging rather than a cause of cellular senescence. Osteoclasts are known to induce a senescent phenotype during in vitro osteoclastogenesis. Consistent with increased HIF-2α expression, the expression of p16 and p21 was upregulated during osteoclastogenesis of bone marrow macrophages. ChIP following overexpression or knockdown of HIF-2α using adenovirus revealed that p16 and p21 are direct targets of HIF-2α in osteoclasts. Osteoblast-specific (Hif-2αfl/fl;Col1a1-Cre) or osteoclast-specific (Hif-2αfl/fl;Ctsk-Cre) conditional knockout of HIF-2α in male mice reversed age-related bone loss. Collectively, our results suggest that HIF-2α acts as a senescence-related intrinsic factor in age-related dysfunction of bone homeostasis.
    DOI:  https://doi.org/10.1038/s12276-021-00594-y
  5. Biomolecules. 2021 Mar 22. pii: 467. [Epub ahead of print]11(3):
    Chemoinformatic Screening for the Selection of Potential Senolytic Compounds from Natural Products.
    Oscar Salvador Barrera-Vázquez, Juan Carlos Gómez-Verjan, Gil Alfonso Magos-Guerrero.
      Cellular senescence is a cellular condition that involves significant changes in gene expression and the arrest of cell proliferation. Recently, it has been suggested in experimental models that the elimination of senescent cells with pharmacological methods delays, prevents, and improves multiple adverse outcomes related to age. In this sense, the so-called senoylitic compounds are a class of drugs that selectively eliminates senescent cells (SCs) and that could be used in order to delay such adverse outcomes. Interestingly, the first senolytic drug (navitoclax) was discovered by using chemoinformatic and network analyses. Thus, in the present study, we searched for novel senolytic compounds through the use of chemoinformatic tools (fingerprinting and network pharmacology) over different chemical databases (InflamNat and BIOFACQUIM) coming from natural products (NPs) that have proven to be quite remarkable for drug development. As a result of screening, we obtained three molecules (hinokitiol, preussomerin C, and tanshinone I) that could be considered senolytic compound candidates since they share similarities in structure with senolytic leads (tunicamycin, ginsenoside Rb1, ABT 737, rapamycin, navitoclax, timosaponin A-III, digoxin, roxithromycin, and azithromycin) and targets involved in senescence pathways with potential use in the treatment of age-related diseases.
    Keywords:  aging; chemoinformatics; database; natural products; senescence; senolytics
    DOI:  https://doi.org/10.3390/biom11030467
  6. Curr Mol Biol Rep. 2020 Dec;6(4): 161-172
    Senolytics: targeting senescent cells for age-associated diseases.
    Iman M A Al-Naggar, George A Kuchel, Ming Xu.
      
    Keywords:  Aging; Cellular senescence; Healthspan; Lifespan; Senolytics
    DOI:  https://doi.org/10.1007/s40610-020-00140-1
  7. Mol Cells. 2021 Mar 31. 44(3): 136-145
    Transcriptomic Analysis of Cellular Senescence: One Step Closer to Senescence Atlas.
    Sohee Kim, Chuna Kim.
      Senescent cells that gradually accumulate during aging are one of the leading causes of aging. While senolytics can improve aging in humans as well as mice by specifically eliminating senescent cells, the effect of the senolytics varies in different cell types, suggesting variations in senescence. Various factors can induce cellular senescence, and the rate of accumulation of senescent cells differ depending on the organ. In addition, since the heterogeneity is due to the spatiotemporal context of senescent cells, in vivo studies are needed to increase the understanding of senescent cells. Since current methods are often unable to distinguish senescent cells from other cells, efforts are being made to find markers commonly expressed in senescent cells using bulk RNA-sequencing. Moreover, single-cell RNA (scRNA) sequencing, which analyzes the transcripts of each cell, has been utilized to understand the in vivo characteristics of the rare senescent cells. Recently, transcriptomic cell atlases for each organ using this technology have been published in various species. Novel senescent cells that do not express previously established marker genes have been discovered in some organs. However, there is still insufficient information on senescent cells due to the limited throughput of the scRNA sequencing technology. Therefore, it is necessary to improve the throughput of the scRNA sequencing technology or develop a way to enrich the rare senescent cells. The in vivo senescent cell atlas that is established using rapidly developing single-cell technologies will contribute to the precise rejuvenation by specifically removing senescent cells in each tissue and individual.
    Keywords:  aging; cellular senescence; heterogeneity; single-cell RNA sequencing; transcriptomics
    DOI:  https://doi.org/10.14348/molcells.2021.2239
  8. Aging Cell. 2021 Mar 29. e13353
    Declined miR-181a-5p expression is associated with impaired natural killer cell development and function with aging.
    Jiao Lu, Shan Li, Xiaopeng Li, Wenming Zhao, Xuefeng Duan, Xiuling Gu, Jianqiao Xu, Bolan Yu, Luis J Sigal, Zhongjun Dong, Lixin Xie, Min Fang.
      MicroRNAs (miRNAs) regulate gene expression and thereby influence cell development and function. Numerous studies have shown the significant roles of miRNAs in regulating immune cells including natural killer (NK) cells. However, little is known about the role of miRNAs in NK cells with aging. We previously demonstrated that the aged C57BL/6 mice have significantly decreased proportion of mature (CD27- CD11b+ ) NK cells compared with young mice, indicating impaired maturation of NK cells with aging. Here, we performed deep sequencing of CD27+ NK cells from young and aged mice. Profiling of the miRNome (global miRNA expression levels) revealed that 49 miRNAs displayed a twofold or greater difference in expression between young and aged NK cells. Among these, 30 miRNAs were upregulated and 19 miRNAs were downregulated in the aged NK cells. We found that the expression level of miR-l8la-5p was increased with the maturation of NK cells, and significantly decreased in NK cells from the aged mice. Knockdown of miR-181a-5p inhibited NK cell development in vitro and in vivo. Furthermore, miR-181a-5p is highly conserved in mice and human. MiR-181a-5p promoted the production of IFN-γ and cytotoxicity in stimulated NK cells from both mice and human. Importantly, miR-181a-5p level markedly decreased in NK cells from PBMC of elderly people. Thus, our results demonstrated that the miRNAs profiles in NK cells change with aging, the decreased level of miR-181a-5p contributes to the defective NK cell development and function with aging. This opens new strategies to preserve or restore NK cell function in the elderly.
    Keywords:  MiR-181a-5p; MiRNome; NK cells; aging; development; function
    DOI:  https://doi.org/10.1111/acel.13353
  9. NPJ Aging Mech Dis. 2021 Apr 01. 7(1): 7
    Human skin aging is associated with increased expression of the histone variant H2A.J in the epidermis.
    Claudia E Rübe, Caroline Bäumert, Nadine Schuler, Anna Isermann, Zoé Schmal, Matthias Glanemann, Carl Mann, Harry Scherthan.
      Cellular senescence is an irreversible growth arrest that occurs as a result of damaging stimuli, including DNA damage and/or telomere shortening. Here, we investigate histone variant H2A.J as a new biomarker to detect senescent cells during human skin aging. Skin biopsies from healthy volunteers of different ages (18-90 years) were analyzed for H2A.J expression and other parameters involved in triggering and/or maintaining cellular senescence. In the epidermis, the proportions of H2A.J-expressing keratinocytes increased from ≈20% in young to ≈60% in aged skin. Inverse correlations between Ki67- and H2A.J staining in germinative layers may reflect that H2A.J-expressing cells having lost their capacity to divide. As cellular senescence is triggered by DNA-damage signals, persistent 53BP1-foci, telomere lengths, and telomere-associated damage foci were analyzed in epidermal keratinocytes. Only slight age-related telomere attrition and few persistent nuclear 53BP1-foci, occasionally colocalizing with telomeres, suggest that unprotected telomeres are not a significant cause of senescence during skin aging. Quantification of integrin-α6+ basal cells suggests that the number and function of stem/progenitor cells decreased during aging and their altered proliferation capacities resulted in diminished tissue renewal with epidermal thinning. Collectively, our findings suggest that H2A.J is a sensitive marker of epidermal aging in human skin.
    DOI:  https://doi.org/10.1038/s41514-021-00060-z
  10. Semin Cancer Biol. 2021 Mar 25. pii: S1044-579X(21)00071-7. [Epub ahead of print]
    Biological functions of therapy-induced senescence in cancer.
    Eleni Fitsiou, Abel Soto-Gamez, Marco Demaria.
      Therapy-induced cellular senescence is a state of stable growth arrest induced by common cancer treatments such as chemotherapy and radiation. In an oncogenic context, therapy-induced senescence can have different consequences. By blocking cellular proliferation and by facilitating immune cell infiltration, it functions as tumor suppressive mechanism. By fueling the proliferation of bystander cells and facilitating metastasis, it acts as a tumor promoting factor. This dual role is mainly attributed to the differential expression and secretion of a set of pro-inflammatory cytokines and tissue remodeling factors, collectively known as the Senescence-Associated Secretory Phenotype (SASP). Here, we describe cell-autonomous and non-cell-autonomous mechanisms that senescent cells activate in response to chemotherapy and radiation leading to tumor suppression and tumor promotion. We present the current state of knowledge on the stimuli that affect the activation of these opposing mechanisms and the effect of senescent cells on their micro-environment eg. by regulating the functions of immune cells in tumor clearance as well as strategies to eliminate senescent tumor cells before exerting their deleterious side-effects.
    Keywords:  SASP; cancer; immune system; senolytics; therapy-induced senescence
    DOI:  https://doi.org/10.1016/j.semcancer.2021.03.021
  11. Aging (Albany NY). 2021 Mar 26. 13
    Transcriptome and lipidome profile of human mesenchymal stem cells with reduced senescence and increased trilineage differentiation ability upon drug treatment.
    Yue Chen, Xinglan An, Zengmiao Wang, Shuanghong Guan, Hongyu An, Qingyuan Huang, Haobo Zhang, Lin Liang, Bo Huang, Huiyu Wang, Min Lu, Huan Nie, Jun Wang, Xiangpeng Dai, Xin Lu.
      Human Mesenchymal stem cells (hMSCs) are multi-potential cells which are widely used in cell therapy. However, the frequently emerged senescence and decrease of differentiation capabilities limited the broad applications of MSC. Several strategies such as small molecules treatment have been widely studied and used to improve the stem characteristics bypassing the senescence but the exact mechanisms for them to reduce senescence have not been fully studied. In this study, hMSCs were treated by rapamycin, oltipraz, metformin, and vitamin C for the indicated time and these cells were subjected to senescence evaluation and trilineage differentiation. Furthermore, transcriptomics and lipidomics datasets of hMSCs after drug treatment were analyzed to interpret biological pathways responsible for their anti-senescence effects. Although four drugs exhibited significant activities in promoting MSC osteogenic differentiation, metformin is the optimal drug to promote trilineage differentiation. GO terms illustrated that the anti-aging effects of drugs were mainly associated with cellular senescence, mitotic and meiosis process. Biosynthesis of phosphatidylcholines (PC) and phosphatidylethanolamine (PE) were inhibited whereas production of phosphatidylinositols (PIs) and saturated fatty acids (SFA)/ mono-unsaturated fatty acids (MUFA) conversion was activated. Medium free fatty acids (FFA) was increased in hMSCs with different anti-aging phenotypes. Therefore, we established a comprehensive method in assessing drug intervention based on the results of transcriptomics and lipidomics. The method can be used to study different biological phenotypes upon drug intervention in MSC which will extend the clinical application of hMSCs.
    Keywords:  aging; drugs; hMSCs; lipidomics; transcriptomics
    DOI:  https://doi.org/10.18632/aging.202759
  12. Nat Aging. 2021 Jan;1(1): 73-86
    Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and lifespan in mice.
    Nicole E Richardson, Elizabeth N Konon, Haley S Schuster, Alexis T Mitchell, Colin Boyle, Allison C Rodgers, Megan Finke, Lexington R Haider, Deyang Yu, Victoria Flores, Heidi H Pak, Soha Ahmad, Sareyah Ahmed, Abigail Radcliff, Jessica Wu, Elizabeth M Williams, Lovina Abdi, Dawn S Sherman, Timothy Hacker, Dudley W Lamming.
      Protein restricted (PR) diets promote health and longevity in many species. While the precise components of a PR diet that mediate the beneficial effects to longevity have not been defined, we recently showed that many metabolic effects of PR can be attributed to reduced dietary levels of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine. Here, we demonstrate that restricting dietary BCAAs increases the survival of two different progeroid mouse models, delays frailty and promotes the metabolic health of wild-type C57BL/6J mice when started in midlife, and leads to a 30% increase in lifespan and a reduction in frailty in male, but not female, wild-type mice when fed lifelong. Our results demonstrate that restricting dietary BCAAs can increase healthspan and longevity in mice, and suggest that reducing dietary BCAAs may hold potential as a translatable intervention to promote healthy aging.
    Keywords:  branched-chain amino acids; healthspan; lifespan; mTOR; mTORC1; progeria; protein restriction; rapamycin
    DOI:  https://doi.org/10.1038/s43587-020-00006-2
  13. Aging Cell. 2021 Mar 31. e13328
    17-a-estradiol late in life extends lifespan in aging UM-HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex.
    David E Harrison, Randy Strong, Peter Reifsnyder, Navasuja Kumar, Elizabeth Fernandez, Kevin Flurkey, Martin A Javors, Marisa Lopez-Cruzan, Francesca Macchiarini, James F Nelson, Alessandro Bitto, Amy L Sindler, Gino Cortopassi, Kylie Kavanagh, Lin Leng, Richard Bucala, Nadia Rosenthal, Adam Salmon, Timothy M Stearns, Molly Bogue, Richard A Miller.
      In genetically heterogeneous mice produced by the CByB6F1 x C3D2F1 cross, the "non-feminizing" estrogen, 17-α-estradiol (17aE2), extended median male lifespan by 19% (p < 0.0001, log-rank test) and 11% (p = 0.007) when fed at 14.4 ppm starting at 16 and 20 months, respectively. 90th percentile lifespans were extended 7% (p = 0.004, Wang-Allison test) and 5% (p = 0.17). Body weights were reduced about 20% after starting the 17aE2 diets. Four other interventions were tested in males and females: nicotinamide riboside, candesartan cilexetil, geranylgeranylacetone, and MIF098. Despite some data suggesting that nicotinamide riboside would be effective, neither it nor the other three increased lifespans significantly at the doses tested. The 17aE2 results confirm and extend our original reports, with very similar results when started at 16 months compared with mice started at 10 months of age in a prior study. The consistently large lifespan benefit in males, even when treatment is started late in life, may provide information on sex-specific aspects of aging.
    Keywords:  17-α-estradiol; candesartan cilexetil; geranylgeranylacetone; heterogeneous mice; lifespan; macrophage migration inhibitory factor; nicotinamide riboside
    DOI:  https://doi.org/10.1111/acel.13328
  14. Nat Commun. 2021 Apr 01. 12(1): 2014
    Skeletal muscle transcriptome in healthy aging.
    Robert A Tumasian, Abhinav Harish, Gautam Kundu, Jen-Hao Yang, Ceereena Ubaida-Mohien, Marta Gonzalez-Freire, Mary Kaileh, Linda M Zukley, Chee W Chia, Alexey Lyashkov, William H Wood, Yulan Piao, Christopher Coletta, Jun Ding, Myriam Gorospe, Ranjan Sen, Supriyo De, Luigi Ferrucci.
      Age-associated changes in gene expression in skeletal muscle of healthy individuals reflect accumulation of damage and compensatory adaptations to preserve tissue integrity. To characterize these changes, RNA was extracted and sequenced from muscle biopsies collected from 53 healthy individuals (22-83 years old) of the GESTALT study of the National Institute on Aging-NIH. Expression levels of 57,205 protein-coding and non-coding RNAs were studied as a function of aging by linear and negative binomial regression models. From both models, 1134 RNAs changed significantly with age. The most differentially abundant mRNAs encoded proteins implicated in several age-related processes, including cellular senescence, insulin signaling, and myogenesis. Specific mRNA isoforms that changed significantly with age in skeletal muscle were enriched for proteins involved in oxidative phosphorylation and adipogenesis. Our study establishes a detailed framework of the global transcriptome and mRNA isoforms that govern muscle damage and homeostasis with age.
    DOI:  https://doi.org/10.1038/s41467-021-22168-2
  15. Int J Mol Sci. 2021 Mar 18. pii: 3107. [Epub ahead of print]22(6):
    Understanding the Potential Role of Sirtuin 2 on Aging: Consequences of SIRT2.3 Overexpression in Senescence.
    Noemi Sola-Sevilla, Ana Ricobaraza, Ruben Hernandez-Alcoceba, Maria S Aymerich, Rosa M Tordera, Elena Puerta.
      Sirtuin 2 (SIRT2) has been associated to aging and age-related pathologies. Specifically, an age-dependent accumulation of isoform 3 of SIRT2 in the CNS has been demonstrated; however, no study has addressed the behavioral or molecular consequences that this could have on aging. In the present study, we have designed an adeno-associated virus vector (AAV-CAG-Sirt2.3-eGFP) for the overexpression of SIRT2.3 in the hippocampus of 2 month-old SAMR1 and SAMP8 mice. Our results show that the specific overexpression of this isoform does not induce significant behavioral or molecular effects at short or long term in the control strain. Only a tendency towards a worsening in the performance in acquisition phase of the Morris Water Maze was found in SAMP8 mice, together with a significant increase in the pro-inflammatory cytokine Il-1β. These results suggest that the age-related increase of SIRT2.3 found in the brain is not responsible for induction or prevention of senescence. Nevertheless, in combination with other risk factors, it could contribute to the progression of age-related processes. Understanding the specific role of SIRT2 on aging and the underlying molecular mechanisms is essential to design new and more successful therapies for the treatment of age-related diseases.
    Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; aging; neuroinflammation; senescence; sirtuin 2
    DOI:  https://doi.org/10.3390/ijms22063107
  16. Sci Transl Med. 2021 Mar 31. pii: eaaz6314. [Epub ahead of print]13(587):
    Reprogramming lipid metabolism prevents effector T cell senescence and enhances tumor immunotherapy.
    Xia Liu, Celine L Hartman, Lingyun Li, Carolyn J Albert, Fusheng Si, Aiqin Gao, Lan Huang, Yangjing Zhao, Wenli Lin, Eddy C Hsueh, Lizong Shen, Qixiang Shao, Daniel F Hoft, David A Ford, Guangyong Peng.
      The functional state of T cells is a key determinant for effective antitumor immunity and immunotherapy. Cellular metabolism, including lipid metabolism, controls T cell differentiation, survival, and effector functions. Here, we report that development of T cell senescence driven by both malignant tumor cells and regulatory T cells is a general feature in cancers. Senescent T cells have active glucose metabolism but exhibit unbalanced lipid metabolism. This unbalanced lipid metabolism results in changes of expression of lipid metabolic enzymes, which, in turn, alters lipid species and accumulation of lipid droplets in T cells. Tumor cells and Treg cells drove elevated expression of group IVA phospholipase A2, which, in turn, was responsible for the altered lipid metabolism and senescence induction observed in T cells. Mitogen-activated protein kinase signaling and signal transducer and activator of transcription signaling coordinately control lipid metabolism and group IVA phospholipase A2 activity in responder T cells during T cell senescence. Inhibition of group IVA phospholipase A2 reprogrammed effector T cell lipid metabolism, prevented T cell senescence in vitro, and enhanced antitumor immunity and immunotherapy efficacy in mouse models of melanoma and breast cancer in vivo. Together, these findings identify mechanistic links between T cell senescence and regulation of lipid metabolism in the tumor microenvironment and provide a new target for tumor immunotherapy.
    DOI:  https://doi.org/10.1126/scitranslmed.aaz6314
  17. Proc Natl Acad Sci U S A. 2021 Mar 23. pii: e2007194118. [Epub ahead of print]118(12):
    JNK signaling prevents biliary cyst formation through a CASPASE-8-dependent function of RIPK1 during aging.
    Katrin Müller, Hanna Honcharova-Biletska, Christiane Koppe, Michèle Egger, Lap Kwan Chan, Anne T Schneider, Lena Küsgens, Friederike Böhm, Yannick Boege, Marc E Healy, Johannes Schmitt, Sarah Comtesse, Mirco Castoldi, Christian Preisinger, Marta Szydlowska, Enrico Focaccia, Nadine T Gaisa, Sven H Loosen, Simone Jörs, Frank Tacke, Christoph Roderburg, Verena Keitel, Johannes G Bode, Peter Boor, Roger J Davis, Thomas Longerich, Fabian Geisler, Mathias Heikenwalder, Achim Weber, Mihael Vucur, Tom Luedde.
      The c-Jun N-terminal kinase (JNK) signaling pathway mediates adaptation to stress signals and has been associated with cell death, cell proliferation, and malignant transformation in the liver. However, up to now, its function was experimentally studied mainly in young mice. By generating mice with combined conditional ablation of Jnk1 and Jnk2 in liver parenchymal cells (LPCs) (JNK1/2LPC-KO mice; KO, knockout), we unraveled a function of the JNK pathway in the regulation of liver homeostasis during aging. Aging JNK1/2LPC-KO mice spontaneously developed large biliary cysts that originated from the biliary cell compartment. Mechanistically, we could show that cyst formation in livers of JNK1/2LPC-KO mice was dependent on receptor-interacting protein kinase 1 (RIPK1), a known regulator of cell survival, apoptosis, and necroptosis. In line with this, we showed that RIPK1 was overexpressed in the human cyst epithelium of a subset of patients with polycystic liver disease. Collectively, these data reveal a functional interaction between JNK signaling and RIPK1 in age-related progressive cyst development. Thus, they provide a functional linkage between stress adaptation and programmed cell death (PCD) in the maintenance of liver homeostasis during aging.
    Keywords:  MK2; cholangiocytes; liver; liver cysts; programmed cell death
    DOI:  https://doi.org/10.1073/pnas.2007194118
  18. Elife. 2021 Mar 30. pii: e62483. [Epub ahead of print]10
    Selenium supplementation inhibits IGF-1 signaling and confers methionine restriction-like healthspan benefits to mice.
    Jason D Plummer, Spike Dl Postnikoff, Jessica K Tyler, Jay E Johnson.
      Methionine restriction (MR) dramatically extends the healthspan of several organisms. Methionine-restricted rodents have less age-related pathology and increased longevity as compared with controls, and recent studies suggest that humans might benefit similarly. Mechanistically, it is likely that the decreased IGF-1 signaling that results from MR underlies the benefits of this regimen. Thus, we hypothesized that interventions that decrease IGF-1 signaling would also produce MR-like healthspan benefits. Selenium supplementation inhibits IGF-1 signaling in rats and has been studied for its putative healthspan benefits. Indeed, we show that feeding mice a diet supplemented with sodium selenite results in an MR-like phenotype, marked by protection against diet-induced obesity, as well as altered plasma levels of IGF-1, FGF-21, adiponectin, and leptin. Selenomethionine supplementation results in a similar, albeit less robust response, and also extends budding yeast lifespan. Our results indicate that selenium supplementation is sufficient to produce MR-like healthspan benefits for yeast and mammals.
    Keywords:  S. cerevisiae; aging; biochemistry; chemical biology; genetics; genomics; histone deacetylase; lifespan; metabolism; mitophagy; mouse; selenomethionine
    DOI:  https://doi.org/10.7554/eLife.62483
  19. Sci Rep. 2021 Mar 31. 11(1): 7243
    cGAS-STING cytosolic DNA sensing pathway is suppressed by JAK2-STAT3 in tumor cells.
    Manuel Adrian Suter, Nikki Y Tan, Chung Hwee Thiam, Muznah Khatoo, Paul A MacAry, Veronique Angeli, Stephan Gasser, Y L Zhang.
      Deficiencies in DNA repair and DNA degrading nucleases lead to accumulation of cytosolic DNA. cGAS is a critical DNA sensor for the detection of cytosolic DNA and subsequent activation of the STING signaling pathway. Here, we show that the cGAS-STING pathway was unresponsive to STING agonists and failed to induce type I interferon (IFN) expression in many tested human tumor cells including DU145 prostate cancer cells. Inhibition of IL-6 or the downstream JAK2/STAT3 signaling restored responsiveness to STING agonists in DU145 cells. STING activity in murine TRAMP-C2 prostate cancer cells was critical for tumor rejection and immune cell infiltration. Endogenous STING agonists including double-stranded DNA and RNA:DNA hybrids present in TRAMP-C2 cells contribute to tumor rejection, but tumor growth was further suppressed by administration of cGAMP. Intratumoral co-injections of IL-6 significantly reduced the anti-tumor effects of cGAMP. In summary, STING in tumor cells contributes to tumor rejection in prostate cancer cells, but its functions are frequently suppressed in tumor cells in part via JAK2 and STAT3 pathways.
    DOI:  https://doi.org/10.1038/s41598-021-86644-x
  20. Front Cell Dev Biol. 2021 ;9 656201
    Targeting the Mitochondria-Proteostasis Axis to Delay Aging.
    Andreas Zimmermann, Corina Madreiter-Sokolowski, Sarah Stryeck, Mahmoud Abdellatif.
      Human life expectancy continues to grow globally, and so does the prevalence of age-related chronic diseases, causing a huge medical and economic burden on society. Effective therapeutic options for these disorders are scarce, and even if available, are typically limited to a single comorbidity in a multifaceted dysfunction that inevitably affects all organ systems. Thus, novel therapies that target fundamental processes of aging itself are desperately needed. In this article, we summarize current strategies that successfully delay aging and related diseases by targeting mitochondria and protein homeostasis. In particular, we focus on autophagy, as a fundamental proteostatic process that is intimately linked to mitochondrial quality control. We present genetic and pharmacological interventions that effectively extend health- and life-span by acting on specific mitochondrial and pro-autophagic molecular targets. In the end, we delve into the crosstalk between autophagy and mitochondria, in what we refer to as the mitochondria-proteostasis axis, and explore the prospect of targeting this crosstalk to harness maximal therapeutic potential of anti-aging interventions.
    Keywords:  aging; anti-aging targets; autophagy; mitochondria; proteostasis
    DOI:  https://doi.org/10.3389/fcell.2021.656201
  21. Biology (Basel). 2021 Mar 24. pii: 253. [Epub ahead of print]10(4):
    Telomere Length and Oxidative Stress and Its Relation with Metabolic Syndrome Components in the Aging.
    Graciela Gavia-García, Juana Rosado-Pérez, Taide Laurita Arista-Ugalde, Itzen Aguiñiga-Sánchez, Edelmiro Santiago-Osorio, Víctor Manuel Mendoza-Núñez.
      A great amount of scientific evidence supports that Oxidative Stress (OxS) can contribute to telomeric attrition and also plays an important role in the development of certain age-related diseases, among them the metabolic syndrome (MetS), which is characterised by clinical and biochemical alterations such as obesity, dyslipidaemia, arterial hypertension, hyperglycaemia, and insulin resistance, all of which are considered as risk factors for type 2 diabetes mellitus (T2DM) and cardiovascular diseases, which are associated in turn with an increase of OxS. In this sense, we review scientific evidence that supports the association between OxS with telomere length (TL) dynamics and the relationship with MetS components in aging. It was analysed whether each MetS component affects the telomere length separately or if they all affect it together. Likewise, this review provides a summary of the structure and function of telomeres and telomerase, the mechanisms of telomeric DNA repair, how telomere length may influence the fate of cells or be linked to inflammation and the development of age-related diseases, and finally, how the lifestyles can affect telomere length.
    Keywords:  aging; lifestyles; metabolic syndrome; oxidative stress; telomerase; telomere
    DOI:  https://doi.org/10.3390/biology10040253
  22. Nat Aging. 2021 Mar;1(3): 255-268
    Olfactory perception of food abundance regulates dietary restriction-mediated longevity via a brain-to-gut signal.
    Bi Zhang, Heejin Jun, Jun Wu, Jianfeng Liu, X Z Shawn Xu.
      The role of food nutrients in mediating the positive effect of dietary restriction (DR) on longevity has been extensively characterized, but how non-nutrient food components regulate lifespan is not well understood. Here, we show that food-associated odors shorten the lifespan of C. elegans under DR but not those fed ad libitum, revealing a specific effect of food odors on DR-mediated longevity. Food odors act on a neural circuit comprising the sensory neurons ADF and CEP, and the interneuron RIC. This olfactory circuit signals the gut to suppress DR-mediated longevity via octopamine, the mammalian homolog of norepinephrine, by regulating the energy sensor AMPK through a Gq-PLCβ-CaMKK-dependent mechanism. In mouse primary cells, we find that norepinephrine signaling regulates AMPK through a similar mechanism. Our results identify a brain-gut axis that regulates DR-mediated longevity by relaying olfactory information about food abundance from the brain to the gut.
    DOI:  https://doi.org/10.1038/s43587-021-00039-1
  23. Nat Commun. 2021 Mar 31. 12(1): 1981
    Inactivating histone deacetylase HDA promotes longevity by mobilizing trehalose metabolism.
    Ruofan Yu, Xiaohua Cao, Luyang Sun, Jun-Yi Zhu, Brian M Wasko, Wei Liu, Emeline Crutcher, Haiying Liu, Myeong Chan Jo, Lidong Qin, Matt Kaeberlein, Zhe Han, Weiwei Dang.
      Histone acetylations are important epigenetic markers for transcriptional activation in response to metabolic changes and various stresses. Using the high-throughput SEquencing-Based Yeast replicative Lifespan screen method and the yeast knockout collection, we demonstrate that the HDA complex, a class-II histone deacetylase (HDAC), regulates aging through its target of acetylated H3K18 at storage carbohydrate genes. We find that, in addition to longer lifespan, disruption of HDA results in resistance to DNA damage and osmotic stresses. We show that these effects are due to increased promoter H3K18 acetylation and transcriptional activation in the trehalose metabolic pathway in the absence of HDA. Furthermore, we determine that the longevity effect of HDA is independent of the Cyc8-Tup1 repressor complex known to interact with HDA and coordinate transcriptional repression. Silencing the HDA homologs in C. elegans and Drosophila increases their lifespan and delays aging-associated physical declines in adult flies. Hence, we demonstrate that this HDAC controls an evolutionarily conserved longevity pathway.
    DOI:  https://doi.org/10.1038/s41467-021-22257-2
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