bims-senagi 2022-08-14 papers

bims-senagi

Biomed News

on Senescence and aging

Issue of 2022–08–14
34 papers selected by
Maria Grazia Vizioli, Mayo Clinic

Cellular senescence and senolytics: the path to the clinic.
Proteolysis dysfunction in the process of aging and age-related diseases.
Mechanisms involved in hematopoietic stem cell aging.
Synergism of BCL-2 family inhibitors facilitates selective elimination of senescent cells.
High-throughput sequencing analysis of nuclear-encoded mitochondrial genes reveals a genetic signature of human longevity.
Mitochondria-targeted esculetin mitigates atherosclerosis in the setting of aging via the modulation of SIRT1-mediated vascular cell senescence and mitochondrial function in Apoe-/- mice.
Mitochondrial uncoupling protein-2 reprograms metabolism to induce oxidative stress and myofibroblast senescence in age-associated lung fibrosis.
Therapy-induced senescence promotes breast cancer cells plasticity by inducing Lipocalin-2 expression.
Senolytic drugs relieve pain by reducing peripheral nociceptive signaling without modifying joint tissue damage in spontaneous osteoarthritis.
Keeping the beat against time: Mitochondrial fitness in the aging heart.
PBX1-SIRT1 Positive Feedback Loop Attenuates ROS-Mediated HF-MSC Senescence and Apoptosis.
NAD+ to assess health in aging humans.
Mettl14-driven senescence-associated secretory phenotype facilitates somatic cell reprogramming.
Cellular Senescence: The Villain of Metabolic Disease?: Discovery of a distinct senescent cell population in obesity-induced metabolic dysfunction.
Therapeutic application of quercetin in aging-related diseases: SIRT1 as a potential mechanism.
The Complement System, Aging, and Aging-Related Diseases.
Aging Relevant Metabolite Itaconate Inhibits Inflammatory Bone Loss.
Artemisia argyi exhibits anti-aging effects through decreasing the senescence in aging stem cells.
LINE-1 RNA causes heterochromatin erosion and is a target for amelioration of senescent phenotypes in progeroid syndromes.
Quercetin Alleviates Pulmonary Fibrosis in Mice Exposed to Silica by Inhibiting Macrophage Senescence.
RSL1D1 modulates cell senescence and proliferation via regulation of PPARγ mRNA stability.
Immunomodulation in age-related disorders and nanotechnology interventions.
Preserving and rejuvenating old organs for transplantation: novel treatments including the potential of senolytics.
Disruption of growth hormone receptor in adipocytes improves insulin sensitivity and lifespan in mice.
Impaired mitochondria promote aging-associated sebaceous gland dysfunction and pathology.
Effect of Physical Activity/Exercise on Oxidative Stress and Inflammation in Muscle and Vascular Aging.
Lipidomics profiling of biological aging in American Indians: the Strong Heart Family Study.
Age-related increase of mitochondrial content in human memory CD4+ T cells contributes to ROS-mediated increased expression of proinflammatory cytokines.
The cGAS/STING signaling pathway: a cross-talk of infection, senescence and tumors.
Nicotinamide riboside alleviates exercise intolerance in ANT1-deficient mice.
ARF2-PIF5 interaction controls transcriptional reprogramming in the ABS3-mediated plant senescence pathway.
Dysregulated lipolysis and lipophagy in lipid droplets of macrophages from high fat diet-fed obese mice.
MITOCHONDRIAL DNA INSERTIONS INTO NUCLEAR DNA AFFECTING CHROMOSOME SEGREGATION: INSIGHTS FOR A NOVEL MECHANISM OF IMMUNOSENESCENCE IN MICE.
Glucose derived carbon nanosphere (CSP) conjugated TTK21, an activator of the histone acetyltransferases CBP/p300, ameliorates amyloid-beta 1-42 induced deficits in plasticity and associativity in hippocampal CA1 pyramidal neurons.

Nat Med. 2022 Aug 11.

Cellular senescence and senolytics: the path to the clinic.

Selim Chaib, Tamar Tchkonia, James L Kirkland.

Interlinked and fundamental aging processes appear to be a root-cause contributor to many disorders and diseases. One such process is cellular senescence, which entails a state of cell cycle arrest in response to damaging stimuli. Senescent cells can arise throughout the lifespan and, if persistent, can have deleterious effects on tissue function due to the many proteins they secrete. In preclinical models, interventions targeting those senescent cells that are persistent and cause tissue damage have been shown to delay, prevent or alleviate multiple disorders. In line with this, the discovery of small-molecule senolytic drugs that selectively clear senescent cells has led to promising strategies for preventing or treating multiple diseases and age-related conditions in humans. In this Review, we outline the rationale for senescent cells as a therapeutic target for disorders across the lifespan and discuss the most promising strategies-including recent and ongoing clinical trials-for translating small-molecule senolytics and other senescence-targeting interventions into clinical use.

DOI: https://doi.org/10.1038/s41591-022-01923-y
Front Aging. 2022 ;3 927630

Proteolysis dysfunction in the process of aging and age-related diseases.

Natalia Frankowska, Katarzyna Lisowska, Jacek M Witkowski.

  In this review, we discuss in detail the most relevant proteolytic systems that together with chaperones contribute to creating the proteostasis network that is kept in dynamic balance to maintain overall functionality of cellular proteomes. Data accumulated over decades demonstrate that the effectiveness of elements of the proteostasis network declines with age. In this scenario, failure to degrade misfolded or faulty proteins increases the risk of protein aggregation, chronic inflammation, and the development of age-related diseases. This is especially important in the context of aging-related modification of functions of the immune system.

Keywords:  aging; autophagy; chaperones; lysosome; proteases; proteostasis; ubiquitin-proteasome system

DOI:  https://doi.org/10.3389/fragi.2022.927630
Cell Mol Life Sci. 2022 Aug 08. 79(9): 473

Mechanisms involved in hematopoietic stem cell aging.

Takeshi Fujino, Shuhei Asada, Susumu Goyama, Toshio Kitamura.

  Hematopoietic stem cells (HSCs) undergo progressive functional decline over time due to both internal and external stressors, leading to aging of the hematopoietic system. A comprehensive understanding of the molecular mechanisms underlying HSC aging will be valuable in developing novel therapies for HSC rejuvenation and to prevent the onset of several age-associated diseases and hematological malignancies. This review considers the general causes of HSC aging that range from cell-intrinsic factors to cell-extrinsic factors. In particular, epigenetics and inflammation have been implicated in the linkage of HSC aging, clonality, and oncogenesis. The challenges in clarifying mechanisms of HSC aging have accelerated the development of therapeutic interventions to rejuvenate HSCs, the major goal of aging research; these details are also discussed in this review.

Keywords:  Aging; Clonal hematopoiesis; Hematological malignancy; Hematopoietic stem cell; Rejuvenation

DOI:  https://doi.org/10.1007/s00018-022-04356-5
Aging (Albany NY). 2022 Aug 08. 14(undefined):

Synergism of BCL-2 family inhibitors facilitates selective elimination of senescent cells.

David Rysanek, Pavla Vasicova, Jayaprakash Narayana Kolla, David Sedlak, Ladislav Andera, Jiri Bartek, Zdenek Hodny.

  Accumulation of senescent cells in tissues with advancing age participates in the pathogenesis of several human age-associated diseases. Specific senescent secretome, the resistance of senescent cells to apoptotic stimuli, and lack of immune system response contribute to the accumulation of senescent cells and their adverse effects in tissues. Inhibition of antiapoptotic machinery, augmented in senescent cells, by BCL-2 protein family inhibitors represents a promising approach to eliminate senescent cells from tissues. This study aimed to explore synergistic and selective senolytic effects of anti-apoptotic BCL-2 family targeting compounds, particularly BH3 mimetics. Using human non-transformed cells RPE-1, BJ, and MRC-5 brought to ionizing radiation-, oncogene-, drug-induced and replicative senescence, we found synergy in combining MCL-1 selective inhibitors with other BH3 mimetics. In an attempt to uncover the mechanism of such synergy, we revealed that the surviving subpopulation of cells resistant to individually applied ABT-737/ABT-263, MIK665, ABT-199, and S63845 BCL-2 family inhibitors showed elevated MCL-1 compared to untreated control cells indicating the presence of a subset of cells expressing high MCL-1 levels and, therefore, resistant to BCL-2 inhibitors within the original population of senescent cells. Overall, we found that combining BCL-2 inhibitors can be beneficial for eliminating senescent cells, thereby enabling use of lower, potentially less toxic, doses of drugs compared to monotherapy, thereby overcoming the resistance of the subpopulation of senescent cells to monotherapy.

Keywords:  BCL-2; MCL-1; cellular senescence; homoharringtonine; senolytics

DOI:  https://doi.org/10.18632/aging.204207
Geroscience. 2022 Aug 10.

High-throughput sequencing analysis of nuclear-encoded mitochondrial genes reveals a genetic signature of human longevity.

Brenda Gonzalez, Archana Tare, Seungjin Ryu, Simon C Johnson, Gil Atzmon, Nir Barzilai, Matt Kaeberlein, Yousin Suh.

  Mitochondrial dysfunction is a well-known contributor to aging and age-related diseases. The precise mechanisms through which mitochondria impact human lifespan, however, remain unclear. We hypothesize that humans with exceptional longevity harbor rare variants in nuclear-encoded mitochondrial genes (mitonuclear genes) that confer resistance against age-related mitochondrial dysfunction. Here we report an integrated functional genomics study to identify rare functional variants in ~ 660 mitonuclear candidate genes discovered by target capture sequencing analysis of 496 centenarians and 572 controls of Ashkenazi Jewish descent. We identify and prioritize longevity-associated variants, genes, and mitochondrial pathways that are enriched with rare variants. We provide functional gene variants such as those in MTOR (Y2396Lfs*29), CPS1 (T1406N), and MFN2 (G548*) as well as LRPPRC (S1378G) that is predicted to affect mitochondrial translation. Taken together, our results suggest a functional role for specific mitonuclear genes and pathways in human longevity.

Keywords:  Aging; Centenarian; Genetic variant; Longevity; Mitochondria

DOI:  https://doi.org/10.1007/s11357-022-00634-z
Atherosclerosis. 2022 Jul 20. pii: S0021-9150(22)01364-8. [Epub ahead of print]356 28-40

Mitochondria-targeted esculetin mitigates atherosclerosis in the setting of aging via the modulation of SIRT1-mediated vascular cell senescence and mitochondrial function in Apoe-/- mice.

Santosh Karnewar, Sriravali Pulipaka, Sujana Katta, Devayani Panuganti, Praveen Kumar Neeli, Rajamannar Thennati, Mahesh Kumar Jerald, Srigiridhar Kotamraju.

   BACKGROUND AND AIMS: Age is a dominant and independent risk factor for the development of atherosclerosis, a major cardiovascular disease, and if left untreated leads to myocardial infarction and death. Mitochondria-targeted anti-oxidants are evolving as a new class of compounds that can alter the pathophysiology of age-related diseases, including atherosclerosis, where mitochondrial dysfunction plays a critical role in disease progression.
METHODS: We recently synthesized an alkyl TPP + -tagged esculetin (mitochondria-targeted esculetin or Mito-Esc). Apoe-/- mice were chronically (14 months) administered with Mito-Esc to investigate its efficacy in the mitigation of atherosclerosis in the setting of aging. We monitored BP, and performed various biochemical assays, histopathology, immunohistochemistry, inflammatory factors, qPCR, and Western blotting. Simultaneously, human aortic endothelial cells (HAECs) were used as a model system to study the mechanistic aspects.
RESULTS: A chronic low-dose administration of Mito-Esc to Apoe-/- mice greatly prevented alterations in lipid profile, blood pressure, and atherosclerotic plaque formation in the setting of aging. Mito-Esc administration significantly reduced vascular senescence and pro-inflammatory cytokines levels and prevented dysregulation of mitochondrial biogenesis markers in aortic tissue. Further, Mito-Esc treatment prevented replicative and stress-induced premature senescence (SIPS) in HAEC. Importantly, Mito-Esc treatment delayed endothelial cell senescence by increasing human telomerase reverse transcriptase (hTERT) levels via SIRT1 activation. Moreover, Mito-Esc treatment by altering miR-19b and miR-30c via a SIRT1 activation significantly inhibited the increase in PAI-1 levels in HAEC as well as in the serum of Apoe-/- mice. In addition, Mito-Esc treatment improved mitochondrial function in late passage (aged) HAECs by enhancing the oxygen consumption rate (OCR). Furthermore, Mito-Esc administration counteracted the decline in GSH and nitrite levels in Apoe-/- mice and in HAECs.
CONCLUSIONS: Overall, Mito-Esc alleviates atherosclerosis in the setting of aging by delaying vascular senescence and pro-inflammatory processes, and by improving mitochondrial biogenesis and function.

Keywords:  Aging; Aortic endothelial cells; Atherosclerosis; Mitochondria-targeted anti-oxidant; Oxygen consumption rate; Senescence; Sirtuins

DOI:  https://doi.org/10.1016/j.atherosclerosis.2022.07.012
Aging Cell. 2022 Aug 07.

Mitochondrial uncoupling protein-2 reprograms metabolism to induce oxidative stress and myofibroblast senescence in age-associated lung fibrosis.

Sunad Rangarajan, Morgan L Locy, Diptiman Chanda, Ashish Kurundkar, Deepali Kurundkar, Jennifer L Larson-Casey, Pilar Londono, Rushita A Bagchi, Brian Deskin, Hanan Elajaili, Eva S Nozik, Jessy S Deshane, Jaroslaw W Zmijewski, Oliver Eickelberg, Victor J Thannickal.

  Mitochondrial dysfunction has been associated with age-related diseases, including idiopathic pulmonary fibrosis (IPF). We provide evidence that implicates chronic elevation of the mitochondrial anion carrier protein, uncoupling protein-2 (UCP2), in increased generation of reactive oxygen species, altered redox state and cellular bioenergetics, impaired fatty acid oxidation, and induction of myofibroblast senescence. This pro-oxidant senescence reprogramming occurs in concert with conventional actions of UCP2 as an uncoupler of oxidative phosphorylation with dissipation of the mitochondrial membrane potential. UCP2 is highly expressed in human IPF lung myofibroblasts and in aged fibroblasts. In an aging murine model of lung fibrosis, the in vivo silencing of UCP2 induces fibrosis regression. These studies indicate a pro-fibrotic function of UCP2 in chronic lung disease and support its therapeutic targeting in age-related diseases associated with impaired tissue regeneration and organ fibrosis.

Keywords:  UCP2; cellular senescence; fibroblast; fibrosis; myofibroblast; oxidative stress; uncoupling protein-2

DOI:  https://doi.org/10.1111/acel.13674
Oncogene. 2022 Aug 11.

Therapy-induced senescence promotes breast cancer cells plasticity by inducing Lipocalin-2 expression.

Jorge Morales-Valencia, Lena Lau, Teresa Martí-Nin, Ugur Ozerdem, Gregory David.

The acquisition of novel detrimental cellular properties following exposure to cytotoxic drugs leads to aggressive and metastatic tumors that often translates into an incurable disease. While the bulk of the primary tumor is eliminated upon exposure to chemotherapeutic treatment, residual cancer cells and non-transformed cells within the host can engage a stable cell cycle exit program named senescence. Senescent cells secrete a distinct set of pro-inflammatory factors, collectively termed the senescence-associated secretory phenotype (SASP). Upon exposure to the SASP, cancer cells undergo cellular plasticity resulting in increased proliferation, migration and epithelial-to-mesenchymal transition. The molecular mechanisms by which the SASP regulates these pro-tumorigenic features are poorly understood. Here, we report that breast cancer cells exposed to the SASP strongly upregulate Lipocalin-2 (LCN2). Furthermore, we demonstrate that LCN2 is critical for SASP-induced increased migration in breast cancer cells, and its inactivation potentiates the response to chemotherapeutic treatment in mouse models of breast cancer. Finally, we show that neoadjuvant chemotherapy treatment leads to LCN2 upregulation in residual human breast tumors, and correlates with worse overall survival. These findings provide the foundation for targeting LCN2 as an adjuvant therapeutic approach to prevent the emergence of aggressive tumors following chemotherapy.

DOI: https://doi.org/10.1038/s41388-022-02433-4
Aging (Albany NY). 2022 Aug 10. 14(undefined):

Senolytic drugs relieve pain by reducing peripheral nociceptive signaling without modifying joint tissue damage in spontaneous osteoarthritis.

Tae-Hwan Gil, Haiyan Zheng, Hyo Gyeong Lee, Ji-Won Shin, Sun Wook Hwang, Ki-Mo Jang, Ok Hee Jeon.

  Aging is a risk factor for the development of osteoarthritis (OA), a progressive joint disease leading to cartilage damage, pain, and loss of function. In a mouse model of OA, senolytic drugs to selectively clear senescent cells (SnCs) that accumulate with injury or aging yielded a chondroprotective effect; however, this therapeutic benefit was limited in aged mice. Due to inconsistency between cartilage destruction and pain-associated symptoms, we studied the therapeutic effect of senolytics on joint pain in spontaneous OA. We orally treated 21- and 22-month old mice with an ABT263 and Dasatinib and Quercetin (D+Q) drug combination. Selective elimination of the SnCs that accumulated in the articular cartilage and synovium by these two drugs did not alter cartilage degeneration and abnormal bone changes during spontaneous OA progression. Treatment reduced thermal and mechanical hyperalgesia associated with OA and peripheral sensitization through decreased expression of axon guidance proteins (nerve growth factor NGF/TrkA) and nociceptive neuron (calcitonin gene-related peptide, CGRP) projection to the synovium, subchondral bone marrow, and dorsal root ganglion, and knee joint angiogenesis. Selective removal of the SnCs from in vitro cultures of synovial cells from human OA patients also decreased expression of senescent markers, axonal growth-promoting factors, such as NGF, and angiogenesis markers. We suggest that systemic administration of ABT263 and D+Q is an exciting therapeutic approach to age-related OA pain.

Keywords:  nociceptive pathways; pain; senescence; senolytics; spontaneous osteoarthritis

DOI:  https://doi.org/10.18632/aging.204204
Front Aging. 2022 ;3 951417

Keeping the beat against time: Mitochondrial fitness in the aging heart.

Arielys Mendoza, Jason Karch.

  The process of aging strongly correlates with maladaptive architectural, mechanical, and biochemical alterations that contribute to the decline in cardiac function. Consequently, aging is a major risk factor for the development of heart disease, the leading cause of death in the developed world. In this review, we will summarize the classic and recently uncovered pathological changes within the aged heart with an emphasis on the mitochondria. Specifically, we describe the metabolic changes that occur in the aging heart as well as the loss of mitochondrial fitness and function and how these factors contribute to the decline in cardiomyocyte number. In addition, we highlight recent pharmacological, genetic, or behavioral therapeutic intervention advancements that may alleviate age-related cardiac decline.

Keywords:  ROS; autophagy; cell death; metabolism; mitochondria; mitochondrial biogenesis; mitochondrial fitness; mitophagy

DOI:  https://doi.org/10.3389/fragi.2022.951417
Stem Cell Rev Rep. 2022 Aug 12.

PBX1-SIRT1 Positive Feedback Loop Attenuates ROS-Mediated HF-MSC Senescence and Apoptosis.

Yuan Wang, Yutong Sui, Ye Niu, Dan Liu, Qi Xu, Feilin Liu, Kuiyang Zuo, Mingsheng Liu, Wei Sun, Ziyu Wang, Zinan Liu, Fei Zou, Jiahong Shi, Xiaomei Liu, Jinyu Liu.

  Stem cell senescence and depletion are major causes of aging and aging-related diseases. The NAD (Nicotinamide adenine dinucleotide) - SIRT1 (Silent Information Regulator 1) - PARP1 (Poly (ADP-ribose) polymerase-1) axis has gained interest owing to its significant role in regulating stem cell senescence and organismal aging. A recent study from our lab showed that pre-B-cell leukemia transcription factor1 (PBX1) overexpression attenuates hair follicle-derived mesenchymal stem cells (HF-MSCs) senescence and apoptosis by regulating ROS-mediated DNA damage via PARP1 downregulation; thus, suggesting that PARP1 downregulation is a common manifestation of the roles of both PBX1 and SIRT1 in HF-MSCs senescence attenuation, and implying a potential link between PBX1 and SIRT1. To this end, HF-MSCs overexpressing PBX1, overexpressing both PBX1 and PARP1, downregulating SIRT1, and overexpressing PBX1 as well as downregulating SIRT1 were generated, and senescence, apoptosis, DNA damage, and repair biomarkers were analyzed. Our results showed that (1) PBX1 overexpression alleviated HF-MSCs senescence and apoptosis accompanied by SIRT1 upregulation, PARP1 downregulation, and increased intracellular NAD and ATP levels. (2) SIRT1 knockdown enhanced cellular senescence and apoptosis, accompanied by increased ROS accumulation, DNA damage aggravation, and decreased intracellular NAD and ATP levels. (3) PBX1 overexpression rescued HF-MSCs senescence and apoptosis induced by SIRT1 knockdown. (4) PBX1 rescued PARP1 overexpression-mediated ATP and NAD depletion, accompanied by increased SIRT1 expression. Collectively, our results revealed that a positive interaction feedback loop exists between PBX1 and SIRT1. To the best of our knowledge we are the first to report that there is a PBX1-SIRT1-PARP1 axis that plays a critical role in alleviating HF-MSCs senescence and apoptosis. We provide a new perspective on the mechanisms underlying stem cell senescence as well as age-related disease prevention and treatment.

Keywords:  Apoptosis; DNA damage; Hair follicle mesenchymal stem cells; PARP1; PBX 1; SIRT1; Senescence

DOI:  https://doi.org/10.1007/s12015-022-10425-w
Aging (Albany NY). 2022 Aug 06. undefined(undefined):

NAD+ to assess health in aging humans.

Georges E Janssens, Riekelt H Houtkooper, Joris Hoeks.



Keywords:  NAD +; aging; exercise; frailty; healthspan

DOI:  https://doi.org/10.18632/aging.204220
Stem Cell Reports. 2022 Aug 09. pii: S2213-6711(22)00370-8. [Epub ahead of print]17(8): 1799-1809

Mettl14-driven senescence-associated secretory phenotype facilitates somatic cell reprogramming.

Chenxiang Xi, Jiatong Sun, Xiaocui Xu, You Wu, Xiaochen Kou, Yanhong Zhao, Jiacheng Shen, Yu Dong, Kang Chen, Zhongqu Su, Dan Liu, Wen Ye, Yingdong Liu, Ran Zhang, Yiliang Xu, Hong Wang, Lujiang Hao, Li Wu, Shaorong Gao.

  The METTL3-METTL14 complex, the "writer" of N6-methyladenosine (m6A), plays an important role in many biological processes. Previous studies have shown that Mettl3 overexpression can increase the level of m6A and promote somatic cell reprogramming. Here, we demonstrate that Mettl14, another component of the methyltransferase complex, can significantly enhance the generation of induced pluripotent stem cells (iPSCs) in an m6A-independent manner. In cooperation with Oct4, Sox2, Klf4, and c-Myc, overexpressed Mettl14 transiently promoted senescence-associated secretory phenotype (SASP) gene expression in non-reprogrammed cells in the late stage of reprogramming. Subsequently, we demonstrated that interleukin-6 (IL-6), a component of the SASP, significantly enhanced somatic cell reprogramming. In contrast, blocking the SASP using a senolytic agent or a nuclear factor κB (NF-κB) inhibitor impaired the effect of Mettl14 on reprogramming. Our results highlight the m6A-independent function of Mettl14 in reprogramming and provide new insight into the interplay between senescence and reprogramming in vitro.

Keywords:  Mettl14; m(6)A methylation; reprogramming; senescence-associated secretory phenotype (SASP)

DOI:  https://doi.org/10.1016/j.stemcr.2022.06.012
Mol Cells. 2022 Aug 31. 45(8): 531-533

Cellular Senescence: The Villain of Metabolic Disease?: Discovery of a distinct senescent cell population in obesity-induced metabolic dysfunction.

Gung Lee.

Senescent p21high cells in epididymal white adipose tissue (eWAT) aggravate metabolic dysfunction in obese animals. In obesity, p21high cells are specifically accumulated in stromal vascular fraction of eWAT and they have increased expression of inflammatory genes and NFκB signaling pathway. Transplantation of p21high cells provokes glucose intolerance whereas clearance of p21high cells by senolytic agents relieves insulin resistance in obese animals.

DOI: https://doi.org/10.14348/molcells.2022.0084
Front Immunol. 2022 ;13 943321

Therapeutic application of quercetin in aging-related diseases: SIRT1 as a potential mechanism.

Zhifu Cui, Xingtao Zhao, Felix Kwame Amevor, Xiaxia Du, Yan Wang, Diyan Li, Gang Shu, Yaofu Tian, Xiaoling Zhao.

  Quercetin, a naturally non-toxic flavonoid within the safe dose range with antioxidant, anti-apoptotic and anti-inflammatory properties, plays an important role in the treatment of aging-related diseases. Sirtuin 1 (SIRT1), a member of NAD+-dependent deacetylase enzyme family, is extensively explored as a potential therapeutic target for attenuating aging-induced disorders. SIRT1 possess beneficial effects against aging-related diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Depression, Osteoporosis, Myocardial ischemia (M/I) and reperfusion (MI/R), Atherosclerosis (AS), and Diabetes. Previous studies have reported that aging increases tissue susceptibility, whereas, SIRT1 regulates cellular senescence and multiple aging-related cellular processes, including SIRT1/Keap1/Nrf2/HO-1 and SIRTI/PI3K/Akt/GSK-3β mediated oxidative stress, SIRT1/NF-κB and SIRT1/NLRP3 regulated inflammatory response, SIRT1/PGC1α/eIF2α/ATF4/CHOP and SIRT1/PKD1/CREB controlled phosphorylation, SIRT1-PINK1-Parkin mediated mitochondrial damage, SIRT1/FoxO mediated autophagy, and SIRT1/FoxG1/CREB/BDNF/Trkβ-catenin mediated neuroprotective effects. In this review, we summarized the role of SIRT1 in the improvement of the attenuation effect of quercetin on aging-related diseases and the relationship between relevant signaling pathways regulated by SIRT1. Moreover, the functional regulation of quercetin in aging-related markers such as oxidative stress, inflammatory response, mitochondrial function, autophagy and apoptosis through SIRT1 was discussed. Finally, the prospects of an extracellular vesicles (EVs) as quercetin loading and delivery, and SIRT1-mediated EVs as signal carriers for treating aging-related diseases, as well as discussed the ferroptosis alleviation effects of quercetin to protect against aging-related disease via activating SIRT1. Generally, SIRT1 may serve as a promising therapeutic target in the treatment of aging-related diseases via inhibiting oxidative stress, reducing inflammatory responses, and restoring mitochondrial dysfunction.

Keywords:  aging-related diseases; inflammatory response; mitochondrial dysfunction; oxidative stress; quercetin; sirtuin 1

DOI:  https://doi.org/10.3389/fimmu.2022.943321
Int J Mol Sci. 2022 Aug 04. pii: 8689. [Epub ahead of print]23(15):

The Complement System, Aging, and Aging-Related Diseases.

Runzi Zheng, Yanghuan Zhang, Ke Zhang, Yang Yuan, Shuting Jia, Jing Liu.

  The complement system is a part of the immune system and consists of multiple complement components with biological functions such as defense against pathogens and immunomodulation. The complement system has three activation pathways: the classical pathway, the lectin pathway, and the alternative pathway. Increasing evidence indicates that the complement system plays a role in aging. Complement plays a role in inflammatory processes, metabolism, apoptosis, mitochondrial function, and Wnt signaling pathways. In addition, the complement system plays a significant role in aging-related diseases, including Alzheimer's disease, age-related macular degeneration, and osteoarthritis. However, the effect of complement on aging and aging-related diseases is still unclear. Thus, a better understanding of the potential relationship between complement, aging, and aging-related diseases will provide molecular targets for treating aging, while focusing on the balance of complement in during treatment. Inhibition of a single component does not result in a good outcome. In this review, we discussed the research progress and effects of complement in aging and aging-related diseases.

Keywords:  C3; aging; complement system

DOI:  https://doi.org/10.3390/ijms23158689
Front Endocrinol (Lausanne). 2022 ;13 885879

Aging Relevant Metabolite Itaconate Inhibits Inflammatory Bone Loss.

Yuting Wang, Song Li, Liming Zhao, Peng Cheng, Jian Liu, Fengjing Guo, Jun Xiao, Wentao Zhu, Anmin Chen.

  Progressive bone loss during aging makes osteoporosis one of the most common and life impacting conditions in geriatric populations. The bone homeostasis is maintained through persistent remodeling mediated by bone-forming osteoblast and bone-resorbing osteoclast. Inflammaging, a condition characterized by increased pro-inflammatory markers in the blood and other tissues during aging, has been reported to be associated with skeletal stem/progenitor cell dysfunction, which will result in impaired bone formation. However, the role of age-related inflammation and metabolites in regulation of osteoclast remains largely unknown. In the present study, we observed dichotomous phenotypes of anti-inflammatory metabolite itaconate in responding to inflammaging. Itaconate is upregulated in macrophages during aging but has less reactivity in responding to RANKL stimulation in aged macrophages. We confirmed the inhibitory effect of itaconate in regulating osteoclast differentiation and activation, and further verified the rescue role of itaconate in lipopolysaccharides induced inflammatory bone loss animal model. Our findings revealed that itaconate is a crucial regulatory metabolite during inflammaging that inhibits osteoclast to maintain bone homeostasis.

Keywords:  aging; inflammation; itaconate; osteoclast; osteoporosis

DOI:  https://doi.org/10.3389/fendo.2022.885879
Aging (Albany NY). 2022 Aug 09. 14(undefined):

Artemisia argyi exhibits anti-aging effects through decreasing the senescence in aging stem cells.

Tsung-Jung Ho, Debakshee Goswami, Wei-Wen Kuo, Chia-Hua Kuo, Shih Cheng Yen, Pi-Yu Lin, Shinn-Zong Lin, Dennis Jine-Yuan Hsieh, Marthandam Asokan Shibu, Chih-Yang Huang.

  Aging is accompanied by functional loss of many cellular pathways, creating an increased risk of many age-related complications (ARC). Aging causes stem cell exhaustion with a concomitant increase in cellular dysfunction. Recently, interest in senotherapeutics has been growing rapidly to promote healthy aging and as an intervention for ARCs. This research focused on screening the senomorphic properties of Artemisia argyi, as an emerging strategy for longevity, and prevention or treatment of ARCs. In this study, we aimed to find the clinical efficacy of daily consumption of Artemisia argyi water extract (AAW) on aging. In vitro 0.1μM Doxorubicin induced senescent human adipose derived mesenchymal stem cells was treated with different concentrations of AAW to show its anti-aging effect. 15 months old SHR rats (n=6) were treated with 7.9 mg/ml AAW for 4 weeks and anti-aging effect was evaluated. In vitro study showed the protective effect of AAW in telomere shortening and helps in maintaining a balance in the expression of anti-aging protein Klotho and TERT. AAW effectively reduced mitochondrial superoxide and also provided a protective shield against senescence markers like over-expression of p21 and formation of double strand breaks, which is known to cause premature aging. Moreover, animal studies indicated that AAW promoted the expression of Klotho in naturally aging rats. In addition, AAW successfully restored the decline cardiac function and improved the grip strength and memory of aging rat. These findings showed that therapeutic targeting of senescent stem cells by AAW restored stem cell homeostasis and improves overall health.

Keywords:  Artemisia argyi; anti-aging; antioxidant; klotho; stem cell

DOI:  https://doi.org/10.18632/aging.204210
Sci Transl Med. 2022 Aug 10. 14(657): eabl6057

LINE-1 RNA causes heterochromatin erosion and is a target for amelioration of senescent phenotypes in progeroid syndromes.

Francesco Della Valle, Pradeep Reddy, Mako Yamamoto, Peng Liu, Alfonso Saera-Vila, Dalila Bensaddek, Huoming Zhang, Javier Prieto Martinez, Leila Abassi, Mirko Celii, Alejandro Ocampo, Estrella Nuñez Delicado, Arianna Mangiavacchi, Riccardo Aiese Cigliano, Concepcion Rodriguez Esteban, Steve Horvath, Juan Carlos Izpisua Belmonte, Valerio Orlando.

Constitutive heterochromatin is responsible for genome repression of DNA enriched in repetitive sequences, telomeres, and centromeres. During physiological and pathological premature aging, heterochromatin homeostasis is profoundly compromised. Here, we showed that LINE-1 (Long Interspersed Nuclear Element-1; L1) RNA accumulation was an early event in both typical and atypical human progeroid syndromes. L1 RNA negatively regulated the enzymatic activity of the histone-lysine N-methyltransferase SUV39H1 (suppression of variegation 3-9 homolog 1), resulting in heterochromatin loss and onset of senescent phenotypes in vitro. Depletion of L1 RNA in dermal fibroblast cells from patients with different progeroid syndromes using specific antisense oligonucleotides (ASOs) restored heterochromatin histone 3 lysine 9 and histone 3 lysine 27 trimethylation marks, reversed DNA methylation age, and counteracted the expression of senescence-associated secretory phenotype genes such as p16, p21, activating transcription factor 3 (ATF3), matrix metallopeptidase 13 (MMP13), interleukin 1a (IL1a), BTG anti-proliferation factor 2 (BTG2), and growth arrest and DNA damage inducible beta (GADD45b). Moreover, systemic delivery of ASOs rescued the histophysiology of tissues and increased the life span of a Hutchinson-Gilford progeria syndrome mouse model. Transcriptional profiling of human and mouse samples after L1 RNA depletion demonstrated that pathways associated with nuclear chromatin organization, cell proliferation, and transcription regulation were enriched. Similarly, pathways associated with aging, inflammatory response, innate immune response, and DNA damage were down-regulated. Our results highlight the role of L1 RNA in heterochromatin homeostasis in progeroid syndromes and identify a possible therapeutic approach to treat premature aging and related syndromes.

DOI: https://doi.org/10.1126/scitranslmed.abl6057
Front Pharmacol. 2022 ;13 912029

Quercetin Alleviates Pulmonary Fibrosis in Mice Exposed to Silica by Inhibiting Macrophage Senescence.

Fei Geng, Mengying Xu, Lan Zhao, Haoming Zhang, Jiarui Li, Fuyu Jin, Yaqian Li, Tian Li, Xinyu Yang, Shifeng Li, Xuemin Gao, Wenchen Cai, Na Mao, Ying Sun, Heliang Liu, Hong Xu, Zhongqiu Wei, Fang Yang.

  Quercetin exerts anti-inflammatory, anti-oxidant and other protective effects. Previous studies have shown that senescent cells, such as fibroblasts and type II airway epithelial cells, are strongly implicated in the development of pulmonary fibrosis pathology. However, the role of senescent macrophages during silicosis remains unclear. We investigated the effects of quercetin on macrophage senescence and pulmonary fibrosis, and explored underlying mechanisms. Mice were randomized to six model groups. Vitro model was also established by culturing RAW264.7 macrophages with silica (SiO2). We examined the effects of quercetin on fibrosis, senescence-associated β-galactosidase (SA-β-Gal) activity, and senescence-specific genes (p16, p21, and p53). We showed that quercetin reduced pulmonary fibrosis and inhibited extracellular matrix (ECM) formation. Quercetin also attenuated macrophage senescence induced by SiO2 both in vitro and in vivo. In addition, quercetin significantly decreased the expressions of the senescence-associated secretory phenotype (SASP), including proinflammatory factors (interleukin-1α (Il-1α), Il-6, tumor necrosis factor-α (TNF-α), and transforming growth factor-β1 (TGF-β1)) and matrix metalloproteinases (MMP2, MMP9, and MMP12). In conclusion, quercetin mediated its anti-fibrotic effects by inhibiting macrophage senescence, possibly via SASP.

Keywords:  SASP; macrophage; quercetin; senescence; silicosis

DOI:  https://doi.org/10.3389/fphar.2022.912029
Life Sci. 2022 Aug 05. pii: S0024-3205(22)00548-3. [Epub ahead of print] 120848

RSL1D1 modulates cell senescence and proliferation via regulation of PPARγ mRNA stability.

Zhe Jiang, Fengxin Hao, Feng Zhu, Fuwen Yuan, Liwei Ma, Guodong Li, Jun Chen, Tanjun Tong.

   AIMS: In this study, we will examine if RSL1D1 influences PPARγ expression and explore the underlying mechanism that RSL1D1 regulates PPARγ expression. Moreover, the significance of RSL1D1-PPARγ pathway in cell senescence and proliferation will also be determined.
MAIN METHODS: Our main methods include western blotting, immunoprecipitation (IP), real-time PCR, RNA Immunoprecipitation (RIP), biotin-labeled RNA pull down assay, dual luciferase reporter gene assay, senescence-associated β-galactosidase staining, cell proliferation assay, colony formation assay, wound healing assay, blood biochemistry test and Oil red O staining.
KEY FINDINGS: By analyzing gene chip results we find that the expression of RSL1D1 and PPARγ might be correlated. Then we show that RSL1D1 is a posttranscriptional regulator of PPARγ. RSL1D1 overexpression elevates, while RSL1D1 knockdown inhibits, PPARγ mRNA and protein expression levels. Mechanistically, we find that RSL1D1 directly interacts with the 3'-untranslated region of PPARγ mRNA, and then promotes its stability and increases PPARγ protein expression level. We further demonstrate that RSL1D1 modulates cellular senescence and cell proliferation partially via PPARγ-regulated downstream target genes such as PTEN/p27, NF-κB, GLUT4, and ACL. Moreover, we find that RSL1D1 regulates PPARγ expression and function in a HuR-dependent manner. Last, we show that RSL1D1 knockout in mouse adipose tissue shortens mouse lifespan and leads to hepatic damage which may impair liver damage repair function.
SIGNIFICANCE: Collectively, our findings unveil a novel posttranscriptional regulation of PPARγ by RSL1D1 and uncover a critical role of RSL1D1-PPARγ-PPARγ downstream target genes in regulating cellular senescence and cell proliferation.

Keywords:  CSIG; Cell senescence; HuR; PPARγ; Post transcriptional regulation

DOI:  https://doi.org/10.1016/j.lfs.2022.120848
Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2022 Aug 10. e1840

Immunomodulation in age-related disorders and nanotechnology interventions.

Uday Chintapula, Tanmayee Chikate, Deepsundar Sahoo, Amie Kieu, Ingrid D Guerrero Rodriguez, Kytai T Nguyen, Daniel Trott.

  Recently, the aging population has increased exponentially around the globe bringing more challenges to improve quality of life in those populations while reducing the economic burden on healthcare systems. Aging is associated with changes in the immune system culminating in detrimental effects such as immune dysfunction, immunosenescence, and chronic inflammation. Age-related decline of immune functions is associated with various pathologies including cardiovascular, autoimmune, neurodegenerative, and infectious diseases to name a few. Conventional treatment addresses the onset of age-related diseases by early detection of risk factors, administration of vaccines as preventive care, immunomodulatory treatment, and other dietary supplements. However, these approaches often come with systemic side-effects, low bioavailability of therapeutic agents, and poor outcomes seen in the elderly. Recent innovations in nanotechnology have led to the development of novel biomaterials/nanomaterials, which explore targeted drug delivery and immunomodulatory interactions in vivo. Current nanotechnology-based immunomodulatory approaches that have the potential to be used as therapeutic interventions for some prominent age-related diseases are discussed here. Finally, we explore challenges and future aspects of nanotechnology in the treatments of age-related disorders to improve quality of life in the elderly. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Keywords:  age-related diseases; aging; immunomodulation; nanoparticles; nanotechnology

DOI:  https://doi.org/10.1002/wnan.1840
Curr Opin Organ Transplant. 2022 Aug 10.

Preserving and rejuvenating old organs for transplantation: novel treatments including the potential of senolytics.

Tomohisa Matsunaga, Maximilian J Roesel, Andreas Schroeter, Yao Xiao, Hao Zhou, Stefan G Tullius.

PURPOSE OF REVIEW: Older donors have the potential to close the gap between demand and supply in solid organs transplantation. Utilizing older organs, at the same time, has been associated with worse short- and long-term outcomes. Here, we introduce potential mechanisms on how treatments during machine perfusion (MP) may safely improve the utilization of older organs.
RECENT FINDINGS: Consequences of ischemia reperfusion injury (IRI), a process of acute, sterile inflammation leading to organ injury are more prominent in older organs. Of relevance, organ age and IRI seem to act synergistically, leading to an increase of damage associated molecular patterns that trigger innate and adaptive immune responses. While cold storage has traditionally been considered the standard of care in organ preservation, accumulating data support that both hypothermic and normothermic MP improve organ quality, particularly in older organs. Furthermore, MP provides the opportunity to assess the quality of organs while adding therapeutic agents. Experimental data have already demonstrated the potential of applying treatments during MP. New experimental show that the depletion of senescent cells that accumulate in old organs improves organ quality and transplant outcomes.
SUMMARY: As the importance of expanding the donor pool is increasing, MP and novel treatments bear the potential to assess and regenerate older organs, narrowing the gap between demand and supply.

DOI: https://doi.org/10.1097/MOT.0000000000001019
Endocrinology. 2022 Aug 11. pii: bqac129. [Epub ahead of print]

Disruption of growth hormone receptor in adipocytes improves insulin sensitivity and lifespan in mice.

Edward O List, Darlene E Berryman, Julie Slyby, Silvana Duran-Ortiz, Kevin Funk, Elise S Bisset, Susan E Howlett, John J Kopchick.

  Growth hormone receptor knockout (GHRKO) mice have been used for 25 years to uncover some of the many actions of growth hormone (GH). Since they are extremely long-lived with enhanced insulin sensitivity and protected from multiple age-related diseases, they are often used to study healthy aging. To determine the impact that adipose tissue has on the GHRKO phenotype, our laboratory recently created and characterized adipocyte-specific GHRKO (AdGHRKO) mice, which have increased adiposity but appear healthy with enhanced insulin sensitivity. To test the hypothesis that removal of GH action in adipocytes might partially replicate the increased lifespan and healthspan observed in global GHRKO mice, we assessed adiposity, cytokines/adipokines, glucose homeostasis, frailty and lifespan in aging AdGHRKO mice of both sexes. Our results show that disrupting the GH receptor gene in adipocytes improved insulin sensitivity at advanced age and increased lifespan in male AdGHRKO mice. AdGHRKO mice also exhibited increased fat mass, reduced circulating levels of insulin, c-peptide, adiponectin, resistin, and lowered frailty scores with improved grip strength at advanced ages. Comparison of published mean lifespan data from GHRKO mice to that from AdGHRKO and muscle-specific GHRKO mice, suggests that ~23% of lifespan extension in male GHRKO is due to GHR disruption in adipocytes vs ~19% in muscle. Females benefited less from GHR disruption in these two tissues with ~19% and ~0%, respectively. These data indicate that removal of GH's action, even in a single tissue, is sufficient for observable health benefits which promote long term health, reduce frailty, and increase longevity.

Keywords:  adipocyte; adipose tissue; growth hormone; growth hormone receptor; tissue-specific knockout

DOI:  https://doi.org/10.1210/endocr/bqac129
Am J Pathol. 2022 Aug 07. pii: S0002-9440(22)00214-0. [Epub ahead of print]

Impaired mitochondria promote aging-associated sebaceous gland dysfunction and pathology.

Noha S Ahmed, Jeremy B Foote, Keshav K Singh.

  Mitochondrial dysfunction is one of the hallmarks of aging. Changes in sebaceous gland function and sebum production have been reported during aging. Here we report the direct effects of mitochondrial dysfunction on sebaceous gland morphology and function. We utilized a mitochondrial DNA depleter mouse as a model for introducing mitochondrial dysfunction in the whole animal. We characterized the effects on skin sebaceous glands and modified sebaceous glands of the eyelid, lip, clitoral and preputial glands. The mtDNA depleter mice show gross morphologic and histopathologic changes in sebaceous glands associated with increased infiltration by mast cells, neutrophils, and polarized macrophages. Consistently, there was increased expression of proinflammatory cytokines. The inflammatory changes were associated with abnormal sebocyte accumulation of lipid, defective sebum delivery at the skin surface, and the upregulation of key lipogenesis regulating genes and androgen receptor. The mitochondrial DNA depleter mice expressed aging-associated senescent marker. We also observed increased sebocyte proliferation and aberrant expression of stem cell markers. These studies provide for the first time a causal link between mitochondrial dysfunction and abnormal sebocyte function within sebaceous and modified sebaceous glands throughout the whole body of the animal. Our studies suggest that mitochondrial DNA depleter mouse may serve as a novel tool to develop targeted therapeutics to address sebaceous gland disorders in aging humans.

Keywords:  Aging; Inflammation; Mitochondrial DNA; Mitochondrial dysfunction; Modified sebaceous glands; Sebaceous glands

DOI:  https://doi.org/10.1016/j.ajpath.2022.07.006
Int J Mol Sci. 2022 Aug 05. pii: 8713. [Epub ahead of print]23(15):

Effect of Physical Activity/Exercise on Oxidative Stress and Inflammation in Muscle and Vascular Aging.

Mariam El Assar, Alejandro Álvarez-Bustos, Patricia Sosa, Javier Angulo, Leocadio Rodríguez-Mañas.

  Functional status is considered the main determinant of healthy aging. Impairment in skeletal muscle and the cardiovascular system, two interrelated systems, results in compromised functional status in aging. Increased oxidative stress and inflammation in older subjects constitute the background for skeletal muscle and cardiovascular system alterations. Aged skeletal muscle mass and strength impairment is related to anabolic resistance, mitochondrial dysfunction, increased oxidative stress and inflammation as well as a reduced antioxidant response and myokine profile. Arterial stiffness and endothelial function stand out as the main cardiovascular alterations related to aging, where increased systemic and vascular oxidative stress and inflammation play a key role. Physical activity and exercise training arise as modifiable determinants of functional outcomes in older persons. Exercise enhances antioxidant response, decreases age-related oxidative stress and pro-inflammatory signals, and promotes the activation of anabolic and mitochondrial biogenesis pathways in skeletal muscle. Additionally, exercise improves endothelial function and arterial stiffness by reducing inflammatory and oxidative damage signaling in vascular tissue together with an increase in antioxidant enzymes and nitric oxide availability, globally promoting functional performance and healthy aging. This review focuses on the role of oxidative stress and inflammation in aged musculoskeletal and vascular systems and how physical activity/exercise influences functional status in the elderly.

Keywords:  aging; cardiovascular system; exercise; inflammation; muscle; oxidative stress; physical activity

DOI:  https://doi.org/10.3390/ijms23158713
Geroscience. 2022 Aug 11.

Lipidomics profiling of biological aging in American Indians: the Strong Heart Family Study.

Pooja Subedi, Helena Palma-Gudiel, Oliver Fiehn, Lyle G Best, Elisa T Lee, Barbara V Howard, Jinying Zhao.

  Telomeres shorten with age and shorter leukocyte telomere length (LTL) has been associated with various age-related diseases. Thus, LTL has been considered a biomarker of biological aging. Dyslipidemia is an established risk factor for most age-related metabolic disorders. However, little is known about the relationship between LTL and dyslipidemia. Lipidomics is a new biochemical technique that can simultaneously identify and quantify hundreds to thousands of small molecular lipid species. In a large population comprising 1843 well-characterized American Indians in the Strong Heart Family Study, we examined the lipidomic profile of biological aging assessed by LTL. Briefly, LTL was quantified by qPCR. Fasting plasma lipids were quantified by untargeted liquid chromatography-mass spectrometry. Lipids associated with LTL were identified by elastic net modeling. Of 1542 molecular lipids identified (518 known, 1024 unknown), 174 lipids (36 knowns) were significantly associated with LTL, independent of chronological age, sex, BMI, hypertension, diabetes status, smoking status, bulk HDL-C, and LDL-C. These findings suggest that altered lipid metabolism is associated with biological aging and provide novel insights that may enhance our understanding of the relationship between dyslipidemia, biological aging, and age-related diseases in American Indians.

Keywords:  American Indians; Biological aging; Biomarkers; Lipidomics; Strong Heart Study; Telomere length

DOI:  https://doi.org/10.1007/s11357-022-00638-9
Front Immunol. 2022 ;13 911050

Age-related increase of mitochondrial content in human memory CD4+ T cells contributes to ROS-mediated increased expression of proinflammatory cytokines.

Yuling Chen, Yuanchun Ye, Pierre-Louis Krauß, Pelle Löwe, Moritz Pfeiffenberger, Alexandra Damerau, Lisa Ehlers, Thomas Buttgereit, Paula Hoff, Frank Buttgereit, Timo Gaber.

  Cellular metabolism modulates effector functions in human CD4+ T (Th) cells by providing energy and building blocks. Conversely, cellular metabolic responses are modulated by various influences, e.g., age. Thus, we hypothesized that metabolic reprogramming in human Th cells during aging modulates effector functions and contributes to "inflammaging", an aging-related, chronic, sterile, low-grade inflammatory state characterized by specific proinflammatory cytokines. Analyzing the metabolic response of human naive and memory Th cells from young and aged individuals, we observed that memory Th cells exhibit higher glycolytic and mitochondrial fluxes than naive Th cells. In contrast, the metabolism of the latter was not affected by donor age. Memory Th cells from aged donors showed a higher respiratory capacity, mitochondrial content, and intracellular ROS production than those from young donors without altering glucose uptake and cellular ATP levels, which finally resulted in higher secreted amounts of proinflammatory cytokines, e.g., IFN-γ, IP-10 from memory Th cells taken from aged donors after TCR-stimulation which were sensitive to ROS inhibition. These findings suggest that metabolic reprogramming in human memory Th cells during aging results in an increased expression of proinflammatory cytokines through enhanced ROS production, which may contribute to the pathogenesis of inflammaging.

Keywords:  ROS; aging; cytokines; memory Th cells; metabolism; proliferation

DOI:  https://doi.org/10.3389/fimmu.2022.911050
Cell Cycle. 2022 Aug 10. 1-19

The cGAS/STING signaling pathway: a cross-talk of infection, senescence and tumors.

Peng-Hui Zeng, Wen-Jun Yin.

  The cGAS/STING signaling pathway is an important part of the cytoplasmic DNA sensor, which can trigger a type I interferon response to microbial infection when pathogenic DNA is detected. However, continuous inhibition of cGAS/STING signaling by viral infection may be an important cause of tumorigenesis. At the same time, recent studies have shown that although the cGAS/STING signaling pathway also plays a core role in anti-tumor immunity and cell senescence, the inflammatory response induced by cGAS/STING signaling will also promote tumorigenesis in different backgrounds. Here, we discuss the role of cGAS/STING in the context of infection, senescence, and tumors, especially with respect to progression, to facilitate a better understanding of the mechanism of the cGAS/STING pathway.

Keywords:  cGAS/sting; infection; senescence; tumors

DOI:  https://doi.org/10.1080/15384101.2022.2109899
Mol Metab. 2022 Aug 06. pii: S2212-8778(22)00129-6. [Epub ahead of print] 101560

Nicotinamide riboside alleviates exercise intolerance in ANT1-deficient mice.

Patrick M Schaefer, Jessica Huang, Arrienne Butic, Caroline Perry, Tal Yardeni, Wendy Tan, Ryan Morrow, Joseph A Baur, Douglas C Wallace.

   OBJECTIVE: Mitochondrial disorders are often characterized by muscle weakness and fatigue. Null mutations in the heart-muscle adenine nucleotide translocator isoform 1 (ANT1) of both humans and mice cause cardiomyopathy and myopathy associated with exercise intolerance and muscle weakness. Here we decipher the molecular underpinnings of ANT1-deficiency-mediated exercise intolerance.
METHODS: This was achieved by correlating exercise physiology, mitochondrial function and metabolomics of mice deficient in ANT1 and comparing this to control mice.
RESULTS: We demonstrate a peripheral limitation of skeletal muscle mitochondrial respiration and a reduced complex I respiration in ANT1-deficient mice. Upon exercise, this results in a lack of NAD+ leading to a substrate limitation and stalling of the TCA cycle and mitochondrial respiration, further limiting skeletal muscle mitochondrial respiration. Treatment of ANT1-deficient mice with nicotinamide riboside increased NAD+ levels in skeletal muscle and liver, which increased the exercise capacity and the mitochondrial respiration.
CONCLUSION: Increasing NAD + levels with nicotinamide riboside can alleviate the exercise intolerance associated to ANT1-deficiency, indicating the therapeutic potential of NAD+-stimulating compounds in mitochondrial myopathies.

Keywords:  Exercise; Mitochondrial disorder; NAD(+)/NADH; Nicotinamide riboside

DOI:  https://doi.org/10.1016/j.molmet.2022.101560
EMBO J. 2022 Aug 09. e110988

ARF2-PIF5 interaction controls transcriptional reprogramming in the ABS3-mediated plant senescence pathway.

Hui Xue, Jingjing Meng, Pei Lei, Yongxin Cao, Xue An, Min Jia, Yan Li, Haofeng Liu, Jen Sheen, Xiayan Liu, Fei Yu.

  One of the hallmarks of plant senescence is the global transcriptional reprogramming coordinated by a plethora of transcription factors (TFs). However, mechanisms underlying the interactions between different TFs in modulating senescence remain obscure. Previously, we discovered that plant ABS3 subfamily MATE transporter genes regulate senescence and senescence-associated transcriptional changes. In a genetic screen for mutants suppressing the accelerated senescence phenotype of the gain-of-function mutant abs3-1D, AUXIN RESPONSE FACTOR 2 (ARF2) and PHYTOCHROME-INTERACTING FACTOR 5 (PIF5) were identified as key TFs responsible for transcriptional regulation in the ABS3-mediated senescence pathway. ARF2 and PIF5 (as well as PIF4) interact directly and function interdependently to promote senescence, and they share common target genes such as key senescence promoting genes ORESARA 1 (ORE1) and STAY-GREEN 1 (SGR1) in the ABS3-mediated senescence pathway. In addition, we discovered reciprocal regulation between ABS3-subfamily MATEs and the ARF2 and PIF5/4 TFs. Taken together, our findings reveal a regulatory paradigm in which the ARF2-PIF5/4 functional module facilitates the transcriptional reprogramming in the ABS3-mediated senescence pathway.

Keywords:  ABS3; ARF2; PIF5; senescence; transcriptional regulation

DOI:  https://doi.org/10.15252/embj.2022110988
J Cell Mol Med. 2022 Aug 13.

Dysregulated lipolysis and lipophagy in lipid droplets of macrophages from high fat diet-fed obese mice.

Yohannes Getiye, Tatiana Angel Rice, Brandon D Phillips, Daniel Fidel Carrillo, Guanglong He.

  Obesity is associated with lipid droplet (LD) accumulation, dysregulated lipolysis and chronic inflammation. Previously, the caspase recruitment domain-containing protein 9 (CARD9) has been identified as a potential contributor to obesity-associated abnormalities including cardiac dysfunction. In the current study, we explored a positive feedback signalling cycle of dysregulated lipolysis, CARD9-associated inflammation, impaired lipophagy and excessive LD accumulation in sustaining the chronic inflammation associated with obesity. C57BL/6 WT and CARD9-/- mice were fed with normal diet (ND, 12% fat) or a high fat diet (HFD, 45% fat) for 5 months. Staining of LDs from peritoneal macrophages (PMs) revealed a significant increase in the number of cells with LD and the number of LD per cell in the HFD-fed WT but not CARD9-/- obese mice. Rather, CARD9 KO significantly increased the mean LD size. WT obese mice showed down regulation of lipolytic proteins with increased diacylglycerol (DAG) content, and CARD9 KO normalized DAG with restored lipolytic protein expression. The build-up of DAG in the WT obese mice is further associated with activation of PKCδ, NF-κB and p38 MAPK inflammatory signalling in a CARDD9-dependent manner. Inhibition of adipose triglyceride lipase (ATGL) by Atglistatin (Atg) resulted in similar effects as in CARD9-/- mice. Interestingly, CARD9 KO and Atg treatment enhanced lipophagy. In conclusion, HFD feeding likely initiated a positive feedback signalling loop from dysregulated lipolysis, CARD9-dependent inflammation, impaired lipophagy, to excessive LD accumulation and sustained inflammation. CARD9 KO and Atg treatment protected against the chronic inflammation by interrupting this feedforward cycle.

Keywords:  CARD9; DAG-PKCδ; autophagy; lipid droplet; lipolysis; lipophagy

DOI:  https://doi.org/10.1111/jcmm.17513
Mech Ageing Dev. 2022 Aug 09. pii: S0047-6374(22)00104-X. [Epub ahead of print] 111722

MITOCHONDRIAL DNA INSERTIONS INTO NUCLEAR DNA AFFECTING CHROMOSOME SEGREGATION: INSIGHTS FOR A NOVEL MECHANISM OF IMMUNOSENESCENCE IN MICE.

Mónica González-Sánchez, Víctor García-Martínez, Sara Bravo, Hikaru Kobayashi, Irene Martínez de Toda, Blanca González-Bermúdez, Gustavo R Plaza, Mónica De la Fuente.

  Mitochondrial DNA sequences were found inserted in the nuclear genome of mouse peritoneal T lymphocytes that increased progressively with aging. These insertions were preferentially located at the pericentromeric heterochromatin. In the same individuals, binucleated T-cells with micronuclei showed a significantly increased frequency associated with age. Most of them were positive for centromere sequences, reflecting the loss of chromatids or whole chromosomes. The proliferative capacity of T lymphocytes decreased with age as well as the glutathione reductase activity, whereas the oxidized glutathione and malondialdehyde concentrations exhibited a significant increase. These results may point to a common process that provides insights for a new approach to understanding immunosenescence. We propose a novel mechanism in which mitochondrial fragments, originated by the increased oxidative stress status during aging, accumulate inside the nuclear genome of T lymphocytes in a time-dependent way. The primary entrance of mitochondrial fragments at the pericentromeric regions may compromise chromosome segregation, causing genetic loss that leads to micronuclei formation, rendering aneuploid cells with reduced proliferation capacity, one of the hallmark of immunosenescence. Future experiments deciphering the mechanistic basis of this phenomenon are needed.

Keywords:  NUMTs; immunosenescence; lymphoproliferation; micronuclei; mtDNA; oxidative stress

DOI:  https://doi.org/10.1016/j.mad.2022.111722
Aging Cell. 2022 Aug 12. e13675

Glucose derived carbon nanosphere (CSP) conjugated TTK21, an activator of the histone acetyltransferases CBP/p300, ameliorates amyloid-beta 1-42 induced deficits in plasticity and associativity in hippocampal CA1 pyramidal neurons.

Akash K Singh, Sin H Neo, Christine Liwang, Karen K L Pang, Jason C K Leng, Sarmistha H Sinha, Mahesh S Shetty, Madavan Vasudevan, Vinay J Rao, Ila Joshi, Muthusamy Eswaramoorthy, Maria V Pavon, Ang R Sheila, Sheeja Navakkode, Tapas K Kundu, Sreedharan Sajikumar.

  The master epigenetic regulator lysine acetyltransferase (KAT) p300/CBP plays a pivotal role in neuroplasticity and cognitive functions. Recent evidence has shown that in several neurodegenerative diseases, including Alzheimer's disease (AD), the expression level and function of p300/CBP are severely compromised, leading to altered gene expression causing pathological conditions. Here, we show that p300/CBP activation by a small-molecule TTK21, conjugated to carbon nanosphere (CSP) ameliorates Aβ-impaired long-term potentiation (LTP) induced by high-frequency stimulation, theta burst stimulation, and synaptic tagging/capture (STC). This functional rescue was correlated with CSP-TTK21-induced changes in transcription and translation. Mechanistically, we observed that the expression of a large number of synaptic plasticity- and memory-related genes was rescued, presumably by the restoration of p300/CBP mediated acetylation. Collectively, these results suggest that small-molecule activators of p300/CBP could be a potential therapeutic molecule for neurodegenerative diseases like AD.

Keywords:  CREB-binding protein; TTK21; long-term potentiation; synaptic tagging; synaptic tagging/ capture

DOI:  https://doi.org/10.1111/acel.13675