bims-senagi 2021-06-06 papers

bims-senagi

Biomed News

on Senescence and aging

Issue of 2021‒06‒06
37 papers selected by
Maria Grazia Vizioli
Mayo Clinic

Nucleotide-binding domain and leucine-rich-repeat-containing protein X1 deficiency induces nicotinamide adenine dinucleotide decline, mechanistic target of rapamycin activation, and cellular senescence and accelerates aging lung-like changes.
CELLULAR SENESCENCE IN VASCULAR WALL MESENCHYMAL STROMAL CELLS, A POSSIBLE CONTRIBUTION TO THE DEVELOPMENT OF AORTIC ANEURYSM.
miR-21 and miR-146a: the microRNAs of inflammaging and age-related diseases.
p16-3MR: A Novel Model to Study Cellular Senescence in Cigarette Smoke-Induced Lung Injuries.
Loss of Fis1 impairs proteostasis during skeletal muscle aging in Drosophila.
GRSF1 deficiency in skeletal muscle reduces endurance in aged mice.
Single-nucleus transcriptomic landscape of primate hippocampal aging.
Histone deficiency and accelerated replication stress in T cell aging.
Age-related defects in autophagy alter the secretion of paracrine factors from bone marrow mononuclear cells.
Extracellular Vesicles and Hematopoietic Stem Cell Aging.
Attenuation of age-elevated blood factors by repositioning plasmapheresis: A novel perspective and approach.
Aging of the progenitor cells that initiate prostate cancer.
Onset of Senescence and Steatosis in Hepatocytes as a Consequence of a Shift in the Diacylglycerol/Ceramide Balance at the Plasma Membrane.
Senescence of donor cells impairs fat graft regeneration by suppressing adipogenesis and increasing expression of senescence-associated secretory phenotype factors.
Age-Related Changes in Bone-Marrow Mesenchymal Stem Cells.
Lifelong Aerobic Exercise Alleviates Sarcopenia by Activating Autophagy and Inhibiting Protein Degradation via the AMPK/PGC-1α Signaling Pathway.
Diabetes induces macrophage dysfunction through cytoplasmic dsDNA/AIM2 associated pyroptosis.
Mitophagy and Oxidative Stress: The Role of Aging.
Interactive effects of aging and aerobic capacity on energy metabolism-related metabolites of serum, skeletal muscle, and white adipose tissue.
Hallmarks of Aging in Macrophages: Consequences to Skin Inflammaging.
Aging and Options to Halt Declining Immunity to Virus Infections.
Blood Immunosenescence Signatures Reflecting Age, Frailty and Tumor Immune Infiltrate in Patients with Early Luminal Breast Cancer.
Acer Truncatum Seed Oil Alleviates Learning and Memory Impairments of Aging Mice.
Metabolipidomic profiling reveals an age-related deficiency of skeletal muscle pro-resolving mediators that contributes to maladaptive tissue remodeling.
Aging Reduces Insulin Clearance in Mice.
Aging of the Retina: Molecular and Metabolic Turbulences and Potential Interventions.
Changes in Circadian Rhythms Dysregulate Inflammation in Ageing: Focus on Leukocyte Trafficking.
Critical role of the CD44lowCD62Llow CD8+ T cell subset in restoring antitumor immunity in aged mice.
Human muscle stem cells are refractory to aging.
Canonical NF-κB signaling maintains corneal epithelial integrity and prevents corneal aging via retinoic acid.
Mechanisms of angiogenic incompetence in Hutchinson-Gilford progeria via downregulation of endothelial NOS.
Potential of Mesenchymal Stem Cells in the Rejuvenation of the Aging Immune System.
Sulodexide reduces glucose induced senescence in human retinal endothelial cells.
Role of Adiponectin-Notch pathway in cognitive dysfunction associated with depression and in the therapeutic effect of physical exercise.
Mitochondrial DNA: cellular genotoxic stress sentinel.
Neutrophils hit reverse in ageing.
Neuronal loss and microgliosis are restricted to the core of Aβ deposits in mouse models of Alzheimer's disease.

Aging Cell. 2021 Jun 04. e13410

Nucleotide-binding domain and leucine-rich-repeat-containing protein X1 deficiency induces nicotinamide adenine dinucleotide decline, mechanistic target of rapamycin activation, and cellular senescence and accelerates aging lung-like changes.

Hyeon Jun Shin, Sang-Hun Kim, Hong-Jai Park, Min-Sun Shin, Insoo Kang, Min-Jong Kang.

  Mitochondrial dysfunction has long been implicated to have a causative role in organismal aging. A mitochondrial molecule, nucleotide-binding domain and leucine-rich-repeat-containing protein X1 (NLRX1), represents the only NLR family member that targets this cellular location, implying that NLRX1 probably establishes a fundamental link between mitochondrial functions and cellular physiology. However, the significance of NLRX1 function in cellular senescence, a key conceptual constituent in aging biology, is yet to be defined. Here, we demonstrate that molecular hallmarks involved in aging biology including NAD+ decline, and activation of mTOR, p53, and p16INK4A are significantly enhanced in NLRX1 deficiency in vitro. Mechanistic studies of replicative cellular senescence in the presence or absence of NLRX1 in vitro reveal that NLRX1-deficient fibroblasts fail to maintain optimal NAD+ /NADH ratio, which instigates the decline of SIRT1 and the activation of mTOR, p16INK4A , and p53, leading to the increase in senescence-associated beta-galactosidase (SA-β-gal)-positive cells. Importantly, the enhanced cellular senescence response in NLRX1 deficiency is significantly attenuated by pharmacological inhibition of mTOR signaling in vitro. Finally, our in vivo murine studies reveal that NLRX1 decreases with age in murine lungs and NLRX1 deficiency in vivo accelerates pulmonary functional and structural changes that recapitulate the findings observed in human aging lungs. In conclusion, the current study provides evidence for NLRX1 as a crucial regulator of cellular senescence and in vivo lung aging.

Keywords:  NAD+ (nicotinamide adenine dinucleotide); NLRX1 (nucleotide-binding domain and leucine-rich-repeat-containing protein X1); cellular senescence; lung aging; mTOR (mechanistic target of rapamycin)

DOI:  https://doi.org/10.1111/acel.13410
Mech Ageing Dev. 2021 May 29. pii: S0047-6374(21)00087-7. [Epub ahead of print] 111515

CELLULAR SENESCENCE IN VASCULAR WALL MESENCHYMAL STROMAL CELLS, A POSSIBLE CONTRIBUTION TO THE DEVELOPMENT OF AORTIC ANEURYSM.

Gabriella Teti, Francesca Chiarini, Eleonora Mazzotti, Alessandra Ruggeri, Francesco Carano, Mirella Falconi.

  Cellular senescence is a hallmark of ageing and it plays a key role in the development of age-related diseases. Abdominal aortic aneurysm (AAA) is an age related degenerative vascular disorder, characterized by a progressive dilatation of the vascular wall and high risk of rupture over time. Nowadays, no pharmacological therapies are available and the understanding of the molecular mechanisms that lead to AAA onset and development are poorly defined. In this study we investigated the cellular features of senescence in vascular mesenchymal stromal cells, isolated from pathological (AAA - MSCs) and healthy (h - MSCs) segments of human abdominal aorta and their implication in impairing the vascular repair ability of MSCs. Cell proliferation, ROS production, cell surface area, the expression of cyclin dependent kinase inhibitors p21CIP1 and p16INK4a, the activation of the DNA damage response and a dysregulated autophagy showed a senescent state in AAA - MSCs compared to h-MSCs. Moreover, a reduced ability to differentiate toward endothelial cells was observed in AAA - MSCs. All these data suggest that the accumulation of senescent vascular MSCs over time impairs their remodeling ability during ageing. This condition could support the onset and development of AAA.

Keywords:  abdominal aorta aneurysm; cellular senescence; endothelial differentiation; vascular MSCs

DOI:  https://doi.org/10.1016/j.mad.2021.111515
Ageing Res Rev. 2021 May 31. pii: S1568-1637(21)00121-5. [Epub ahead of print] 101374

miR-21 and miR-146a: the microRNAs of inflammaging and age-related diseases.

Fabiola Olivieri, Francesco Prattichizzo, Angelica Giuliani, Giulia Matacchione, Maria Rita Rippo, Jacopo Sabbatinelli, Massimiliano Bonafè.

  The first paper on "inflammaging" published in 2001 paved the way for a unifying theory on how and why aging turns out to be the main risk factor for the development of the most common age-related diseases (ARDs). The most exciting challenge on this topic was explaining how systemic inflammation steeps up with age and why it shows different rates among individuals of the same chronological age. The "epigenetic revolution" in the past twenty years conveyed that the assessment of the individual genetic make-up is not enough to depict the trajectories of age-related inflammation. Accordingly, others and we have been focusing on the role of non-coding RNA, i.e. microRNAs (miRNAs) in inflammaging. The results obtained in the latest 10 years underpinned the key role of a miRNAs subset that we have called inflammamiRs, owing to their ability to master (NF-κB)-driven inflammatory pathways. In this review, we will focus on two inflammamiRs, i.e. miR-21-5p and miR-146a-5p, which target a variety of molecules belonging to the NF-κB/NLRP3 pathways. The interplay between miR-146a-5p and IL-6 in the context of aging and ARDs will also be highlighted. We will also provide the most relevant evidence suggesting that circulating inflammamiRs, along with IL-6, can measure the degree of inflammaging.

Keywords:  MicroRNA; NF-κB; cell senescence; inflammaging; miR-146a-5p; miR-21-5p

DOI:  https://doi.org/10.1016/j.arr.2021.101374
Int J Mol Sci. 2021 May 03. pii: 4834. [Epub ahead of print]22(9):

p16-3MR: A Novel Model to Study Cellular Senescence in Cigarette Smoke-Induced Lung Injuries.

Gagandeep Kaur, Isaac K Sundar, Irfan Rahman.

  Cellular senescence and lung aging are associated with the pathogenesis of chronic obstructive pulmonary disease (COPD). COPD progresses with aging, and chronic smoking is the key susceptibility factor in lung pathological changes concurrent with mitochondrial dysfunction and biological aging. However, these processes involving cigarette smoke (CS)-mediated lung cellular senescence are difficult to distinguish. One of the impediments to studying cellular senescence in relation to age-related lung pathologies is the lack of a suitable in vivo model. In view of this, we provide evidence that supports the suitability of p16-3MR mice to studying cellular senescence in CS-mediated and age-related lung pathologies. p16-3MR mice have a trimodal reporter fused to the promoter of the p16INK4a gene that enables detection, isolation, and selective elimination of senescent cells, thus making them a suitable model to study cellular senescence. To determine their suitability in CS-mediated lung pathologies, we exposed young (12-14 months) and old (17-20 months) p16-3MR mice to 30 day CS exposure and studied the expression of senescent genes (p16, p21, and p53) and SASP-associated markers (MMP9, MMP12, PAI-1, and FN-1) in air- and CS-exposed mouse lungs. Our results showed that this model could detect cellular senescence using luminescence and isolate cells undergoing senescence with the help of tissue fluorescence in CS-exposed young and old mice. Our results from the expression of senescence markers and SASP-associated genes in CS-exposed young and old p16-3MR mice were comparable with increased lung cellular senescence and SASP in COPD. We further showed alteration in the; (i) tissue luminescence and fluorescence, (ii) mRNA and protein expressions of senescent markers and SASP genes, and (iii) SA-β-gal activity in CS-exposed young and old p16-3MR mice as compared to their air controls. Overall, we showed that p16-3MR is a competent model for studying the cellular senescence in CS-induced pathologies. Hence, the p16-3MR reporter mouse model may be used as a novel tool for understanding the pathobiology of cellular senescence and other underlying mechanisms involved in COPD and fibrosis.

Keywords:  COPD; SASP; cellular senescence; cigarette smoke; mitochondrial dysfunction; p16

DOI:  https://doi.org/10.3390/ijms22094834
Aging Cell. 2021 Jun 01. e13379

Loss of Fis1 impairs proteostasis during skeletal muscle aging in Drosophila.

Tai-Ting Lee, Po-Lin Chen, Matthew P Su, Jian-Chiuan Li, Yi-Wen Chang, Rei-Wen Liu, Hsueh-Fen Juan, Jinn-Moon Yang, Shih-Peng Chan, Yu-Chen Tsai, Sophia von Stockum, Elena Ziviani, Azusa Kamikouchi, Horng-Dar Wang, Chun-Hong Chen.

  Increased levels of dysfunctional mitochondria within skeletal muscle are correlated with numerous age-related physiopathological conditions. Improving our understanding of the links between mitochondrial function and muscle proteostasis, and the role played by individual genes and regulatory networks, is essential to develop treatments for these conditions. One potential player is the mitochondrial outer membrane protein Fis1, a crucial fission factor heavily involved in mitochondrial dynamics in yeast but with an unknown role in higher-order organisms. By using Drosophila melanogaster as a model, we explored the effect of Fis1 mutations generated by transposon Minos-mediated integration. Mutants exhibited a higher ratio of damaged mitochondria with age as well as elevated reactive oxygen species levels compared with controls. This caused an increase in oxidative stress, resulting in large accumulations of ubiquitinated proteins, accelerated muscle function decline, and mitochondrial myopathies in young mutant flies. Ectopic expression of Fis1 isoforms was sufficient to suppress this phenotype. Loss of Fis1 led to unbalanced mitochondrial proteostasis within fly muscle, decreasing both flight capabilities and lifespan. Fis1 thus clearly plays a role in fly mitochondrial dynamics. Further investigations into the detailed function of Fis1 are necessary for exploring how mitochondrial function correlates with muscle health during aging.

Keywords:   Drosophila melanogaster ; Fis1; aging; mitochondria

DOI:  https://doi.org/10.1111/acel.13379
Aging (Albany NY). 2021 Jun 02. 13

GRSF1 deficiency in skeletal muscle reduces endurance in aged mice.

Riley K Driscoll, Linda K Krasniewski, Samuel G Cockey, Jen-Hao Yang, Yulan Piao, Elin Lehrmann, Yongqing Zhang, Marc Michel, Ji Heon Noh, Chang-Yi Cui, Myriam Gorospe.

  GRSF1 is a mitochondrial RNA-binding protein important for maintaining mitochondrial function. We found that GRSF1 is highly expressed in cultured skeletal myoblasts differentiating into myotubes. To understand the physiological function of GRSF1 in vivo, we generated mice in which GRSF1 was specifically ablated in skeletal muscle. The conditional knockout mice (Grsf1cKO) appeared normal until 7-9 months of age. Importantly, however, a reduction of muscle endurance compared to wild-type controls was observed in 16- to 18-month old Grsf1cKO mice. Transcriptomic analysis revealed more than 200 mRNAs differentially expressed in Grsf1cKO muscle at this age. Notably, mRNAs encoding proteins involved in mitochondrial function, inflammation, and ion transport, including Mgarp, Cxcl10, Nfkb2, and Sln mRNAs, were significantly elevated in aged Grsf1cKO muscle. Our findings suggest that GRSF1 deficiency exacerbates the functional decline of aged skeletal muscle, likely through multiple downstream effector proteins.

Keywords:  GRSF1; RNA-binding protein; mouse aging; skeletal muscle aging

DOI:  https://doi.org/10.18632/aging.203151
Protein Cell. 2021 May 30.

Single-nucleus transcriptomic landscape of primate hippocampal aging.

Hui Zhang, Jiaming Li, Jie Ren, Shuhui Sun, Shuai Ma, Weiqi Zhang, Yang Yu, Yusheng Cai, Kaowen Yan, Wei Li, Baoyang Hu, Piu Chan, Guo-Guang Zhao, Juan Carlos Izpisua Belmonte, Qi Zhou, Jing Qu, Si Wang, Guang-Hui Liu.

  The hippocampus plays a crucial role in learning and memory, and its progressive deterioration with age is functionally linked to a variety of human neurodegenerative diseases. Yet a systematic profiling of the aging effects on various hippocampal cell types in primates is still missing. Here, we reported a variety of new aging-associated phenotypic changes of the primate hippocampus. These include, in particular, increased DNA damage and heterochromatin erosion with time, alongside loss of proteostasis and elevated inflammation. To understand their cellular and molecular causes, we established the first single-nucleus transcriptomic atlas of primate hippocampal aging. Among the 12 identified cell types, neural transiently amplifying progenitor cell (TAPC) and microglia were most affected by aging. In-depth dissection of gene-expression dynamics revealed impaired TAPC division and compromised neuronal function along the neurogenesis trajectory; additionally elevated pro-inflammatory responses in the aged microglia and oligodendrocyte, as well as dysregulated coagulation pathways in the aged endothelial cells may contribute to a hostile microenvironment for neurogenesis. This rich resource for understanding primate hippocampal aging may provide potential diagnostic biomarkers and therapeutic interventions against age-related neurodegenerative diseases.

Keywords:  aging; hippocampus; primate; single-cell RNA sequencing

DOI:  https://doi.org/10.1007/s13238-021-00852-9
J Clin Invest. 2021 06 01. pii: 143632. [Epub ahead of print]131(11):

Histone deficiency and accelerated replication stress in T cell aging.

Chulwoo Kim, Jun Jin, Zhongde Ye, Rohit R Jadhav, Claire E Gustafson, Bin Hu, Wenqiang Cao, Lu Tian, Cornelia M Weyand, Jörg J Goronzy.

  With increasing age, individuals are more vulnerable to viral infections such as with influenza or the SARS-CoV-2 virus. One age-associated defect in human T cells is the reduced expression of miR-181a. miR-181ab1 deficiency in peripheral murine T cells causes delayed viral clearance after infection, resembling human immune aging. Here we show that naive T cells from older individuals as well as miR-181ab1-deficient murine T cells develop excessive replication stress after activation, due to reduced histone expression and delayed S-phase cell cycle progression. Reduced histone expression was caused by the miR-181a target SIRT1 that directly repressed transcription of histone genes by binding to their promoters and reducing histone acetylation. Inhibition of SIRT1 activity or SIRT1 silencing increased histone expression, restored cell cycle progression, diminished the replication-stress response, and reduced the production of inflammatory mediators in replicating T cells from old individuals. Correspondingly, treatment with SIRT1 inhibitors improved viral clearance in mice with miR-181a-deficient T cells after LCMV infection. In conclusion, SIRT1 inhibition may be beneficial to treat systemic viral infection in older individuals by targeting antigen-specific T cells that develop replication stress due to miR-181a deficiency.

Keywords:  Adaptive immunity; Aging; Cell cycle; Cellular senescence

DOI:  https://doi.org/10.1172/JCI143632
Aging (Albany NY). 2021 Jun 04. 13

Age-related defects in autophagy alter the secretion of paracrine factors from bone marrow mononuclear cells.

Azadeh Yeganeh, Faisal J Alibhai, Stephanie W Tobin, Fievel Lim, Jun Wu, Shuhong Li, Richard D Weisel, Ren-Ke Li.

  Bone marrow mononuclear cell therapy improves cardiac repair after myocardial infarction (MI), in-part through signaling to resident cardiac cells, such as fibroblasts, which regulate scar formation. The efficacy of cell therapy declines with age, as aging of both donor and recipient cells decreases repair responses. Autophagy regulates the microenvironment by both extracellular vesicle (EV)-dependent and independent secretion pathways. We hypothesized that age-related autophagy changes in bone marrow cells (BMCs) alter paracrine signaling, contributing to lower cell therapy efficacy. Here, we demonstrate that young Sca-1+ BMCs exhibited a higher LC3II/LC3I ratio compared to old Sca-1+ BMCs, which was accentuated when BMCs were cultured under hypoxia. To examine the effect on paracrine signaling, old cardiac fibroblasts were cultured with conditioned medium (CM) from young and old Sca-1+ BMCs. Young, but not old CM, enhanced fibroblast proliferation, migration, and differentiation, plus reduced senescence. These beneficial effects were lost when autophagy or EV secretion in BMCs was blocked pharmacologically, or by siRNA knockdown of Atg7. Therefore, both EV-dependent and -independent paracrine signaling from young BMCs is responsible for paracrine stimulation of old cardiac fibroblasts. In vivo, bone marrow chimerism of old mice with young BMCs increased the number of LC3b+ cells in the heart compared to old mice reconstituted with old BMCs. These data suggest that the deterioration of autophagy with aging negatively impacts the paracrine effects of BMCs, and provide mechanistic insight into the age-related decline in cell therapy efficacy that could be targeted to improve the function of old donor cells.

Keywords:  aging; autophagy; bone marrow; fibroblasts; secretome

DOI:  https://doi.org/10.18632/aging.203127
Arterioscler Thromb Vasc Biol. 2021 Jun 03. ATVBAHA120314643

Extracellular Vesicles and Hematopoietic Stem Cell Aging.

Laura R Goldberg.

  Extracellular vesicles (EVs), important mediators of intercellular communication, play a critical role in modulating hematopoiesis within the bone marrow microenvironment. Although few studies have explicitly examined the connections between EVs and hematopoietic stem cell (HSC) aging, there is a growing body of evidence that implicates EVs in numerous age-related biologic processes and diseases. This, coupled with their tremendous capacity to influence hematopoiesis, suggests EVs may be key mediators of HSC aging. This review provides an overview of the effects of aging on HSCs, the role of EVs in aging in general, and then details key work in EV modulation of normal and malignant hematopoiesis, with a particular focus on how these effects may translate into the ability of EVs to drive HSC aging. Finally, it describes an exciting emerging literature that provides direct evidence for EV modulation of HSC phenotypes during natural aging and highlights their potential in HSC rejuvenation. Taken collectively, this body of research has profound implications for the future of HSC aging studies. More clearly defining how EVs modify HSC function in an age-dependent fashion and determining the molecular mechanisms by which they drive these age-related HSC phenotype changes will undoubtedly yield innovative strategies to delay or even reverse age-related hematologic dysfunction.

Keywords:  aging; extracellular vesicles; hematopoiesis; phenotype; stem cell

DOI:  https://doi.org/10.1161/ATVBAHA.120.314643
Transfus Apher Sci. 2021 May 21. pii: S1473-0502(21)00128-2. [Epub ahead of print] 103162

Attenuation of age-elevated blood factors by repositioning plasmapheresis: A novel perspective and approach.

Melod Mehdipour, Jessy Etienne, Chao Liu, Taha Mehdipour, Cameron Kato, Michael Conboy, Irina Conboy, Dobri D Kiprov.

  Aging is associated with the impairment of stem cell activation, leading to the functional decline of tissues and increasing the risk for age-associated diseases. The old, damaged or unrepaired tissues disturb distant tissue homeostasis by secreting factors into the circulation, which may not only serve as biomarkers for specific age-associated pathologies but also induce a variety of degenerative phenotypes. In this review, we summarize and discuss systemic determinants that perpetuate age-related tissue dysfunction. We further elaborate on the effects of attenuating these circulating factors by highlighting recent advances which utilize plasmapheresis in a pre-clinical or clinical setting. Overall, we postulate that repositioning therapeutic plasma exchange (TPE) to dilute the systemic factors, which become deleterious at their age-elevated levels, could be a rapidly effective rejuvenation therapy that recalibrates crucial signaling pathways to a youthful state.

Keywords:  Age-associated diseases; Aging; Blood; Inflammation; Plasma; Plasmapheresis; Rejuvenation; Senescence-associated secretory phenotype (SASP); Senescent cells; Systemic factors; Tissue repair

DOI:  https://doi.org/10.1016/j.transci.2021.103162
Cancer Lett. 2021 May 28. pii: S0304-3835(21)00238-X. [Epub ahead of print]515 28-35

Aging of the progenitor cells that initiate prostate cancer.

Jack Freeland, Preston D Crowell, Jenna M Giafaglione, Paul C Boutros, Andrew S Goldstein.

  Many organs experience a loss of tissue mass and a decline in regenerative capacity during aging. In contrast, the prostate continues to grow in volume. In fact, age is the most important risk factor for prostate cancer. However, the age-related factors that influence the composition, morphology and molecular features of prostate epithelial progenitor cells, the cells-of-origin for prostate cancer, are poorly understood. Here, we review the evidence that prostate luminal progenitor cells are expanded with age. We explore the age-related changes to the microenvironment that may influence prostate epithelial cells and risk of transformation. Finally, we raise a series of questions about models of aging and regulators of prostate aging which need to be addressed. A fundamental understanding of aging in the prostate will yield critical insights into mechanisms that promote the development of age-related prostatic disease.

Keywords:  Epithelium; Microenvironment; Mutations; Old; Organoid

DOI:  https://doi.org/10.1016/j.canlet.2021.05.014
Cells. 2021 May 21. pii: 1278. [Epub ahead of print]10(6):

Onset of Senescence and Steatosis in Hepatocytes as a Consequence of a Shift in the Diacylglycerol/Ceramide Balance at the Plasma Membrane.

Gergana Deevska, Patrick P Dotson, Mihail Mitov, D Allan Butterfield, Mariana Nikolova-Karakashian.

  Ceramide and diacylglycerol (DAG) are bioactive lipids and mediate many cellular signaling pathways. Sphingomyelin synthase (SMS) is the single metabolic link between the two, while SMS2 is the only SMS form located at the plasma membrane. SMS2 functions were investigated in HepG2 cell lines stably expressing SMS2. SMS2 overexpression did not alter sphingomyelin (SM), phosphatidylcholine (PC), or ceramide levels. DAG content increased by approx. 40% and led to downregulation of DAG-dependent protein kinase C (PKC). SMS2 overexpression also induced senescence, characterized by positivity for β-galactosidase activity and heterochromatin foci. HepG2-SMS2 cells exhibited protruded mitochondria and suppressed mitochondrial respiration rates. ATP production and the abundance of Complex V were substantially lower in HepG2-SMS2 cells as compared to controls. SMS2 overexpression was associated with inflammasome activation based on increases in IL-1β and nlpr3 mRNA levels. HepG2-SMS2 cells exhibited lipid droplet accumulation, constitutive activation of AMPK based on elevated 172Thr phosphorylation, increased AMPK abundance, and insensitivity to insulin suppression of AMPK. Thus, our results show that SMS2 regulates DAG homeostasis and signaling in hepatocytes and also provide proof of principle for the concept that offset in bioactive lipids' production at the plasma membrane can drive the senescence program in association with steatosis and, seemingly, by cell-autonomous mechanisms.

Keywords:  AMP kinase; ceramide; diacylglycerol; lipid droplets; mitochondria; protein kinase C; senescence; sphingomyelin synthase

DOI:  https://doi.org/10.3390/cells10061278
Stem Cell Res Ther. 2021 May 29. 12(1): 311

Senescence of donor cells impairs fat graft regeneration by suppressing adipogenesis and increasing expression of senescence-associated secretory phenotype factors.

Xihang Chen, Jingwei Feng, Qiang Chang, Feng Lu, Yi Yuan.

  BACKGROUND: Fat grafting has been regarded as a promising approach for regenerative therapy. Given the rapidly aging population, better understanding of the effect of age on fat graft outcomes and the underlying mechanisms is urgently needed.METHODS: C57/BL6 mice [old (O, 18-20-month-old) and young (Y, 4-month-old)] were randomized to four fat graft groups [old-to-old (O-O), young-to-young (Y-Y), old-to-young (O-Y), and young-to-old (Y-O)]. Detailed cellular events before and after grafting were investigated by histological staining, RNA sequencing, and real-time polymerase chain reaction. The adipogenic differentiation potential of adipose-derived mesenchymal stem cells (AD-MSCs) from old or young donors was investigated in vitro. Additionally, adipogenesis of AD-MSCs derived from old recipients was evaluated in the culture supernatant of old or young donor fat tissue.
RESULTS: After 12 weeks, the volume of fat grafts did not significantly differ between the O-O and O-Y groups or between the Y-Y and Y-O groups, but was significantly smaller in the O-O group than in the Y-O group and in the O-Y group than in the Y-Y group. Compared with fat tissue from young mice, senescence-associated secretory phenotype (SASP) factors were upregulated in fat tissue from old mice. Compared with the Y-O group, adipogenesis markers were downregulated in the O-O group, while SASP factors including interleukin (IL)-6, tumor necrosis factor-α, and IL-1β were upregulated. In vitro, AD-MSCs from old donors showed impaired adipogenesis compared with AD-MSCs from young donors. Additionally, compared with the culture supernatant of young donor fat tissue, the culture supernatant of old donor fat tissue significantly decreased adipogenesis of AD-MSCs derived from old recipients, which might be attributable to increased levels of SASP factors.
CONCLUSIONS: Age has detrimental effects on fat graft outcomes by suppressing adipogenesis of AD-MSCs and upregulating expression of SASP factors, and fat graft outcomes are more dependent on donor age than on recipient age. Thus, rejuvenating fat grafts from old donors or banking younger adipose tissue for later use may be potential approaches to improve fat graft outcomes in older adults.

Keywords:  Adipogenesis; Adipose-derived mesenchymal stem cells; Donor age; Fat grafting; Senescence-associated secretory phenotype

DOI:  https://doi.org/10.1186/s13287-021-02383-w
Cells. 2021 May 21. pii: 1273. [Epub ahead of print]10(6):

Age-Related Changes in Bone-Marrow Mesenchymal Stem Cells.

Valentina A Babenko, Denis N Silachev, Tatyana I Danilina, Kirill V Goryunov, Irina B Pevzner, Ljubava D Zorova, Vasily A Popkov, Valery P Chernikov, Egor Y Plotnikov, Gennady T Sukhikh, Dmitry B Zorov.

  The use of stem cells is part of a strategy for the treatment of a large number of diseases. However, the source of the original stem cells for use is extremely important and determines their therapeutic potential. Mesenchymal stromal cells (MSC) have proven their therapeutic effectiveness when used in a number of pathological models. However, it remains an open question whether the chronological age of the donor organism affects the effectiveness of the use of MSC. The asymmetric division of stem cells, the result of which is some residential stem cells acquiring a non-senile phenotype, means that stem cells possess an intrinsic ability to preserve juvenile characteristics, implying an absence or at least remarkable retardation of senescence in stem cells. To test whether residential MSC senesce, we evaluated the physiological changes in the MSC from old rats, with a further comparison of the neuroprotective properties of MSC from young and old animals in a model of traumatic brain injury. We found that, while the effect of administration of MSC on lesion volume was minimal, functional recovery was remarkable, with the highest effect assigned to fetal cells; the lowest effect was recorded for cells isolated from adult rats and postnatal cells, having intermediate potency. MSC from the young rats were characterized by a faster growth than adult MSC, correlating with levels of proliferating cell nuclear antigen (PCNA). However, there were no differences in respiratory activity of MSC from young and old rats, but young cells showed much higher glucose utilization than old ones. Autophagy flux was almost the same in both types of cells, but there were remarkable ultrastructural differences in old and young cells.

Keywords:  aging; glucose utilization; glycolysis; mesenchymal stromal cells; mitochondria; oxidative phosphorylation; proliferation; senescence; stem; therapy; traumatic brain injury

DOI:  https://doi.org/10.3390/cells10061273
Metabolites. 2021 May 18. pii: 323. [Epub ahead of print]11(5):

Lifelong Aerobic Exercise Alleviates Sarcopenia by Activating Autophagy and Inhibiting Protein Degradation via the AMPK/PGC-1α Signaling Pathway.

Jiling Liang, Hu Zhang, Zhengzhong Zeng, Liangwen Wu, Ying Zhang, Yanju Guo, Jun Lv, Cenyi Wang, Jingjing Fan, Ning Chen.

  Sarcopenia is an aging-induced syndrome characterized by a progressive reduction of skeletal muscle mass and strength. Increasing evidence has attested that appropriate and scientific exercise could induce autophagy or optimize the functional status of autophagy, which plays a critical role in senescent muscular dystrophy. As a publicly recognized strategy for extending lifespan and improving the health of the elderly, the underlying mechanisms of lifelong regular aerobic exercise for the prevention of sarcopenia have not been fully elucidated. To explore the role of lifelong aerobic exercise in the beneficial regulation of autophagic signaling pathways in senescent skeletal muscle, the natural aging mice were used as the sarcopenia model and subjected to lifelong treadmill running to evaluate corresponding parameters related to skeletal muscle atrophy and autophagic signaling pathways. Compared with the young control mice, the aged mice showed a significant reduction in skeletal muscle mass, gastrocnemius muscle weight/body weight (GMW/BW) ratio, and cross-sectional areas (CSA) of skeletal muscle fibers (p < 0.01). In contrast, lifelong aerobic exercise effectively rescued these reduced biomarkers associated with muscle atrophy. Moreover, as shown in the activated AMPK/PGC-1α signaling pathway, lifelong aerobic exercise successfully prevented the aging-induced impairment of the ubiquitin-proteasome system (UPS), excessive apoptosis, defective autophagy, and mitochondrial dysfunction. The exercise-induced autophagy suppressed the key regulatory components of the UPS, inhibited excessive apoptosis, and optimized mitochondrial quality control, thereby preventing and delaying aging-induced skeletal muscle atrophy.

Keywords:  apoptosis; autophagy; lifelong aerobic exercise; mitochondrial quality control; sarcopenia; ubiquitin-proteasome system

DOI:  https://doi.org/10.3390/metabo11050323
J Leukoc Biol. 2021 Jun 04.

Diabetes induces macrophage dysfunction through cytoplasmic dsDNA/AIM2 associated pyroptosis.

Lulingxiao Nie, PengFei Zhao, Ziqi Yue, Peng Zhang, Ning Ji, Qianming Chen, Qi Wang.

  Diabetes is emerging as a severe global health problem that threatens health and increases socioeconomic burden. Periodontal impairment is one of its well-recognized complications. The destruction of the periodontal defense barrier makes it easier for periodontal pathogens to invade in, triggering a greater inflammatory response, and causing secondary impairment. Macrophages are the major immune cells in periodontium, forming the frontier line of local innate immune barrier. Here, we explored the periodontal impairments and functional changes of macrophages under the diabetic and aging conditions. Besides, we further explored the molecular mechanism of how hyperglycemia and aging contribute to this pathogenesis. To test this, we used young and aged mice to build diabetic mice, and metformin treatment was applied to a group of them. We demonstrated that under hyperglycemia conditions, macrophage functions, such as inflammatory cytokines secretion, phagocytosis, chemotaxis, and immune response, were disturbed. Simultaneously, this condition elevated the local senescent cell burden and induced secretion of senescence-associated secretory phenotype. Meanwhile, we found that expressions of Gasdermin D (GSDMD) and caspase-1 were up-regulated in diabetic conditions, suggesting that the local senescent burden and systemic proinflammatory state during diabetes were accompanied by the initiation of pyroptosis. Furthermore, we found that the changes in aged condition were similar to those in diabetes, suggesting a hyperglycemia-induced pre-aging state. In addition, we show that metformin treatment alleviated and remarkably reversed these functional abnormalities. Our data demonstrated that diabetes initiated macrophage pyroptosis, which further triggered macrophage function impairments and gingival destructions. This pathogenesis could be reversed by metformin.

Keywords:  diabetes mellitus; macrophage; metformin; pyroptosis

DOI:  https://doi.org/10.1002/JLB.3MA0321-745R
Antioxidants (Basel). 2021 May 17. pii: 794. [Epub ahead of print]10(5):

Mitophagy and Oxidative Stress: The Role of Aging.

Anna De Gaetano, Lara Gibellini, Giada Zanini, Milena Nasi, Andrea Cossarizza, Marcello Pinti.

  Mitochondrial dysfunction is a hallmark of aging. Dysfunctional mitochondria are recognized and degraded by a selective type of macroautophagy, named mitophagy. One of the main factors contributing to aging is oxidative stress, and one of the early responses to excessive reactive oxygen species (ROS) production is the induction of mitophagy to remove damaged mitochondria. However, mitochondrial damage caused at least in part by chronic oxidative stress can accumulate, and autophagic and mitophagic pathways can become overwhelmed. The imbalance of the delicate equilibrium among mitophagy, ROS production and mitochondrial damage can start, drive, or accelerate the aging process, either in physiological aging, or in pathological age-related conditions, such as Alzheimer's and Parkinson's diseases. It remains to be determined which is the prime mover of this imbalance, i.e., whether it is the mitochondrial damage caused by ROS that initiates the dysregulation of mitophagy, thus activating a vicious circle that leads to the reduced ability to remove damaged mitochondria, or an alteration in the regulation of mitophagy leading to the excessive production of ROS by damaged mitochondria.

Keywords:  Alzheimer; PINK1; Parkinson; Reactive Oxygen Species; aging; mitochondria; mitophagy

DOI:  https://doi.org/10.3390/antiox10050794
Geroscience. 2021 Jun 05.

Interactive effects of aging and aerobic capacity on energy metabolism-related metabolites of serum, skeletal muscle, and white adipose tissue.

Haihui Zhuang, Sira Karvinen, Timo Törmäkangas, Xiaobo Zhang, Xiaowei Ojanen, Vidya Velagapudi, Markku Alen, Steven L Britton, Lauren G Koch, Heikki Kainulainen, Sulin Cheng, Petri Wiklund.

  Aerobic capacity is a strong predictor of longevity. With aging, aerobic capacity decreases concomitantly with changes in whole body metabolism leading to increased disease risk. To address the role of aerobic capacity, aging, and their interaction on metabolism, we utilized rat models selectively bred for low and high intrinsic aerobic capacity (LCRs/HCRs) and compared the metabolomics of serum, muscle, and white adipose tissue (WAT) at two time points: Young rats were sacrificed at 9 months of age, and old rats were sacrificed at 21 months of age. Targeted and semi-quantitative metabolomics analysis was performed on the ultra-pressure liquid chromatography tandem mass spectrometry (UPLC-MS) platform. The effects of aerobic capacity, aging, and their interaction were studied via regression analysis. Our results showed that high aerobic capacity is associated with an accumulation of isovalerylcarnitine in muscle and serum at rest, which is likely due to more efficient leucine catabolism in muscle. With aging, several amino acids were downregulated in muscle, indicating more efficient amino acid metabolism, whereas in WAT less efficient amino acid metabolism and decreased mitochondrial β-oxidation were observed. Our results further revealed that high aerobic capacity and aging interactively affect lipid metabolism in muscle and WAT, possibly combating unfavorable aging-related changes in whole body metabolism. Our results highlight the significant role of WAT metabolism for healthy aging.

Keywords:  Aerobic capacity; Aging; Metabolites; Metabolomics

DOI:  https://doi.org/10.1007/s11357-021-00387-1
Cells. 2021 May 26. pii: 1323. [Epub ahead of print]10(6):

Hallmarks of Aging in Macrophages: Consequences to Skin Inflammaging.

Gabriela Rapozo Guimarães, Palloma Porto Almeida, Leandro de Oliveira Santos, Leane Perim Rodrigues, Juliana Lott de Carvalho, Mariana Boroni.

  The skin is our largest organ and the outermost protective barrier. Its aging reflects both intrinsic and extrinsic processes resulting from the constant insults it is exposed to. Aging in the skin is accompanied by specific epigenetic modifications, accumulation of senescent cells, reduced cellular proliferation/tissue renewal, altered extracellular matrix, and a proinflammatory environment favoring undesirable conditions, including disease onset. Macrophages (Mφ) are the most abundant immune cell type in the skin and comprise a group of heterogeneous and plastic cells that are key for skin homeostasis and host defense. However, they have also been implicated in orchestrating chronic inflammation during aging. Since Mφ are related to innate and adaptive immunity, it is possible that age-modified skin Mφ promote adaptive immunity exacerbation and exhaustion, favoring the emergence of proinflammatory pathologies, such as skin cancer. In this review, we will highlight recent findings pertaining to the effects of aging hallmarks over Mφ, supporting the recognition of such cell types as a driving force in skin inflammaging and age-related diseases. We will also present recent research targeting Mφ as potential therapeutic interventions in inflammatory skin disorders and cancer.

Keywords:  age-associated diseases; aging; immunosenescence

DOI:  https://doi.org/10.3390/cells10061323
Front Immunol. 2021 ;12 681449

Aging and Options to Halt Declining Immunity to Virus Infections.

Miguel Ángel Palacios-Pedrero, Albert D M E Osterhaus, Tanja Becker, Husni Elbahesh, Guus F Rimmelzwaan, Giulietta Saletti.

  Immunosenescence is a process associated with aging that leads to dysregulation of cells of innate and adaptive immunity, which may become dysfunctional. Consequently, older adults show increased severity of viral and bacterial infections and impaired responses to vaccinations. A better understanding of the process of immunosenescence will aid the development of novel strategies to boost the immune system in older adults. In this review, we focus on major alterations of the immune system triggered by aging, and address the effect of chronic viral infections, effectiveness of vaccination of older adults and strategies to improve immune function in this vulnerable age group.

Keywords:  aging; cell mediated immunity; immunosenescence; vaccine; virus infections

DOI:  https://doi.org/10.3389/fimmu.2021.681449
Cancers (Basel). 2021 May 02. pii: 2185. [Epub ahead of print]13(9):

Blood Immunosenescence Signatures Reflecting Age, Frailty and Tumor Immune Infiltrate in Patients with Early Luminal Breast Cancer.

Lieze Berben, Asier Antoranz, Cindy Kenis, Ann Smeets, Hanne Vos, Patrick Neven, Giuseppe Floris, Hans Wildiers, Sigrid Hatse.

  BACKGROUND: Immune/senescence-related host factors play a pivotal role in numerous biological and pathological process like aging, frailty and cancer. The assessment of these host factors via robust, non-invasive, and easy-to-measure blood biomarkers could improve insights in these processes. Here, we investigated in a series of breast cancer patients in which way single circulating biomarkers or biomarker panels relate to chronological age, frailty status, and tumor-associated inflammatory microenvironment.METHODS: An extensive panel of blood immune/senescence markers and the tumor immune infiltrate was studied in young, middle-aged, and old patients with an early invasive hormone-sensitive, HER2-negative breast cancer. In the old group, clinical frailty was estimated via the G8-scores.
RESULTS: Several three-blood biomarker panels proved to be able to separate old chronological age from young age very efficiently. Clinically more important, several three-blood biomarker panels were strongly associated with clinical frailty. Performance of blood biomarker panels for prediction of the tumor immune infiltrate was lower.
CONCLUSION: Immune/senescence blood biomarker panels strongly correlate with chronological age, and clinically more importantly with frailty status in early breast cancer patients. They require further investigation on their ability to provide a more complete picture on clinical frailty status and direct personalized therapy in older persons.

Keywords:  aging; blood biomarkers; breast cancer; frailty; tumor immune infiltrate

DOI:  https://doi.org/10.3390/cancers13092185
Front Cell Dev Biol. 2021 ;9 680386

Acer Truncatum Seed Oil Alleviates Learning and Memory Impairments of Aging Mice.

Xiao Li, Ting Li, Xiao Yue Hong, Jian Jun Liu, Xi Fei Yang, Gong Ping Liu.

  Aging, characterized by a time-dependent functional decline of physiological integrity, is the major independent risk factor for many neurodegeneration diseases. Therefore, it's necessary to look for natural food supplements to extend the healthy lifespan of aging people. We here treated normal aging mice with acer truncatum seed oil, and found that the seed oil significantly improved the learning and memory ability. Proteomics revealed that the seed oil administration changed many proteins expression involving in biological processes, including complement and coagulation cascades, inflammatory response pathway and innate immune response. BDNF/TrkB signaling pathway was also activated by acer truncatum seed oil treatment. And the seed oil administration increased the expression of postsynaptic related proteins including PSD95, GluA1, and NMDAR1, and decreased the mRNA level of inflammatory factors containing IL-1β, TNF-α, and IL-6. These findings suggest that acer truncatum seed oil holds a promise as a therapeutic food supplement for delaying aging with multiple mechanisms.

Keywords:  BDNF; acer truncatum seed oil; aging; learning memory; proteomics

DOI:  https://doi.org/10.3389/fcell.2021.680386
Aging Cell. 2021 Jun 02. e13393

Metabolipidomic profiling reveals an age-related deficiency of skeletal muscle pro-resolving mediators that contributes to maladaptive tissue remodeling.

James F Markworth, Lemuel A Brown, Eunice Lim, Jesus A Castor-Macias, Jacqueline Larouche, Peter C D Macpherson, Carol Davis, Carlos A Aguilar, Krishna Rao Maddipati, Susan V Brooks.

  Specialized pro-resolving mediators actively limit inflammation and support tissue regeneration, but their role in age-related muscle dysfunction has not been explored. We profiled the mediator lipidome of aging muscle via liquid chromatography-tandem mass spectrometry and tested whether treatment with the pro-resolving mediator resolvin D1 (RvD1) could rejuvenate the regenerative ability of aged muscle. Aged mice displayed chronic muscle inflammation and this was associated with a basal deficiency of pro-resolving mediators 8-oxo-RvD1, resolvin E3, and maresin 1, as well as many anti-inflammatory cytochrome P450-derived lipid epoxides. Following muscle injury, young and aged mice produced similar amounts of most pro-inflammatory eicosanoid metabolites of cyclooxygenase (e.g., prostaglandin E2 ) and 12-lipoxygenase (e.g., 12-hydroxy-eicosatetraenoic acid), but aged mice produced fewer markers of pro-resolving mediators including the lipoxins (15-hydroxy-eicosatetraenoic acid), D-resolvins/protectins (17-hydroxy-docosahexaenoic acid), E-resolvins (18-hydroxy-eicosapentaenoic acid), and maresins (14-hydroxy-docosahexaenoic acid). Similar absences of downstream pro-resolving mediators including lipoxin A4 , resolvin D6, protectin D1/DX, and maresin 1 in aged muscle were associated with greater inflammation, impaired myofiber regeneration, and delayed recovery of strength. Daily intraperitoneal injection of RvD1 had minimal impact on intramuscular leukocyte infiltration and myofiber regeneration but suppressed inflammatory cytokine expression, limited fibrosis, and improved recovery of muscle function. We conclude that aging results in deficient local biosynthesis of specialized pro-resolving mediators in muscle and that immunoresolvents may be attractive novel therapeutics for the treatment of muscular injuries and associated pain in the elderly, due to positive effects on recovery of muscle function without the negative side effects on tissue regeneration of non-steroidal anti-inflammatory drugs.

Keywords:  aging; cellular immunology; inflammation; injury; mass spectrometry; sarcopenia; satellite stem cell; skeletal muscle

DOI:  https://doi.org/10.1111/acel.13393
Front Endocrinol (Lausanne). 2021 ;12 679492

Aging Reduces Insulin Clearance in Mice.

Carine Marmentini, Gabriela M Soares, Gabriela A Bronczek, Silvano Piovan, Cecília E Mareze-Costa, Everardo M Carneiro, Antonio C Boschero, Mirian A Kurauti.

  Hyperinsulinemia is frequently associated with aging and may cause insulin resistance in elderly. Since insulin secretion and clearance decline with age, hyperinsulinemia seems to be maintained, primarily, due to a decrease in the insulin clearance. To investigate these aging effects, 3- and 18-month-old male C57BL/6 mice were subjected to intraperitoneal glucose and insulin tolerance tests (ipGTT and ipITT) and, during the ipGTT, plasma c-peptide and insulin were measure to evaluate in vivo insulin clearance. Glucose-stimulated insulin secretion in isolated pancreatic islets was also assessed, and liver samples were collected for molecular analyses (western blot). Although insulin sensitivity was not altered in the old mice, glucose tolerance, paradoxically, seems to be increased, accompanied by higher plasma insulin, during ipGTT. While insulin secretion did not increase, insulin clearance was reduced in the old mice, as suggested by the lower c-peptide:insulin ratio, observed during ipGTT. Carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1) and insulin-degrading enzyme (IDE), as well as the activity of this enzyme, were reduced in the liver of old mice, justifying the decreased insulin clearance observed in these mice. Therefore, loss of hepatic CEACAM1 and IDE function may be directly related to the decline in insulin clearance during aging.

Keywords:  CEACAM1; hepatic insulin clearance; hyperinsulinemia; insulin secretion; insulin sensitivity; insulin-degrading enzyme

DOI:  https://doi.org/10.3389/fendo.2021.679492
Annu Rev Vis Sci. 2021 Jun 01.

Aging of the Retina: Molecular and Metabolic Turbulences and Potential Interventions.

Laura Campello, Nivedita Singh, Jayshree Advani, Anupam K Mondal, Ximena Corso-Diaz, Anand Swaroop.

Multifaceted and divergent manifestations across tissues and cell types have curtailed advances in deciphering the cellular events that accompany advanced age and contribute to morbidities and mortalities. Increase in human lifespan during the past century has heightened awareness of the need to prevent age-associated frailty of neuronal and sensory systems to allow a healthy and productive life. In this review, we discuss molecular and physiological attributes of aging of the retina, with a goal of understanding age-related impairment of visual function. We highlight the epigenome-metabolism nexus and proteostasis as key contributors to retinal aging and discuss lifestyle changes as potential modulators of retinal function. Finally, we deliberate promising intervention strategies for promoting healthy aging of the retina for improved vision. Expected final online publication date for the Annual Review of Vision Science, Volume 7 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-vision-100419-114940
Front Immunol. 2021 ;12 673405

Changes in Circadian Rhythms Dysregulate Inflammation in Ageing: Focus on Leukocyte Trafficking.

Poppy Nathan, Julie Elizabeth Gibbs, G Ed Rainger, Myriam Chimen.

  Leukocyte trafficking shows strong diurnal rhythmicity and is tightly regulated by circadian rhythms. As we age, leukocyte trafficking becomes dysregulated, contributing to the increased systemic, low-grade, chronic inflammation observed in older adults. Ageing is also associated with diminished circadian outputs and a dysregulation of the circadian rhythm. Despite this, there is little evidence to show the direct impact of age-associated dampening of circadian rhythms on the dysregulation of leukocyte trafficking. Here, we review the core mammalian circadian clock machinery and discuss the changes that occur in this biological system in ageing. In particular, we focus on the changes that occur to leukocyte trafficking rhythmicity with increasing age and consider how this impacts inflammation and the development of immune-mediated inflammatory disorders (IMIDs). We aim to encourage future ageing biology research to include a circadian approach in order to fully elucidate whether age-related circadian changes occur as a by-product of healthy ageing, or if they play a significant role in the development of IMIDs.

Keywords:  chronotherapy; circadian rhythm; inflammation; leukocytes; trafficking

DOI:  https://doi.org/10.3389/fimmu.2021.673405
Proc Natl Acad Sci U S A. 2021 Jun 08. pii: e2103730118. [Epub ahead of print]118(23):

Critical role of the CD44lowCD62Llow CD8+ T cell subset in restoring antitumor immunity in aged mice.

Yuka Nakajima, Kenji Chamoto, Takuma Oura, Tasuku Honjo.

  CD8+ T cells play a central role in antitumor immune responses that kill cancer cells directly. In aged individuals, CD8+ T cell immunity is strongly suppressed, which is associated with cancer and other age-related diseases. The mechanism underlying this age-related decrease in immune function remains largely unknown. This study investigated the role of T cell function in age-related unresponsiveness to PD-1 blockade cancer therapy. We found inefficient generation of CD44lowCD62Llow CD8+ T cell subset (P4) in draining lymph nodes of tumor-bearing aged mice. In vitro stimulation of naive CD8+ T cells first generated P4 cells, followed by effector/memory T cells. The P4 cells contained a unique set of genes related to enzymes involved in one-carbon (1C) metabolism, which is critical to antigen-specific T cell activation and mitochondrial function. Consistent with this finding, 1C-metabolism-related gene expression and mitochondrial respiration were down-regulated in aged CD8+ T cells compared with young CD8+ T cells. In aged OVA-specific T cell receptor (TCR) transgenic mice, ZAP-70 was not activated, even after inoculation with OVA-expressing tumor cells. The attenuation of TCR signaling appeared to be due to elevated expression of CD45RB phosphatase in aged CD8+ T cells. Surprisingly, strong stimulation by nonself cell injection into aged PD-1-deficient mice restored normal levels of CD45RB and ameliorated the emergence of P4 cells and 1C metabolic enzyme expression in CD8+ T cells, and antitumor activity. These findings indicate that impaired induction of the P4 subset may be responsible for the age-related resistance to PD-1 blockade, which can be rescued by strong TCR stimulation.

Keywords:  PD-1; T cell subset; aging; immunotherapy; one-carbon metabolism

DOI:  https://doi.org/10.1073/pnas.2103730118
Aging Cell. 2021 Jun 05. e13411

Human muscle stem cells are refractory to aging.

James S Novak, Davi A G Mázala, Marie Nearing, Ravi Hindupur, Prech Uapinyoying, Nayab F Habib, Tessa Dickson, Olga B Ioffe, Brent T Harris, Marie N Fidelia-Lambert, Christopher T Rossi, D Ashely Hill, Kathryn R Wagner, Eric P Hoffman, Terence A Partridge.

  Age-related loss of muscle mass and strength is widely attributed to limitation in the capacity of muscle resident satellite cells to perform their myogenic function. This idea contains two notions that have not been comprehensively evaluated by experiment. First, it entails the idea that we damage and lose substantial amounts of muscle in the course of our normal daily activities. Second, it suggests that mechanisms of muscle repair are in some way exhausted, thus limiting muscle regeneration. A third potential option is that the aged environment becomes inimical to the conduct of muscle regeneration. In the present study, we used our established model of human muscle xenografting to test whether muscle samples taken from cadavers, of a range of ages, maintained their myogenic potential after being transplanted into immunodeficient mice. We find no measurable difference in regeneration across the range of ages investigated up to 78 years of age. Moreover, we report that satellite cells maintained their myogenic capacity even when muscles were grafted 11 days postmortem in our model. We conclude that the loss of muscle mass with increasing age is not attributable to any intrinsic loss of myogenicity and is most likely a reflection of progressive and detrimental changes in the muscle microenvironment such as to disfavor the myogenic function of these cells.

Keywords:  aging; human satellite cells; muscle regeneration; myogenic capacity; sarcopenia

DOI:  https://doi.org/10.1111/acel.13411
Elife. 2021 Jun 04. pii: e67315. [Epub ahead of print]10

Canonical NF-κB signaling maintains corneal epithelial integrity and prevents corneal aging via retinoic acid.

Qian Yu, Soma Biswas, Gang Ma, Peiquan Zhao, Baojie Li, Jing Li.

  Disorders of the transparent cornea affect millions of people worldwide. However, how to maintain and/or regenerate this organ remains unclear. Here, we show that Rela (encoding a canonical NF-kB subunit) ablation in K14+ corneal epithelial stem cells not only disrupts corneal regeneration but also results in age-dependent epithelial deterioration, which triggers aberrant wound healing processes including stromal remodeling, neovascularization, epithelial metaplasia, and plaque formation at the central cornea. These anomalies are largely recapitulated in normal mice that age naturally. Mechanistically, Rela deletion suppresses expression of Aldh1a1, an enzyme required for retinoic acid synthesis from vitamin A. Retinoic acid administration blocks development of ocular anomalies in Krt14-Cre; Relaf/f mice and naturally aged mice. Moreover, epithelial metaplasia and plaque formation are preventable by inhibition of angiogenesis. This study thus uncovers major mechanisms governing corneal maintenance, regeneration and aging and identifies the NF-kB-retinoic acid pathway as a therapeutic target for corneal disorders.

Keywords:  cell biology; developmental biology; mouse

DOI:  https://doi.org/10.7554/eLife.67315
Aging Cell. 2021 Jun 04. e13388

Mechanisms of angiogenic incompetence in Hutchinson-Gilford progeria via downregulation of endothelial NOS.

Yantenew G Gete, Luke W Koblan, Xiaojing Mao, Mason Trappio, Bhushan Mahadik, John P Fisher, David R Liu, Kan Cao.

  Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder with features of accelerated aging. The majority of HGPS cases are caused by a de novo point mutation in the LMNA gene (c.1824C>T; p.G608G) resulting in progerin, a toxic lamin A protein variant. Children with HGPS typically die from coronary artery diseases or strokes at an average age of 14.6 years. Endothelial dysfunction is a known driver of cardiovascular pathogenesis; however, it is currently unknown how progerin antagonizes normal angiogenic function in HGPS. Here, we use human iPSC-derived endothelial cell (iPSC-EC) models to study angiogenesis in HGPS. We cultured normal and HGPS iPSC-ECs under both static and fluidic culture conditions. HGPS iPSC-ECs show reduced endothelial nitric oxide synthase (eNOS) expression and activity compared with normal controls and concomitant decreases in intracellular nitric oxide (NO) level, which result in deficits in capillary-like microvascular network formation. Furthermore, the expression of matrix metalloproteinase 9 (MMP-9) was reduced in HGPS iPSC-ECs, while the expression of tissue inhibitor metalloproteinases 1 and 2 (TIMP1 and TIMP2) was upregulated relative to healthy controls. Finally, we used an adenine base editor (ABE7.10max-VRQR) to correct the pathogenic c.1824C>T allele in HGPS iPSC-ECs. Remarkably, ABE7.10max-VRQR correction of the HGPS mutation significantly reduced progerin expression to a basal level, rescued nuclear blebbing, increased intracellular NO level, normalized the misregulated TIMPs, and restored angiogenic competence in HGPS iPSC-ECs. Together, these results provide molecular insights of endothelial dysfunction in HGPS and suggest that ABE could be a promising therapeutic approach for correcting HGPS-related cardiovascular phenotypes.

Keywords:  ABE; aging; eNOS; endothelial cells; progeria

DOI:  https://doi.org/10.1111/acel.13388
Int J Mol Sci. 2021 May 27. pii: 5749. [Epub ahead of print]22(11):

Potential of Mesenchymal Stem Cells in the Rejuvenation of the Aging Immune System.

Genieve Ee Chia Yeo, Min Hwei Ng, Fazlina Binti Nordin, Jia Xian Law.

  Rapid growth of the geriatric population has been made possible with advancements in pharmaceutical and health sciences. Hence, age-associated diseases are becoming more common. Aging encompasses deterioration of the immune system, known as immunosenescence. Dysregulation of the immune cell production, differentiation, and functioning lead to a chronic subclinical inflammatory state termed inflammaging. The hallmarks of the aging immune system are decreased naïve cells, increased memory cells, and increased serum levels of pro-inflammatory cytokines. Mesenchymal stem cell (MSC) transplantation is a promising solution to halt immunosenescence as the cells have excellent immunomodulatory functions and low immunogenicity. This review compiles the present knowledge of the causes and changes of the aging immune system and the potential of MSC transplantation as a regenerative therapy for immunosenescence.

Keywords:  aging; frailty; immune system; inflammaging; mesenchymal stem cells

DOI:  https://doi.org/10.3390/ijms22115749
Sci Rep. 2021 Jun 01. 11(1): 11532

Sulodexide reduces glucose induced senescence in human retinal endothelial cells.

A Gericke, K Suminska-Jasińska, A Bręborowicz.

Chronic exposure of retinal endothelium cells to hyperglycemia is the leading cause of diabetic retinopathy. We evaluated the effect of high glucose concentration on senescence in human retinal endothelial cells (HREC) and modulation of that effect by Sulodexide. Experiments were performed on HREC undergoing in vitro replicative senescence in standard medium or medium supplemented with glucose 20 mmol/L (GLU) or mannitol 20 mnol/L (MAN). Effect of Sulodexide 0.5 LRU/mL (SUL) on the process of HREC senescence was studied. Glucose 20 mmol/L accelerates senescence of HREC: population doubling time (+ 58%, p < 0.001) β-galactosidase activity (+ 60%, p < 0.002) intracellular oxidative stress (+ 65%, p < 0.01), expression of p53 gene (+ 118%, p < 0.001). Senescent HREC had also reduced transendothelial electrical resistance (TEER) (- 30%, p < 0.001). Mannitol 20 mmol/L used in the same scenario as glucose did not induce HREC senescence. In HREC exposed to GLU and SUL, the senescent changes were smaller. HREC, which became senescent in the presence of GLU, demonstrated higher expression of genes regulating the synthesis of Il6 and VEGF-A, which was reflected by increased secretion of these cytokines (IL6 + 125%, p < 0.001 vs control and VEGF-A + 124% p < 0.001 vs control). These effects were smaller in the presence of SUL, and additionally, an increase of TEER in the senescent HREC was observed. Chronic exposure of HREC to high glucose concentration in medium accelerates their senescence, and that process is reduced when the cells are simultaneously exposed to Sulodexide. Additionally, Sulodexide decreases the secretion of IL6 and VEGF-A from senescent HREC and increases their TEER.

DOI: https://doi.org/10.1038/s41598-021-90987-w
Aging Cell. 2021 May 30. e13387

Role of Adiponectin-Notch pathway in cognitive dysfunction associated with depression and in the therapeutic effect of physical exercise.

Jingjing You, Linshan Sun, Jiangong Wang, Fengjiao Sun, Wentao Wang, Dan Wang, Xueli Fan, Dunjiang Liu, Zhicheng Xu, Changyun Qiu, Jinbo Chen, Haijing Yan, Bin Liu.

  A substantial percentage of late-life depression patients also have an cognitive impairment, which severely affects the life quality, while the co-occurring mechanisms are still unclear. Physical exercise can ameliorate both depressive behaviors and cognitive dysfunction, but the molecular mechanisms underlying its beneficial effects remain elusive. In this study, we uncover a novel adipose tissue to hippocampus crosstalk mediated by Adiponectin-Notch pathway, with an impact on hippocampal neurogenesis and cognitive function. Adiponectin, an adipocyte-derived hormone, could activate Notch signaling in the hippocampus through upregulating ADAM10 and Notch1, two key molecules in the Notch signaling. Chronic stress inhibits the Adiponectin-Notch pathway and induces impaired hippocampal neurogenesis and cognitive dysfunction, which can be rescued by AdipoRon and running. Inhibition Notch signaling by DAPT mimics the adverse effects of chronic stress on hippocampal neurogenesis and cognitive function. Adiponectin knockout mice display depressive-like behaviors, associated with inhibited Notch signaling, impaired hippocampal neurogenesis and cognitive dysfunction. Physical exercise could activate Adiponectin-Notch pathway, and improve hippocampal neurogenesis and cognitive function, while deleting adiponectin gene or inhibiting Notch signaling blocks its beneficial effects. Together, our data not only suggest that Adiponectin-Notch pathway is involved in the pathogenesis of cognitive dysfunction associated with depression, but also contributes to the therapeutic effect of physical exercise. This work helps to decipher the etiology of cognitive impairment associated with depression and hence will provide a potential innovative therapeutic target for these patients.

Keywords:  Notch; aging; behavior; chronic stimulation; cognition dysfunction; endocrinology; mouse models; neural stem cells

DOI:  https://doi.org/10.1111/acel.13387
Trends Biochem Sci. 2021 Jun 01. pii: S0968-0004(21)00106-7. [Epub ahead of print]

Mitochondrial DNA: cellular genotoxic stress sentinel.

Zheng Wu, Alva G Sainz, Gerald S Shadel.

  High copy number, damage prone, and lean on repair mechanisms are unique features of mitochondrial DNA (mtDNA) that are hard to reconcile with its essentiality for oxidative phosphorylation, the primary function ascribed to this maternally inherited component of our genome. We propose that mtDNA is also a genotoxic stress sentinel, as well as a direct second messenger of this type of cellular stress. Here, we discuss existing evidence for this sentinel/effector role through the ability of mtDNA to escape the confines of the mitochondrial matrix and activate nuclear DNA damage/repair responses via interferon-stimulated gene products and other downstream effectors. However, this arrangement may come at a cost, leading to cancer chemoresistance and contributing to inflammation, disease pathology, and aging.

Keywords:  DNA repair; cGAS-STING; chemoresistance; interferon-stimulated gene (ISG); mtDNA; retrograde signaling

DOI:  https://doi.org/10.1016/j.tibs.2021.05.004
Nat Rev Immunol. 2021 Jun 02.

Neutrophils hit reverse in ageing.

Kirsty Minton.

DOI: https://doi.org/10.1038/s41577-021-00569-0
Aging Cell. 2021 May 25. e13380

Neuronal loss and microgliosis are restricted to the core of Aβ deposits in mouse models of Alzheimer's disease.

Jing Zhang, Na Wu, Shubo Wang, Zitong Yao, Fuchuan Xiao, Jing Lu, Baian Chen.

  Amyloid-β (Aβ) deposits, pathologic tau, and neurodegeneration are major pathological hallmarks of Alzheimer's disease (AD). The relationship between neuronal loss and Aβ deposits is one of the fundamental questions in the pathogenesis of AD. However, this relationship is controversial. One main reason for the conflicting results may be the confounding effects of pathologic tau, which often coexists with Aβ deposits in the brains of AD patients. To clarify the relationship between neuronal loss and Aβ deposits, mouse models of AD, which develop abundant Aβ deposits in the aged brain without pathologic tau, were used to examine the co-localization of NeuN-positive neurons, NF-H-positive axons, MBP-positive myelin sheaths, and Aβ deposits. Neuronal loss, as measured by decreased staining of the neuronal cell body, axon, and myelin sheath, as well as the IBA-1-positive microglia, was significantly increased in the core area of cerebral Aβ deposits, but not in adjacent areas. Furthermore, neuronal loss in the core area of cerebral Aβ deposits was correlated with Aβ deposit size. These results clearly indicate that neuronal loss is restricted to the core of Aβ deposits, and this restricted loss probably occurs because the Aβ deposit attracts microglia, which cluster in the core area where Aβ toxicity and neuroinflammation toxicity are restrained. These findings may contribute to our understanding of the relationship between neuronal loss and Aβ deposits in the absence of pathologic tau.

Keywords:  Alzheimer's disease; Aβ deposits; axon loss; microglia; myelin sheath loss; neuron loss

DOI:  https://doi.org/10.1111/acel.13380