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Molecular Research of Aging Stress Response

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 46381

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Special Issue Editors

Prof. Dr. Takahiko Shimizu

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Guest Editor

Aging Stress Response Research Project Team, National Center for Geriatrics and Gerontology, 7-430 Morioka, Obu, Aichi 474-8511, Japan
Interests: aging; senescence; age-related disease; stress response; DNA damage; oxidative stress; inflammatory response; ER stress response; mitochondrial stress response; reactive oxygen species (ROS); superoxide dismutase (SOD)

Prof. Dr. Akira Shimamoto

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Guest Editor

Department of Regenerative Research, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University 1-1-1 Daigaku-street, Sanyo-Onoda City, Yamaguchi, 756-0884, Japan
Interests: stem cells; senescence; cell cycle; quiescence; stem cell niche; senescence-associated secretory phenotype: SASP; telomere; reactive oxygen species; DNA damage; p53

Special Issue Information

Dear Colleagues,

Aging is closely related to abnormalities in adaptation to various environmental stresses, such as DNA damage response, redox response to oxidative stress, inflammatory stress response to tissue damage, endoplasmic reticulum stress response, mitochondrial stress response, etc. It is extremely important to elucidate the aging process of these various system response mechanisms during aging in order to clarify the aging mechanism. It is also significant in aging research to understand how these aging stress response mechanisms protect or damage cells and tissues at the molecular level. This Special Issue invites and welcomes papers that clarify the relationship between the molecular basis of various stress responses and aging, including age-related diseases.

Prof. Dr. Takahiko Shimizu
Prof. Dr. Akira Shimamoto
Guest Editors

Manuscript Submission Information

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Keywords

aging
senescence
age-related disease
stress response
DNA damage
oxidative stress
inflammatory response
ER stress response
mitochondrial stress response
reactive oxygen species (ROS)
superoxide dismutase (SOD)

Published Papers (13 papers)

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Research

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18 pages, 3562 KiB

Open AccessArticle

Polo-Like Kinase 2 Plays an Essential Role in Cytoprotection against MG132-Induced Proteasome Inhibition via Phosphorylation of Serine 19 in HSPB5

by Shuji Ueda, Moeka Nishihara, Yuuki Hioka, Ken-ichi Yoshino, Soichiro Yamada, Minoru Yamanoue and Yasuhito Shirai

Int. J. Mol. Sci. 2022, 23(19), 11257; https://doi.org/10.3390/ijms231911257 - 24 Sep 2022

Cited by 3 | Viewed by 2143

Abstract

Protein homeostasis, including protein folding, refolding, and degradation, is thought to decline with aging. HSPB5 (also known as αB-crystallin) prevents target protein aggregation as a molecular chaperone and exhibits a cytoprotective function against various cell stresses. To elucidate the effect of HSPB5 on endoplasmic reticulum (ER) stress, we searched for novel binding proteins of HSPB5 using the proximity-dependent biotin labeling method. Proteins presumed to interact with HSPB5 in cells treated with the proteasome inhibitor MG132 were identified by a reversible biotin-binding capacity method combining tamavidin2-REV magnetic beads and mass spectrometry. We discovered a new binding protein for HSPB5, polo-like kinase 2 (PLK2), which is an apoptosis-related enzyme. The expression of PLK2 was upregulated by MG132 treatment, and it was co-localized with HSPB5 near the ER in L6 muscle cells. Inhibition of PLK2 decreased ER stress-induced phosphorylation of serine 19 in HSPB5 and increased apoptosis by activation of caspase 3 under ER stress. Overexpression of HSPB5 (WT) suppressed the ER stress-induced caspase 3 activity, but this was not observed with phospho-deficient HSPB5 (3A) mutants. These results clarify the role of HSPB5 phosphorylation during ER stress and suggest that the PLK2/HSPB5 pathway plays an essential role in cytoprotection against proteasome inhibition-induced ER stress. Full article

(This article belongs to the Special Issue Molecular Research of Aging Stress Response)

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12 pages, 1982 KiB

Open AccessArticle

Pathological Relationship between Intracellular Superoxide Metabolism and p53 Signaling in Mice

by Kenji Watanabe, Shuichi Shibuya, Yusuke Ozawa, Toshihiko Toda and Takahiko Shimizu

Int. J. Mol. Sci. 2021, 22(7), 3548; https://doi.org/10.3390/ijms22073548 - 29 Mar 2021

Cited by 1 | Viewed by 1908

Abstract

Intracellular superoxide dismutases (SODs) maintain tissue homeostasis via superoxide metabolism. We previously reported that intracellular reactive oxygen species (ROS), including superoxide accumulation caused by cytoplasmic SOD (SOD1) or mitochondrial SOD (SOD2) insufficiency, induced p53 activation in cells. SOD1 loss also induced several age-related pathological changes associated with increased oxidative molecules in mice. To evaluate the contribution of p53 activation for SOD1 knockout (KO) (Sod1⁻^/−) mice, we generated SOD1 and p53 KO (double-knockout (DKO)) mice. DKO fibroblasts showed increased cell viability with decreased apoptosis compared with Sod1⁻^/− fibroblasts. In vivo experiments revealed that p53 insufficiency was not a great contributor to aging-like tissue changes but accelerated tumorigenesis in Sod1⁻^/− mice. Furthermore, p53 loss failed to improve dilated cardiomyopathy or the survival in heart-specific SOD2 conditional KO mice. These data indicated that p53 regulated ROS-mediated apoptotic cell death and tumorigenesis but not ROS-mediated tissue degeneration in SOD-deficient models. Full article

(This article belongs to the Special Issue Molecular Research of Aging Stress Response)

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10 pages, 1209 KiB

Open AccessArticle

Xanthine Oxidoreductase-Mediated Superoxide Production Is Not Involved in the Age-Related Pathologies in Sod1-Deficient Mice

by Shuichi Shibuya, Kenji Watanabe, Yusuke Ozawa and Takahiko Shimizu

Int. J. Mol. Sci. 2021, 22(7), 3542; https://doi.org/10.3390/ijms22073542 - 29 Mar 2021

Cited by 6 | Viewed by 3861

Abstract

Reactive oxygen species (ROS) metabolism is regulated by the oxygen-mediated enzyme reaction and antioxidant mechanism within cells under physiological conditions. Xanthine oxidoreductase (XOR) exhibits two inter-convertible forms (xanthine oxidase (XO) and xanthine dehydrogenase (XDH)), depending on the substrates. XO uses oxygen as a substrate and generates superoxide (O₂^•−) in the catalytic pathway of hypoxanthine. We previously showed that superoxide dismutase 1 (SOD1) loss induced various aging-like pathologies via oxidative damage due to the accumulation of O₂^•− in mice. However, the pathological contribution of XO-derived O₂^•− production to aging-like tissue damage induced by SOD1 loss remains unclear. To investigate the pathological significance of O₂^•− derived from XOR in Sod1^−/− mice, we generated Sod1-null and XO-type- or XDH-type-knock-in (KI) double-mutant mice. Neither XO-type- nor XDH-type KI mutants altered aging-like phenotypes, such as anemia, fatty liver, muscle atrophy, and bone loss, in Sod1^−/− mice. Furthermore, allopurinol, an XO inhibitor, or apocynin, a nicotinamide adenine dinucleotide phosphate oxidase (NOX) inhibitor, failed to improve aging-like tissue degeneration and ROS accumulation in Sod1^−/− mice. These results showed that XOR-mediated O₂^•− production is relatively uninvolved in the age-related pathologies in Sod1^−/− mice. Full article

(This article belongs to the Special Issue Molecular Research of Aging Stress Response)

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8 pages, 672 KiB

Open AccessCommunication

A Non-Toxic Concentration of Telomerase Inhibitor BIBR1532 Fails to Reduce TERT Expression in a Feeder-Free Induced Pluripotent Stem Cell Model of Human Motor Neurogenesis

by Virenkumar A. Pandya, Hamish Crerar, Jamie S. Mitchell and Rickie Patani

Int. J. Mol. Sci. 2021, 22(6), 3256; https://doi.org/10.3390/ijms22063256 - 23 Mar 2021

Cited by 5 | Viewed by 2314

Abstract

Several studies have shown that human induced pluripotent stem cell (iPSC)-derivatives are essentially fetal in terms of their maturational status. Inducing ageing in iPSC-motor neuron (MN) models of amyotrophic lateral sclerosis (ALS) has the potential to capture pathology with higher fidelity and consequently improve translational success. We show here that the telomerase inhibitor BIBR1532, hypothesised to recapitulate the telomere attrition hallmark of ageing in iPSC-MNs, was in fact cytotoxic to feeder-free iPSCs when used at doses previously shown to be effective in iPSCs grown on a layer of mouse embryonic fibroblasts. Toxicity in feeder-free cultures was not rescued by co-treatment with Rho Kinase (ROCK) inhibitor (Y-27632). Moreover, the highest concentration of BIBR1532 compatible with continued iPSC culture proved insufficient to induce detectable telomerase inhibition. Our data suggest that direct toxicity by BIBR1532 is the most likely cause of iPSC death observed, and that culture methods may influence enhanced toxicity. Therefore, recapitulation of ageing hallmarks in iPSC-MNs, which might reveal novel and relevant human disease targets in ALS, is not achievable in feeder-free culture through the use of this small molecule telomerase inhibitor. Full article

(This article belongs to the Special Issue Molecular Research of Aging Stress Response)

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13 pages, 2262 KiB

Open AccessArticle

Intense Pulsed Light Attenuates UV-Induced Hyperimmune Response and Pigmentation in Human Skin Cells

by Juewon Kim, Jeongin Lee and Hyunjung Choi

Int. J. Mol. Sci. 2021, 22(6), 3173; https://doi.org/10.3390/ijms22063173 - 20 Mar 2021

Cited by 7 | Viewed by 3513

Abstract

The skin of an organism is affected by various environmental factors and fights against aging stress via mechanical and biochemical responses. Photoaging induced by ultraviolet B (UVB) irradiation is common and is the most vital factor in the senescence phenotype of skin, and so, suppression of UVB stress-induced damage is critical. To lessen the UVB-induced hyperimmune response and hyperpigmentation, we investigated the ameliorative effects of intense pulsed light (IPL) treatment on the photoaged phenotype of skin cells. Normal human epidermal keratinocytes and human epidermal melanocytes were exposed to 20 mJ/cm² of UVB. After UVB irradiation, the cells were treated with green (525–530 nm) and yellow (585–592 nm) IPL at various time points prior to the harvest step. Subsequently, various signs of excessive immune response, including expression of proinflammatory and melanogenic genes and proteins, cellular oxidative stress level, and antioxidative enzyme activity, were examined. We found that IPL treatment reduced excessive cutaneous immune reactions by suppressing UVB-induced proinflammatory cytokine expression. IPL treatment prevented hyperpigmentation, and combined treatment with green and yellow IPL synergistically attenuated both processes. IPL treatment may exert protective effects against UVB injury in skin cells by attenuating inflammatory cytokine and melanogenic gene overexpression, possibly by reducing intracellular oxidative stress. IPL treatment also preserves antioxidative enzyme activity under UVB irradiation. This study suggests that IPL treatment is a useful strategy against photoaging, and provides evidence supporting clinical approaches with non-invasive light therapy. Full article

(This article belongs to the Special Issue Molecular Research of Aging Stress Response)

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14 pages, 3612 KiB

Open AccessArticle

Effects of CREG1 on Age-Associated Metabolic Phenotypes and Renal Senescence in Mice

by Michihiro Hashimoto, Ayumi Goto, Yuki Endo, Masataka Sugimoto, Jun Ueda and Hitoshi Yamashita

Int. J. Mol. Sci. 2021, 22(3), 1276; https://doi.org/10.3390/ijms22031276 - 28 Jan 2021

Cited by 6 | Viewed by 2598

Abstract

Cellular repressor of E1A-stimulated genes 1 (CREG1) is a secreted glycoprotein that accelerates p16-dependent cellular senescence in vitro. We recently reported the ability of CREG1 to stimulate brown adipogenesis using adipocyte P2-CREG1-transgenic (Tg) mice; however, little is known about the effect of CREG1 on aging-associated phenotypes. In this study, we investigated the effects of CREG1 on age-related obesity and renal dysfunction in Tg mice. Increased brown fat formation was detected in aged Tg mice, in which age-associated metabolic phenotypes such as body weight gain and increases in blood glucose were improved compared with those in wild-type (WT) mice. Blood CREG1 levels increased significantly in WT mice with age, whereas the age-related increase was suppressed, and its levels were reduced, in the livers and kidneys of Tg mice relative to those in WT mice at 25 months. Intriguingly, the mRNA levels of Ink4a, Arf, and senescence-associated secretory phenotype (SASP)-related genes and p38MAPK activity were significantly lowered in the aged kidneys of Tg mice, in which the morphological abnormalities of glomeruli as well as filtering function seen in WT kidneys were alleviated. These results suggest the involvement of CREG1 in kidney aging and its potential as a target for improving age-related renal dysfunction. Full article

(This article belongs to the Special Issue Molecular Research of Aging Stress Response)

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14 pages, 1836 KiB

Open AccessArticle

L-Arginine Exerts Excellent Anti-Stress Effects on Stress-Induced Shortened Lifespan, Cognitive Decline and Depression

by Monira Pervin, Keiko Unno, Tomokazu Konishi and Yoriyuki Nakamura

Int. J. Mol. Sci. 2021, 22(2), 508; https://doi.org/10.3390/ijms22020508 - 6 Jan 2021

Cited by 14 | Viewed by 3606

Abstract

The anti-stress potential of dietary L-arginine (Arg) was assessed in psychosocially stress-loaded senescence-accelerated (SAMP10) mice. Although this strain of mouse is sensitive to stress, daily administration of Arg at 3 mg/kg significantly suppressed aging-related cognitive decline and behavioral depression at nine months of age and counteracted stress-induced shortened lifespan. To investigate the mechanism of the anti-stress effect of Arg in the brain, early changes in oxidative damage and gene expression levels were measured using SAMP10 mice that were stress-loaded for three days. Increased lipid peroxidation in the brains of stressed mice was significantly lowered by Arg intake. Several genes associated with oxidative stress response and neuronal excitotoxic cell death, including Nr4a1, Arc, and Cyr61, remarkably increased in response to psychosocial stress; however, their expression was significantly suppressed in mice that ingested Arg even under stress conditions. In contrast, the genes that maintain mitochondrial functions and neuronal survival, including Hba-a2 and Hbb-b2, were significantly increased in mice that ingested Arg. These results indicate that Arg reduces oxidative damage and enhances mitochondrial functions in the brain. We suggest that the daily intake of Arg plays important roles in reducing stress-induced brain damage and slowing aging. Full article

(This article belongs to the Special Issue Molecular Research of Aging Stress Response)

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Review

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18 pages, 987 KiB

Open AccessReview

Fundamental Clock of Biological Aging: Convergence of Molecular, Neurodegenerative, Cognitive and Psychiatric Pathways: Non-Equilibrium Thermodynamics Meet Psychology

by Victor V. Dyakin, Nuka V. Dyakina-Fagnano, Laura B. Mcintire and Vladimir N. Uversky

Int. J. Mol. Sci. 2022, 23(1), 285; https://doi.org/10.3390/ijms23010285 - 28 Dec 2021

Cited by 7 | Viewed by 3154

Abstract

In humans, age-associated degrading changes, widely observed in molecular and cellular processes underly the time-dependent decline in spatial navigation, time perception, cognitive and psychological abilities, and memory. Cross-talk of biological, cognitive, and psychological clocks provides an integrative contribution to healthy and advanced aging. At the molecular level, genome, proteome, and lipidome instability are widely recognized as the primary causal factors in aging. We narrow attention to the roles of protein aging linked to prevalent amino acids chirality, enzymatic and spontaneous (non-enzymatic) post-translational modifications (PTMs ^SP), and non-equilibrium phase transitions. The homochirality of protein synthesis, resulting in the steady-state non-equilibrium condition of protein structure, makes them prone to multiple types of enzymatic and spontaneous PTMs, including racemization and isomerization. Spontaneous racemization leads to the loss of the balanced prevalent chirality. Advanced biological aging related to irreversible PTMs ^SP has been associated with the nontrivial interplay between somatic (molecular aging) and mental (psychological aging) health conditions. Through stress response systems (SRS), the environmental and psychological stressors contribute to the age-associated “collapse” of protein homochirality. The role of prevalent protein chirality and entropy of protein folding in biological aging is mainly overlooked. In a more generalized context, the time-dependent shift from enzymatic to the non-enzymatic transformation of biochirality might represent an important and yet underappreciated hallmark of aging. We provide the experimental arguments in support of the racemization theory of aging. Full article

(This article belongs to the Special Issue Molecular Research of Aging Stress Response)

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11 pages, 845 KiB

Open AccessReview

Mitochondrial Unfolded Protein Responses in White Adipose Tissue: Lipoatrophy, Whole-Body Metabolism and Lifespan

by Masaki Kobayashi, Yuichiro Nezu, Ryoma Tagawa and Yoshikazu Higami

Int. J. Mol. Sci. 2021, 22(6), 2854; https://doi.org/10.3390/ijms22062854 - 11 Mar 2021

Cited by 9 | Viewed by 2635

Abstract

The mitochondrial unfolded protein response (UPR^mt) is a stress response mediated by the expression of genes such as chaperones, proteases, and mitokines to maintain mitochondrial proteostasis. Certain genetically modified mice, which defect mitochondrial proteins specifically in adipocytes, developed atrophy of the white adipose tissue, resisted diet-induced obesity, and had altered whole-body metabolism. UPR^mt, which has beneficial functions for living organisms, is termed “mitohormesis”, but its specific characteristics and detailed regulatory mechanism have not been elucidated to date. In this review, we discuss the function of UPR^mt in adipose atrophy (lipoatrophy), whole-body metabolism, and lifespan based on the concept of mitohormesis. Full article

(This article belongs to the Special Issue Molecular Research of Aging Stress Response)

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14 pages, 1215 KiB

Open AccessReview

Control of Mesenchymal Stromal Cell Senescence by Tryptophan Metabolites

by Kenneth K. Wu

Int. J. Mol. Sci. 2021, 22(2), 697; https://doi.org/10.3390/ijms22020697 - 12 Jan 2021

Cited by 18 | Viewed by 3675

Abstract

Cellular senescence contributes to aging and age-related disorders. High glucose (HG) induces mesenchymal stromal/stem cell (MSC) senescence, which hampers cell expansion and impairs MSC function. Intracellular HG triggers metabolic shift from aerobic glycolysis to oxidative phosphorylation, resulting in reactive oxygen species (ROS) overproduction. It causes mitochondrial dysfunction and morphological changes. Tryptophan metabolites such as 5-methoxytryptophan (5-MTP) and melatonin attenuate HG-induced MSC senescence by protecting mitochondrial integrity and function and reducing ROS generation. They upregulate the expression of antioxidant enzymes. Both metabolites inhibit stress-induced MSC senescence by blocking p38 MAPK signaling pathway, NF-κB, and p300 histone acetyltransferase activity. Furthermore, melatonin upregulates SIRT-1, which reduces NF-κB activity by de-acetylation of NF-κB subunits. Melatonin and 5-MTP are a new class of metabolites protecting MSCs against replicative and stress-induced cellular senescence. They provide new strategies to improve the efficiency of MSC-based therapy for diverse human diseases. Full article

(This article belongs to the Special Issue Molecular Research of Aging Stress Response)

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16 pages, 1523 KiB

Open AccessReview

Molecular Aspects of Senescence and Organismal Ageing—DNA Damage Response, Telomeres, Inflammation and Chromatin

by Natalia Sławińska and Renata Krupa

Int. J. Mol. Sci. 2021, 22(2), 590; https://doi.org/10.3390/ijms22020590 - 8 Jan 2021

Cited by 25 | Viewed by 4740

Abstract

Cells can become senescent in response to stress. Senescence is a process characterised by a stable proliferative arrest. Sometimes it can be beneficial—for example, it can suppress tumour development or take part in tissue repair. On the other hand, studies show that it is also involved in the ageing process. DNA damage response (DDR) is triggered by DNA damage or telomere shortening during cell division. When left unresolved, it may lead to the activation of senescence. Senescent cells secrete certain proteins in larger quantities. This phenomenon is referred to as senescence-associated secretory phenotype (SASP). SASP can induce senescence in other cells; evidence suggests that overabundance of senescent cells contributes to ageing. SASP proteins include proinflammatory cytokines and metalloproteinases, which degrade the extracellular matrix. Shortening of telomeres is another feature associated with organismal ageing. Older organisms have shorter telomeres. Restoring telomerase activity in mice not only slowed but also partially reversed the symptoms of ageing. Changes in chromatin structure during senescence include heterochromatin formation or decondensation and loss of H1 histones. During organismal ageing, cells can experience heterochromatin loss, DNA demethylation and global histone loss. Cellular and organismal ageing are both complex processes with many aspects that are often related. The purpose of this review is to bring some of these aspects forward and provide details regarding them. Full article

(This article belongs to the Special Issue Molecular Research of Aging Stress Response)

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13 pages, 1469 KiB

Open AccessReview

Whole Blood Metabolomics in Aging Research

by Hiroshi Kondoh, Masahiro Kameda and Mitsuhiro Yanagida

Int. J. Mol. Sci. 2021, 22(1), 175; https://doi.org/10.3390/ijms22010175 - 26 Dec 2020

Cited by 29 | Viewed by 5980

Abstract

Diversity is observed in the wave of global aging because it is a complex biological process exhibiting individual variability. To assess aging physiologically, markers for biological aging are required in addition to the calendar age. From a metabolic perspective, the aging hypothesis includes the mitochondrial hypothesis and the calorie restriction (CR) hypothesis. In experimental models, several compounds or metabolites exert similar lifespan-extending effects, like CR. However, little is known about whether these metabolic modulations are applicable to human longevity, as human aging is greatly affected by a variety of factors, including lifestyle, genetic or epigenetic factors, exposure to stress, diet, and social environment. A comprehensive analysis of the human blood metabolome captures complex changes with individual differences. Moreover, a non-targeted analysis of the whole blood metabolome discloses unexpected aspects of human biology. By using such approaches, markers for aging or aging-relevant conditions were identified. This information should prove valuable for future diagnosis or clinical interventions in diseases relevant to aging. Full article

(This article belongs to the Special Issue Molecular Research of Aging Stress Response)

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22 pages, 2510 KiB

Open AccessReview

The Aging Stress Response and Its Implication for AMD Pathogenesis

by Janusz Blasiak, Elzbieta Pawlowska, Anna Sobczuk, Joanna Szczepanska and Kai Kaarniranta

Int. J. Mol. Sci. 2020, 21(22), 8840; https://doi.org/10.3390/ijms21228840 - 22 Nov 2020

Cited by 26 | Viewed by 4931

Abstract

Aging induces several stress response pathways to counterbalance detrimental changes associated with this process. These pathways include nutrient signaling, proteostasis, mitochondrial quality control and DNA damage response. At the cellular level, these pathways are controlled by evolutionarily conserved signaling molecules, such as 5’AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), insulin/insulin-like growth factor 1 (IGF-1) and sirtuins, including SIRT1. Peroxisome proliferation-activated receptor coactivator 1 alpha (PGC-1α), encoded by the PPARGC1A gene, playing an important role in antioxidant defense and mitochondrial biogenesis, may interact with these molecules influencing lifespan and general fitness. Perturbation in the aging stress response may lead to aging-related disorders, including age-related macular degeneration (AMD), the main reason for vision loss in the elderly. This is supported by studies showing an important role of disturbances in mitochondrial metabolism, DDR and autophagy in AMD pathogenesis. In addition, disturbed expression of PGC-1α was shown to associate with AMD. Therefore, the aging stress response may be critical for AMD pathogenesis, and further studies are needed to precisely determine mechanisms underlying its role in AMD. These studies can include research on retinal cells produced from pluripotent stem cells obtained from AMD donors with the mutations, either native or engineered, in the critical genes for the aging stress response, including AMPK, IGF1, MTOR, SIRT1 and PPARGC1A. Full article

(This article belongs to the Special Issue Molecular Research of Aging Stress Response)

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