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Molecular Bases of Senescence

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 49848

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Special Issue Editors

Prof. Dr. Giorgio Fanò-Illic

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Guest Editor

Interuniversity Institute of Myology (IIM) 66100 Chieti (Italy), A&C M-C Foundation for Translational Myology, 35100 Padova (Italy), Free University of Alcatraz, 06024 Gubbio, Italy
Interests: human muscle senescence; skeletal muscle physiology; adaptive responses to hypoxia and microgravity; growth factors and transcription factors in excitable cells; Oxidative stress; brain physiology: cognitive aspects
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Patrizia Mecocci

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Guest Editor

1. Institute of Gerontology and Geriatrics, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy
2. Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
Interests: supplement; vitamin D; depression; dementia; Alzheimer; aging; oxidative stress; inflammation
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Stefania Fulle

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Guest Editor

Department of Neuroscience, Imaging and Clinical Sciences, University ”G. d’Annunzio” Chieti-Pescara, 66100 Chieti, Italy
Interests: oxidative stress and antioxidant enzymes; cellular signalling; growth factors; muscular trophism; muscle stem cells; regenerative aspects of space flight; sarcopenia
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue aims to highlight the contributions of epigenetic and eugenic factors in establishing the longevity and life span of a living organism. The starting hypothesis, which is present in the scientific literature currently available, is that lifestyle and environmental factors play a preponderant role during the early stages of existence, whereas genetics becomes fundamental to establish the complete life span of an organism.

To verify this possibility, we propose gathering original contributions and analyses of data already present in the scientific literature concerning different aspects that form the basis of this theory. In particular:

the presence or not of a unique centre able to determine the senescence of the whole organism
the molecular effects of environmental inductors (oxidative stress, pro-inflammatory factors, caloric supply, nutrients, etc.);
the different mechanisms: (a) cellular (proteostasis, autophagy, inflammation, etc.); (b) signalling (NF-kB, TOR, sirtuins, etc.); and (c) the intercellular pathways (localized growth factors, miRNA, etc.) able to accelerate or inhibit the aging process; and
the aspects related to the senescence of the muscular apparatus (sarcopenia) and alterations of the nervous system (degeneration/regeneration ratio, brain areas with different sensitivities, etc.) including those of cognitive and pathological interest as well as the Alzheimer's disease and Parkinson’s disorder.

Prof. Dr. Giorgio Fanò-Illic
Prof. Dr. Patrizia Mecocci
Prof. Dr. Stefania Fulle
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

aging process
oxidative stress
proteostasis
autophagy
inflammation
cellular signalling
growth factors
miRNA
stem cells
sarcopenia
Alzheimer's disease
Parkinson’s disorder
nutrition

Published Papers (14 papers)

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Editorial

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6 pages, 819 KiB

Open AccessEditorial

Editorial for the Special Issue “Molecular Bases of Senescence”

by Giorgio Fanò-Illic, Stefania Fulle and Patrizia Mecocci

Int. J. Mol. Sci. 2021, 22(21), 11873; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111873 - 02 Nov 2021

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Abstract

The increasing life expectancy of populations worldwide represents the most evident success of the last century thanks to varying interacting social and medical achievements [...] Full article

(This article belongs to the Special Issue Molecular Bases of Senescence)

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Research

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16 pages, 3279 KiB

Open AccessArticle

Distinct Age-Specific miRegulome Profiling of Isolated Small and Large Intestinal Epithelial Cells in Mice

by Juneyoung Lee, Attayeb Mohsen, Anik Banerjee, Louise D. McCullough, Kenji Mizuguchi, Motomu Shimaoka, Hiroshi Kiyono and Eun Jeong Park

Int. J. Mol. Sci. 2021, 22(7), 3544; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073544 - 29 Mar 2021

Cited by 7 | Viewed by 2860

Abstract

The intestinal epithelium serves as a dynamic barrier to protect the host tissue from exposure to a myriad of inflammatory stimuli in the luminal environment. Intestinal epithelial cells (IECs) encompass differentiated and specialized cell types that are equipped with regulatory genes, which allow for sensing of the luminal environment. Potential inflammatory cues can instruct IECs to undergo a diverse set of phenotypic alterations. Aging is a primary risk factor for a variety of diseases; it is now well-documented that aging itself reduces the barrier function and turnover of the intestinal epithelium, resulting in pathogen translocation and immune priming with increased systemic inflammation. In this study, we aimed to provide an effective epigenetic and regulatory outlook that examines age-associated alterations in the intestines through the profiling of microRNAs (miRNAs) on isolated mouse IECs. Our microarray analysis revealed that with aging, there is dysregulation of distinct clusters of miRNAs that was present to a greater degree in small IECs (22 miRNAs) compared to large IECs (three miRNAs). Further, miRNA–mRNA interaction network and pathway analyses indicated that aging differentially regulates key pathways between small IECs (e.g., toll-like receptor-related cascades) and large IECs (e.g., cell cycle, Notch signaling and small ubiquitin-related modifier pathway). Taken together, current findings suggest novel gene regulation pathways by epithelial miRNAs in aging within the gastrointestinal tissues. Full article

(This article belongs to the Special Issue Molecular Bases of Senescence)

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23 pages, 3778 KiB

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Understanding the Potential Role of Sirtuin 2 on Aging: Consequences of SIRT2.3 Overexpression in Senescence

by Noemi Sola-Sevilla, Ana Ricobaraza, Ruben Hernandez-Alcoceba, Maria S. Aymerich, Rosa M. Tordera and Elena Puerta

Int. J. Mol. Sci. 2021, 22(6), 3107; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063107 - 18 Mar 2021

Cited by 10 | Viewed by 3543

Abstract

Sirtuin 2 (SIRT2) has been associated to aging and age-related pathologies. Specifically, an age-dependent accumulation of isoform 3 of SIRT2 in the CNS has been demonstrated; however, no study has addressed the behavioral or molecular consequences that this could have on aging. In the present study, we have designed an adeno-associated virus vector (AAV-CAG-Sirt2.3-eGFP) for the overexpression of SIRT2.3 in the hippocampus of 2 month-old SAMR1 and SAMP8 mice. Our results show that the specific overexpression of this isoform does not induce significant behavioral or molecular effects at short or long term in the control strain. Only a tendency towards a worsening in the performance in acquisition phase of the Morris Water Maze was found in SAMP8 mice, together with a significant increase in the pro-inflammatory cytokine Il-1β. These results suggest that the age-related increase of SIRT2.3 found in the brain is not responsible for induction or prevention of senescence. Nevertheless, in combination with other risk factors, it could contribute to the progression of age-related processes. Understanding the specific role of SIRT2 on aging and the underlying molecular mechanisms is essential to design new and more successful therapies for the treatment of age-related diseases. Full article

(This article belongs to the Special Issue Molecular Bases of Senescence)

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14 pages, 1877 KiB

Open AccessArticle

Aged Skeletal Muscle Retains the Ability to Remodel Extracellular Matrix for Degradation of Collagen Deposition after Muscle Injury

by Wan-Jing Chen, I-Hsuan Lin, Chien-Wei Lee and Yi-Fan Chen

Int. J. Mol. Sci. 2021, 22(4), 2123; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22042123 - 20 Feb 2021

Cited by 23 | Viewed by 4929

Abstract

Aging causes a decline in skeletal muscle function, resulting in a progressive loss of muscle mass, quality, and strength. A weak regenerative capacity is one of the critical causes of dysfunctional skeletal muscle in elderly individuals. The extracellular matrix (ECM) maintains the tissue framework structure in skeletal muscle. As shown by previous reports and our data, the gene expression of ECM components decreases with age, but the accumulation of collagen substantially increases in skeletal muscle. We examined the structural changes in ECM in aged skeletal muscle and found restricted ECM degradation. In aged skeletal muscles, several genes that maintain ECM structure, such as transforming growth factor β (TGF-β), tissue inhibitors of metalloproteinases (TIMPs), matrix metalloproteinases (MMPs), and cathepsins, were downregulated. Muscle injury can induce muscle repair and regeneration in young and adult skeletal muscles. Surprisingly, muscle injury could not only efficiently induce regeneration in aged skeletal muscle, but it could also activate ECM remodeling and the clearance of ECM deposition. These results will help elucidate the mechanisms of muscle fibrosis with age and develop innovative antifibrotic therapies to decrease excessive collagen deposition in aged muscle. Full article

(This article belongs to the Special Issue Molecular Bases of Senescence)

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26 pages, 4066 KiB

Open AccessArticle

Non-Coding RNAs in the Transcriptional Network That Differentiates Skeletal Muscles of Sedentary from Long-Term Endurance- and Resistance-Trained Elderly

by Paola De Sanctis, Giuseppe Filardo, Provvidenza Maria Abruzzo, Annalisa Astolfi, Alessandra Bolotta, Valentina Indio, Alessandro Di Martino, Christian Hofer, Helmut Kern, Stefan Löfler, Maurilio Marcacci, Marina Marini, Sandra Zampieri and Cinzia Zucchini

Int. J. Mol. Sci. 2021, 22(4), 1539; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041539 - 03 Feb 2021

Cited by 15 | Viewed by 3303

Abstract

In a previous study, the whole transcriptome of the vastus lateralis muscle from sedentary elderly and from age-matched athletes with an exceptional record of high-intensity, life-long exercise training was compared—the two groups representing the two extremes on a physical activity scale. Exercise training enabled the skeletal muscle to counteract age-related sarcopenia by inducing a wide range of adaptations, sustained by the expression of protein-coding genes involved in energy handling, proteostasis, cytoskeletal organization, inflammation control, and cellular senescence. Building on the previous study, we examined here the network of non-coding RNAs participating in the orchestration of gene expression and identified differentially expressed micro- and long-non-coding RNAs and some of their possible targets and roles. Unsupervised hierarchical clustering analyses of all non-coding RNAs were able to discriminate between sedentary and trained individuals, regardless of the exercise typology. Validated targets of differentially expressed miRNA were grouped by KEGG analysis, which pointed to functional areas involved in cell cycle, cytoskeletal control, longevity, and many signaling pathways, including AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR), which had been shown to be pivotal in the modulation of the effects of high-intensity, life-long exercise training. The analysis of differentially expressed long-non-coding RNAs identified transcriptional networks, involving lncRNAs, miRNAs and mRNAs, affecting processes in line with the beneficial role of exercise training. Full article

(This article belongs to the Special Issue Molecular Bases of Senescence)

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12 pages, 1333 KiB

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CK2 Down-Regulation Increases the Expression of Senescence-Associated Secretory Phenotype Factors through NF-κB Activation

by Junbin Song and Young-Seuk Bae

Int. J. Mol. Sci. 2021, 22(1), 406; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010406 - 02 Jan 2021

Cited by 14 | Viewed by 2594

Abstract

Senescent cells secrete pro-inflammatory factors, and a hallmark feature of senescence is senescence-associated secretory phenotype (SASP). The aim of this study is to investigate the protein kinase CK2 (CK2) effects on SASP factors expression in cellular senescence and organism aging. Here CK2 down-regulation induced the expression of SASP factors, including interleukin (IL)-1β, IL-6, and matrix metalloproteinase (MMP) 3, through the activation of nuclear factor-κB (NF-κB) signaling in MCF-7 and HCT116 cells. CK2 down-regulation-mediated SIRT1 inactivation promoted the degradation of inhibitors of NF-κB (IκB) by activating the AKT-IκB kinase (IKK) axis and increased the acetylation of lysine 310 on RelA/p65, an important site for the activity of NF-κB. kin-10 (the ortholog of CK2β) knockdown increased zmp-1, -2, and -3 (the orthologs of MMP) expression in nematodes, but AKT inhibitor triciribine and SIRT activator resveratrol significantly abrogated the increased expression of these genes. Finally, antisense inhibitors of miR-186, miR-216b, miR-337-3p, and miR-760 suppressed CK2α down-regulation, activation of the AKT-IKK-NF-κB axis, RelA/p65 acetylation, and expression of SASP genes in cells treated with lipopolysaccharide. Therefore, this study indicated that CK2 down-regulation induces the expression of SASP factors through NF-κB activation, which is mediated by both activation of the SIRT1-AKT-IKK axis and RelA/p65 acetylation, suggesting that the mixture of the four miRNA inhibitors can be used as anti-inflammatory agents. Full article

(This article belongs to the Special Issue Molecular Bases of Senescence)

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18 pages, 2122 KiB

Open AccessArticle

Linking ABCC6 Deficiency in Primary Human Dermal Fibroblasts of PXE Patients to p21-Mediated Premature Cellular Senescence and the Development of a Proinflammatory Secretory Phenotype

by Janina Tiemann, Thomas Wagner, Christopher Lindenkamp, Ricarda Plümers, Isabel Faust, Cornelius Knabbe and Doris Hendig

Int. J. Mol. Sci. 2020, 21(24), 9665; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249665 - 18 Dec 2020

Cited by 11 | Viewed by 2130

Abstract

Pseudoxanthoma elasticum (PXE) is a rare autosomal-recessive disorder that is mainly caused by mutations in the ATP-binding cassette sub-family C member 6 (ABCC6) gene. Clinically PXE is characterized by a loss of skin elasticity, arteriosclerosis or visual impairments. It also shares some molecular characteristics with known premature aging syndromes like the Hutchinson–Gilford progeria syndrome (HGPS). However, little is known about accelerated aging processes, especially on a cellular level for PXE now. Therefore, this study was performed to reveal a potential connection between premature cellular aging and PXE pathogenesis by analyzing cellular senescence, a corresponding secretory phenotype and relevant factors of the cell cycle control in primary human dermal fibroblasts of PXE patients. Here, we could show an increased senescence-associated β-galactosidase (SA-β-Gal) activity as well as an increased expression of proinflammatory factors of a senescence-associated secretory phenotype (SASP) like interleukin 6 (IL6) and monocyte chemoattractant protein-1 (MCP1). We further observed an increased gene expression of the cyclin-dependent kinase inhibitor (CDKI) p21, but no simultaneous induction of p53 gene expression. These data indicate that PXE is associated with premature cellular senescence, which is possibly triggered by a p53-independent p21-mediated mechanism leading to a proinflammatory secretory phenotype. Full article

(This article belongs to the Special Issue Molecular Bases of Senescence)

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20 pages, 6938 KiB

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Histone Variant H2A.J Marks Persistent DNA Damage and Triggers the Secretory Phenotype in Radiation-Induced Senescence

by Anna Isermann, Carl Mann and Claudia E. Rübe

Int. J. Mol. Sci. 2020, 21(23), 9130; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239130 - 30 Nov 2020

Cited by 20 | Viewed by 2748

Abstract

Irreparable double-strand breaks (DSBs) in response to ionizing radiation (IR) trigger prolonged DNA damage response (DDR) and induce premature senescence. Profound chromatin reorganization with formation of senescence-associated heterochromatin foci (SAHF) is an essential epigenetic mechanism for controlling the senescence-associated secretory phenotype (SASP). To decipher molecular mechanisms provoking continuous DDR leading to premature senescence, radiation-induced DSBs (53BP1-foci) and dynamics of histone variant H2A.J incorporation were analyzed together with chromatin re-modeling in human fibroblasts after IR exposure. High-resolution imaging by transmission electron microscopy revealed that persisting 53BP1-foci developed into DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS), consistently located at the periphery of SAHFs. Quantitative immunogold-analysis by electron microscopy revealed that H2A.J, steadily co-localizing with 53BP1, is increasingly incorporated into DNA-SCARS during senescence progression. Strikingly, shRNA-mediated H2A.J depletion in fibroblasts modified senescence-associated chromatin re-structuring and abolished SASP, thereby shutting down the production of inflammatory mediators. These findings provide mechanistic insights into biological phenomena of SASP and suggest that H2A.J inhibition could ablate SASP, without affecting the senescence-associated growth arrest. Full article

(This article belongs to the Special Issue Molecular Bases of Senescence)

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15 pages, 4101 KiB

Open AccessArticle

Resveratrol Pretreatment Ameliorates Concanavalin A-Induced Advanced Renal Glomerulosclerosis in Aged Mice through Upregulation of Sirtuin 1-Mediated Klotho Expression

by Chin-Chang Chen, Zi-Yu Chang, Fuu-Jen Tsai and Shih-Yin Chen

Int. J. Mol. Sci. 2020, 21(18), 6766; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186766 - 15 Sep 2020

Cited by 16 | Viewed by 3372

Abstract

Aging kidneys are characterized by an increased vulnerability to glomerulosclerosis and a measurable decline in renal function. Evidence suggests that renal and systemic klotho and sirtuin 1 (SIRT1) deficiencies worsen kidney damage induced by exogenous stresses. The aim of this study was to explore whether resveratrol would attenuate concanavalin A (Con A)-induced renal oxidative stress and advanced glomerulosclerosis in aged mice. Aged male C57BL/6 mice were treated orally with resveratrol (30 mg/kg) seven times (12 h intervals) prior to the administration of a single tail-vein injection of Con A (20 mg/kg). The plasma and urinary levels of kidney damage markers were evaluated. The kidney histopathology, renal parameters, and oxidative stress levels were measured. Furthermore, klotho was downregulated in mouse kidney mesangial cells that were pretreated with 25 µM resveratrol followed by 20 µg/mL Con A. The urinary albumin/creatinine ratio, blood urea nitrogen, kidney mesangial matrix expansion, tubulointerstitial fibrosis, and renal levels of α-smooth muscle actin, transforming growth factor beta, fibronectin, procollagen III propeptide, and collagen type I significantly increased in Con A-treated aged mice. Aged mice kidneys also showed markedly increased levels of 8-hydroxydeoxyguanosine (8-OH-dG) and reactive oxygen species (ROS), with reduced superoxide dismutase activity and levels of glutathione, klotho, and SIRT1 after Con A challenge. Furthermore, in kidney mesangial cells, klotho silencing abolished the effects of resveratrol on the Con A-mediated elevation of the indices of oxidative stress and the expression of glomerulosclerosis-related factors. These findings suggest that resveratrol protects against Con A-induced advanced glomerulosclerosis in aged mice, ameliorating renal oxidative stress via the SIRT1-mediated klotho expression. Full article

(This article belongs to the Special Issue Molecular Bases of Senescence)

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12 pages, 1127 KiB

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Effect of a Cognitive Training Program on the Platelet APP Ratio in Patients with Alzheimer’s Disease

by Tiziana Casoli, Cinzia Giuli, Marta Balietti, Paolo Fabbietti and Fiorenzo Conti

Int. J. Mol. Sci. 2020, 21(14), 5110; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21145110 - 20 Jul 2020

Cited by 4 | Viewed by 2117

Abstract

In patients with Alzheimer’s disease (AD), synaptic plasticity seems to be involved in cognitive improvement induced by cognitive training. The platelet amyloid precursor protein (APP) ratio (APPr), i.e., the ratio between two APP isoforms, may be a useful peripheral biomarker to investigate synaptic plasticity pathways. This study evaluates the changes in neuropsychological/cognitive performance and APPr induced by cognitive training in AD patients participating in the “My Mind Project”. Neuropsychological/cognitive variables and APPr were evaluated in the trained group (n = 28) before a two-month experimental protocol, immediately after its termination at follow-up 1 (FU1), after 6 months at follow-up 2 (FU2), and after 24 months at follow-up 3 (FU3). The control group (n = 31) received general psychoeducational training for two months. Some memory and attention parameters were significantly improved in trained vs. control patients at FU1 and FU2 compared to baseline (Δ values). At FU3, APPr and Mini Mental State Examination (MMSE) scores decreased in trained patients. Δ APPr correlated significantly with the Δ scores of (i) MMSE at FU1, (ii) the prose memory test at FU2, and (iii) Instrumental Activities of Daily Living (IADL), the semantic word fluency test, Clinical Dementia Rating (CDR), and the attentive matrices test at FU3. Our data demonstrate that the platelet APPr correlates with key clinical variables, thereby proving that it may be a reliable biomarker of brain function in AD patients. Full article

(This article belongs to the Special Issue Molecular Bases of Senescence)

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14 pages, 1999 KiB

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Alterations of Extracellular Matrix Mechanical Properties Contribute to Age-Related Functional Impairment of Human Skeletal Muscles

by Piero Pavan, Elena Monti, Michela Bondí, Chenglei Fan, Carla Stecco, Marco Narici, Carlo Reggiani and Lorenzo Marcucci

Int. J. Mol. Sci. 2020, 21(11), 3992; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113992 - 02 Jun 2020

Cited by 47 | Viewed by 5178

Abstract

Aging of human skeletal muscles is associated with increased passive stiffness, but it is still debated whether muscle fibers or extracellular matrix (ECM) are the determinants of such change. To answer this question, we compared the passive stress generated by elongation of fibers alone and arranged in small bundles in young healthy (Y: 21 years) and elderly (E: 67 years) subjects. The physiological range of sarcomere length (SL) 2.5–3.3 μm was explored. The area of ECM between muscle fibers was determined on transversal sections with picrosirius red, a staining specific for collagen fibers. The passive tension of fiber bundles was significantly higher in E compared to Y at all SL. However, the resistance to elongation of fibers alone was not different between the two groups, while the ECM contribution was significantly increased in E compared to Y. The proportion of muscle area occupied by ECM increased from 3.3% in Y to 8.2% in E. When the contribution of ECM to bundle tension was normalized to the fraction of area occupied by ECM, the difference disappeared. We conclude that, in human skeletal muscles, the age-related reduced compliance is due to an increased stiffness of ECM, mainly caused by collagen accumulation. Full article

(This article belongs to the Special Issue Molecular Bases of Senescence)

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31 pages, 6389 KiB

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Skeletal Muscle Gene Expression in Long-Term Endurance and Resistance Trained Elderly

by Alessandra Bolotta, Giuseppe Filardo, Provvidenza Maria Abruzzo, Annalisa Astolfi, Paola De Sanctis, Alessandro Di Martino, Christian Hofer, Valentina Indio, Helmut Kern, Stefan Löfler, Maurilio Marcacci, Sandra Zampieri, Marina Marini and Cinzia Zucchini

Int. J. Mol. Sci. 2020, 21(11), 3988; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113988 - 02 Jun 2020

Cited by 16 | Viewed by 4959

Abstract

Physical exercise is deemed the most efficient way of counteracting the age-related decline of skeletal muscle. Here we report a transcriptional study by next-generation sequencing of vastus lateralis biopsies from elderly with a life-long high-level training practice (n = 9) and from age-matched sedentary subjects (n = 5). Unsupervised mixture distribution analysis was able to correctly categorize trained and untrained subjects, whereas it failed to discriminate between individuals who underwent a prevalent endurance (n = 5) or a prevalent resistance (n = 4) training, thus showing that the training mode was not relevant for sarcopenia prevention. KEGG analysis of transcripts showed that physical exercise affected a high number of metabolic and signaling pathways, in particular those related to energy handling and mitochondrial biogenesis, where AMPK and AKT-mTOR signaling pathways are both active and balance each other, concurring to the establishment of an insulin-sensitive phenotype and to the maintenance of a functional muscle mass. Other pathways affected by exercise training increased the efficiency of the proteostatic mechanisms, consolidated the cytoskeletal organization, lowered the inflammation level, and contrasted cellular senescence. This study on extraordinary individuals who trained at high level for at least thirty years suggests that aging processes and exercise training travel the same paths in the opposite direction. Full article

(This article belongs to the Special Issue Molecular Bases of Senescence)

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Review

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Biological Aspects of Selected Myokines in Skeletal Muscle: Focus on Aging

by Rosa Mancinelli, Franco Checcaglini, Francesco Coscia, Paola Gigliotti, Stefania Fulle and Giorgio Fanò-Illic

Int. J. Mol. Sci. 2021, 22(16), 8520; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168520 - 07 Aug 2021

Cited by 41 | Viewed by 5999

Abstract

In the last decade, clear evidence has emerged that the cellular components of skeletal muscle are important sites for the release of proteins and peptides called “myokines”, suggesting that skeletal muscle plays the role of a secretory organ. After their secretion by muscles, these factors serve many biological functions, including the exertion of complex autocrine, paracrine and/or endocrine effects. In sum, myokines affect complex multi-organ processes, such as skeletal muscle trophism, metabolism, angiogenesis and immunological response to different physiological (physical activity, aging, etc.) or pathological states (cachexia, dysmetabolic conditions, chronic inflammation, etc.). The aim of this review is to describe in detail a number of myokines that are, to varying degrees, involved in skeletal muscle aging processes and belong to the group of proteins present in the functional environment surrounding the muscle cell known as the “Niche”. The particular myokines described are those that, acting both from within the cell and in an autocrine manner, have a defined relationship with the modulation of oxidative stress in muscle cells (mature or stem) involved in the regulatory (metabolic or regenerative) processes of muscle aging. Myostatin, IGF-1, NGF, S100 and irisin are examples of specific myokines that have peculiar features in their mechanisms of action. In particular, the potential role of one of the most recently characterized myokines—irisin, directly linked to an active lifestyle—in reducing if not reversing senescence-induced oxidative damage is discussed in terms of its possible application as an agent able to counteract the deleterious effects of muscle aging. Full article

(This article belongs to the Special Issue Molecular Bases of Senescence)

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15 pages, 984 KiB

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Chronological Age Affects MSC Senescence In Vitro—A Systematic Review

by Konstantinos Kapetanos, Dimitrios Asimakopoulos, Neophytos Christodoulou, Antonia Vogt and Wasim Khan

Int. J. Mol. Sci. 2021, 22(15), 7945; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157945 - 26 Jul 2021

Cited by 11 | Viewed by 3541

Abstract

The use of mesenchymal stromal cells (MSCs) in regenerative medicine and tissue engineering is well established, given their properties of self-renewal and differentiation. However, several studies have shown that these properties diminish with age, and understanding the pathways involved are important to provide regenerative therapies in an ageing population. In this PRISMA systematic review, we investigated the effects of chronological donor ageing on the senescence of MSCs. We identified 3023 studies after searching four databases including PubMed, Web of Science, Cochrane, and Medline. Nine studies met the inclusion and exclusion criteria and were included in the final analyses. These studies showed an increase in the expression of p21, p53, p16, ROS, and NF-κB with chronological age. This implies an activated DNA damage response (DDR), as well as increased levels of stress and inflammation in the MSCs of older donors. Additionally, highlighting the effects of an activated DDR in cells from older donors, a decrease in the expression of proliferative markers including Ki67, MAPK pathway elements, and Wnt/β-catenin pathway elements was observed. Furthermore, we found an increase in the levels of SA-β-galactosidase, a specific marker of cellular senescence. Together, these findings support an association between chronological age and MSC senescence. The precise threshold for chronological age where the reported changes become significant is yet to be defined and should form the basis for further scientific investigations. The outcomes of this review should direct further investigations into reversing the biological effects of chronological age on the MSC senescence phenotype. Full article

(This article belongs to the Special Issue Molecular Bases of Senescence)

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