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Aging: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches

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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 (20 June 2024) | Viewed by 24618

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Prof. Dr. Darío Acuña-Castroviejo

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Centro de Investigación Biomédica, Instituto de Biotecnología, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, 18016 Granada, Spain
Interests: melatonin; mitochondria; aging; neurodegeneration; sepsis; oxidative stress
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Dear Colleagues,

Aging is the gradual deterioration of functional integrity and systemic homeostasis, concluding in death. During the last century, improvements in health care have notably increased the quality and expectancy of life in humans, but have consequently led to frailty and morbidity. The complexity of aging is determined by the following hallmarks: chronodisruption, genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Advances in research have facilitated the identification of genes that regulate aging, such as those implicated in the molecular machinery of the biological clock, nutrient-sensing pathways, growth factor pathways, mitochondria function, inflammation, and the immune system. Human genetic studies, genetically modified mouse models, and studies on the evolution of lifespan in nature have revealed new avenues to understand the molecular genetics of aging. However, genetic regulation of the elderly remains inscrutable. Furthermore, differences in sex and environmental influences remain unknown and are future challenges within the scientific community. Elucidating the genetic mechanisms that underlie aging is essential for mitigating age-related diseases, reducing fragility, and promoting a healthy human lifespan.

This Special Issue, “Aging: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches”, will discuss the current state of the art, challenges, and opportunities in the field of molecular genetics of aging. Authors are encouraged to submit original research manuscripts and related review articles.

Prof. Dr. Darío Acuña-Castroviejo
Guest Editor

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

human aging
molecular clock
aging genes
epigenetics
nutrigenomics
inflammaging
stem cells
telomeres
mitochondria

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Research

Jump to: Review

15 pages, 1323 KiB

Open AccessArticle

Cancerous Conditions Accelerate the Aging of Skeletal Muscle via Mitochondrial DNA Damage

by Yi Luo, Rina Fujiwara-Tani, Isao Kawahara, Kei Goto, Shota Nukaga, Ryoichi Nishida, Chie Nakashima, Takamitsu Sasaki, Yoshihiro Miyagawa, Ruiko Ogata, Kiyomu Fujii, Hitoshi Ohmori and Hiroki Kuniyasu

Int. J. Mol. Sci. 2024, 25(13), 7060; https://doi.org/10.3390/ijms25137060 - 27 Jun 2024

Viewed by 1636

Abstract

Skeletal muscle aging and sarcopenia result in similar changes in the levels of aging markers. However, few studies have examined cancer sarcopenia from the perspective of aging. Therefore, this study investigated aging in cancer sarcopenia and explored its causes in vitro and in vivo. In mouse aging, in vitro cachexia, and mouse cachexia models, skeletal muscles showed similar changes in aging markers including oxidative stress, fibrosis, reduced muscle differentiation potential, and telomere shortening. Furthermore, examination of mitochondrial DNA from skeletal muscle revealed a 5 kb deletion in the major arc; truncation of complexes I, IV, and V in the electron transport chain; and reduced oxidative phosphorylation (OXPHOS). The mouse cachexia model demonstrated high levels of high-mobility group box-1 (HMGB1) and tumor necrosis factor-α (TNFα) in cancer ascites. Continuous administration of neutralizing antibodies against HMGB1 and TNFα in this model reduced oxidative stress and abrogated mitochondrial DNA deletion. These results suggest that in cancer sarcopenia, mitochondrial oxidative stress caused by inflammatory cytokines leads to mitochondrial DNA damage, which in turn leads to decreased OXPHOS and the promotion of aging. Full article

(This article belongs to the Special Issue Aging: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches)

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13 pages, 1684 KiB

Open AccessArticle

PARG Protein Regulation Roles in Drosophila Longevity Control

by Guillaume Bordet and Alexei V. Tulin

Int. J. Mol. Sci. 2024, 25(11), 6189; https://doi.org/10.3390/ijms25116189 - 4 Jun 2024

Viewed by 1205

Abstract

Aging, marked by a gradual decline in physiological function and heightened vulnerability to age-related diseases, remains a complex biological process with multifaceted regulatory mechanisms. Our study elucidates the critical role of poly(ADP–ribose) glycohydrolase (PARG), responsible for catabolizing poly(ADP–ribose) (pADPr) in the aging process by modulating the expression of age-related genes in Drosophila melanogaster. Specifically, we uncover the regulatory function of the uncharacterized PARG C-terminal domain in controlling PARG activity. Flies lacking this domain exhibit a significantly reduced lifespan compared to wild-type counterparts. Furthermore, we observe progressive dysregulation of age-related gene expression during aging, accelerated in the absence of PARG activity, culminating in a premature aging phenotype. Our findings reveal the critical involvement of the pADPr pathway as a key player in the aging process, highlighting its potential as a therapeutic target for mitigating age-related effects. Full article

(This article belongs to the Special Issue Aging: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches)

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16 pages, 2931 KiB

Open AccessArticle

Ageing and Polypharmacy in Mesenchymal Stromal Cells: Metabolic Impact Assessed by Hyperspectral Imaging of Autofluorescence

by Chandrasekara M. N. Chandrasekara, Gizem Gemikonakli, John Mach, Rui Sang, Ayad G. Anwer, Adnan Agha, Ewa M. Goldys, Sarah N. Hilmer and Jared M. Campbell

Int. J. Mol. Sci. 2024, 25(11), 5830; https://doi.org/10.3390/ijms25115830 - 27 May 2024

Cited by 1 | Viewed by 1398

Abstract

The impact of age on mesenchymal stromal cell (MSC) characteristics has been well researched. However, increased age is concomitant with increased prevalence of polypharmacy. This adjustable factor may have further implications for the functionality of MSCs and the effectiveness of autologous MSC procedures. We applied hyperspectral microscopy of cell autofluorescence—a non-invasive imaging technique used to characterise cytometabolic heterogeneity—to identify changes in the autofluorescence signals of MSCs from (1) young mice, (2) old mice, (3) young mice randomised to receive polypharmacy (9–10 weeks of oral therapeutic doses of simvastatin, metoprolol, oxycodone, oxybutynin and citalopram), and (4) old mice randomised to receive polypharmacy. Principal Component Analysis and Logistic Regression Analysis were used to assess alterations in spectral and associated metabolic characteristics. Modelling demonstrated that cells from young mice receiving polypharmacy had less NAD(P)H and increased porphyrin relative to cells from old control mice, allowing for effective separation of the two groups (AUC of ROC curve > 0.94). Similarly, cells from old polypharmacy mice were accurately separated from those from young controls due to lower levels of NAD(P)H (p < 0.001) and higher porphyrin (p < 0.001), allowing for an extremely accurate logistic regression (AUC of ROC curve = 0.99). This polypharmacy regimen may have a more profound impact on MSCs than ageing, and can simultaneously reduce optical redox ratio (ORR) and increase porphyrin levels. This has implications for the use of autologous MSCs for older patients with chronic disease. Full article

(This article belongs to the Special Issue Aging: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches)

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12 pages, 2484 KiB

Open AccessArticle

Transplantation of Mesenchymal Stem Cells Derived from Old Rats Improves Healing and Biomechanical Properties of Vaginal Tissue Following Surgical Incision in Aged Rats

by Ofra Ben Menachem-Zidon, Benjamin Reubinoff and David Shveiky

Int. J. Mol. Sci. 2024, 25(11), 5714; https://doi.org/10.3390/ijms25115714 - 24 May 2024

Cited by 2 | Viewed by 1160

Abstract

Pelvic floor dysfunction encompasses a group of disorders that negatively affect the quality of women’s lives. These include pelvic organ prolapse (POP), urinary incontinence, and sexual dysfunction. The greatest risk factors for prolapse are increased parity and older age, with the largest group requiring surgical intervention being post-menopausal women over 65. Prolapse recurrence rates following surgery were reported to be as high as 30%. This may be attributed to ineffective healing in the elderly. Autologous stem cell transplantation during surgery may improve surgical results. In our previous studies, we showed that the transplantation of bone marrow-derived mesenchymal stem cells (MSCs) from young donor rats improved the healing of full-thickness vaginal surgical incision in the vaginal wall of old rats, demonstrated by both histological and functional analysis. In order to translate these results into the clinical reality of autologous MSC transplantation in elderly women, we sought to study whether stem cells derived from old donor animals would provide the same effect. In this study, we demonstrate that MSC transplantation attenuated the inflammatory response, increased angiogenesis, and exhibited a time-dependent impact on MMP9 localization. Most importantly, transplantation improved the restoration of the biomechanical properties of the vagina, resulting in stronger healed vaginal tissue. These results may pave the way for further translational studies focusing on the potential clinical autologous adjuvant transplantation of MSCs for POP repair for the improvement of surgical outcomes. Full article

(This article belongs to the Special Issue Aging: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches)

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15 pages, 6073 KiB

Open AccessArticle

Genome-Wide Epistatic Network Analyses of Semantic Fluency in Older Adults

by Qihua Tan, Weilong Li, Marianne Nygaard, Ping An, Mary Feitosa, Mary K. Wojczynski, Joseph Zmuda, Konstantin Arbeev, Svetlana Ukraintseva, Anatoliy Yashin, Kaare Christensen and Jonas Mengel-From

Int. J. Mol. Sci. 2024, 25(10), 5257; https://doi.org/10.3390/ijms25105257 - 11 May 2024

Viewed by 1575

Abstract

Semantic fluency impairment has been attributed to a wide range of neurocognitive and psychiatric conditions, especially in the older population. Moderate heritability estimates on semantic fluency were obtained from both twin and family-based studies suggesting genetic contributions to the observed variation across individuals. Currently, effort in identifying the genetic variants underlying the heritability estimates for this complex trait remains scarce. Using the semantic fluency scale and genome-wide SNP genotype data from the Long Life Family Study (LLFS), we performed a genome-wide association study (GWAS) and epistasis network analysis on semantic fluency in 2289 individuals aged over 60 years from the American LLFS cohorts and replicated the findings in 1129 individuals aged over 50 years from the Danish LLFS cohort. In the GWAS, two SNPs with genome-wide significance (rs3749683, p = 2.52 × 10⁻⁸; rs880179, p = 4.83 × 10⁻⁸) mapped to the CMYAS gene on chromosome 5 were detected. The epistasis network analysis identified five modules as significant (4.16 × 10⁻⁵ < p < 7.35 × 10⁻³), of which two were replicated (p < 3.10 × 10⁻³). These two modules revealed significant enrichment of tissue-specific gene expression in brain tissues and high enrichment of GWAS catalog traits, e.g., obesity-related traits, blood pressure, chronotype, sleep duration, and brain structure, that have been reported to associate with verbal performance in epidemiological studies. Our results suggest high tissue specificity of genetic regulation of gene expression in brain tissues with epistatic SNP networks functioning jointly in modifying individual verbal ability and cognitive performance. Full article

(This article belongs to the Special Issue Aging: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches)

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10 pages, 1497 KiB

Open AccessArticle

Telomere Length, Mitochondrial DNA, and Micronucleus Yield in Response to Oxidative Stress in Peripheral Blood Mononuclear Cells

by Andrea Borghini, Rudina Ndreu, Paola Canale, Jonica Campolo, Irene Marinaro, Antonella Mercuri, Stefano Turchi and Maria Grazia Andreassi

Int. J. Mol. Sci. 2024, 25(3), 1428; https://doi.org/10.3390/ijms25031428 - 24 Jan 2024

Cited by 6 | Viewed by 2729

Abstract

Telomere shortening, chromosomal damage, and mitochondrial dysfunction are major initiators of cell aging and biomarkers of many diseases. However, the underlying correlations between nuclear and mitochondrial DNA alterations remain unclear. We investigated the relationship between telomere length (TL) and micronucleus (MN) and their association with mitochondrial DNA copy number (mtDNAcn) in peripheral blood mononuclear cells (PBMCs) in response to 100 μM and 200 μM of hydrogen peroxide (H₂O₂) at 44, 72, and 96 h. Significant TL shortening was observed after both doses of H₂O₂ and at all times (all p < 0.05). A concomitant increase in MN was found at 72 h (p < 0.01) and persisted at 96 h (p < 0.01). An increase in mtDNAcn (p = 0.04) at 200 µM of H₂O₂ was also found. In PBMCs treated with 200 µM H₂O₂, a significant inverse correlation was found between TL and MN (r = −0.76, p = 0.03), and mtDNA content was directly correlated with TL (r = 0.6, p = 0.04) and inversely related to MN (r = −0.78, p = 0.02). Telomere shortening is the main triggering mechanism of chromosomal damage in stimulated T lymphocytes under oxidative stress. The significant correlations between nuclear DNA damage and mtDNAcn support the notion of a telomere–mitochondria axis that might influence age-associated pathologies and be a target for the development of relevant anti-aging drugs. Full article

(This article belongs to the Special Issue Aging: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches)

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29 pages, 3398 KiB

Open AccessArticle

Risk Polymorphisms of FNDC5, BDNF, and NTRK2 and Poor Education Interact and Aggravate Age-Related Cognitive Decline

by Alessandra Mendonça Tomás, Natáli Valim Oliver Bento-Torres, Naina Yuki Vieira Jardim, Patrícia Martins Moraes, Victor Oliveira da Costa, Antônio Conde Modesto, André Salim Khayat, João Bento-Torres and Cristovam Wanderley Picanço-Diniz

Int. J. Mol. Sci. 2023, 24(24), 17210; https://doi.org/10.3390/ijms242417210 - 7 Dec 2023

Cited by 1 | Viewed by 1539

Abstract

Cognitive abilities tend to decline with aging, with variation between individuals, and many studies seek to identify genetic biomarkers that more accurately anticipate risks related to pathological aging. We investigated the influence of BDNF, NTRK2, and FNDC5 single nucleotide polymorphisms (SNPs) on the cognitive performance of young and older adults with contrasting educational backgrounds. We addressed three questions: (1) Is education associated with reduced age-related cognitive decline? (2) Does the presence of SNPs explain the variation in cognitive performance observed late in life? (3) Is education differentially associated with cognition based on the presence of BDNF, NTRK2, or FNDC5 polymorphisms? We measured the cognitive functions of young and older participants, with lower and higher education, using specific and sensitive tests of the Cambridge Automated Neuropsychological Test Assessment Battery. A three-way ANOVA revealed that SNPs were associated with differential performances in executive functions, episodic memory, sustained attention, mental and motor response speed, and visual recognition memory and that higher educational levels improved the affected cognitive functions. The results revealed that distinct SNPs affect cognition late in life differentially, suggesting their utility as potential biomarkers and emphasizing the importance of cognitive stimulation that advanced education early in life provides. Full article

(This article belongs to the Special Issue Aging: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches)

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Review

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27 pages, 4721 KiB

Open AccessReview

Pharmacotherapeutic Considerations on Telomere Biology: The Positive Effect of Pharmacologically Active Substances on Telomere Length

by Miruna-Maria Apetroaei, Persefoni Fragkiadaki, Bruno Ștefan Velescu, Stella Baliou, Elisavet Renieri, Cristina Elena Dinu-Pirvu, Doina Drăgănescu, Ana Maria Vlăsceanu, Marina Ionela (Ilie) Nedea, Denisa Ioana Udeanu, Anca Oana Docea, Artistidis Tsatsakis and Andreea Letiția Arsene

Int. J. Mol. Sci. 2024, 25(14), 7694; https://doi.org/10.3390/ijms25147694 - 13 Jul 2024

Cited by 7 | Viewed by 3541

Abstract

Telomeres are part of chromatin structures containing repeated DNA sequences, which function as protective caps at the ends of chromosomes and prevent DNA degradation and recombination, thus ensuring the integrity of the genome. While telomere length (TL) can be genetically inherited, TL shortening has been associated with ageing and multiple xenobiotics and bioactive substances. TL has been characterised as a reliable biomarker for the predisposition to developing chronic pathologies and their progression. This narrative review aims to provide arguments in favour of including TL measurements in a complex prognostic and diagnostic panel of chronic pathologies and the importance of assessing the effect of different pharmacologically active molecules on the biology of telomeres. Medicines used in the management of cardiovascular diseases, diabetes, schizophrenia, hormone replacement therapy at menopause, danazol, melatonin, and probiotics have been studied for their positive protective effects against TL shortening. All these classes of drugs are analysed in the present review, with a particular focus on the molecular mechanisms involved. Full article

(This article belongs to the Special Issue Aging: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches)

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12 pages, 281 KiB

Open AccessReview

Platelets and Neurodegenerative Diseases: Current Knowledge and Future Perspectives

by Antonella Gallo, Alice Lipari, Silvino Di Francesco, Eleonora Ianuà, Rosa Liperoti, Maria Camilla Cipriani, Anna Maria Martone, Erica De Candia, Francesco Landi and Massimo Montalto

Int. J. Mol. Sci. 2024, 25(12), 6292; https://doi.org/10.3390/ijms25126292 - 7 Jun 2024

Cited by 2 | Viewed by 1452

Abstract

Platelets have a fundamental role in mediating hemostasis and thrombosis. However, more recently, a new idea is making headway, highlighting the importance of platelets as significant actors in modulating immune and inflammatory responses. In particular, platelets have an important role in the development of vascular amyloid-b-peptide(ab) deposits, known to play a relevant role in Alzheimer’s disease (AD) through accumulation and deposition within the frontal cortex and hippocampus in the brain. The involvement of platelets in the pathogenesis of AD opens up the highly attractive possibility of applying antiplatelet therapy for the treatment and/or prevention of AD, but conclusive results are scarce. Even less is known about the potential role of platelets in mild cognitive impairment (MCI). The aim to this brief review is to summarize current knowledge on this topic and to introduce the new perspectives on the possible role of platelet activation as therapeutic target both in AD and MCI. Full article

(This article belongs to the Special Issue Aging: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches)

28 pages, 816 KiB

Open AccessReview

Genomic Instability and Epigenetic Changes during Aging

by Lucía López-Gil, Amparo Pascual-Ahuir and Markus Proft

Int. J. Mol. Sci. 2023, 24(18), 14279; https://doi.org/10.3390/ijms241814279 - 19 Sep 2023

Cited by 40 | Viewed by 6954

Abstract

Aging is considered the deterioration of physiological functions along with an increased mortality rate. This scientific review focuses on the central importance of genomic instability during the aging process, encompassing a range of cellular and molecular changes that occur with advancing age. In particular, this revision addresses the genetic and epigenetic alterations that contribute to genomic instability, such as telomere shortening, DNA damage accumulation, and decreased DNA repair capacity. Furthermore, the review explores the epigenetic changes that occur with aging, including modifications to histones, DNA methylation patterns, and the role of non-coding RNAs. Finally, the review discusses the organization of chromatin and its contribution to genomic instability, including heterochromatin loss, chromatin remodeling, and changes in nucleosome and histone abundance. In conclusion, this review highlights the fundamental role that genomic instability plays in the aging process and underscores the need for continued research into these complex biological mechanisms. Full article

(This article belongs to the Special Issue Aging: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches)

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