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Molecular Genetics of Aging: Current State-of-the-Art, Challenges and Opportunities
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Molecular Genetics of Aging: Current State-of-the-Art, Challenges and Opportunities

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

Deadline for manuscript submissions: closed (20 July 2023) | Viewed by 17264

Special Issue Editors

Prof. Dr. Darío Acuña-Castroviejo

E-Mail Website
Guest Editor
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
Special Issues, Collections and Topics in MDPI journals
Dr. David Della-Morte

E-Mail Website
Guest Editor
1. Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
2. Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
3. Department of Human Sciences and Quality of Life Promotion, San Raffaele Roma Open University, 00166 Rome, Italy
Interests: neuroprotection; vascular diseases; aging; genetics; epidemiology; metabolic disorders; antioxidants; nutrition in vascular diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

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 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 among the scientific community. Elucidating the genetic mechanisms that underlie aging is essential to mitigating age-related diseases, reducing fragility and promoting a healthy human lifespan.

This Special Issue “Molecular Genetics of Aging: Current State-of-the-Art, Challenges and Opportunities” 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
Dr. David Della-Morte
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

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

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Published Papers (5 papers)

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Research

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14 pages, 5573 KiB  
Article
Biochemical Targets and Molecular Mechanism of Matrine against Aging
by Kaiyue Sun, Yingzi Zhang, Yingliang Li, Pengyu Yang and Yingting Sun
Int. J. Mol. Sci. 2023, 24(12), 10098; https://doi.org/10.3390/ijms241210098 - 14 Jun 2023
Cited by 2 | Viewed by 1747
Abstract
The aim of this study is to explore the potential targets and molecular mechanism of matrine (MAT) against aging. Bioinformatic-based network pharmacology was used to investigate the aging-related targets and MAT-treated targets. A total of 193 potential genes of MAT against aging were [...] Read more.
The aim of this study is to explore the potential targets and molecular mechanism of matrine (MAT) against aging. Bioinformatic-based network pharmacology was used to investigate the aging-related targets and MAT-treated targets. A total of 193 potential genes of MAT against aging were obtained and then the top 10 key genes (cyclin D1, cyclin-dependent kinase 1, Cyclin A2, androgen receptor, Poly [ADP-ribose] polymerase-1 (PARP1), histone-lysine N-methyltransferase, albumin, mammalian target of rapamycin, histone deacetylase 2, and matrix metalloproteinase 9) were filtered by the molecular complex detection, maximal clique centrality (MMC) algorithm, and degree. The Metascape tool was used for analyzing biological processes and pathways of the top 10 key genes. The main biological processes were response to an inorganic substance and cellular response to chemical stress (including cellular response to oxidative stress). The major pathways were involved in cellular senescence and the cell cycle. After an analysis of major biological processes and pathways, it appears that PARP1/nicotinamide adenine dinucleotide (NAD+)-mediated cellular senescence may play an important role in MAT against aging. Molecular docking, molecular dynamics simulation, and in vivo study were used for further investigation. MAT could interact with the cavity of the PARP1 protein with the binding energy at −8.5 kcal/mol. Results from molecular dynamics simulations showed that the PARP1-MAT complex was more stable than PARP1 alone and that the binding-free energy of the PARP1-MAT complex was −15.962 kcal/mol. The in vivo study showed that MAT could significantly increase the NAD+ level of the liver of d-gal-induced aging mice. Therefore, MAT could interfere with aging through the PARP1/NAD+-mediated cellular senescence signaling pathway. Full article
(This article belongs to the Special Issue Molecular Genetics of Aging: Current State-of-the-Art, Challenges and Opportunities)
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11 pages, 2117 KiB  
Article
Leukocyte Telomere Length Predicts Severe Disability in Relapsing-Remitting Multiple Sclerosis and Correlates with Mitochondrial DNA Copy Number
by Gabriela del Carmen López-Armas, Martha Eloisa Ramos-Márquez, Mónica Navarro-Meza, Miguel Ángel Macías-Islas, Ana Miriam Saldaña-Cruz, Abraham Zepeda-Moreno, Fernando Siller-López and José Alfonso Cruz-Ramos
Int. J. Mol. Sci. 2023, 24(2), 916; https://doi.org/10.3390/ijms24020916 - 4 Jan 2023
Cited by 4 | Viewed by 2011
Abstract
Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease that affects the nervous system. Peripheral blood leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNA-CN) are potential biomarkers of neurological disability and neural damage. Our objective was to assess the LTL and [...] Read more.
Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease that affects the nervous system. Peripheral blood leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNA-CN) are potential biomarkers of neurological disability and neural damage. Our objective was to assess the LTL and mtDNA-CN in relapsing-remitting MS (RRMS). We included 10 healthy controls, 75 patients with RRMS, 50 of whom had an Expanded Disability Status Scale (EDSS) from 0 to 3 (mild to moderate disability), and 25 had an EDSS of 3.5 to 7 (severe disability). We use the Real-Time Polymerase Chain Reaction (qPCR) technique to quantify absolute LTL and absolute mtDNA-CN. ANOVA test show differences between healthy control vs. severe disability RRMS and mild-moderate RRMS vs. severe disability RRMS (p = 0.0130). LTL and mtDNA-CN showed a linear correlation in mild-moderate disability RRMS (r = 0.378, p = 0.007). Furthermore, we analyzed LTL between RRMS groups with a ROC curve, and LTL can predict severe disability (AUC = 0.702, p = 0.0018, cut-off < 3.0875 Kb, sensitivity = 75%, specificity = 62%), whereas the prediction is improved with a logistic regression model including LTL plus age (AUC = 0.762, p = 0.0001, sensitivity = 79.17%, specificity = 80%). These results show that LTL is a biomarker of disability in RRMS and is correlated with mtDNA-CN in mild-moderate RRMS patients. Full article
(This article belongs to the Special Issue Molecular Genetics of Aging: Current State-of-the-Art, Challenges and Opportunities)
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17 pages, 330 KiB  
Communication
Alu Deletions in LAMA2 and CDH4 Genes Are Key Components of Polygenic Predictors of Longevity
by Vera V. Erdman, Denis D. Karimov, Ilsia A. Tuktarova, Yanina R. Timasheva, Timur R. Nasibullin and Gulnaz F. Korytina
Int. J. Mol. Sci. 2022, 23(21), 13492; https://doi.org/10.3390/ijms232113492 - 4 Nov 2022
Cited by 1 | Viewed by 2032
Abstract
Longevity is a unique human phenomenon and a highly stable trait, characterized by polygenicity. The longevity phenotype occurs due to the ability to successfully withstand the age-related genomic instability triggered by Alu elements. The purpose of our cross-sectional study was to evaluate the [...] Read more.
Longevity is a unique human phenomenon and a highly stable trait, characterized by polygenicity. The longevity phenotype occurs due to the ability to successfully withstand the age-related genomic instability triggered by Alu elements. The purpose of our cross-sectional study was to evaluate the combined contribution of ACE*Ya5ACE, CDH4*Yb8NBC516, COL13A1*Ya5ac1986, HECW1*Ya5NBC182, LAMA2*Ya5-MLS19, PLAT*TPA25, PKHD1L1*Yb8AC702, SEMA6A*Yb8NBC597, STK38L*Ya5ac2145 and TEAD1*Ya5ac2013 Alu elements to longevity. The study group included 2054 unrelated individuals aged from 18 to 113 years who are ethnic Tatars from Russia. We analyzed the dynamics of the allele and genotype frequencies of the studied Alu polymorphic loci in the age groups of young (18–44 years old), middle-aged (45–59 years old), elderly (60–74 years old), old seniors (75–89 years old) and long-livers (90–113 years old). Most significant changes in allele and genotype frequencies were observed between the long-livers and other groups. The search for polygenic predictors of longevity was performed using the APSampler program. Attaining longevity was associated with the combinations LAMA2*ID + CDH4*D (OR = 2.23, PBonf = 1.90 × 10−2) and CDH4*DD + LAMA2*ID + HECW1*D (OR = 4.58, PBonf = 9.00 × 10−3) among persons aged between 18 and 89 years, LAMA2*ID + CDH4*D + SEMA6A*I for individuals below 75 years of age (OR = 3.13, PBonf = 2.00 × 10−2), LAMA2*ID + HECW1*I for elderly people aged 60 and older (OR = 3.13, PBonf = 2.00 × 10−2) and CDH4*DD + LAMA2*D + HECW1*D (OR = 4.21, PBonf = 2.60 × 10−2) and CDH4*DD + LAMA2*D + ACE*I (OR = 3.68, PBonf = 1.90 × 10−2) among old seniors (75–89 years old). The key elements of combinations associated with longevity were the deletion alleles of CDH4 and LAMA2 genes. Our results point to the significance for human longevity of the Alu polymorphic loci in CDH4, LAMA2, HECW1, SEMA6A and ACE genes, involved in the integration systems. Full article
(This article belongs to the Special Issue Molecular Genetics of Aging: Current State-of-the-Art, Challenges and Opportunities)
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20 pages, 4622 KiB  
Article
Age and Chronodisruption in Mouse Heart: Effect of the NLRP3 Inflammasome and Melatonin Therapy
by Marisol Fernández-Ortiz, Ramy K. A. Sayed, Yolanda Román-Montoya, María Ángeles Rol de Lama, José Fernández-Martínez, Yolanda Ramírez-Casas, Javier Florido-Ruiz, Iryna Rusanova, Germaine Escames and Darío Acuña-Castroviejo
Int. J. Mol. Sci. 2022, 23(12), 6846; https://doi.org/10.3390/ijms23126846 - 20 Jun 2022
Cited by 9 | Viewed by 3897
Abstract
Age and age-dependent inflammation are two main risk factors for cardiovascular diseases. Aging can also affect clock gene-related impairments such as chronodisruption and has been linked to a decline in melatonin synthesis and aggravation of the NF-κB/NLRP3 innate immune response known as inflammaging. [...] Read more.
Age and age-dependent inflammation are two main risk factors for cardiovascular diseases. Aging can also affect clock gene-related impairments such as chronodisruption and has been linked to a decline in melatonin synthesis and aggravation of the NF-κB/NLRP3 innate immune response known as inflammaging. The molecular drivers of these mechanisms remain unknown. This study investigated the impact of aging and NLRP3 expression on the cardiac circadian system, and the actions of melatonin as a potential therapy to restore daily rhythms by mitigating inflammaging. We analyzed the circadian expression and rhythmicity of clock genes in heart tissue of wild-type and NLRP3-knockout mice at 3, 12, and 24 months of age, with and without melatonin treatment. Our results support that aging, NLRP3 inflammasome, and melatonin affected the cardiac clock genes expression, except for Rev-erbα, which was not influenced by genotype. Aging caused small phase changes in Clock, loss of rhythmicity in Per2 and Rorα, and mesor dampening of Clock, Bmal1, and Per2. NLRP3 inflammasome influenced the acrophase of Clock, Per2, and Rorα. Melatonin restored the acrophase and the rhythm of clock genes affected by age or NLRP3 activation. The administration of melatonin re-established murine cardiac homeostasis by reversing age-associated chronodisruption. Altogether, these results highlight new findings about the effects aging and NLRP3 inflammasome have on clock genes in cardiac tissue, pointing to continuous melatonin as a promising therapy to placate inflammaging and restore circadian rhythm in heart muscle. Additionally, light microscopy analysis showed age-related morphological impairments in cardiomyocytes, which were less severe in mice lacking NLRP3. Melatonin supplementation preserved the structure of cardiac muscle fibers in all experimental groups. Full article
(This article belongs to the Special Issue Molecular Genetics of Aging: Current State-of-the-Art, Challenges and Opportunities)
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Review

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24 pages, 749 KiB  
Review
Inflammaging: Implications in Sarcopenia
by Eduardo Antuña, Cristina Cachán-Vega, Juan Carlos Bermejo-Millo, Yaiza Potes, Beatriz Caballero, Ignacio Vega-Naredo, Ana Coto-Montes and Claudia Garcia-Gonzalez
Int. J. Mol. Sci. 2022, 23(23), 15039; https://doi.org/10.3390/ijms232315039 - 30 Nov 2022
Cited by 67 | Viewed by 6355
Abstract
In a world in which life expectancy is increasing, understanding and promoting healthy aging becomes a contemporary demand. In the elderly, a sterile, chronic and low-grade systemic inflammation known as “inflammaging” is linked with many age-associated diseases. Considering sarcopenia as a loss of [...] Read more.
In a world in which life expectancy is increasing, understanding and promoting healthy aging becomes a contemporary demand. In the elderly, a sterile, chronic and low-grade systemic inflammation known as “inflammaging” is linked with many age-associated diseases. Considering sarcopenia as a loss of strength and mass of skeletal muscle related to aging, correlations between these two terms have been proposed. Better knowledge of the immune system players in skeletal muscle would help to elucidate their implications in sarcopenia. Characterizing the activators of damage sensors and the downstream effectors explains the inference with skeletal muscle performance. Sarcopenia has also been linked to chronic diseases such as diabetes, metabolic syndrome and obesity. Implications of inflammatory signals from these diseases negatively affect skeletal muscle. Autophagic mechanisms are closely related with the inflammasome, as autophagy eliminates stress signaling sent by damage organelles, but also acts with an immunomodulatory function affecting immune cells and cytokine release. The use of melatonin, an antioxidant, ROS scavenger and immune and autophagy modulator, or senotherapeutic compounds targeting senescent cells could represent strategies to counteract inflammation. This review aims to present the many factors regulating skeletal muscle inflammaging and their major implications in order to understand the molecular mechanisms involved in sarcopenia. Full article
(This article belongs to the Special Issue Molecular Genetics of Aging: Current State-of-the-Art, Challenges and Opportunities)
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