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Molecular Biology of Senescence and Anti-Aging Strategies
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Molecular Biology of Senescence and Anti-Aging Strategies

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 July 2025) | Viewed by 9114

Special Issue Editors

Dr. Nicola Alessio

E-Mail Website
Guest Editor
Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
Interests: stem cells; cell therapy; secretome; extracellular-vesicle; exosomes; differentiation; inflammation; diseases
Special Issues, Collections and Topics in MDPI journals
Dr. James T. Arnone

E-Mail Website
Guest Editor
Department of Biological and Environmental Sciences, Le Moyne College, Syracuse, NY 13214, USA
Interests: gene expression; genetics; genomics; aging; biochemistry; molecular biology; fungi
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Senescence, a natural aging process, is a complex interplay of genetic, epigenetic, and environmental factors. To counteract its effects, researchers are exploring innovative anti-aging strategies. Genetic interventions, including the manipulation of longevity-associated genes, show promise in enhancing cellular repair mechanisms. Caloric restriction and nutrient sensing, proven to extend lifespan in various organisms, are under scrutiny for their impact on aging pathways. Senolytic and senomorphic drugs aim to eliminate or modify senescent cells, potentially delaying the progression of age-related diseases. Telomere maintenance strategies, focused on preserving chromosomal integrity, also offer avenues for combating cellular senescence and promoting healthier aging.

IJMS sets up this Special Issue, focusing on the current understanding and future research directions regarding the molecular mechanisms of senescence and anti-aging strategies. We welcome original research articles and review articles relating to this hot topic.

Dr. Nicola Alessio
Dr. James T. Arnone
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

  • cellular senescence
  • aging
  • delaying senescence
  • aging-associated diseases

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Published Papers (5 papers)

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Research

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12 pages, 863 KB  
Article
Hyaluronic and Succinic Acid: New Biostimulating Combination to Counteract Dermal and Subcutaneous Aging
by Alfredo Martinez-Gutierrez, Helena Cami, Teresa Noya, Susana Gómez-Escalante, Aina Miró Llosas and Mari Carmen González
Int. J. Mol. Sci. 2025, 26(15), 7548; https://doi.org/10.3390/ijms26157548 - 5 Aug 2025
Viewed by 1812
Abstract
Various biomaterials are currently employed for dermal biostimulation and filling purposes, with hyaluronic acid (HA)-based fillers among those with the most favorable safety profile, albeit exhibiting a limited biostimulatory effect. This study suggests that hyaluronic acid and succinic acid (SA) can significantly induce [...] Read more.
Various biomaterials are currently employed for dermal biostimulation and filling purposes, with hyaluronic acid (HA)-based fillers among those with the most favorable safety profile, albeit exhibiting a limited biostimulatory effect. This study suggests that hyaluronic acid and succinic acid (SA) can significantly induce beneficial effects on skin cells by targeting key aging hallmarks. Human dermal senescent fibroblasts and aged adipocytes were treated with HA + SA, and various aging characteristics were examined through gene expression analysis and microscopy staining. HA was found to stimulate autophagy gene expression, while SA modulated senescence-gene expression, and the combination of these compounds induced mitophagy in senescent fibroblasts. Additionally, the HA + SA promoted adipogenesis, increased IGF1, and decreased TNFA gene expression in aged adipocytes. Furthermore, the conditioned medium from adipocytes treated with HA + SA upregulated key dermal genes such as COL3A1 and EGF. The findings of this study suggest that HA and SA compounds can be used for the biostimulation of aged skin through the regulation of senescence-associated gene expression and cell communication between dermal fibroblasts and subcutaneous adipocytes. Full article
(This article belongs to the Special Issue Molecular Biology of Senescence and Anti-Aging Strategies)
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14 pages, 2063 KB  
Article
Effects of PACAP Deficiency on Immune Dysfunction and Peyer’s Patch Integrity in Adult Mice
by Jason Sparks, Matyas Meggyes, Lilla Makszin, Viktoria Jehn, Hedvig Lugosi, Dora Reglodi and Laszlo Szereday
Int. J. Mol. Sci. 2024, 25(19), 10676; https://doi.org/10.3390/ijms251910676 - 3 Oct 2024
Cited by 1 | Viewed by 1975
Abstract
PACAP (pituitary adenylate cyclase activating polypeptide) is a widespread neuropeptide with cytoprotective and anti-inflammatory effects. It plays a role in innate and adaptive immunity, but data are limited about gut-associated lymphoid tissue. We aimed to reveal differences in Peyer’s patches between wild-type (WT) [...] Read more.
PACAP (pituitary adenylate cyclase activating polypeptide) is a widespread neuropeptide with cytoprotective and anti-inflammatory effects. It plays a role in innate and adaptive immunity, but data are limited about gut-associated lymphoid tissue. We aimed to reveal differences in Peyer’s patches between wild-type (WT) and PACAP-deficient (KO) mice. Peyer’s patch morphology from young (3-months-old) and aging (12–15-months-old) mice was examined, along with flow cytometry to assess immune cell populations, expression of checkpoint molecules (PD-1, PD-L1, TIM-3, Gal-9) and functional markers (CD69, granzyme B, perforin) in CD3+, CD4+, and CD8+ T cells. We found slight differences between aging, but not in young, WT, and KO mice. In WT mice, aging reduced CD8+ T cell numbers frequency and altered checkpoint molecule expression (higher TIM-3, granzyme B; lower Gal-9, CD69). CD4+ T cell frequency was higher with similar checkpoint alterations, indicating a regulatory shift. In PACAP KO mice, aging did not change cell population frequencies but led to higher TIM-3, granzyme B and lower PD-1, PD-L1, Gal-9, and CD69 expression in CD4+ and CD8+ T cells, with reduced overall T cell activity. Thus, PACAP deficiency impacts immune dysfunction by altering checkpoint molecules and T cell functionality, particularly in CD8+ T cells, suggesting complex immune responses by PACAP, highlighting its role in intestinal homeostasis and potential implications for inflammatory bowel diseases. Full article
(This article belongs to the Special Issue Molecular Biology of Senescence and Anti-Aging Strategies)
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Review

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59 pages, 1977 KB  
Review
Heterogeneity of Cellular Senescence, Senotyping, and Targeting by Senolytics and Senomorphics in Lung Diseases
by Said Ali Ozdemir, Md Imam Faizan, Gagandeep Kaur, Sadiya Bi Shaikh, Khursheed Ul Islam and Irfan Rahman
Int. J. Mol. Sci. 2025, 26(19), 9687; https://doi.org/10.3390/ijms26199687 - 4 Oct 2025
Viewed by 497
Abstract
Cellular senescence, a state of stable cell cycle arrest accompanied by a complex senescence-associated secretory phenotype (SASP), is a fundamental biological process implicated as a key driver of lung aging and lung age-related diseases (LARDs). This review provides a comprehensive overview of the [...] Read more.
Cellular senescence, a state of stable cell cycle arrest accompanied by a complex senescence-associated secretory phenotype (SASP), is a fundamental biological process implicated as a key driver of lung aging and lung age-related diseases (LARDs). This review provides a comprehensive overview of the rapidly evolving field of senotyping based on cellular heterogeneity in lung development and aging in health and disease. It also delves into the molecular mechanisms driving senescence and SASP production, highlighting pathways such as p53/p21, p16INK4a/RB, mTOR, and p38 MAPK as therapeutic targets. The involvement of various novel SASP proteins, such as GDP15, cytokines/chemokines, growth factors, and DNA damage response proteins. We further highlight the effectiveness of senotherapeutics in mitigating the detrimental effects of senescent cell (SnC) accumulation within the lungs. It also outlines two main therapeutic approaches: senolytics, which selectively trigger apoptosis in SnCs, and senomorphics (also known as senostatics), which mitigate the detrimental effects of the SASP without necessarily removing the senescent cells. Various classes of senolytic and senomorphic drugs are currently in clinical trials including natural products (e.g., quercetin, fisetin, resveratrol) and repurposed drugs (e.g., dasatinib, navitoclax, metformin, rapamycin) that has demonstrated therapeutic promise in improving tissue function, alleviating LARDs, and extending health span. We discuss the future of these strategies in lung research and further elaborate upon the usability of novel approaches including HSP90 inhibitors, senolytic CAR-T cells, Antibody drug conjugate and galactose-modified prodrugs in influencing the field of personalized medicine in future. Overall, this comprehensive review highlights the progress made so far and the challenges faced in the field of cellular senescence including SnC heterogeneity, states of senescence, senotyping, immunosenescence, drug delivery, target specificity, long-term safety, and the need for robust cell-based biomarkers. Future perspectives, such as advanced delivery systems, and combination therapies, are considered critical for translating the potential of senotherapeutics into effective clinical applications for age-related pulmonary diseases/conditions. Full article
(This article belongs to the Special Issue Molecular Biology of Senescence and Anti-Aging Strategies)
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35 pages, 1184 KB  
Review
Which Approach to Choose to Counteract Musculoskeletal Aging? A Comprehensive Review on the Multiple Effects of Exercise
by Angela Falvino, Roberto Bonanni, Umberto Tarantino, Virginia Tancredi and Ida Cariati
Int. J. Mol. Sci. 2025, 26(15), 7573; https://doi.org/10.3390/ijms26157573 - 5 Aug 2025
Cited by 4 | Viewed by 1974
Abstract
Aging is a complex physiological process that profoundly affects the functionality of the musculoskeletal system, contributing to an increase in the incidence of diseases such as osteoporosis, osteoarthritis, and sarcopenia. Cellular senescence plays a crucial role in these degenerative processes, promoting chronic inflammation [...] Read more.
Aging is a complex physiological process that profoundly affects the functionality of the musculoskeletal system, contributing to an increase in the incidence of diseases such as osteoporosis, osteoarthritis, and sarcopenia. Cellular senescence plays a crucial role in these degenerative processes, promoting chronic inflammation and tissue dysfunction through the senescence-associated secretory phenotype (SASP). Recently, senotherapeutics have shown promising results in improving musculoskeletal health. Natural compounds such as resveratrol, rapamycin, quercetin, curcumin, vitamin E, genistein, fisetin, and epicatechin act on key signaling pathways, offering protective effects against musculoskeletal decline. On the other hand, molecules such as dasatinib, navitoclax, UBX0101, panobinostat, and metformin have been shown to be effective in eliminating or modulating senescent cells. However, understanding the mechanisms of action, long-term safety, and bioavailability remain areas for further investigation. In this context, physical exercise emerges as an effective non-pharmacological countermeasure, capable of directly modulating cellular senescence and promoting tissue regeneration, representing an integrated strategy to combat age-related diseases. Therefore, we have provided an overview of the main anti-aging compounds and examined the potential of physical exercise as a strategy in the management of age-related musculoskeletal disorders. Further studies should focus on identifying synergistic combinations of pharmacological and non-pharmacological interventions to optimize the effectiveness of anti-aging strategies and promoting healthier musculoskeletal aging. Full article
(This article belongs to the Special Issue Molecular Biology of Senescence and Anti-Aging Strategies)
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14 pages, 753 KB  
Review
Potential Role of Inflammasomes in Aging
by Gilyoung Lee and Geun-Shik Lee
Int. J. Mol. Sci. 2025, 26(14), 6768; https://doi.org/10.3390/ijms26146768 - 15 Jul 2025
Viewed by 1880
Abstract
The aging process is associated with the emergence of low-grade, sterile inflammation, called inflammaging, which can accelerate aging-related diseases, such as neurodegenerative, cardiovascular, and musculoskeletal diseases. Recent studies have focused on the novel concept that inflammasomes represent a key innate immune pathway, mechanistically [...] Read more.
The aging process is associated with the emergence of low-grade, sterile inflammation, called inflammaging, which can accelerate aging-related diseases, such as neurodegenerative, cardiovascular, and musculoskeletal diseases. Recent studies have focused on the novel concept that inflammasomes represent a key innate immune pathway, mechanistically participating in aging-induced stress recognition. This review summarizes the advancements in inflammasome research related to aging. Particular attention is given to the close relationship between aging and inflammasomes and how these processes impact the health of the elderly. Inflammaging has various causes, such as metabolic disorders, changes in the gut microbiota, and immunosenescence. Hence, the connection between inflammasomes and these causes must be explored. This paper describes inflammasomes as a significant contributing factor among the mechanisms that make individuals susceptible to aging-related diseases and discusses the potential role of inflammasome regulation in effectively counteracting aging. Full article
(This article belongs to the Special Issue Molecular Biology of Senescence and Anti-Aging Strategies)
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