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Advances in Age-Related Diseases: Molecular Mechanisms, Treatments, and Clinical Implications

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 December 2025) | Viewed by 17516

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Special Issue Editors

Dr. Stefano Cacciatore

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1. Department of Geriatrics, Orthopedics and Rheumatology, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, Italy
2. Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy
Interests: sarcopenia; nutrition; body composition; frailty; healthy aging; cardiovascular disease
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Dr. Emanuele Marzetti

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Department of Geriatrics, Orthopedics and Rheumatology, Catholic University of the Sacred Heart, 00168 Rome, Italy
Interests: neurodegeneration; exercise science; strength & conditioning; muscle physiology; muscle function; inflammation; exercise physiology; exercise performance; sports science; cell biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Aging is a multifactorial biological process that drives increased susceptibility to chronic diseases, including neurodegenerative disorders, cardiometabolic disease, and musculoskeletal impairments. Advances in molecular biology, omics sciences, and translational medicine have uncovered key hallmarks of aging, such as genomic instability, mitochondrial dysfunction, cellular senescence, and dysregulated proteostasis. These discoveries provide crucial insights into the pathogenesis of age-related diseases and pave the way for innovative therapeutic approaches, including senolytics, stem cell therapies, and gene editing. However, while biomedical interventions hold promise, aging is influenced by a complex interplay of genetic, environmental, and lifestyle factors. Translating scientific advancements into impactful clinical and public health strategies presents a unique opportunity to develop targeted prevention and treatment approaches. Furthermore, a deeper exploration of how pharmacological and non-pharmacological interventions shape aging processes is essential for extending healthspan and improving quality of life.

We are pleased to invite you to contribute to this Special Issue, "Advances in Age-Related Diseases: Molecular Mechanisms, Treatments, and Clinical Implications", which aims to explore recent progress in the field, focusing on molecular pathways of aging, biomarkers for early disease detection, novel pharmacological and non-pharmacological interventions, and the clinical impact of emerging therapies.

We welcome original research articles and reviews on (but not limited to) the following themes:

Cellular senescence and inflammation in aging;
Oxidative stress and mitochondrial dysfunction;
Genetic and epigenetic regulation of age-related diseases;
Precision medicine and biomarkers for aging-related conditions;
Pharmacological interventions and repurposing strategies;
Translational and clinical research in geriatric medicine.

We look forward to receiving your contributions.

Dr. Stefano Cacciatore
Dr. Emanuele Marzetti
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 250 words) can be sent to the Editorial Office for assessment.

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. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). 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
age-related diseases
cellular senescence
mitochondrial dysfunction
inflammation and oxidative stress
biomarkers
precision medicine
pharmacological interventions
healthy aging
translational geriatric research

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Published Papers (8 papers)

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Research

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22 pages, 12907 KB

Open AccessArticle

Empagliflozin Alleviates Osteoarthritis Progression by Attenuating Inflammation, Restoring Impaired Autophagy, and Ameliorating Chondrocyte Senescence

by Junhong Li, Guihua Yu, Shiheng Wang, Zekai Zhang, Yu Wen, Luting Yu, Xin Gan, Hao Kang, Jinming Zhang and Lu He

Biomedicines 2026, 14(4), 828; https://doi.org/10.3390/biomedicines14040828 - 5 Apr 2026

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Abstract

Background: Osteoarthritis (OA) is a multifactorial disease, including inflammation, autophagy and senescence. Published work has indicated that empagliflozin (EMP) exhibits robust anti-inflammatory and anti-senescence effects, while its role in autophagy appears paradoxical. Here, we aim to identify the chondroprotective effect of EMP on OA. Methods: An OA model was established both in vitro, by stimulating primary chondrocytes (isolated from C57BL/6J mice) with IL-1β, and in vivo, by performing (Destabilized medial meniscus) DMM surgery on C57BL/6J mice. (Western blot) WB and (quantitative real-time polymerase chain reaction) qRT-PCR analysis were employed to detect the gene expression. (Immunofluorescence) IF staining was employed to detect the expression and location of target protein. SA-β-gal staining was employed to evaluate cellular senescence. Autophagic flux was assessed using a GFP-RFP-LC3 adenoviral vector. Network pharmacology was applied to identify potential pathways for experimental validation. The effects of EMP in vivo were evaluated by μ-CT, histological and (Immunohistochemistry) IHC staining. Results: EMP promoted anabolism, inhibited the inflammatory response and catabolism in IL-1β stimulated chondrocytes. EMP enhanced autophagic activity and attenuated senescent phenotype in vitro. Mechanistically, EMP regulated the PI3K/Akt/mTOR and AMPK pathways. The chondroprotective effects of EMP were reversed by (3-methyladenine) 3-MA. EMP also ameliorated OA-related phenotype in DMM models. Compared with (Kartogenin) KGN, EMP showed more pronounced suppression of inflammatory and catabolic markers, while both compounds similarly promoted anabolic marker expression. Conclusions: These in vitro and in vivo data collectively indicates that EMP can alleviate OA both in IL-1β stimulated chondrocytes and DMM induced models. Beyond its established role in diabetes management, EMP is evaluated in the context of OA, emerging as a novel and promising therapeutic agent for OA. Full article

(This article belongs to the Special Issue Advances in Age-Related Diseases: Molecular Mechanisms, Treatments, and Clinical Implications)

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15 pages, 494 KB

Open AccessArticle

Flexible Loading Phase Treat-and-Extend Regimen with Faricimab for Neovascular Age-Related Macular Degeneration: A Real-World Study

by Akira Machida, Junko Kurihara, Yuki Hirata, Eriko Machida, Ryuya Murakami, Akari Oka, Ai Yoneda, Eiko Tsuiki and Akio Oishi

Biomedicines 2025, 13(12), 2909; https://doi.org/10.3390/biomedicines13122909 - 27 Nov 2025

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Abstract

Background/Objectives: We aimed to evaluate the efficacy of a flexible loading-phase treat-and-extend regimen using faricimab, in which the number of loading-phase intravitreal injections was tailored to individual disease activity. Methods: This observational cohort study included 50 treatment-naïve eyes with neovascular age-related macular degeneration, treated with faricimab in Japan; approximately half of the eyes had polypoidal choroidal vasculopathy (PCV). Disease activity after one injection was assessed at the second visit (4 weeks later) to determine the treatment interval for subsequent injections. The primary outcome measure was the injection interval and visual/anatomical outcomes at 1 year after treatment initiation. Results: Of the 50 eyes, 43 completed a 1-year follow-up, including 27 eyes with PCV. The mean logarithm of the minimum angle of resolution best-corrected visual acuity improved from 0.35 ± 0.32 to 0.19 ± 0.3 over 1 year. Overall, 60.5% achieved 16-week intervals, and 74.4% reached intervals of ≥12 weeks. A shorter loading phase (two or three injections) was associated with fewer total injections and higher rates of fluid resolution, without compromising visual outcomes. The presence of PCV and ellipsoid zone disruption were identified as risk factors for failure to extend treatment intervals beyond 16 weeks. Conclusions: A flexible loading-phase treat-and-extend regimen using faricimab yields outcomes comparable to those of the TENAYA protocol, with fewer injections, despite the high proportion of eyes with PCV. This simple approach is straightforward in design and may reduce treatment burden while maintaining efficacy. Full article

(This article belongs to the Special Issue Advances in Age-Related Diseases: Molecular Mechanisms, Treatments, and Clinical Implications)

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19 pages, 3416 KB

Open AccessCommunication

Distinctive Gene Expression Profiles and Biological Responses of Skin Fibroblasts to Nicotinamide Mononucleotide: Implications for Longevity Effects on Skin

by Seongsu Kang, Jiwon Park, Eunbyul Cho, Dohyun Kim, Sanghyun Ye, Eui Taek Jeong, Seung-Hyun Jun and Nae-Gyu Kang

Biomedicines 2025, 13(10), 2395; https://doi.org/10.3390/biomedicines13102395 - 29 Sep 2025

Cited by 3 | Viewed by 5640

Abstract

Background/Objectives: Enhancement of cellular NAD⁺ mediated by NMN has emerged as a pivotal strategy in modulating the aging process. This study aimed to systematically investigate the anti-aging effects of NMN on human skin fibroblasts, focusing on how the former contributes to the improvement of cellular health and function. This study elucidated the molecular and functional mechanisms by which NMN contributes to the attenuation of skin aging. Methods: We performed extensive in vitro and transcriptomic analyses. Human skin fibroblasts were treated with NMN, and the induced biological responses were observed under oxidative stress/photo-aging models. Results: Transcriptome analysis revealed distinct gene expression patterns for NAD⁺ and its precursors (NMN, NR, and NAM), showing significant differences between NMN and other precursors (NR and NMN). NMN seemed to be significantly involved in cytokine and chemokine activity. It significantly elevated cellular NAD⁺ levels, activated sirtuin and autophagy pathways, and enhanced mitochondrial function, collectively maintaining cellular homeostasis under stress. Furthermore, it suppressed cellular senescence, promoted cell proliferation, supported extracellular matrix integrity, and accelerated wound healing. Conclusions: The study provided essential mechanistic evidence supporting the anti-aging effects of NMN in skin cells and addressed the current lack of scientific validation of NMN-based topical applications. The findings established a solid academic background for future translational research and the development of NMN-based therapeutics and cosmeceuticals. Full article

(This article belongs to the Special Issue Advances in Age-Related Diseases: Molecular Mechanisms, Treatments, and Clinical Implications)

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Review

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16 pages, 1619 KB

Open AccessReview

The Gut–Muscle Axis in Sarcopenia: Mechanisms, Evidence Gaps and Translational Challenges

by Stefano Andrea Marchitto, Gabriele Abbatecola, Rola S. Zeidan, Lauren Morgan, Riccardo Calvani, Anna Picca, Mathias Schlögl, Matteo Tosato, Christiaan Leeuwenburgh, Stephen D. Anton, Francesco Landi, Emanuele Marzetti and Stefano Cacciatore

Biomedicines 2026, 14(5), 976; https://doi.org/10.3390/biomedicines14050976 - 23 Apr 2026

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Abstract

Sarcopenia is an age-related skeletal muscle disorder characterized by reduced muscle mass, strength, and physical performance, as well as increased risk of disability, hospitalization, and mortality. Emerging evidence suggests that gut microbiota alterations may contribute to muscle decline via a microbiota–gut–muscle axis, acting as a context-dependent modulator rather than a primary causal driver. This narrative review synthesizes mechanistic, clinical, and translational evidence linking gut dysbiosis to sarcopenia. Preclinical studies show that microbiota modulation (e.g., antibiotics, probiotics, prebiotics, postbiotics, fecal microbiota transplantation) affects muscle mass, strength, and metabolism through pathways including inflammation, mitochondrial dysfunction, altered short-chain fatty acid production, and impaired anabolic signaling. In humans, observational studies associate lower microbial diversity and reduced short-chain fatty acid-producing taxa with poorer muscle outcomes, but findings are heterogeneous and non-causal. Interventional trials remain limited and characterized by small sample sizes, with effects more consistent for functional outcomes than muscle mass. Overall, the gut microbiota represents a modifiable contributor within the complex biology of sarcopenia. Future studies should integrate microbiome profiling and multi-omics approaches within well-designed clinical trials to identify responder phenotypes and define the role of microbiota-targeted strategies within multimodal interventions. Full article

(This article belongs to the Special Issue Advances in Age-Related Diseases: Molecular Mechanisms, Treatments, and Clinical Implications)

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48 pages, 6786 KB

Open AccessReview

Mechanistic Links Between the Gut Microbiome and Longevity Therapeutics

by Noelia Garzon-Escamilla, Miriam Medina-Cardena, Preeti Roy, Jessica Trent, Joud Jamous, Yalini Somesan and Sandy J. Denslow

Biomedicines 2026, 14(2), 316; https://doi.org/10.3390/biomedicines14020316 - 30 Jan 2026

Cited by 1 | Viewed by 2659

Abstract

Aging is a multifactorial biological process marked by the progressive decline in cellular and physiological functions, increasing susceptibility to chronic diseases and mortality. Recent research has identified the gut microbiome as a key modulator of aging, influencing immune regulation, metabolic homeostasis, and neuroendocrine signaling. A diverse and balanced gut microbiota promotes healthspan by supporting gut barrier integrity, nutrient metabolism, and anti-inflammatory responses, whereas dysbiosis contributes to the onset and progression of age-related diseases, including neurodegeneration, cardiovascular conditions, cancer, and metabolic disorders. Currently, anti-aging interventions targeting key aging pathways, such as insulin/IGF-1 signaling, mTOR, AMPK, and sirtuins, are a major focus in the field of geroscience. Compounds such as metformin, rapamycin, anti-inflammatories, GLP-1 agonists, senolytics, spermidine, SGLT2 inhibitors, and sirtuin activators have shown lifespan extension in animal models. In humans, some of these interventions are associated with improvements in healthspan-related outcomes, including metabolic, cardiovascular, musculoskeletal, respiratory, cognitive and ocular functions. Notably, the gut microbiome may serve as both a mediator and modulator of these interventions, influencing drug metabolism, efficacy, and host responses. This review synthesizes current evidence on the gut microbiome’s role in aging, examining its role as both mediator and modulator of longevity interventions and how microbiome-associated mechanisms intersect with emerging anti-aging therapeutics. Full article

(This article belongs to the Special Issue Advances in Age-Related Diseases: Molecular Mechanisms, Treatments, and Clinical Implications)

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24 pages, 1098 KB

Open AccessReview

The Tip-of-the-Tongue Phenomenon: Cognitive, Neural, and Neurochemical Perspectives

by Chenwei Xie and William Shiyuan Wang

Biomedicines 2026, 14(2), 269; https://doi.org/10.3390/biomedicines14020269 - 25 Jan 2026

Cited by 1 | Viewed by 2376

Abstract

The tip-of-the-tongue (TOT) phenomenon is a transient state in which speakers momentarily fail to retrieve a known word despite preserved semantic knowledge and a strong sense of imminent recall. This review integrates cognitive and neural evidence with emerging neurochemical perspectives to develop a comprehensive biomedical framework for word-finding failures. Cognitive models of semantic–phonological transmission and interloper interference have been refined through structural, functional, and metabolic imaging to elucidate the mechanisms underlying TOT states across the lifespan. Functional neuroimaging implicates a left-lateralized fronto-temporal network, particularly the inferior frontal gyrus (IFG), anterior cingulate cortex (ACC), and temporal pole, in retrieval monitoring and conflict resolution. Structural MRI and diffusion imaging link increased TOT frequency to reduced integrity of the arcuate and uncinate fasciculi and diminished network efficiency. Proton magnetic resonance spectroscopy (¹H-MRS) introduces a neurochemical dimension, with studies of related language tasks implicating lower γ-aminobutyric acid (GABA) and altered glutamate concentrations in frontal and temporal cortices as potential contributors to slower naming and heightened retrieval interference. Together, these findings converge on a model in which transient lexical blocks arise from local disruptions in excitation–inhibition (E/I) balance that impair signal propagation within language circuits. By uniting behavioral, neuroimaging, and neurochemical perspectives, TOT research reveals how subtle perturbations in cortical homeostasis manifest as everyday cognitive lapses and highlights potential biomedical strategies to maintain communicative efficiency across the lifespan. Full article

(This article belongs to the Special Issue Advances in Age-Related Diseases: Molecular Mechanisms, Treatments, and Clinical Implications)

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17 pages, 725 KB

Open AccessReview

The Dual Role of RUNX1 in Inflammation-Driven Age-Related Diseases: From Molecular Mechanisms to Clinical Translation

by Kexin Chen and Si Wang

Biomedicines 2025, 13(12), 2999; https://doi.org/10.3390/biomedicines13122999 - 7 Dec 2025

Viewed by 1507

Abstract

Age-related diseases such as cardiovascular disorders, neurodegeneration, and metabolic syndrome share a unifying pathological signature—persistent low-grade inflammation or “inflammaging”. Among the transcriptional regulators that orchestrate this process, RUNX1 has emerged as a pivotal molecular hub linking inflammation, cellular senescence, and tissue dysfunction. Traditionally recognized for its role in hematopoietic lineage specification, RUNX1 is now known to exert context-dependent regulatory functions across diverse organ systems. Its activation in aged tissues is driven by convergent pro-inflammatory and stress-related pathways—including NF-κB, MAPK, JAK/STAT, and oxidative signaling—that reinforce RUNX1 transcriptional activity through epigenetic reprogramming and chromatin remodeling. Sustained RUNX1 upregulation contributes to cellular senescence, fibrotic remodeling, and regenerative blockade, forming a self-perpetuating cycle of “inflammation amplification–functional decline”. In the cardiovascular, nervous, and hematopoietic systems, aberrant RUNX1 activation underlies fibrosis, neuroinflammation, and clonal hematopoiesis, respectively, establishing RUNX1 as a shared driver of age-associated pathology. The isoform-specific and temporally dynamic regulation of RUNX1 underpins its dual pro- and anti-inflammatory roles, highlighting its translational potential as both a biomarker and therapeutic target. A range of emerging intervention strategies has demonstrated promising capacity to precisely modulate RUNX1 activity. Collectively, these advances position RUNX1 at the intersection of inflammation, epigenetic instability, and tissue degeneration, opening new avenues for targeted intervention in inflammaging and age-related diseases. Full article

(This article belongs to the Special Issue Advances in Age-Related Diseases: Molecular Mechanisms, Treatments, and Clinical Implications)

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Other

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25 pages, 2016 KB

Open AccessSystematic Review

Preventive and Therapeutic Interventions in Solar Elastosis and Photoaging: A Comprehensive Systematic Review

by Francesco Leonforte, Tiziano Pergolizzi, Vito Nicosia, Fabio Nicoli, Giovanni Genovese, Cristina Genovese, Kidakorn Kiranantawat, Rosario Perrotta and Antonio Mistretta

Biomedicines 2025, 13(11), 2758; https://doi.org/10.3390/biomedicines13112758 - 11 Nov 2025

Viewed by 1459

Abstract

Background/Objectives: Solar elastosis, a key histopathological alteration in skin photodamage, results from chronic UV exposure and photoaging. Clinically, it manifests as deep wrinkles, laxity, and a dull complexion. The growing demand for effective treatments has spurred the development of numerous therapeutic strategies. This systematic review aims to synthesize and critically evaluate the scientific evidence regarding interventions for treating the clinical and histological manifestations of solar elastosis, to provide an updated overview and guide future clinical practice. Methods: PubMed, Scopus, ProQuest, and Web of Science databases were searched for articles published in the last ten years. Clinical studies on adults with signs of solar elastosis and photoaging, evaluating therapeutic interventions, were included. Primary outcomes were clinical and histopathological improvements, while secondary outcomes included skin elasticity, safety, and patient satisfaction. This review was registered in the PROSPERO database under registration number CRD420251086680. Results: Twenty-two studies, totaling 608 participants, were included. The analyzed therapies comprised a wide range of strategies, including energy-based devices (laser, radiofrequency), stem cell derivatives, bioactive topical compounds, and growth factor-rich plasma. Device-assisted and biologically augmented interventions consistently improved visible photoaging outcomes and skin elasticity, with selective histologic remodeling, heterogeneous effects on barrier function, and an overall acceptable safety profile, with mild and transient adverse events. Patient satisfaction was consistently high. Conclusions: Therapeutic strategies in solar elastosis and photoaging, particularly those combining energy-based devices with regenerative agents, have proven effective in improving the structural and functional aspects of photodamaged skin. Although the results are promising, the current literature is limited by methodological heterogeneity and small sample sizes. High-quality randomized controlled trials with long-term follow-up are needed to establish standardized, evidence-based protocols. Full article

(This article belongs to the Special Issue Advances in Age-Related Diseases: Molecular Mechanisms, Treatments, and Clinical Implications)

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