bims-caglex 2025-06-29 papers

bims-caglex

Biomed News

on Cellular aging and life extension

Issue of 2025–06–29
seventeen papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño

Preclinical Evidence That Mesoglycan Unfolds Complex Anti-Aging Effects in Photoaged Female Facial Skin.
Targeting Senescence: A Review of Senolytics and Senomorphics in Anti-Aging Interventions.
Lithocholic Acid, Calorie Restriction, and Halting Aging.
Identification of miR-106b-5p as a senolytic miRNA.
Biological properties, synthetic pathways and anti-aging mechanisms of nicotinamide mononucleotide (NMN): Research progress and challenges.
Design, Synthesis, and Evaluation of Nitroxide Radical Derivatives Based on Rhein as Potential Anti-Aging Agents Targeting the Keap1-Nrf2 Pathway.
Attenuation of primate aging via systemic infusion of senescence-resistant mesenchymal progenitor cells.
Calorie restriction mimetics against aging and inflammation.
Multipotent anti-aging recombinant human elastin: Counteracting zebrafish caudal fin shrinkage and D-galactose-induced intrinsic skin aging in mice.
Acetyl Hexapeptide-8 in Cosmeceuticals-A Review of Skin Permeability and Efficacy.
Identifying the target, mechanism, and agonist of α-ketoglutaric acid in delaying mesenchymal stem cell senescence.
Development and Application of a Senolytic Predictor for Discovery of Novel Senolytic Compounds and Herbs.
Senotherapy for chronic lung disease.
CD38-Targeting Peptide Vaccine Ameliorates Aging-Associated Phenotypes in Mice.
SS-31 Targets NOS2 to Enhance Osteogenic Differentiation in Aged BMSCs by Restoring Mitochondrial Function.
Extension of replicative lifespan by synthetic engineered telomerase RNA in patient induced pluripotent stem cells.
Comparative analysis of mouse strains for in vivo induction of reprogramming factors.

Int J Mol Sci. 2025 Jun 17. pii: 5787. [Epub ahead of print]26(12):

Preclinical Evidence That Mesoglycan Unfolds Complex Anti-Aging Effects in Photoaged Female Facial Skin.

Assaf Zeltzer, Aviad Keren, Ralf Paus, Amos Gilhar.

  Novel senotherapeutics are needed to reverse aging-related skin decline. The research question addressed was whether mesoglycan, a clinically approved glycosaminoglycan formulation known to enhance perfusion, angiogenesis, and VEGF-A signaling, possesses therapeutic potential for rejuvenating photo aged human skin. To test this, we treated full-thickness photoaged facial human skin samples (mean age: 72 ± 5 years) from seven women ex vivo. The samples were treated with topical or medium-delivered mesoglycan (100, 200, and 300 µM) for 6 days under serum-free conditions that accelerate skin aging. Biomarkers associated with aging were assessed using quantitative immunohistomorphometry. Mesoglycan treatment improved key skin aging biomarkers at all doses. Compared to vehicle-treated skin, mesoglycan broadly enhanced epidermal structure and function, improved pigmentation-related markers, reduced cellular senescence, boosted mitochondrial performance and antioxidant defenses, and improved dermal matrix structure and microvasculature density. Notably, mesoglycan also upregulated VEGF-A and VEGFR2, promoting skin rejuvenation. Medium-delivered mesoglycan produced stronger overall effects, while rete ridge reappearance was observed exclusively after topical application. Mesoglycan demonstrates senotherapeutic potential in photoaged human skin, acting via complementary pathways, including VEGF-A upregulation. Although medium-delivered mesoglycan yielded the greatest biomarker improvements topical application restored rete ridges, a sign of epidermal reorganization and also significantly enhanced basement membrane structure, pigmentation, mitochondrial function and antioxidant defenses, while avoiding systemic exposure, making it the safer and more feasible route for localized skin anti-aging.

Keywords:  VEGF-A; angiogenesis; glycosaminoglycan; inflammation; mesoglycan; perfusion; photoaging; senotherapeutics; skin aging; skin rejuvenation

DOI:  https://doi.org/10.3390/ijms26125787
Biomolecules. 2025 Jun 13. pii: 860. [Epub ahead of print]15(6):

Targeting Senescence: A Review of Senolytics and Senomorphics in Anti-Aging Interventions.

Timur Saliev, Prim B Singh.

  Cellular senescence is a fundamental mechanism in aging, marked by irreversible growth arrest and diverse functional changes, including, but not limited to, the development of a senescence-associated secretory phenotype (SASP). While transient senescence contributes to beneficial processes such as tissue repair and tumor suppression, the persistent accumulation of senescent cells is implicated in tissue dysfunction, chronic inflammation, and age-related diseases. Notably, the SASP can exert both pro-inflammatory and immunosuppressive effects, depending on cell type, tissue context, and temporal dynamics, particularly in early stages where it may be profibrotic and immunomodulatory. Recent advances in senotherapeutics have led to two principal strategies for targeting senescent cells: senolytics, which selectively induce their apoptosis, and senomorphics, which modulate deleterious aspects of the senescence phenotype, including the SASP, without removing the cells. This review critically examines the molecular mechanisms, therapeutic agents, and clinical potential of both approaches in the context of anti-aging interventions. We discuss major classes of senolytics, such as tyrosine kinase inhibitors, BCL-2 family inhibitors, and natural polyphenols, alongside senomorphics including mTOR and JAK inhibitors, rapalogs, and epigenetic modulators. Additionally, we explore the biological heterogeneity of senescent cells, challenges in developing specific biomarkers, and the dualistic role of senescence in physiological versus pathological states. The review also highlights emerging tools, such as targeted delivery systems, multi-omics integration, and AI-assisted drug discovery, which are advancing precision geroscience and shaping future anti-aging strategies.

Keywords:  aging; anti-aging therapy; cellular senescence; longevity; senescence-associated secretory phenotype (SASP); senolytics; senomorphics

DOI:  https://doi.org/10.3390/biom15060860
Adv Biol (Weinh). 2025 Jun 25. e00110

Lithocholic Acid, Calorie Restriction, and Halting Aging.

Cade Ward, Michael M Shahid, Grace Hohman, Mohamed A Eldeeb.

  While aging is a natural biological process, it is associated with a greater risk for multiple diseases, including cancer, neurodegeneration, and cardiovascular disease. Thus, it is important to study the biochemical mechanisms involved in aging to understand how to treat and prevent these health conditions. The discovery that calorie restriction (CR) promoted longevity in various organisms is a major breakthrough for aging research. Molecular studies of CR have revealed that it mediates its anti-aging effects by activating key signaling pathways, including the AMPK pathway. This pathway is important for regulating various processes, including energy homeostasis, metabolism, and proteostasis. Despite the advantages associated with CR, this practice can have detrimental effects, including decreased liver, body, and muscle mass. Additionally, CR is difficult to track and maintain, limiting its long-term potential. Interestingly, direct activation of the AMPK pathway offers a potential approach to increase longevity and quality of life without dietary restrictions. Remarkably, a recent discovery revealed that lithocholic acid (LCA), a metabolite from bile acid, could directly activate the AMPK pathway. Activation of the AMPK pathway by LCA leads to the beneficial effects of CR without the negative effects. These recent findings point to the possibility that supplementation of specific doses of LCA could offer a novel approach to induce anti-aging pathways that lead to increased longevity and improved quality of life.

Keywords:  AMPK; aging; calorie restriction; cell signaling; neurodegeneration; protein degradation

DOI:  https://doi.org/10.1002/adbi.202500110
EBioMedicine. 2025 Jun 18. pii: S2352-3964(25)00254-3. [Epub ahead of print]117 105810

Identification of miR-106b-5p as a senolytic miRNA.

Tianpeng Zhang, Allancer Nunes, Ryan O'Kelly, Luise Angelini, Michal M Masternak, Yousin Suh, Xiao Dong, Laura J Niedernhofer, Paul D Robbins.

   BACKGROUND: Cellular senescence contributes to ageing and age-related diseases. While miR-106b-5p is elevated in centenarians and GH-deficient models of healthy ageing, its role in senescence was unclear.
METHODS: Senolytic effects of miR-106b-5p were evaluated in etoposide-induced senescent IMR90 fibroblasts and HUVECs, and in male naturally aged mice using liposome-mediated delivery. Cellular assays, qPCR, Western blotting, and RNA-seq were performed to assess senescence and SASP markers, apoptosis pathways, and molecular mechanisms.
FINDINGS: miR-106b-5p selectively eliminated senescent cells without affecting non-senescent cells. It enhanced p53 K120 acetylation and upregulated PUMA, while reducing PCAF expression. In male aged mice, systemic delivery of miR-106b-5p reduced markers of senescence and SASP in multiple tissues and lowered serum IL-6 levels.
INTERPRETATION: miR-106b-5p functions as a senolytic miRNA via modulation of the p53-PUMA axis and SASP suppression. It holds promise as a therapeutic agent to mitigate age-related cellular dysfunction and inflammation.
FUNDING: Supported by NIH (U19 AG056278, R01 AG063543, P01 AG062413, U54 AG079754, U54 AG076041, R01 AG069819, P01 AI172501), the Glenn Foundation, and NSF grant #2317758.

Keywords:  Ageing and inflammation; Cellular senescence; SASP; Senolytic therapy; miR-106b-5p; p53-PUMA axis

DOI:  https://doi.org/10.1016/j.ebiom.2025.105810
Biogerontology. 2025 Jun 23. 26(4): 124

Biological properties, synthetic pathways and anti-aging mechanisms of nicotinamide mononucleotide (NMN): Research progress and challenges.

Enhui Wang, Yuting Wang, Zhaofeng Zhang, Yanfei Jiang, Chunyue Zhao.

  The increasing global population aging has made the prevention and control of aging-related diseases a major public health challenge in the twenty-first century. Nicotinamide mononucleotide (NMN), as a precursor of nicotinamide adenine dinucleotide (NAD+), has garnered significant attention in recent years for its anti-aging potential. This review comprehensively reviews the metabolic pathways and molecular mechanisms of NMN, comparing the technical characteristics and industrialization prospects of chemical synthesis, microbial fermentation, and enzyme-catalyzed synthesis. The molecular targets and networks of NMN in core aging mechanisms, such as DNA damage repair, mitochondrial function regulation, inflammatory response balance, gut microbiota remodeling, and autophagy pathway activation, are analyzed. The molecular mechanism of NMN in slowing down the aging process through multi-target synergistic effects is elucidated. However, critical issues such as age-stratified dosage modeling, long-term safety, and efficacy of NMN still require in-depth research. This review provides a theoretical basis and research direction for translational research and precise anti-aging strategies of NMN.

Keywords:  Anti-aging; Autophagy; Chemical/biological synthesis; Gut microbiota; Nicotinamide adenine dinucleotide; Nicotinamide mononucleotide

DOI:  https://doi.org/10.1007/s10522-025-10270-7
Drug Des Devel Ther. 2025 ;19 5153-5167

Design, Synthesis, and Evaluation of Nitroxide Radical Derivatives Based on Rhein as Potential Anti-Aging Agents Targeting the Keap1-Nrf2 Pathway.

Jie Wang, Xuejing Peng, Xinyue Zhang, Jia Lin, Qili Zhang, Jiaojiao Li, Longchen Cui, Lei Zhao.

   Purpose: Targeting the crucial Keap1-Nrf2-ARE antioxidant pathway, we selected Rhein - a natural anthraquinone from traditional Chinese medicine with established Keap1-Nrf2 inhibitory activity as our lead compound. Through rational structural modification by incorporating nitroxide radicals at the 3-carboxyl position, we aimed to develop enhanced Keap1-Nrf2 modulators with anti-aging potential.
Patients and Methods: A series of rhein nitroxide derivatives were synthesized, and their free radical scavenging activity was assessed in vitro using DPPH and ABTS methods. Compound 4b, demonstrating significant activity, was selected for further evaluation. Its effects on the survival of L02 hepatocytes under oxidative stress and the lifespan and stress tolerance of Caenorhabditis elegans (C. elegans) were investigated. Additionally, the impacts of 4b on antioxidant enzyme activity, malondialdehyde (MDA) levels, and reactive oxygen species (ROS) accumulation under oxidative stress were assessed. Molecular docking was conducted to analyze interactions between 4b and the Kelch domain of Keap1.
Results: Compound 4b exhibited potent free radical scavenging activity, with IC50 values of 0.51 ± 0.09 mM against DPPH radicals and 0.12 ± 0.03 mM against ABTS radicals. It significantly improved the survival rate of L02 hepatocytes under oxidative stress, maintaining 95.42% viability (p < 0.01). In the C. elegans model, 4b extended the average lifespan and enhanced stress resistance, increasing GSH activity, reducing MDA content, and decreasing ROS accumulation. Molecular docking showed that 4b penetrates deeply into the Kelch domain of Keap1, forming stable interactions with key residues.
Conclusion: Compound 4b demonstrates superior antioxidant and anti-aging effects compared to the parent compound rhein, representing a highly promising anti-aging candidate and Keap1-Nrf2 signaling pathway modulator with potential as a novel therapeutic agent for age-related diseases.

Keywords:  anti-aging; antioxidant; keap1-Nrf2 pathway; nitroxide radical; rhein

DOI:  https://doi.org/10.2147/DDDT.S516209
Cell Regen. 2025 Jun 27. 14(1): 27

Attenuation of primate aging via systemic infusion of senescence-resistant mesenchymal progenitor cells.

Aisha Siddique, Ismail M Shakir, Mo Li.

Aging is characterized by progressive functional decline driven by stem cell exhaustion, chronic inflammation, and cellular senescence. Mesenchymal progenitor cells (MPCs), which play a central role in tissue repair, are particularly vulnerable to age-associated dysfunction. Lei et al. (Cell 188:1-22, 2025) address this limitation by engineering human embryonic stem cell-derived MPCs with enhanced FOXO3 activity (termed SRCs). Intravenous administration of FOXO3-SRCs to aged cynomolgus macaques significantly slowed aging across multiple organs compared to wild-type MPCs. SRC treatment improved cognitive performance, preserved brain structure, protected bone integrity, and rejuvenated immune function. Transcriptomic and DNA methylation aging clocks revealed substantial reductions in biological age, with the most pronounced rejuvenation observed in the reproductive system, skin, lung, muscle, and hippocampus. These effects were partly attributed to SRC-derived exosomes enriched in gero-protective proteins and metabolites. Importantly, SRCs exhibited robust safety, showing no tumorigenicity or immunogenicity. This work positions FOXO3-enhanced MPCs and their exosomes as promising candidates for systemic anti-aging interventions, shifting the therapeutic paradigm from treating individual diseases to targeting the aging process itself.

DOI: https://doi.org/10.1186/s13619-025-00248-8
Biogerontology. 2025 Jun 24. 26(4): 126

Calorie restriction mimetics against aging and inflammation.

Sakshi Chaudhary, Mani Raj Chaudhary, Manoj Kumar Jena, Prasana Kumar Rath, Bidyut Prava Mishra, Biswaranjan Paital, Ashish Vyas, Dipak Kumar Sahoo, Prabhakar Singh, Mohammad Murtaza Mehdi.

  Geroprotectors, a class of compounds that ameliorate molecular, cellular, or physiological aging-related alterations, have garnered significant attention in the quest to promote healthy aging and extend the human health span. Among these, Calorie Restriction Mimetics (CRMs) have emerged as promising candidates due to their potential to mimic the benefits of calorie restriction, a dietary approach involving reduced calorie intake without malnutrition. Prospective CRMs may include biguanides (metformin and aminoguanidine), which exert effects on the insulin signaling pathway; rapamycin, which interacts with mTOR signaling pathways; and stilbenes (resveratrol), which influences stress signaling pathways and promotes the activation of AMPK, impacting mitochondrial metabolism in addition to the activity of FOXO and sirtuin. Other compounds, such as glycolytic inhibitors, carbohydrate and lipid absorption blockers, polyamines, and polyphenols, which collectively modulate pathways regulating the effects of free radicals, are also under consideration. To propose prospective geroprotective strategies, this article focuses on analyzing the functions of potential CRMs and their mechanisms demonstrating health benefits, the same as that of CR (Calorie Restriction), but without undesirable side effects.

Keywords:  Aging; Calorie restriction mimetics; Geroprotectors; Metformin; Rapamycin; Senotherapeutic drugs

DOI:  https://doi.org/10.1007/s10522-025-10269-0
Int J Biol Macromol. 2025 Jun 24. pii: S0141-8130(25)06022-2. [Epub ahead of print] 145467

Multipotent anti-aging recombinant human elastin: Counteracting zebrafish caudal fin shrinkage and D-galactose-induced intrinsic skin aging in mice.

Lijun Zhu, Wenjie Huang, Jingjing Shi, Fei Li, Xiuxia Sun, Jianxi Xiao.

  The degradation of elastin in aged skin results in the loss of elasticity, the formation of wrinkles, and even a reduced ability for wound healing after injury. However, previous studies about elastin material have been limited by high immunogenicity of animal-derived elastin, the use of single elastin peptide sequences, and residual crosslinking agents. In this study, we designed a multipotent anti-aging recombinant human elastin (rElastin) and utilized it to counteract caudal fin shrinkage in zebrafish and D-galactose-induced intrinsic skin aging in mice. The rElastin demonstrated thermoresponsive reversible phase-transition closely resembling that of natural elastin. In vitro, cell experiments demonstrated that rElastin effectively promoted the proliferation, adhesion, and spreading of HFF-1 cells. In a D-galactose-induced intrinsic aging mouse model, rElastin significantly restored dermal density, skin hydration, and TEWL to levels approaching those of healthy skin. Histological analysis further confirmed that rElastin facilitated the deposition of collagen and regeneration of elastic fibers, thereby promoting structural and functional repair of aging skin. Additionally, rElastin obviously inhibited the tail fin shrinkage after UV radiation. rElastin effectively targets skin symptoms associated with intrinsic aging, providing fresh insights into anti-aging therapies and showcasing strong potential for applications in regenerative medicine and cosmetic dermatology.

Keywords:  Anti-aging; Anti-winkle; Recombinant human elastin; Regeneration

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.145467
Int J Mol Sci. 2025 Jun 14. pii: 5722. [Epub ahead of print]26(12):

Acetyl Hexapeptide-8 in Cosmeceuticals-A Review of Skin Permeability and Efficacy.

Julita Zdrada-Nowak, Agnieszka Surgiel-Gemza, Magdalena Szatkowska.

  Biomimetic peptides represent a growing class of active ingredients in modern cosmeceuticals, designed to mimic the function of the naturally occurring peptides involved in skin homeostasis, repair, and regeneration. Among them, acetyl hexapeptide-8 (AH-8), often referred to as a "botox-like" peptide, has received considerable attention for its potential to dynamically reduce wrinkles through the modulation of neuromuscular activity. AH-8 is widely used in topical formulations intended for anti-aging effects, scar treatment, and skin rejuvenation. This review provides a comprehensive overview of the structure and proposed mechanisms of action of AH-8, with particular focus on its efficacy and skin penetration properties. Due to its hydrophilic nature and relatively large molecular size, AH-8 faces limited permeability through the lipophilic stratum corneum, making effective dermal delivery challenging. Formulation strategies such as oil-in-water (O/W) and multiple water-in-oil-in-water (W/O/W) emulsions have been explored to enhance its delivery, but the ability of AH-8 to reach neuromuscular junctions remains uncertain. Preclinical and clinical studies indicate that AH-8 may reduce wrinkle depth, improve skin elasticity, and enhance hydration. However, the precise biological mechanisms underlying these effects-particularly the peptide's ability to inhibit muscle contraction when applied topically-remain incompletely understood. In some studies, AH-8 has also shown beneficial effects in scar remodeling and sebum regulation. Despite promising cosmetic outcomes, AH-8's low skin penetration limits its bioavailability and therapeutic potential. This review emphasizes the need for further research on formulation science and delivery systems, which are essential for optimizing the effectiveness of peptide-based cosmeceuticals and validating their use as non-invasive alternatives to injectable treatments.

Keywords:  acetyl hexapeptide-8; botox-like peptides; emulsions; skin barrier; skin permeation

DOI:  https://doi.org/10.3390/ijms26125722
Cell Rep. 2025 Jun 25. pii: S2211-1247(25)00688-6. [Epub ahead of print]44(7): 115917

Identifying the target, mechanism, and agonist of α-ketoglutaric acid in delaying mesenchymal stem cell senescence.

Zhao Cui, Jiameng Li, Caifeng Li, Shiwen Deng, Wei Liu, Tong Lei, Junxian Cao, Ziyi Wang, Xiaoxu Wang, Shuhua Ma, Yinhua Zhu, Hongjun Yang, Peng Chen.

  α-ketoglutaric acid (AKG), a tricarboxylic acid cycle metabolite central to aerobic metabolism and longevity, retains unresolved anti-aging protein targets. Here, we demonstrate that reduced isocitrate dehydrogenase 1 (IDH1) expression during senescence lowers AKG production, accelerating the aging of mesenchymal stem cells (MSCs). Exogenous AKG or IDH1 overexpression restores AKG levels, enabling 2-oxoglutarate and Fe(II)-dependent oxygenase domain-containing protein 1 (OGFOD1)-catalyzed hydroxylation of ribosomal protein S23 (RPS23) at proline 62. Mechanistically, AKG stabilizes the OGFOD1-RPS23 complex, enhancing translation accuracy to limit misfolded protein accumulation while sustaining synthesis rates, thereby balancing proteostasis. The natural flavonoid scutellarin (Scu), identified as an IDH1 agonist, elevates AKG to delay MSC senescence. In aged mice, Scu improves cognitive function, reduces osteoporosis and skin aging, and suppresses senescence-associated secretory phenotype. Our findings identify the AKG-IDH1-RPS23 axis as a regulator of stem cell senescence and we propose metabolic reprogramming strategies for anti-aging therapies.

Keywords:  CP: Metabolism; CP: Stem cell research; OGFOD1; RPS23; Scutellarin; isocitrate dehydrogenase; mesenchymal stem cells; protein homeostasis; senescence; α-ketoglutaric acid

DOI:  https://doi.org/10.1016/j.celrep.2025.115917
Molecules. 2025 Jun 19. pii: 2653. [Epub ahead of print]30(12):

Development and Application of a Senolytic Predictor for Discovery of Novel Senolytic Compounds and Herbs.

Jinjun Li, Kai Zhao, Guotai Yang, Haohao Lv, Renxin Zhang, Shuhan Li, Zhiyuan Chen, Min Xu, Naixue Yang, Shaoxing Dai.

  The accumulation of senescent cells is a major contributor to aging and various age-related diseases, making developing senolytic compounds that are capable of clearing these cells an important area of research. However, progress has been hampered by the limited number of known senolytics and the incomplete understanding of their mechanisms. This study presents a powerful senolytic predictor built using phenotypic data and machine learning techniques to identify compounds with potential senolytic activity. A comprehensive training dataset consisting of 111 positive and 3951 negative compounds was curated from the literature. The dataset was used to train machine learning models, incorporating traditional molecular fingerprints, molecular descriptors, and MoLFormer molecular embeddings. By applying MoLFormer-based oversampling and testing different algorithms, it was found that the Support Vector Machine (SVM) and Multilayer Perceptron (MLP) models with MoLFormer embeddings exhibited the best performance, achieving Area Under the Curve (AUC) scores of 0.998 and 0.997, and F1 scores of 0.948 and 0.941, respectively. This senolytic predictor was then used to perform virtual screening of compounds from the DrugBank and TCMbank databases. In the DrugBank database, 98 structurally novel candidate compounds with potential senolytic activity were identified. For TCMbank, 714 potential senolytic compounds were predicted and 81 medicinal herbs with possible senolytic properties were identified. Moreover, pathway enrichment analysis revealed key targets and potential mechanisms underlying senolytic activity. In an experimental screening of predicted compounds, panaxatriol was found to exhibit senolytic activity on the etoposide-induced senescence of the IMR-90 cell line. Additionally, voclosporin was found to extend the lifespan of C. elegans more effectively than metformin, demonstrating the value of our model for drug repurposing. This study not only provides an efficient framework for discovering novel senolytic agents, but also highlights the predicted novel senolytic compounds and herbs as valuable starting points for future research into senolytic drug development.

Keywords:  DrugBank; MoLFormer; TCMbank; machine learning; senolytic compounds; virtual screening

DOI:  https://doi.org/10.3390/molecules30122653
Pharmacol Rev. 2025 May 28. pii: S0031-6997(25)07477-0. [Epub ahead of print]77(4): 100069

Senotherapy for chronic lung disease.

Peter J Barnes.

Chronic respiratory diseases are an enormous burden on healthcare and the third ranked cause of death globally. There is now compelling evidence that acceleration of lung aging and associated cellular senescence is a key driving mechanism of several chronic lung diseases, particularly chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Senescent cells, arising from oxidative stress and unrepaired damage, can accumulate in the lung and develop a senescence-associated secretory phenotype, spreading senescence and resulting in disease progression. In addition, there is a reduction in normally protective antiaging molecules, such as sirtuins, in the lungs. The role of cellular senescence in chronic lung disease has driven interest in senotherapy that targets senescent cells as a novel approach to treating respiratory diseases, and includes repurposing of existing drugs or developing new therapies. Senomorphics, which prevent the development of senescence and inhibit senescence-associated secretory phenotype mediators, include inhibitors of phosphoinositide-3-kinase-mechanistic target of rapamycin signaling, novel antioxidants, and sirtuin activators. Senolytics remove senescent cells by inducing apoptosis and include inhibitors of antiapoptotic proteins, such as B-cell lymphoma-extra large, inhibitors of forkhead box O-4-p53 interaction, heat shock protein 90 inhibitors, and cardiac glycosides. Senotherapies have been effective in animal models of chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis, and several clinical trials are currently underway. The safety of these treatments after long-term administration requires further study, but this could potentially to be a promising approach to treating chronic lung diseases. SIGNIFICANCE STATEMENT: Cellular senescence induced by oxidative stress is a key driving mechanism in chronic lung diseases, such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis and may account for disease progression. Senotherapies, including senomorphics that inhibit senescent cells and senolytics that eliminate them, are promising therapeutic approaches to these common diseases, either with repurposed drugs or several new drugs that are in development.

DOI: https://doi.org/10.1016/j.pharmr.2025.100069
Aging Cell. 2025 Jun 25. e70147

CD38-Targeting Peptide Vaccine Ameliorates Aging-Associated Phenotypes in Mice.

Shangcheng Yu, Zhiqiang Li, Yuxiang Tang, Yuling Chen, Yingying Ma, Kunlin Du, Zhaoyun Zong, Kangze Feng, Yali Wei, Limeng Chen, Haiteng Deng.

  Antiaging vaccines have recently been found to elicit long-term benefits in slowing the aging process. Meanwhile, high CD38 expression in organs is an aging characteristic contributing to a decreased NAD+/NADH ratio. Thus, in the current study, we systematically investigate the effects of a CD38-targeting peptide vaccine (CD38-vaccine) on aging-associated phenotypes in mice. The CD38-vaccine induces a robust T-cell immune response, selectively depletes CD38+ myeloid cells in the spleen, and ameliorates age-related physical and cognitive function decline. Metabolically, vaccination improves glucose tolerance, enhances oxygen consumption, and decreases the number of senescent cells and mRNA levels of senescence-related genes in liver tissues. Vaccination also increases the NAD+/NADH ratio in the liver tissues, enhances oxidative metabolism, and reduces glycolysis. These findings indicate that targeting CD38 via vaccination is a promising strategy for ameliorating aging-associated phenotypes.

Keywords:  CD38; aging; peptide; vaccine

DOI:  https://doi.org/10.1111/acel.70147
Organogenesis. 2025 Dec;21(1): 2519649

SS-31 Targets NOS2 to Enhance Osteogenic Differentiation in Aged BMSCs by Restoring Mitochondrial Function.

Sen Duan, Qindong Zhang, Jinqiang Zhu, Jiaming Wang.

  This study delves into the rejuvenating effects of SS-31 on aged human Bone Marrow-Derived Mesenchymal Stem Cells (BM-MSCs), focusing on its potential to restore their diminished osteogenic differentiation capacity, a critical issue in geriatric medicine and bone tissue engineering. SS-31 significantly improved mitochondrial function, increasing ATP production by 35% and reducing ROS levels by 40% in aged BM-MSCs. Osteogenic differentiation was enhanced, as evidenced by a 2.8-fold increase in ALP activity and a 3.5-fold increase in Alizarin Red S staining intensity. Additionally, SS-31 reduced NOS2 expression by 50%, highlighting its therapeutic potential in age-related bone loss. SS-31 intervention not only normalizes mitochondrial structure and function, reducing ROS levels and enhancing oxygen consumption rates, but also targets the NOS2 gene, a potential drug target, which upon knockdown, leads to a substantial upregulation of osteogenic markers and an improvement in mitochondrial function. In conclusion, the findings of this study highlight the therapeutic potential of SS-31 in reversing the age-related decline in BM-MSC function by specifically inhibiting NOS2 expression and restoring mitochondrial function. This research provides a scientific basis for the development of new treatments for osteoporosis and other age-related bone diseases, emphasizing the importance of targeting mitochondrial function and cellular senescence in regenerative therapies.

Keywords:  Bone Marrow-Derived Mesenchymal Stem Cells; NOS2; SS-31; aging; osteogenic differentiation

DOI:  https://doi.org/10.1080/15476278.2025.2519649
Nat Biomed Eng. 2025 Jun 27.

Extension of replicative lifespan by synthetic engineered telomerase RNA in patient induced pluripotent stem cells.

Neha Nagpal, Suneet Agarwal.

RNA engineering has yielded a new class of medicines but faces limitations depending on RNA size and function. Here we demonstrate the synthesis and enzymatic stabilization of telomerase RNA component (TERC), a therapeutically relevant long non-coding RNA (lncRNA) that extends telomere length and replicative lifespan in human stem cells. Compared with therapeutic mRNAs, engineered TERC RNA (eTERC) depends on avoiding nucleoside base modifications and incorporates a distinct trimethylguanosine 5' cap during in vitro transcription. We show that the non-canonical polymerase TENT4B can be repurposed to enzymatically stabilize synthetic RNAs of any size by catalysing self-limited 2'-O-methyladenosine tailing, which is critical for optimal eTERC function in cells. A single transient exposure to eTERC forestalls telomere-induced senescence in telomerase-deficient human cell lines and lengthens telomeres in induced pluripotent stem cells from nine patients carrying different mutations in telomere-maintenance genes, as well as primary CD34+ blood stem/progenitor cells. Our results provide methods and proof of functional reconstitution for a stabilized, synthetic human lncRNA. eTERC may have therapeutic potential to safely extend replicative capacity in human stem cells.

DOI: https://doi.org/10.1038/s41551-025-01429-1
Cell Rep. 2025 Jun 24. pii: S2211-1247(25)00650-3. [Epub ahead of print]44(7): 115879

Comparative analysis of mouse strains for in vivo induction of reprogramming factors.

Sara Picó, Alba Vílchez-Acosta, João Agostinho de Sousa, María Del Carmen Maza, Calida Mrabti, Alberto Parras, Gabriela Desdín-Micó, Céline Yacoub Maroun, Clémence Branchina, Ferdinand von Meyenn, Alejandro Ocampo.

  In vivo reprogramming through the forced expression of Oct4, Sox2, Klf4, and c-Myc (OSKM) has demonstrated great potential for reversing age-associated phenotypes. However, continuous in vivo OSKM expression has raised safety concerns due to loss of cell identity, decrease in body weight, and premature death. Although cyclic short-term or targeted expression of the reprogramming factors can mitigate some of these detrimental effects, systemic rejuvenation of wild-type mice has remained elusive. To improve the fundamental understanding of in vivo reprogramming, we conduct a comparative analysis of various reprogrammable mouse strains across multiple tissues and organs. In addition, we develop reprogrammable mouse strains by avoiding OSKM expression in specific organs or implementing expression approaches within specific cells, thereby offering safer strategies to induce in vivo reprogramming. We hope that these tools will become valuable resources for future research in this field of research with potential implications to human health.

Keywords:  CP: Stem cell research; OSKM; aging; chimeric; in vivo; induction; rejuvenation; reprogramming; safety; strain; survival

DOI:  https://doi.org/10.1016/j.celrep.2025.115879