bims-caglex Biomed News
on Cellular aging and life extension
Issue of 2025–06–15
eleven papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño



  1. Res Sq. 2025 Jun 06. pii: rs.3.rs-6613032. [Epub ahead of print]
      Aging is marked by the accumulation of senescent cells (SnCs), which contribute to tissue dysfunction and age-related diseases. Senotherapeutics, including senolytics which specifically induce lysis of SnCs and senomorphics, which suppress the senescence phenotype, represent promising therapeutic interventions for mitigating age-related pathologies and extending healthspan. Using a phenotypic-based senescent cell screening assay, we identified fucoidans, a class of sulfated polysaccharides derived from brown algae and seaweed, as novel senotherapeutics. In particular, fucoidan from Fucus vesiculosus (Fucoidan-FV) displayed potent senomorphic activity in different types of SnCs, reduced senescence in multiple tissues in aged mice, and extended healthspan in a mouse model of accelerated aging. Fucoidan-FV also enhanced the deacetylation and mono-ADP-ribosylation (mADPr) activity of SIRT6 and improved DNA repair and reduced senescence, in part, through SIRT6-dependent pathways. In addition, Fucoidan-FV downregulated genes associated with inflammation, Wnt signaling, and ECM remodeling pathways in SnCs and increased expression of genes involved with DNA repair. These findings support the translational potential of fucoidans as novel senotherapeutics that also are able to improve SIRT6-mediated DNA repair.
    DOI:  https://doi.org/10.21203/rs.3.rs-6613032/v1
  2. Cell Reprogram. 2025 Jun 09.
      Sahu et al. (2024) demonstrate that targeted partial reprogramming with Oct4, Sox2, and Klf4 (OSK) delivered via adeno-associated virus (AAV) to Cdkn2a-positive cells rejuvenates senescent cells while maintaining cellular identity. In a progeroid and naturally aged mouse model, a single AAV injection improved lifespan, reduced inflammation, restored tissue integrity, and enhanced wound healing. Complementary results in human fibroblasts confirmed Cdkn2a-driven OSK expression attenuated inflammation-associated genes during replicative senescence and treatments inducing DNA damage. These encouraging results highlight its potential as a safer alternative to systemic senolytic therapies for age-associated disorders.
    Keywords:  Hutchinson-Gilford progeria syndrome; aging; partial reprogramming; senescent cells
    DOI:  https://doi.org/10.1089/cell.2025.0018
  3. Adv Healthc Mater. 2025 Jun 12. e2500217
      Aging is a complex process and the main risk factor for many common human diseases. Traditional aging research using short-lived animal models and two-dimensional cell cultures has led to key discoveries, but their relevance to human aging remains debatable. Microfluidics, a rapidly growing field that manipulates small volumes of fluids within microscale channels, offers new opportunities for aging research. By enabling the development of advanced three-dimensional cellular models that closely mimic human tissues, microfluidics allows more accurate investigation of aging processes while reducing costs, resource use, and culture time. This review explores how microfluidic systems, particularly organ-on-chip models, can improve our understanding of aging and age-related diseases, bridge the gap between animal models and human biology, and support the discovery of rejuvenation therapies. We highlight their role in monitoring aging biomarkers, analyzing functional cellular changes, and identifying longevity-promoting compounds. The ability of microfluidics to detect, analyze, and remove senescent cells is also discussed, along with emerging applications such as partial reprogramming for cellular rejuvenation. Furthermore, we summarize how these devices support single-cell analysis and recreate specific tissue microenvironments that influence aging. Insights from microfluidic approaches hold promise for developing therapeutic strategies to extend healthspan and promote longevity.
    Keywords:  aging research; microfluidics; organ‐on‐a‐chip; rejuvenation
    DOI:  https://doi.org/10.1002/adhm.202500217
  4. Nat Aging. 2025 Jun 11.
      Aging is characterized by a gradual decline of cellular and physiological functions over time and an increased risk of different diseases. RNA therapeutics constitute an emerging approach to target the molecular mechanisms of aging and age-related diseases via rational design and have several advantages over traditional drug therapies, including high specificity, low toxicity and the potential for rapid development and production. Here, we discuss the latest developments in RNA therapeutics designed to promote healthy aging, including RNA activation, messenger RNA therapy, RNA interference, antisense oligonucleotides, aptamers and CRISPR-Cas-mediated RNA editing. We also review the latest preclinical and clinical studies of RNA technology for treating age-related diseases, including neurodegenerative, cardiovascular and musculoskeletal diseases. Finally, we discuss the challenges of RNA technology aimed at supporting healthy aging. We anticipate that the fusion of RNA therapeutics and aging biology will have an important effect on the development of new medicines and maximization of their efficacy.
    DOI:  https://doi.org/10.1038/s43587-025-00895-1
  5. Biomaterials. 2025 Jun 04. pii: S0142-9612(25)00380-1. [Epub ahead of print]324 123461
      Due to the heterogeneity of the senescent phenotype and the lack of a universal biomarker of senescence, the targeting of senescent cells is still an unresolved challenge, and the elimination of senescent cells using specific drugs (senolytics) is still limited in clinical use due to the off-target effects and associated toxicities of current therapeutic strategies. In this study, the induction of senescence in human melanoma cells by palbociclib is found to lead to a senescent phenotype characterized by overexpression of the membrane protein dipeptidyl peptidase 4 (DPP4), previously identified only in ageing contexts. Based on this discovery, a nanoparticle targeting DPP4 overexpression in the senescent surfaceome is designed, synthesized, and characterized to target senescent cancer cells. The nanoparticle based on mesoporous silica is loaded with the senolytic navitoclax, coated with disulfide-containing poly(ethylene glycol) to generate a redox-sensitive gatekeeper (S-S-PEG), and functionalized with an antibody against the DPP4 protein. The ability of the nanoparticles to effectively detect and eliminate senescent cells was confirmed in vitro and in vivo using a mouse model of palbociclib-induced senescent in melanoma. The DPP4-targeted nanoparticle effectively reduces tumor growth and selectively removes senescent cells. Taken together, this study highlights the potential of surfaceome-targeted nanoparticles, as a clinically relevant strategy for improving senolytic therapies.
    Keywords:  Dipeptidyl peptidase 4; Mesoporous silica nanoparticle; Navitoclax; Senescence
    DOI:  https://doi.org/10.1016/j.biomaterials.2025.123461
  6. Nat Rev Drug Discov. 2025 Jun 12.
      Ageing is the most important risk factor for many common human diseases, including cancer, diabetes, neurodegeneration and cardiovascular disease. Consequently, combating ageing itself has emerged as a rational strategy for addressing age-related multimorbidity. Over the past three decades, multiple genetic and pharmacologic interventions have led to substantial extension of lifespan and healthspan in model organisms. However, it is unclear whether these interventions target the causal mechanisms of ageing or downstream consequences. Ample evidence suggests that DNA damage to the somatic genome is a major causal mechanism of ageing, which compromises essential cellular functions such as transcription and replication, and leads to cellular senescence, apoptosis and mutations. Recently, new concepts have emerged to target the main consequences of DNA damage and enhance DNA repair capacities, thereby extending maintenance of the genome. Here, we review advances in this field and discuss approaches to pharmacologically mitigate the adverse effects of DNA damage to delay ageing, prevent mutation-driven cancer and mitigate age-related degenerative diseases.
    DOI:  https://doi.org/10.1038/s41573-025-01212-6
  7. J Am Chem Soc. 2025 Jun 13.
      Mitochondrial dysfunction caused by aging leads to decreased energy metabolism, resulting in functional decline and increased frailty in multiple tissues. Strategies for protecting and activating mitochondria under stressful conditions are required to suppress aging and age-related diseases. However, it is challenging to develop drugs capable of boosting mitochondrial respiration and compensating for the reduced intracellular adenosine triphosphate (ATP) levels. In this study, we developed a prodrug that stimulates the metabolism of intracellular adenine nucleotides (AXP: adenosine monophosphate (AMP), adenosine diphosphate (ADP), and ATP). It enhances AMP-activated protein kinase activity, fatty acid oxidation, oxidative stress resistance, and mitochondrial respiration, thereby increasing the intracellular ATP levels. Furthermore, this prodrug markedly extended the lifespan of Caenorhabditis elegans. AXP-driven stimulation of cellular energy metabolism proposed herein represents a novel geroprotective strategy and paves the way for the development of bioenergetic-molecule therapeutics.
    DOI:  https://doi.org/10.1021/jacs.5c06772
  8. bioRxiv. 2025 May 31. pii: 2025.05.30.656434. [Epub ahead of print]
      Activating Nrf2 with small molecules is a promising strategy for countering aging, oxidative stress, inflammation, and various disorders, including neurodegeneration. The primary regulator of Nrf2 protein stability is Keap1, a redox sensor protein and an adapter in the Cullin III ubiquitin ligase complex, which labels Nrf2 for proteasomal degradation. The known Nrf2 activators either chemically modify sensor thiols in Keap1 or competitively displace Nrf2 from the ubiquitin ligase complex. The latter approach is considered the most suitable for continuous administration, as non-specific chemical modifiers of Keap1 thiols also modify active thiols on other proteins, thus causing side effects. However, when transitioning from homogeneous to cell-based assays, genuine displacement activators show a significant loss in potency by several orders of magnitude. As we demonstrate here, this offset is due to the presence of high micromolar concentrations of Keap1 in both the cell lines and brain tissue. A potential solution could involve targeted delivery of an alkylating agent to Keap1 to achieve the desired specificity. Transcriptomic analysis of a cell-permeable Nrf2 peptide bearing an alkylating fumarate moiety indicates selective activation of the Nrf2 genetic program, confirming the high specificity of this approach. The Nrf2-triggered genetic program has a feedback regulation mechanism through the activation of Bach1, an Nrf2 transcriptional repressor, which is elevated in age-related neurodegeneration. Thus, a benign bipartite Nrf2 activator with Bach1 inhibition properties is needed for maximal benefits. The recently developed heterocyclic carboxamide, HPPE, shows overlap with the Nrf2 pathway activated by the fumarate-linked Nrf2 peptide and with zinc and tin protoporphyrins, which are recognized inhibitors of Bach1. Therefore, HPPE presents a promising and unique combination of the two desired activities that could be further optimized to treat age-related neurodegeneration.
    Highlights: The decrease in potency for reversible displacement activators of Nrf2 in biological assays is attributed to high micromolar concentrations of Keap1 and competition with endogenous Keap1 client proteins.Nrf2 activators specific for Keap1 should combine a displacement scaffold with a substitution that undergoes intracellular conversion into active pro-oxidant or alkylating species.Cell-permeable fumarate-linked Nrf2 peptide solely activates the Nrf2 antioxidant genetic program, as demonstrated by transcriptomic analysis.HPPE, a small bipartite molecule, exhibits properties of both Nrf2 activation and Bach1 inhibition, to bypass feedback regulation by targeting both Keap1 and Bach1.
    DOI:  https://doi.org/10.1101/2025.05.30.656434
  9. Int J Mol Sci. 2025 May 22. pii: 4982. [Epub ahead of print]26(11):
      Aging is characterized by a progressive deterioration in physiological function and an increased susceptibility to age-related diseases, such as cancer. Monoclonal antibodies (mAbs) constitute a novel therapeutic approach aimed at addressing aging mechanisms such as cellular senescence, inflammaging, and immunosenescence. This text presents an overview of mAb methods aimed at the markers of aging and their potential application in cancer treatment. The mAbs can be categorized into senolytics, senescence-associated secretory phenotype (SASP) neutralizers, and immune checkpoint inhibitors, each targeting fewer aging-related pathways relevant to cancer therapeutic enhancement than the last. Translating promising preclinical evidence into enhanced efficacy and safety in cancer therapy presents challenges, particularly in older populations. This study examines the therapeutic efficacy of mAbs in the treatment of cancer and age-related disorders, focusing on their current and future roles in oncology practice.
    Keywords:  SASP; aging; cancer; immunotherapy; monoclonal antibodies; senescence
    DOI:  https://doi.org/10.3390/ijms26114982
  10. Bioact Mater. 2025 Sep;51 318-332
      Senescent bone repair faces significant obstacles due to reduced cellular activity and an unfavorable microenvironment, both of which hinder the osteogenic differentiation of bone marrow-derived stem cells (BMSCs) into osteoblasts (OBs) and subsequent bone formation. Current approaches primarily target senescent cell clearance (senolytics) or suppression of the senescence-associated secretory phenotype (senomorphics), neglecting the complex interactions between BMSCs and the osteogenic microenvironment. In this study, a genetically engineered hydrogel incorporating NAD-dependent deacetylase sirtuins 3 (SIRT3)-loaded nano-vectors and poly (glycerol sebacate)-co-poly (ethylene glycol)/polyacrylic acid (PEGS/PAA) was developed as an "inside-out" strategy for bone regeneration. At the intracellular level, BMSC function is restored, and osteogenesis is promoted through genetically enhanced SIRT3 expression. At the extracellular level, carboxyl functional groups chelate iron ions, simulating a hypoxic environment and promoting synergistic interactions between angiogenesis and osteogenesis. The therapeutic effects of the genetically engineered hydrogel in alleviating senescent damage and enhancing osteogenic differentiation were confirmed in both chemically and naturally induced senescence models in vitro. Local delivery of the hydrogel significantly increased newly formed bone in rat cranial defects. Mechanistically, the central role of SIRT3 in balancing senescence and osteogenesis, as well as its involvement in bone immune signaling pathways, was elucidated through CRISPR/Cas9-mediated editing in mice and transcriptome sequencing. This work presents a novel paradigm that integrates cellular and microenvironmental factors to enhance bone regeneration, offering new hope for treating age-related bone injuries.
    Keywords:  Hypoxia hydrogels; Senescent associated secretory phenotype; Senescent bone marrow-derived stem cells; Senile bone regeneration; Sirtuins 3
    DOI:  https://doi.org/10.1016/j.bioactmat.2025.05.003
  11. Nature. 2025 Jun 11.
      
    Keywords:  Gene therapy; Health care; Stem cells
    DOI:  https://doi.org/10.1038/d41586-025-01779-5