bims-caglex 2025-07-20 papers

bims-caglex

Biomed News

on Cellular aging and life extension

Issue of 2025–07–20
twenty-one papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño

Apheresis for Senescence: Targeting the Senescence-associated Secretory Phenotype to Delay Aging and Age-Related Diseases.
Targeting the hallmarks of aging: mechanisms and therapeutic opportunities.
A Machine-Learning Approach Identifies Rejuvenating Interventions in the Human Brain.
Microgravity Therapy as Treatment for Decelerated Aging and Successful Longevity.
Enhancing Skin Rejuvenation: Using of Engineered Exosome Content Treated With Oleuropein and Fe3O4@CQD/Oleuropein.
Structure-based machine learning screening identifies natural product candidates as potential geroprotectors.
Killing wisely: precision senolytics in the age of frailty.
Advances in Longevity: The Intersection of Regenerative Medicine and Cosmetic Dermatology.
Gene therapy strategies for aging intervention.
In vivo chemical reprogramming is associated with a toxic accumulation of lipid droplets hindering rejuvenation.
GDF11 secreting cell transplant efficiently ameliorates age-related pulmonary fibrosis.
Human adipose-derived stem cell exosomes reduce mitochondrial DNA common deletion through PINK1/Parkin-mediated mitophagy to improve skin photoaging.
Refate identifies chemical compounds to target trans-regulatory networks for cellular conversion.
Therapeutic effects of PDGF-AB/BB against cellular senescence in human intervertebral disc.
Heterochronic parabiosis uncovers AdipoR1 as a critical player in retinal rejuvenation.
Characterizing primary and secondary senescence in vivo.
Interplay between MAPK signaling pathway and autophagy in skin aging: mechanistic insights and therapeutic implications.
Poly-L-Lactic Acid Filler Increases Adipogenesis and Adiponectin in Aged Subcutaneous Tissue.
Dual-Functional Nanoparticles to Reverse Osteoblast Senescence and Enhance Calcium Supplementation for Alleviating Senile Osteoporosis.
Effects of Exosomes From Hypoxia-Induced Adipose-Derived Stem Cells on Ameliorating Photoaging.
Extracellular vesicles from antler blastema progenitor cells reverse bone loss and mitigate aging-related phenotypes in mice and macaques.

Ageing Res Rev. 2025 Jul 10. pii: S1568-1637(25)00178-3. [Epub ahead of print] 102832

Apheresis for Senescence: Targeting the Senescence-associated Secretory Phenotype to Delay Aging and Age-Related Diseases.

Yamac Akgun.

  Aging is driven by cellular senescence and chronic inflammation, largely mediated by the senescence-associated secretory phenotype (SASP). SASP factors promote inflammaging, impair tissue homeostasis, and contribute to age-related diseases such as cardiovascular disease, neurodegeneration, and cancer. Current anti-aging strategies focus on senolytics or SASP inhibitors, yet these approaches have limitations. We discuss therapeutic plasma exchange (TPE) and selective apheresis, as interventions to mitigate SASP-driven aging. TPE removes inflammatory cytokines, metabolic waste, and senescence-associated proteins, while replenishing rejuvenating factors. Selective apheresis could enhance precision by targeting specific SASP components. By reducing systemic inflammation and restoring a youthful proteomic environment, these strategies may improve immune function, tissue regeneration, and overall healthspan. This review explores the mechanistic basis of SASP in aging and evaluates the potential of apheresis-based therapies as viable interventions to delay aging and age-related disease progression.

Keywords:  Age-related diseases; Aging and inflammaging; Senescence-associated secretory phenotype; Therapeutic plasma exchange

DOI:  https://doi.org/10.1016/j.arr.2025.102832
Front Cardiovasc Med. 2025 ;12 1631578

Targeting the hallmarks of aging: mechanisms and therapeutic opportunities.

Fumihiro Sanada, Shinichiro Hayashi, Ryuichi Morishita.

  Aging is a complex biological process characterized by a gradual decline in cellular and physiological function, increasing vulnerability to chronic diseases and mortality. It involves a set of interconnected mechanisms known as the hallmarks of aging, including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, and dysregulated nutrient sensing. These processes act at molecular, cellular, and systemic levels, contributing to age-related disorders such as neurodegeneration, cardiovascular disease, and metabolic syndromes. Emerging therapeutic strategies aim to delay or reverse aging by targeting specific hallmarks. These include senolytics to eliminate senescent cells, NAD+ boosters and mitophagy inducers to improve mitochondrial health, epigenetic reprogramming, and caloric restriction mimetics such as metformin and rapamycin to modulate nutrient-sensing pathways. Advances in regenerative medicine, gene editing, and organ cross-talk modulation are also contributing to the development of personalized, multi-targeted anti-aging therapies. Integration of omics technologies and biomarker research is expected to enhance our ability to monitor biological aging and optimize interventions for healthy longevity. This review highlights the current understanding of the hallmarks of aging and explores potential treatment strategies in light of our recent findings.

Keywords:  aging related disease; biological aging; chronic inflammation; chronological aging; senscence

DOI:  https://doi.org/10.3389/fcvm.2025.1631578
Adv Sci (Weinh). 2025 Jul 14. e03344

A Machine-Learning Approach Identifies Rejuvenating Interventions in the Human Brain.

Guillem Santamaria, Cristina Iglesias, Sascha Jung, Javier Arcos Hodar, Ruben Nogueiras, Antonio Del Sol.

  The increase in life expectancy has caused a rise in age-related brain disorders. Although brain rejuvenation is a promising strategy to counteract brain functional decline, systematic discovery methods for efficient interventions are lacking. A computational platform based on a transcriptional brain aging clock capable of detecting age- and neurodegeneration-related changes is developed. Applied to neurodegeneration-positive samples, it reveals that neurodegenerative disease presence and severity significantly increase predicted age. By screening 43840 transcriptional profiles of chemical and genetic perturbations, it identifies 453 unique rejuvenating interventions, several of which are known to extend lifespan in animal models. Additionally, the identified interventions include drugs already used to treat neurological disorders, Alzheimer's disease among them. A combination of compounds predicted by the platform reduced anxiety, improved memory, and rejuvenated the brain cortex transcriptome in aged mice. These results demonstrate the platform's ability to identify brain-rejuvenating interventions, offering potential treatments for neurodegenerative diseases.

Keywords:  cognitive decline; gene expression; senescence; therapies; transcriptional age

DOI:  https://doi.org/10.1002/advs.202503344
Int J Mol Sci. 2025 Jul 07. pii: 6544. [Epub ahead of print]26(13):

Microgravity Therapy as Treatment for Decelerated Aging and Successful Longevity.

Nadine Mozalbat, Lital Sharvit, Gil Atzmon.

  Aging is a complex biological process marked by a progressive decline in cellular function, leading to age-related diseases such as neurodegenerative disorders, cancer, and cardiovascular diseases. Despite significant advancements in aging research, finding effective interventions to decelerate aging remains a challenge. This review explores microgravity as a novel therapeutic approach to combat aging and promote healthy longevity. The hallmarks of aging, including genomic instability, telomere shortening, and cellular senescence, form the basis for understanding the molecular mechanisms behind aging. Interestingly, microgravity has been shown to accelerate aging-like processes in model organisms and human tissues, making it an ideal environment for studying aging mechanisms in an accelerated manner. Spaceflight studies, such as NASA's Twins Study and experiments aboard the International Space Station (ISS), reveal striking parallels between the physiological changes induced by microgravity and those observed in aging populations, including muscle atrophy, bone density loss, cardiovascular deconditioning, and immune system decline in a microgravity environment. However, upon microgravity recovery, cellular behavior, gene expression, and tissue regeneration were seen, providing vital insights into aging mechanisms and prospective therapeutic approaches. This review examines the potential of microgravity-based technologies to pioneer novel strategies for decelerating aging and enhancing healthspan under natural gravity, paving the way for breakthroughs in longevity therapies.

Keywords:  NASA’s twins study; aging; cellular senescence; hallmarks of aging; longevity; microgravity; spaceflight

DOI:  https://doi.org/10.3390/ijms26136544
J Cosmet Dermatol. 2025 Jul;24(7): e70351

Enhancing Skin Rejuvenation: Using of Engineered Exosome Content Treated With Oleuropein and Fe3O4@CQD/Oleuropein.

Naeimeh Safavizadeh, Zahra Noormohammadi, Mohammad Zaefizadeh, Kazem Nejati-Koshki.

   BACKGROUND: Skin aging, which is affected by intrinsic and extrinsic factors, leads to reduced elastin, collagen, and hydration levels.
AIMS: This study aimed to utilize modified exosomal content with treated Oleuropein and Fe3O4@C/Oleuropein to modulate gene and microRNA expression on the HFFF2 cells in vitro in order to reduce skin aging.
MATERIAL & METHODS: Fe3O4@C/Oleuropein was synthesized using the hydrothermal method and confirmed by XRD, FTIR, and SEM. The MTT assay was conducted to test toxicity Following this, hUC-MSCs and HFFF2 cells were treated with Fe3O4@C/Oleuropein and Oleuropein. Exosomes derived from the treatments were extracted by ultracentrifugation and evaluated by DLS and western blotting. HFFF2 cells were treated with exosomes derived from the treatments. The expression of the studied genes and related microRNAs was measured using qRT-PCR. Also, the effect of exosomes derived from the treatments on HFFF2 cells was evaluated using flow cytometry.
RESULTS: The results showed that the expression of IGF1, IGF1R, COL1A1, ELN, and EGF genes was significantly increased with Oleuropein (500 μg/mL) and Fe3O4@C/Oleuropein (250 μg/mL) treatments, especially when treated with exosomes derived from treatments. Moreover, the expression of hsa-miR-29b-3p, hsa-let-7d-5p, and hsa-let-7e-5p microRNAs was significantly downregulated, and hsa-miR-34a-5p was upregulated in the HFFF2 cells, which was consistent with the exosome cargo derived from treated cells.
CONCLUSIONS: Exosomes can increase gene expression and reduce microRNAs associated with skin antiaging. Using modified exosomal content treated with Oleuropein and Fe3O4@CQD/Oleuropein is generally effective for preventing skin aging and also presents innovative methods for skin care.

Keywords:  Fe3O4@CQD/oleuropein; microRNAs; modified exosomal content; oleuropein; skin rejuvenation

DOI:  https://doi.org/10.1111/jocd.70351
J Cheminform. 2025 Jul 15. 17(1): 106

Structure-based machine learning screening identifies natural product candidates as potential geroprotectors.

Jose Alberto Santiago-de-la-Cruz, Nadia Alejandra Rivero-Segura, Juan Carlos Gomez-Verjan.

  Age-related diseases and syndromes result in poor quality of life and adverse outcomes, representing a challenge to healthcare systems worldwide. Several pharmacological interventions have been proposed to target the aging process to slow its adverse effects. The so-called geroprotectors have been proposed as novel molecules that could maintain the organism's homeostasis, targeting specific aspects linked to the hallmarks of aging and delaying the adverse outcomes associated with age. On the other hand, machine learning (ML) is revolutionising drug design by making the process faster, cheaper, and more efficient.

Keywords:  Age-related diseases; Aging; Cheminformatics; Drug development; Geroprotectors; Machine learning; Natural products

DOI:  https://doi.org/10.1186/s13321-025-01058-5
Genes Dev. 2025 Jul 15.

Killing wisely: precision senolytics in the age of frailty.

Valentin J A Barthet, Scott W Lowe.

  Cellular senescence plays a dual role in tissue biology by promoting tumor suppression and wound healing when transient but driving inflammation, fibrosis, and age-related disease when persistent. The growing recognition that senescent cell clearance can reverse these pathologies has catalyzed efforts to develop therapeutics that preferentially kill senescent cells (also known as "senolytics"). However, clinical translation from bench to bedside remains challenging due to senescent state heterogeneity, limited biomarkers, off-target toxicities, and the frailty of aged patients. Small molecule senolytics, although promising, often lack defined mechanisms of action and pose safety concerns that may constrain their use in older adults. Emerging precision approaches, including those that exploit surface markers and leverage engineered immune therapies, offer a rational and potentially more selective path forward. Here we highlight recent advances in senescence profiling and targeted clearance strategies, emphasizing the need for therapies designed with both biological complexity and the needs of aging populations in mind.

Keywords:  aging; senescence; senolytics

DOI:  https://doi.org/10.1101/gad.353134.125
J Cosmet Dermatol. 2025 Jul;24(7): e70356

Advances in Longevity: The Intersection of Regenerative Medicine and Cosmetic Dermatology.

Diala Haykal, Frederic Flament, Mukta Shadev, Pascale Mora, Cristina Puyat, Brigitte Dréno, Qian Zheng, Hugues Cartier, Michael Gold, Steven Cohen.

   BACKGROUND: Aging is increasingly recognized as a modifiable biological process influenced by genetic, environmental, and lifestyle factors. Recent advances in regenerative medicine and artificial intelligence (AI) have reshaped the field of cosmetic dermatology, shifting the focus from temporary aesthetic improvements to long-term interventions aimed at preserving skin vitality and longevity.
AIM: This narrative review aims to synthesize emerging knowledge from 2010 to 2025 on the integration of regenerative strategies, biological modulators, immunologic regulation, microbiome modulation, and AI-driven personalization in the context of aesthetic longevity. The review also discusses translational potential and ethical considerations surrounding these advancements.
METHODS: A targeted literature search was conducted using PubMed and Scopus to identify peer-reviewed articles from 2010 to 2025. Search terms included "skin aging," "stem cells," "mitochondrial dysfunction," "epigenetic reprogramming," "artificial intelligence in dermatology," and "skin microbiome." Selected studies focused on regenerative and longevity-based interventions with clinical relevance or future applicability in cosmetic dermatology.
RESULTS: Key findings were categorized into six interconnected domains: regenerative medicine, mitochondrial function, epigenetic modulation, immunological balance, microbiome resilience, and AI-driven innovation. These pillars demonstrate a paradigm shift toward biologically informed, personalized strategies that aim to restore and sustain skin health at the molecular level.
CONCLUSION: Cosmetic dermatology is undergoing a transformation toward integrative, proactive care that combines regenerative medicine, AI, and personalized interventions. These approaches offer promising, evidence-based solutions for enhancing both aesthetic outcomes and long-term skin function, while also raising important ethical and regulatory considerations for clinical implementation.

Keywords:  cosmetic dermatology; cosmetic legislations; cosmetic surgery; dermatology; regenerative medicine; stem cells

DOI:  https://doi.org/10.1111/jocd.70356
Cell Insight. 2025 Aug;4(4): 100254

Gene therapy strategies for aging intervention.

Yaobin Jing, Jie Ren, Jing Qu, Guang-Hui Liu.

Aging is characterized by a progressive decline in organ and tissue structure and function, significantly increasing the risk of many chronic diseases. Developing interventions to delay aging holds the potential to reduce the burden of age-associated diseases and promote healthy longevity. Gene therapy has emerged as a clinically transformable approach, leveraging advanced gene editing and delivery systems to target the molecular underpinnings of aging. This review systematically explores the potential of gene therapy strategies in aging intervention, focusing on approaches that enhance genomic and epigenetic stability, restore metabolic homeostasis, modulate immune responses, and rejuvenate senescent cells. By providing a comprehensive overview and forward-looking insights, this article aims to inform future research directions and translational applications of gene therapy in mitigating aging-related decline.

DOI: https://doi.org/10.1016/j.cellin.2025.100254
bioRxiv. 2025 Jun 27. pii: 2025.06.25.661123. [Epub ahead of print]

In vivo chemical reprogramming is associated with a toxic accumulation of lipid droplets hindering rejuvenation.

Wayne Mitchell, Cecília G de Magalhães, Alexander Tyshkovskiy, Yushi Uchida, Ludger J E Goeminne, Takaharu Ichimura, Emery L Ng, Joseph V Bonventre, Vadim N Gladyshev.

Partial reprogramming has emerged as a promising strategy to reset the epigenetic landscape of aged cells towards more youthful profiles. Recent advancements have included the development of chemical reprogramming cocktails that can lower the epigenetic and transcriptomic age of cells and upregulate mitochondrial biogenesis and oxidative phosphorylation. However, the ability for these cocktails to affect biological age in a mammalian aging model has yet to be tested. Here, we have analyzed the effects of partial chemical reprogramming on mitochondrial structure in aged mouse fibroblasts and tested its in vivo efficacy in genetically diverse male UM-HET3 mice. This approach increases the size of mitochondria, alters cristae morphology, causes an increased fusing of mitochondrial networks, and speeds up movement velocity. We also discover that partial chemical reprogramming upregulates the formation of intracellular lipid droplets. At lower doses, the chemical reprogramming cocktail can be safely administered to middle-aged mice using implantable osmotic pumps, albeit with no effect on the transcriptomic age of kidney or liver tissues, and only a modest effect on the expression of OXPHOS complexes. However, at higher doses, the cocktail causes a drastic reduction in body weight and body condition scores. In the livers and kidneys of these animals, we observe significant increases in oil red o staining indicative of excessive lipid droplet accumulation in these organs. Thus, the upregulation of lipid droplet formation during partial chemical reprogramming may cause toxicity hindering the rejuvenation of cells and tissues in aged mammals.

DOI: https://doi.org/10.1101/2025.06.25.661123
Mol Ther. 2025 Jul 16. pii: S1525-0016(25)00539-8. [Epub ahead of print]

GDF11 secreting cell transplant efficiently ameliorates age-related pulmonary fibrosis.

Li Guo, Pascal Duchesneau, Eric D Jong, Evan Sawula, Chengjin Li, Thomas K Waddell, Andras Nagy.

Here, we present a combination of cell and gene therapy that harnesses the regenerative properties of GDF11 in age-related pulmonary fibrosis. Our genome-edited SafeCell-GDF11 mouse ESC line provides controlled proliferation and efficient derivation to lung progenitors while inducibly expressing GDF11. When these cells were transplanted into bleomycin-injured aged mice, they acted as a source of reparative cells, restoring the damaged alveolar epithelium. Furthermore, the transplanted cells acted as an "in situ factory", enabling the production of GDF11 in response to the inducer drug. This approach attenuated age-associated senescence and led to the successful resolution of fibrosis. Our study presents a GDF11-expressing cell-based strategy that demonstrates the feasibility of promoting alveolar regeneration in a mouse model of age-related pulmonary fibrosis. Additionally, this approach offers a versatile tool that can be expanded to incorporate other regenerative and anti-aging factors. This helps overcome limitations such as high production costs and a short half-life of therapeutic factors. One of the strengths of our system is its ability to allow precise regulation of factor-expression when needed to address specific aging phenotypes.

DOI: https://doi.org/10.1016/j.ymthe.2025.07.003
Stem Cell Res Ther. 2025 Jul 15. 16(1): 365

Human adipose-derived stem cell exosomes reduce mitochondrial DNA common deletion through PINK1/Parkin-mediated mitophagy to improve skin photoaging.

Yihao Wang, Wanxing Liao, Yiping Wang, Junlin Liao, Nian Chen, Chiyu Jia, Li Zeng.

   BACKGROUD: Mitochondrial DNA (mtDNA) deletion and oxidative stress are key contributors to skin photoaging. Mitophagy helps mitigate oxidative stress. Human adipose-derived stem cell exosomes (hADSC-Exos) have been shown to counteract skin photoaging. This study aimed to explore the role and mechanism of hADSC-Exos in addressing skin photoaging.
METHODS: hADSC-Exos were isolated, and their surface markers were identified. Human dermal fibroblasts (HDFs) and nude mice were exposed to ultraviolet-B (UVB) irradiation, and treated with hADSC-Exos. Oxidative stress and photoaging were assessed through SA-β-gal staining, p21 expression, mtDNA deletion, reactive oxygen species (ROS) levels, and histological analysis. The PINK1, Parkin, LC3b, and p62 protein levels were measured to evaluate mitophagy. The PINK1 small-interfering RNA (siPINK1) was then used in HDFs to investigate the role of hADSC-Exos in mitophagy.
RESULTS: In UVB-exposed HDFs and nude mice, the number of SA-β-gal-positive cells, along with levels of p21, ROS, and mtDNA deletion, were significantly increased, but these effects were reduced by hADSC-Exos. Moreover, hADSC-Exos treatment significantly elevated PINK1 and Parkin levels, as well as the LC3bII/I ratio, while reducing p62 expression. In photoaged HDFs treated with hADSC-Exos, PINK1 knockout using siRNA decreased the LC3bII/I ratio and levels of PINK1 and Parkin, while increasing p62, ROS, and mtDNA deletion compared to the negative control (NC) group.
CONCLUSION: hADSC-Exos can mitigate skin photoaging by promoting PINK1/Parkin-mediated mitophagy, thereby reducing mtDNA deletion and oxidative stress.

Keywords:  Exosomes; Human adipose-derived stem cell; Mitophagy; Oxidative stress; Photoaging; mtdna common deletion

DOI:  https://doi.org/10.1186/s13287-025-04475-3
bioRxiv. 2025 Jul 12. pii: 2025.07.09.664003. [Epub ahead of print]

Refate identifies chemical compounds to target trans-regulatory networks for cellular conversion.

Di Xiao, Sonu Sahadevan, Melissa M Mangala, Hani Jieun Kim, Anna Fredericks, Hao Huang, Raja Jothi, Patrick Tam, Anai Gonzalez-Cordero, Katherine G Zyner, Pengyi Yang.

Identifying chemical compounds that target trans-regulatory networks (TRNs) underlying molecular programs of cells for directed cellular conversion (i.e. differentiation, reprogramming, transdifferentiation, and dedifferentiation) is a key step towards advancing regenerative medicine. Recent innovations in single-cell omics technologies enabled high-resolution profiling of TRNs that govern cell identity and cell-fate decisions. Here, we introduce Refate, a computational framework that integrates large-scale multimodal single-cell atlas data to quantify cell propensity of genes, together with six drug databases, to identify chemical compounds that target TRNs for directed cellular conversion. The reconstructed TRNs, including protein-protein interactions and gene regulatory networks, alongside chemical compounds that drive the cellular conversion provide greater biological interpretability and improve efficiency and efficacy. We evaluated Refate by testing its ability to uncover known transcription factors and chemical compounds validated in experimental conversions of various cell types. Furthermore, we experimentally validated the attribute of several novel chemical compounds identified by Refate for enhancing the conversion of human embryonic stem cells to human cranial neural crest cells. Together, these findings demonstrate Refate as an effective tool for discovering chemical compounds that target TRNs to enable cellular conversion, advancing efforts towards regenerative medicine.
Highlights: Refate quantifies genes for cellular conversion using multimodal single-cell atlasesRefate uncovers trans-regulatory networks (TRNs) underlying cellular conversionRefate identifies chemical compounds that target TRNs for cellular conversionValidation of Refate identified chemical compounds for hESC to hCNCC conversion.

DOI: https://doi.org/10.1101/2025.07.09.664003
Elife. 2025 Jul 16. pii: RP103073. [Epub ahead of print]13

Therapeutic effects of PDGF-AB/BB against cellular senescence in human intervertebral disc.

Changli Zhang, Martha Elena Diaz-Hernandez, Takanori Fukunaga, Sreekala Shenoy, Sangwook Tim Yoon, Lisbet Haglund, Hicham Drissi.

  Accumulation of senescent cells is closely linked with intervertebral disc (IVD) degeneration, a prevalent age-dependent chronic disorder causing low back pain. While previous studies have highlighted that platelet-derived growth factor (PDGF) mitigated IVD degeneration through anti-apoptotic and pro-anabolic effects, its impact on IVD cell senescence remains elusive. In this study, human NP and AF cells derived from aged, degenerated IVDs were treated with recombinant human (rh) PDGF-AB/BB for 5 d. Transcriptome profiling by mRNA sequencing revealed that NP and AF cells responded to the treatment in similar yet distinct ways. The effects of PDGF-AB and BB on human IVD cells were comparable. Specifically, rhPDGF-AB/BB treatment downregulated genes related to neurogenesis and mechanical stimulus response in AF cells, while in NP cells, metabolic pathways were predominantly suppressed. In both NP and AF cells, rhPDGF-AB/BB treatment upregulated genes involved in cell cycle regulation and response to reduced oxygen levels, while downregulating genes related to senescence-associated phenotype, including oxidative stress, reactive oxygen species (ROS), and mitochondria dysfunction. Network analysis revealed that PDGFRA and IL6 were the top hub genes in treated NP cells. Furthermore, in irradiation-induced senescent NP cells, PDGFRA gene expression was significantly reduced compared to non-irradiated cells. However, rhPDGF-AB/BB treatment increased PDGFRA expression and mitigated the senescence progression through increased cell population in the S phase, reduced SA-β-Gal activity, and decreased expression of senescence-related regulators. Our findings reveal a novel anti-senescence role of PDGF in the IVD, making it a promising potential candidate to delay aging-induced IVD degeneration.

Keywords:  PDGF; cellular senescence; human; intervertebral disc degeneration; irradiation; medicine; oxidative stress; reactive oxygen species

DOI:  https://doi.org/10.7554/eLife.103073
Sci Adv. 2025 Jul 18. 11(29): eadv6642

Heterochronic parabiosis uncovers AdipoR1 as a critical player in retinal rejuvenation.

Yidan Liu, Xiuxing Liu, Jianjie Lv, Qi Zhang, Zhenlan Yang, Xuhao Chen, Chenyang Gu, Chun Zhang, Yehong Zhuo, Wenru Su.

Aging induces substantial structural and functional decline in the retina, yet the molecular drivers of this process remain elusive. In this study, we used heterochronic parabiosis (HP) combined with single-cell RNA sequencing to generate comprehensive transcriptomic profiles of murine retinas from young, aged, and HP pairs, aiming to identify antiaging targets. Our analysis revealed extensive transcriptional alterations across retinal cell types with aging. HP experiments demonstrated that systemic factors from young mice rejuvenated aged retinas and alleviated senescent phenotypes, while aged blood accelerated aging in young mice. Integrative analysis pinpointed adiponectin receptor 1 (AdipoR1) and the downstream adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling pathway as central to the molecular mechanisms underlying retinal rejuvenation. Treatment with the AdipoR1 agonist AdipoRon reversed retinal aging. Mechanistically, AdipoR1-AMPK activation promoted mitochondrial function, contributing to the restoration of youthful cellular phenotypes. Together, our study identifies AdipoR1 as a therapeutic target for retinal aging and provides insights into the molecular programs driving retinal rejuvenation.

DOI: https://doi.org/10.1126/sciadv.adv6642
Nat Aging. 2025 Jul 11.

Characterizing primary and secondary senescence in vivo.

Yuko Sogabe, Hirofumi Shibata, Mio Kabata, Akito Tanaka, Kanae Mitsunaga, Kazunori Sunadome, May Nakajima-Koyama, Michitada Hirano, Eisuke Nishida, Knut Woltjen, Hiroshi Seno, Yasuhiro Yamada, Takuya Yamamoto.

There is robust evidence that senescence can be propagated in vitro through mechanisms including the senescence-associated secretory phenotype, resulting in the non-cell-autonomous induction of secondary senescence. However, the induction, regulation and physiological role of secondary senescence in vivo remain largely unclear. Here we generated senescence-inducible mouse models expressing either the constitutively active form of MEK1 or MKK6 and mCherry, to map primary and secondary senescent cells. Our models recapitulate characteristic features of senescence and demonstrate that primary and secondary phenotypes are highly tissue- and inducer-dependent. Spatially resolved RNA expression analyses at the single-cell level reveal that each senescence induction results in a unique transcriptional profile-even within cells of the same cell type-explaining the heterogeneity of senescent cells in vivo. Furthermore, we show that interleukin-1β, primarily derived from macrophages, induces secondary phenotypes. Our findings provide insight into secondary senescence in vivo and useful tools for understanding and manipulating senescence during aging.

DOI: https://doi.org/10.1038/s43587-025-00917-y
Front Cell Dev Biol. 2025 ;13 1625357

Interplay between MAPK signaling pathway and autophagy in skin aging: mechanistic insights and therapeutic implications.

Xu Liu, Bo Chen, Xuefeng Liu, Xiaoqing Zhang, Jingdong Wu.

  Skin aging manifests as structural degradation, functional decline, and heightened disease susceptibility. Central to this process is the overactivation of the mitogen-activated protein kinase (MAPK) signaling pathway triggered by reactive oxygen species (ROS). Autophagy, a lysosomal degradation mechanism essential for maintaining cellular homeostasis, demonstrates context-dependent duality in skin aging by mediating cytoprotective effects and stress-induced dysfunction. Emerging evidence highlights that the interplay between MAPK signaling and autophagy critically modulates skin aging progression. Despite its therapeutic potential, the lack of effective targeting strategies severely hinders clinical translation. Therefore, this review synthesizes current evidence on MAPK-autophagy interplay across key cutaneous cell populations, namely, keratinocytes, fibroblasts, and melanocytes (including melanoma), revealing cell-type-specific regulatory networks that influence skin aging. Subsequently, we explore the therapeutic potential of natural bioactive compounds targeting this interplay to accelerate the translation of evidence into the progression of strategies for combating skin aging.

Keywords:  MAPK; autophagy; interplay; natural bioactive compounds; skin aging

DOI:  https://doi.org/10.3389/fcell.2025.1625357
Polymers (Basel). 2025 Jun 30. pii: 1826. [Epub ahead of print]17(13):

Poly-L-Lactic Acid Filler Increases Adipogenesis and Adiponectin in Aged Subcutaneous Tissue.

Seyeon Oh, Nala Shin, Sang Ju Lee, Kuk Hui Son, Kyunghee Byun.

  Poly-L-lactic acid (PLLA) filler, which increases volume and collagen synthesis, is used for skin rejuvenation. Subcutaneous adipose tissue (SAT) contains precursors that differentiate into mature adipocytes that secrete adiponectin, which modulates SAT function and increases adipogenesis. During aging, adiponectin and precursor cell functions decrease, reducing adipogenesis and facial volume. Adiponectin also increases collagen synthesis by stimulating fibroblasts. After hydrogen peroxide treatment to induce senescent adipocytes (3T3-L1) and aged skin, follow-up PLLA treatment increased adipogenesis by stimulating the nuclear factor erythroid-2-related factor 2 (NRF2)/peroxisome proliferator-activated receptor gamma (PPARγ)/CCAAT/enhancer binding protein alpha (C/EBPα) pathway. This resulted in increased adiponectin secretion, which promoted collagen synthesis and mitigated the loss of SAT volume. In the senescent adipocyte, PLLA increased NRF2/PPARγ/C/EBPα, adipogenesis factors (fatty acid binding protein 4, lipoprotein lipase, and cluster of differentiation 36), lipogenesis factors (ATP citrate lyase, acetyl-CoA carboxylase, and fatty acid synthase), adiponectin, and lipid droplet size. Treatment of senescent fibroblasts with conditioned medium from PLLA-treated adipocytes increased collagen1 and 3 and decreased matrix metalloproteinase1 and 3 expressions. Similarly, PLLA increased NRF2/PPARγ/C/EBPα, adipogenesis, and lipogenesis factors in aged mouse SAT. Also, PLLA increased adiponectin and adipocyte numbers without hypertrophy and increased collagen accumulation and dermal thickness. In summary, PLLA increased adipogenesis and adiponectin, which increased the volume of SAT and collagen synthesis, thereby rejuvenating aged skin.

Keywords:  adipogenesis; poly-L-lactic acid; skin rejuvenation

DOI:  https://doi.org/10.3390/polym17131826
Adv Healthc Mater. 2025 Jul 15. e2501164

Dual-Functional Nanoparticles to Reverse Osteoblast Senescence and Enhance Calcium Supplementation for Alleviating Senile Osteoporosis.

Caini Yu, Yanling Peng, Tong Yu, Jia Ke, Qi Jiang, Peirong Li, Renxiang Yuan, Tingting Meng, Fuqiang Hu, Jianwei Wang, Hong Yuan.

  Senile osteoporosis (SOP) primarily arises from an imbalance between bone formation and bone resorption. The tightly regulated coupling between osteoblasts and osteoclasts limits the therapeutic efficacy of conventional anti-resorptive agents and anabolic agents. Anti-aging therapy offers a potential strategy to modify the senescent phenotype of bone-associated cells, restore cellular function, and re-establish homeostasis between bone resorption and formation. Calcium-based nanoparticles can effectively deliver therapeutic agents to target sites while simultaneously supplying exogenous calcium. Moreover, restored osteoblast function enhances the cellular capacity to process supplemented exogenous calcium ions, ultimately increasing bone density and further alleviating osteoporosis. In this context, a dual-functional calcium carbonate nanoparticle is engineered. This nanoparticle facilitates the complexation of nicotinamide mononucleotide, enabling targeted delivery to osteoblasts, reversing osteoblast senescence, and restoring their osteogenic function. Simultaneously, through calcium supplementation, the nanoparticle promotes osteoblast differentiation and mineralization. In vitro and in vivo studies have demonstrated the promising therapeutic efficacy of this nanoparticle in treating SOP, providing critical insights for the future development of integrated anti-senescence therapies and calcium supplementation strategies.

Keywords:  amorphous calcium carbonate; nicotinamide mononucleotide; senescent osteoblast; senile osteoporosis; targeted nanoparticles

DOI:  https://doi.org/10.1002/adhm.202501164
Clin Cosmet Investig Dermatol. 2025 ;18 1683-1702

Effects of Exosomes From Hypoxia-Induced Adipose-Derived Stem Cells on Ameliorating Photoaging.

Cuc Bach Huynh, Ngoc Bich Vu, Trung The Van, Phuc Van Pham.

   Introduction: Photoaging, a significant concern in cosmetic dermatology, involves complex skin damage that necessitates effective treatments. Exosomes derived from adipose-derived stem cells (ADSCs), particularly those generated under hypoxic conditions (hypADSC-Exo), have emerged as a promising cell-free therapeutic approach. This study investigates the effects of hypADSC-Exo on reducing human dermal fibroblast (HDF) senescence and mitigating signs of photoaging through topical application in a mouse model.
Methods: Exosomes were isolated from hypoxia-induced human ADSCs via ultracentrifugation and identified using flow cytometry (CD9, CD63, CD81). Transmission electron microscopy (TEM) confirmed the vesicle morphology, while the Bradford assay and nanoparticle tracking analysis (NTA) assessed the protein content and size. In vitro, UV-induced senescent HDFs were treated with hypADSC-Exo. Cell morphology, senescence (SA-β-gal assay), proliferation (Alamar Blue), and gene expression (p16, p21 via qPCR) were evaluated. In vivo, photoaged mice received hypADSC-Exo treatments (50 or 100 μg/mL) twice weekly for six weeks. Skin parameters (wrinkles, thickness, hydration, elasticity) were evaluated biweekly. Skin biopsies were used to assess epidermal and dermal thickness, collagen density, and gene expression of collagen types 1, 3 and MMP-1, 2, and 3.
Results: hypADSC-Exo exhibited a cup-shaped morphology under TEM and expressed exosomal markers CD9, CD63, and CD81. In vitro, hypADSC-Exo improved HDF morphology, reduced SA-β-gal activity, enhanced proliferation, and downregulated p16 and p21. In vivo, it reduced skin wrinkles and thickness. Treated mice exhibited improvement in hydration, elasticity, decreased epidermal and dermal thickness, and increased collagen density. Collagen types 1 and 3 increased slightly, while the levels of MMP-1, 2, and 3 decreased in the exosome group.
Conclusion: Our findings demonstrate that hypADSC-Exo reduces senescence in UV-induced aged HDF and improves photoaging in mice. These effects likely result from decreased MMP-1, 2, 3 expression and increased collagen deposition, making hypADSC-Exo a promising therapy for photoaging.

Keywords:  adipose-derived stem cell; hypoxic exosome; photoaging; senescent dermal fibroblast

DOI:  https://doi.org/10.2147/CCID.S523936
Nat Aging. 2025 Jul 14.

Extracellular vesicles from antler blastema progenitor cells reverse bone loss and mitigate aging-related phenotypes in mice and macaques.

Yiming Hao, Beibei Yu, Mingze Qin, Tao Qin, Jianhong Wang, Yitao Wei, Chengxiang Zhao, Yaowen Xing, Yuan Yuan, Tingfeng Xue, Borui Xue, Yali Zhang, Hongdi Huang, Xiaomei Yu, Yunchao Ji, Minghao Qiu, Yufang Zhou, Bing Xia, Teng Ma, Shengyou Li, Haining Wu, Xue Gao, Yujie Yang, Lingli Guo, Yongfeng Zhang, Zhenguo Wang, Huiling Sun, Xueli Gao, Zujian Huang, Longbao Lv, Dongdong Wu, Zhipeng Li, Yonggang Yao, Wen Wang, Zhuojing Luo, Qiang Qiu, Jinghui Huang.

Antler blastema progenitor cells (ABPCs) are a distinct population of skeletal mesenchymal stem cells found in regenerating deer antlers, with strong stemness and renewal capacity in vitro. Stem cell-derived extracellular vesicles (EVs) are emerging as potential therapeutic candidates that can mediate donor cells' beneficial effects. Here, we tested the effects of ABPC-derived EVs (EVsABPC) on aging in mice and rhesus macaques (Macaca mulatta). We identified a variety of unique factors in EVsABPC and showed that in vitro, EVsABPC attenuated phenotypes of senescence in bone marrow stem cells. In aged mice and macaques, EVsABPC substantially increased femoral bone mineral density. Further, intravenous EVsABPC improved physical performance, enhanced cognitive function and reduced systemic inflammation in aged mice, while reversing epigenetic age by over 3 months. In macaques, EVABPC treatment was also neuroprotective, reduced inflammation, improved locomotor function and reduced epigenetic age by over 2 years. Our findings position ABPCs as an emerging and practical source of EVs with translational value for healthy aging interventions.

DOI: https://doi.org/10.1038/s43587-025-00918-x