bims-caglex Biomed News
on Cellular aging and life extension
Issue of 2025–06–22
fourteen papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño
  1. NAD+ glycohydrolases-CD38 as a therapeutic target in aging: physiological roles, molecular mechanisms, and future opportunities in anti-aging research.
  2. Pyrroloquinoline Quinone Is an Effective Senomorphic Agent to Target the Pro-Inflammatory Phenotype of Senescent Cells.
  3. Rapamycin, Not Metformin, Mirrors Dietary Restriction-Driven Lifespan Extension in Vertebrates: A Meta-Analysis.
  4. FGF21 promotes longevity in diet-induced obesity through metabolic benefits independent of growth suppression.
  5. Multiomic profiling reveals that prostaglandin E2 reverses aged muscle stem cell dysfunction, leading to increased regeneration and strength.
  6. Photoactivatable Exosenolytics Activate Natural Killer Cells for Delaying Osteoarthritis.
  7. Stem Cell-Derived Extracellular Vesicles in Skin Antiaging Treatments.
  8. Klotho Protein: A Multifaceted Guardian of Healthy Aging and Its Therapeutic Potential.
  9. Skin health and biological aging.
  10. Dietary compounds activates sirtuins - a computational modeling approach towards the management of ageing.
  11. Extracellular vesicles in skin health and diseases.
  12. Epigenetic Reprogramming as a Therapeutic Strategy for Neurodegenerative Diseases: A Complex and Novel Approach.
  13. Precise Progerin Targeting Using RfxCas13d: A Therapeutic Avenue for Hutchinson-Gilford Progeria Syndrome.
  14. A review of regenerative medicine and tissue engineering with a focus on wound healing and anti-aging.
  1. Biochem Pharmacol. 2025 Jun 12. pii: S0006-2952(25)00315-6. [Epub ahead of print] 117050
    NAD+ glycohydrolases-CD38 as a therapeutic target in aging: physiological roles, molecular mechanisms, and future opportunities in anti-aging research.
    Jing-Yu Sun, Zhi-Fei Wang, Wen-Hui Xu, Jun Zhao.
      As individuals age, tissue homeostasis and functionality gradually deteriorate, leading to the occurrence and advancement of age-related illnesses. Nicotinamide adenine dinucleotide (NAD+) is essential for metabolism and cellular energy generation. The significance of maintaining adequate the levels of NAD+ within biological systems to ameliorate age-related tissue degeneration and prevent age-related illnesses in senescent animals is now widely recognized, emphasizing the importance of increasing NAD+ levels. Cluster of differentiation 38 (CD38), a multifunctional enzyme, plays a significant role in maintaining the cellular equilibrium of NAD+ through the consumption of NAD+. Recent research has shown a correlation between aging and upregulation of CD38 expression, potentially resulting in a reduction in NAD+ with increasing age. In contrast, the lack of CD38 has been shown to have a beneficial effect on slowing the aging process. Consequently, CD38 has been increasingly identified as a potential therapeutic target for interventions aimed at combatting aging. This study investigated the physiological roles of CD38, its ramifications in the aging process, possible molecular mechanisms associated with its involvement in aging-related diseases, and possible therapeutic applications of small-molecule inhibitors targeting CD38 in the context of aging. In this review, we provide a comprehensive analysis of the potential applications and future opportunities of CD38 in anti-aging research.
    Keywords:  Aging; Anti-aging regulatory target; CD38; CD38 small-molecule inhibitors; Nicotinamide adenine dinucleotide
    DOI:  https://doi.org/10.1016/j.bcp.2025.117050
  2. Aging Cell. 2025 Jun 19. e70138
    Pyrroloquinoline Quinone Is an Effective Senomorphic Agent to Target the Pro-Inflammatory Phenotype of Senescent Cells.
    Birong Jiang, Hongwei Zhang, Qixia Xu, Zhirui Jiang, Ruikun He, Qiang Fu, Yu Sun.
      Cellular senescence is an aging-related mechanism characterized by cell cycle arrest, macromolecular alterations, and a senescence-associated secretory phenotype (SASP). Recent preclinical trials established that senolytic drugs, which target survival mechanisms of senescent cells, can effectively intervene in age-related pathologies. In contrast, senomorphic agents inhibiting SASP expression while preserving the survival of senescent cells have received relatively less attention, with potential benefits hitherto underexplored. By revisiting a previously screened natural product library, which enabled the discovery of procyanidin C1 (PCC1), we noticed pyrroloquinoline quinone (PQQ), a redox cofactor that displayed remarkable potential in serving as a senomorphic agent. In vitro data suggested that PQQ downregulated the full spectrum expression of the SASP, a capacity observed in several stromal cell lines. Proteomics data supported that PQQ directly targets the intracellular protein HSPA8, interference with which disturbs downstream signaling and expression of the SASP. PQQ restrains cancer cell malignancy conferred by senescent stromal cells in culture while reducing drug resistance when combined with chemotherapy in anticancer regimens. In preclinical trials, PQQ alleviates pathological symptoms by preventing organ degeneration in naturally aged mice while reserving senescent cells in the tissue microenvironment. Together, our study supports the feasibility of exploiting a redox-active quinone molecule with senomorphic capacity to achieve geroprotective effects by modulating the SASP, thus providing proof-of-concept evidence for future exploration of natural antioxidant agents to delay aging and ameliorate age-related conditions. Prospective efforts are warranted to determine long-term outcomes and the potential of PQQ for the intervention of geriatric syndromes in clinical settings.
    Keywords:  SASP; age‐related pathologies; aging; cellular senescence; pyrroloquinoline quinone; senomorphics
    DOI:  https://doi.org/10.1111/acel.70138
  3. Aging Cell. 2025 Jun 18. e70131
    Rapamycin, Not Metformin, Mirrors Dietary Restriction-Driven Lifespan Extension in Vertebrates: A Meta-Analysis.
    Edward R Ivimey-Cook, Zahida Sultanova, Alexei A Maklakov.
      Dietary restriction (DR) robustly increases lifespan across taxa. However, in humans, long-term DR is difficult to maintain, leading to the search for compounds that regulate metabolism and increase lifespan without reducing caloric intake. The magnitude of lifespan extension from two such compounds, rapamycin and metformin, remains inconclusive, particularly in vertebrates. Here, we conducted a meta-analysis comparing lifespan extension conferred by rapamycin and metformin to DR-mediated lifespan extension across vertebrates. We assessed whether these effects were sex- and, when considering DR, treatment-specific. In total, we analysed 911 effect sizes from 167 papers covering eight different vertebrate species. We find that DR robustly extends lifespan across log-response means and medians and, importantly, rapamycin-but not metformin-produced a significant lifespan extension. We also observed no consistent effect of sex across all treatments and log-response measures. Furthermore, we found that the effect of DR was robust to differences in the type of DR methodology used. However, high heterogeneity and significant publication bias influenced results across all treatments. Additionally, results were sensitive to how lifespan was reported, although some consistent patterns still emerged. Overall, this study suggests that rapamycin and DR confer comparable lifespan extension across a broad range of vertebrates.
    Keywords:  dietary restriction; lifespan extension; meta‐analysis; metformin; rapamycin; vertebrate
    DOI:  https://doi.org/10.1111/acel.70131
  4. Cell Metab. 2025 Jun 12. pii: S1550-4131(25)00267-0. [Epub ahead of print]
    FGF21 promotes longevity in diet-induced obesity through metabolic benefits independent of growth suppression.
    Christy M Gliniak, Ruth Gordillo, Yun-Hee Youm, Qian Lin, Clair Crewe, Zhuzhen Zhang, Bianca C Field, Teppei Fujikawa, Megan Virostek, Shangang Zhao, Yi Zhu, Clifford J Rosen, Tamas L Horvath, Vishwa Deep Dixit, Philipp E Scherer.
      Approximately 35% of US adults over 65 are obese, highlighting the need for therapies targeting age-related metabolic issues. Fibroblast growth factor 21 (FGF21), a hormone mainly produced by the liver, improves metabolism and extends lifespan. To explore its effects without developmental confounders, we generated mice with adipocyte-specific FGF21 overexpression beginning in adulthood. When fed a high-fat diet, these mice lived up to 3.3 years, resisted weight gain, improved insulin sensitivity, and showed reduced liver steatosis. Aged transgenic mice also displayed lower levels of inflammatory immune cells and lipotoxic ceramides in visceral adipose tissue, benefits that occurred even in the absence of adiponectin, a hormone known to regulate ceramide breakdown. These results suggest that fat tissue is a central site for FGF21's beneficial effects and point to its potential for treating metabolic syndrome and age-related diseases by promoting a healthier metabolic profile under dietary stress and extending healthspan and lifespan.
    Keywords:  FGF21; adipocytes; adiponectin; adipose tissue; aging; ceramides; inflammation; insulin sensitivity; longevity; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2025.05.011
  5. Cell Stem Cell. 2025 Jun 10. pii: S1934-5909(25)00192-4. [Epub ahead of print]
    Multiomic profiling reveals that prostaglandin E2 reverses aged muscle stem cell dysfunction, leading to increased regeneration and strength.
    Yu Xin Wang, Adelaida R Palla, Andrew T V Ho, Daniel C L Robinson, Meenakshi Ravichandran, Glenn J Markov, Thach Mai, Chris Still, Akshay Balsubramani, Surag Nair, Colin A Holbrook, Ann V Yang, Peggy E Kraft, Shiqi Su, David M Burns, Nora D Yucel, Lei S Qi, Anshul Kundaje, Helen M Blau.
      Repair of muscle damage declines with age due to the accumulation of dysfunctional muscle stem cells (MuSCs). Here, we uncover that aged MuSCs have blunted prostaglandin E2 (PGE2)-EP4 receptor signaling, which causes precocious commitment and mitotic catastrophe. Treatment with PGE2 alters chromatin accessibility and overcomes the dysfunctional aged MuSC fate trajectory, increasing viability and triggering cell cycle re-entry. We employ neural network models to learn the complex logic of transcription factors driving the change in accessibility. After PGE2 treatment, we detect increased transcription factor binding at sites with CRE and E-box motifs and reduced binding at sites with AP1 motifs, overcoming the changes that occur with age. We find that short-term exposure of aged MuSCs to PGE2 augments their long-term regenerative capacity upon transplantation. Strikingly, PGE2 injections following myotoxin- or exercise-induced injury overcome the aged niche, leading to enhanced regenerative function of endogenous tissue-resident MuSCs and an increase in strength.
    Keywords:  Prostaglandin E2; aging; epigenetic remodeling; inflammaging; molecular memory; muscle stem cells; neural network analysis; regeneration; rejuvenation; sarcopenia
    DOI:  https://doi.org/10.1016/j.stem.2025.05.012
  6. ACS Nano. 2025 Jun 19.
    Photoactivatable Exosenolytics Activate Natural Killer Cells for Delaying Osteoarthritis.
    Lei Zhang, Kai Xiang, Jinlong Li, Muwei Hao, Zunshuai Zhu, Shaozhen Wang, Han Sun.
      Osteoarthritis (OA) is a classic age-related disorder, and its progression is positively associated with the number of senescent cells in the synovium of the joint. Senolytics have been used to slow or reverse the aging process, which is currently limited by off-target toxicity. Therapeutic efficacy can be achieved by enhancing the immune-mediated clearance of senescent cells. However, the surveillance of senescent cells by the immune system is often hindered by immunosuppressive factors within the inflammatory microenvironment. Herein, we constructed photoactivatable exosenolytics based on microphage-derived exosomes adorned with the gripper ligand aPD-L1 and aging cell-targeting ligands, encapsulating with a photosensitizer and NKG2D ligand activator for the precise antiaging treatment of OA. Exosenolytic-mediated photodynamic therapy can induce the recruitment of natural killer (NK) cells, enhance the gripping effect of NK cells to senescent fibroblast-like synoviocytes, and strengthen the immune system for clearance of senescent synovial cells by activating the cGAS-STING pathway. Importantly, exosenolytics selectively accumulated in senescent fibroblast-like synoviocytes in the inflamed joints of OA mice and effectively suppressed synovial inflammation and progression of OA. Exosenolytics employ an immunological conversion strategy to remodel the senescent immune microenvironment, offering a promising approach for aging immunotherapy.
    Keywords:  GAS-STING pathway; exosenolytics; immunotherapy; natural killer cells; osteoarthritis; senescent fibroblast-like synoviocytes
    DOI:  https://doi.org/10.1021/acsnano.5c03344
  7. ACS Nano. 2025 Jun 17.
    Stem Cell-Derived Extracellular Vesicles in Skin Antiaging Treatments.
    Ji Yeong Park, Se Young Jung, Donghyeon Yoo, Sihun Lee, Dabin Go, Van Dat Bui, Won-Kyo Jung, Dong Gil You, Jae Hyung Park, Wooram Um.
      As the median age of the global population rises and the demand for aesthetic enhancement increases, interest in antiaging skin technologies has been growing significantly. This review first addresses the molecular mechanisms underlying skin aging, followed by an overview of traditional antiaging approaches and their benefits and limitations. Furthermore, it emphasizes the potential of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) as promising alternatives to address the shortcomings of conventional strategies. This article highlights the antiaging effects and therapeutic mechanisms of MSC-EVs in the skin microenvironment and identifies promising targets for skin antiaging interventions based on the functional properties of MSC-EVs. Finally, this review introduces the recent advances and future directions for MSC-EV-based antiaging strategies.
    Keywords:  antiaging therapies; exosomes; extracellular vesicles; regenerative medicines; regenerative therapies; skin aesthetics; skin aging; skin rejuvenation; stem cells
    DOI:  https://doi.org/10.1021/acsnano.4c17406
  8. Int J Nanomedicine. 2025 ;20 7251-7270
    Klotho Protein: A Multifaceted Guardian of Healthy Aging and Its Therapeutic Potential.
    Jianlin Shen, Wenying Bin, Xiaoning Lin, Yue Lai, Xuan Lin, Taiyuan Guan, Huan Liu.
      The Klotho protein, encoded by the KL gene, has garnered significant attention as a pivotal biomolecule in the field of aging research. Its expression levels are closely correlated with both lifespan and overall health status, exerting influence over critical physiological processes such as metabolic homeostasis, oxidative stress response, and inflammation modulation. This review aims to systematically examine the multifaceted roles of Klotho within the context of aging and its implications for various age-associated disorders. We highlight the emerging evidence suggesting that Klotho may serve as a key regulator in age-related pathologies, including cardiovascular diseases, neurodegenerative disorders, and metabolic syndromes. Furthermore, we explore the potential of Klotho as a therapeutic target, positing that interventions aimed at enhancing Klotho activity could offer novel strategies for alleviating the health burdens experienced by the aging population.
    Keywords:  Klotho; aging; inflammation; oxidative stress; population aging
    DOI:  https://doi.org/10.2147/IJN.S514516
  9. Nat Aging. 2025 Jun 17.
    Skin health and biological aging.
    David Furman, Johan Auwerx, Anne-Laure Bulteau, George Church, Virginie Couturaud, Laure Crabbe, Kelvin J A Davies, Anabelle Decottignies, Vadim N Gladyshev, Brian K Kennedy, Nicola Neretti, Carine Nizard, Karl Pays, Daisy Robinton, Vittorio Sebastiano, Rachel E B Watson, Meng C Wang, Knut Woltjen.
      Accumulating evidence indicates that biological aging can be accelerated by environmental exposures, collectively called the 'exposome'. The skin, as the largest and most exposed organ, can be viewed as a 'window' for the deep exploration of the exposome and its effects on systemic aging. The complex interplay across hallmarks of aging in the skin and systemic biological aging suggests that physiological processes associated with skin aging influence, and are influenced by, systemic hallmarks of aging. This bidirectional relationship provides potential avenues for the prevention of accelerated biological aging and the identification of therapeutic targets. We provide a review of the interactions between skin exposure, aging hallmarks in the skin and associated systemic changes, and their implications in treatment and disease. We also discuss key questions that need to be addressed to maintain skin and overall health, highlighting the need for the development of precise biomarkers and advanced skin models.
    DOI:  https://doi.org/10.1038/s43587-025-00901-6
  10. BMC Biotechnol. 2025 Jun 13. 25(1): 47
    Dietary compounds activates sirtuins - a computational modeling approach towards the management of ageing.
    Nail Besli, Mazhar T Kaya, Nilufer Ercin, Ulkan Celik.
      In biogerontology, researchers are actively exploring the manipulation of sirtuin proteins, a family of enzymes that play a crucial role in regulating lifespan and age-related diseases through bioactive compounds found in the diet. This report explores potential new insights by leveraging the innovative intersection of natural bioactive compounds and sirtuin modulation through computational drug design. Using state-of-the-art in silico techniques, including high throughput virtual screening (HTVS) and molecular dynamics (MD) simulation, the study identifies natural compounds from various dietary sources for sirtuin proteins (SIRT 1, 3, 6, 7) related to the cellular process in aging. HTVS was automated with the AutoDock-VINA to pinpoint the novel candidate bioactive compounds for sirtuins, while the MD was conducted with GROMACS. The top hits, fagopyrine, emblicanin B, epicatechin-(4beta- > 8)-epicatechin-(2beta- > 7,4beta- > 8)-catechin (epicatechin), withanolide, and dulcisisoflavone, had superior docking scores ranging from - 12.7 to - 7.2 kcal/mol. The MD displayed steady interactions between target proteins and biocompounds throughout 100 ns without significant conformational shifts. This paper contributes significantly to anti-aging research by presenting a novel, computationally efficient approach to discovering and developing sirtuin-modulating compounds. Highlighting the untapped potential of natural bioactive substances in modulating key biological pathways associated with aging opens new avenues for future experimental exploration of diet-based therapeutic strategies that may support healthy aging.
    Keywords:  Bioactive compound; Healthy-longevity; Molecular dynamics simulation; Sirtuin proteins; Virtual screening
    DOI:  https://doi.org/10.1186/s12896-025-00985-3
  11. Life Sci. 2025 Jun 15. pii: S0024-3205(25)00448-5. [Epub ahead of print] 123813
    Extracellular vesicles in skin health and diseases.
    Wei Fang, Guizhen Wang, Ling Lin, Amir Ajoolabady, Jun Ren.
      The global burden of skin diseases has markedly increased in recent years, posing significant socioeconomic challenges. Although recent technological advances in dermatological care aim to address these issues, further research is needed to develop effective and innovative strategies. Intercellular communication plays a vital role in skin regeneration and repair. Extracellular vesicles (EVs), lipid bilayer-enclosed particles released by nearly all cell types, are categorized into exosomes, microvesicles, and apoptotic bodies based on their biogenesis and size. EVs carry diverse bioactive molecules, including proteins, lipids, and nucleic acids, enabling them to mediate critical cell-cell communication. Recent breakthroughs, particularly through spatially resolved multi-omics approaches, have underscored the essential roles of EVs in both physiological and pathological processes of the skin. In this review, we provide a comprehensive overview of EV biology, with a particular focus on their functions in skin homeostasis, aging, and diseases. We highlight emerging evidence of their therapeutic potential in preclinical models, with emphasis on EV interactions with various skin cell types, inflammatory and autoimmune skin conditions, skin aging, and tissue repair.
    Keywords:  Extracellular vesicles; Skin aging; Skin autoimmune diseases; Skin inflammatory diseases; Therapeutic applications
    DOI:  https://doi.org/10.1016/j.lfs.2025.123813
  12. Eur J Pharmacol. 2025 Jun 18. pii: S0014-2999(25)00607-7. [Epub ahead of print] 177853
    Epigenetic Reprogramming as a Therapeutic Strategy for Neurodegenerative Diseases: A Complex and Novel Approach.
    Abdullah Alkhammash, Ghallab Alotaibi.
      Epigenetic reprogramming has emerged as a promising therapeutic strategy for neurodegenerative diseases by targeting reversible gene expression changes without altering the underlying DNA sequence. This review explores key epigenetic mechanisms, including DNA methylation, histone modifications, non-coding RNAs, and chromatin remodeling, that contribute to neurodegeneration in Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Pharmacological interventions such as DNA methylation modulators, histone deacetylase (HDAC) inhibitors, and non-coding RNA therapies have shown potential in restoring normal gene function. Advanced approaches, including CRISPR-dCas9 epigenetic editing, synthetic transcription factors (STFs), and Yamanaka factor-mediated cellular rejuvenation, offer precise control over disease-associated gene expression. Despite these advancements, several challenges and controversies remain, including off-target effects, delivery limitations, long-term safety concerns, and ethical implications. Emerging research focuses on multi-target combination therapies, integrating epigenetic interventions with stem cell therapy, immune checkpoint inhibitors, and AI-driven precision medicine. Future directions involve the development of non-invasive drug delivery systems, AI-powered biomarker discovery, and personalized epigenome-based treatments to enhance therapeutic outcomes. As research advances, epigenetic reprogramming holds the potential to revolutionize neurodegenerative disease treatment, providing more effective, individualized, and disease-modifying interventions.
    Keywords:  CRISPR-dCas9; DNA methylation; Epigenetic reprogramming; histone modifications; neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177853
  13. Mol Ther. 2025 Jun 14. pii: S1525-0016(25)00468-X. [Epub ahead of print]
    Precise Progerin Targeting Using RfxCas13d: A Therapeutic Avenue for Hutchinson-Gilford Progeria Syndrome.
    Unbin Chae, Hae-Jun Yang, Hanseop Kim, Seung Hwan Lee, Dong Gil Lee, Jeong Young Koo, Seung-Min Ha, Seo-Jong Bak, Mina Joo, Hyun Hee Nam, Kyung-Seob Lim, Philyong Kang, Hee-Chang Son, You Jeong An, Young-Hyun Kim, In-Sung Song, Sang-Hee Lee, Hae Rim Kim, Sang-Mi Cho, Eun-Kyoung Kim, Ki-Hoan Nam, Kyung-Sook Chung, Jae-Yoon Kim, Seon-Yeop Kim, Seon-Kyu Kim, Seon-Young Kim, Dong-Seok Lee, Jin-Man Kim, Young-Ho Park, Sun-Uk Kim.
      Hutchinson-Gilford progeria syndrome (HGPS), an extremely rare progressive genetic disorder, is caused by a point mutation in LMNA that induces progerin production, which disrupts cellular function and triggers premature aging and mortality. Despite extensive efforts, HPGS remains incurable. We successfully implemented a strategy using RfxCas13d to selectively target progerin mRNA at specific junction regions, without unintended cleavage and reduce its expression. This technique discriminated between normal lamin A and progerin, thus providing a safe and targeted therapeutic avenue to treat HGPS. Our approach effectively restored aberrant gene expression and progerin-induced cellular phenotypes, including senescence, mitochondrial dysfunction, and DNA damage in cells with HGPS and LMNAG608G/G608G mice. Notably, LMNAG608G/G608G mice exhibited improved progeroid phenotypes, suggesting a potential therapeutic application of this approach for other diseases resulting from abnormal RNA splicing.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.06.017
  14. Front Surg. 2025 ;12 1504563
    A review of regenerative medicine and tissue engineering with a focus on wound healing and anti-aging.
    Ovya Ganesan, Harriet Kiwanuka, Ryoko Hamaguchi, Dennis P Orgill.
      Regenerative medicine and tissue engineering explore the potential to enhance human healing, which is often limited by wound contraction, scarring, loss of function, and decreased quality of life. Biomaterials like synthetic scaffolds and implantable devices have been developed to circumvent the body's limited natural ability to heal, however, they may introduce their own complications such as toxic side effects. Advances in cell-based therapies, especially those involving embryonic stem cells (ESCs) and human-induced pluripotent stem cells (hiPSCs), offer an enhanced ability to regenerate, circumventing limitations of biomaterials and the body's limited ability to heal. There have been many recent advances in cell-therapies, both scaffold-based and scaffold-free products. Additionally, non-cell-based therapies are gaining traction in wound healing. These products, utilizing their ability to affect the principles of wound healing, have applications in anti-aging. Despite these advances, significant challenges remain. These technologies remain costly, may compromise ethical tenets, and may introduce safety risks. Future work should address these challenges.
    Keywords:  aging; regenerative medicine; stem cells; tissue engineering; wound healing
    DOI:  https://doi.org/10.3389/fsurg.2025.1504563
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