bims-caglex Biomed News
on Cellular aging and life extension
Issue of 2025–07–13
ten papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño
  1. Applications of CRISPR-Cas9 in mitigating cellular senescence and age-related disease progression.
  2. Small molecule compound ZYZ-384 targets SMYD3 to alleviate aging.
  3. The lifespan-extending MEK1 inhibitor trametinib promotes regulation of de novo lipogenesis enzymes by chaperone-mediated autophagy.
  4. Rapamycin for longevity: the pros, the cons, and future perspectives.
  5. p300 inhibition delays premature cellular senescence.
  6. Psilocybin treatment extends cellular lifespan and improves survival of aged mice.
  7. [Expert consensus on the treatment of aging related to growth hormone deficiency].
  8. Advances in Photobiomodulation: Effects on Mesenchymal Stem Cells and their Paracrine Factors.
  9. Elimination of senescent cells with senolytic host-directed therapy reduces tuberculosis progression in mice.
  10. Molecular Regulation of SASP in Cellular Senescence: Therapeutic Implications and Translational Challenges.
  1. Clin Exp Med. 2025 Jul 08. 25(1): 237
    Applications of CRISPR-Cas9 in mitigating cellular senescence and age-related disease progression.
    Alireza Azani, Malihe Sharafi, Reyhaneh Doachi, Sama Akbarzadeh, Parsa Lorestani, Arash Haji Kamanaj Olia, Zahra Zahed, Hossein Gharedaghi, Haniyeh Ghasrsaz, Hassan Foroozand, Hossein Rahimi, Safa Tahmasebi, Qumars Behfar.
      Aging is a multifaceted process influenced by many elements. During cell division, the repetitive DNA sequences at the ends of chromosomes called telomeres protect them from degradation. Telomeres shorten alongside each cell division, eventually contributing to cellular senescence and aging. Telomerase as an enzyme has a role in the maintenance of telomere length. Reduced function of telomerase is linked to acceleration of aging and age-related diseases. By affecting cellular function, mutations in particular genes can cause aging. Genes involved in DNA repair, cellular metabolism, and inflammation play the key roles in this process. Accumulated mutations result in cellular dysfunction and age-related diseases over time. Epigenetic changes are the modifications that impact gene expression without altering the DNA sequence. Lifestyle factors (diet, exercise, stress) and environmental influences (toxins, trauma) can cause epigenetic alterations. DNA methylation as well as histone modifications are examples of epigenetic alterations. They influence how cells work and are essential to the aging process. Understanding these molecular mechanisms is essential for developing interventions to promote healthy aging and prevent age-related diseases. This paper explores the potential of CRISPR/Cas9 as a gene-editing tool to target these mechanisms and mitigate age-related conditions, ultimately enhancing longevity and quality of life.
    Keywords:  Aging; CRISPR-Cas9; Gene editing; Molecular and cellular mechanism
    DOI:  https://doi.org/10.1007/s10238-025-01771-3
  2. Sci Rep. 2025 Jul 10. 15(1): 24802
    Small molecule compound ZYZ-384 targets SMYD3 to alleviate aging.
    Yang Liu, Dan Han, Li Jin, Xuena Xie, Huibo Li, Qian Ding, Yizhun Zhu.
      SMYD3 is a chromatin modifier that facilitates the trimethylation of histone 3 lysine 4 (H3K4) to induce diverse biological activities. We have provided a brief demonstration of the anti-aging effect of ZYZ-384, a newly developed inhibitor targeting SMYD3. In order to validate the anti-senescence effect of ZYZ-384, we utilized angiotensin II to induce senescence in two types of human endothelial cells (HMEC-1) and mouse endothelial cells (SVEC4-10), creating cellular models for senescence. Additionally, we employed D-galactose-induced subacute senescence animal models as well as natural senescence animal models. At the cellular level, we assessed proliferation capacity and intracellular markers associated with aging. Aging markers, SASP and differential metabolites were evaluated at an organismal level using animal models. Compared to senescent cells or animals, ZYZ-384 application significantly inhibited levels of aging markers in both senescent cell and senescent animal models while promoting cell proliferation. Furthermore, it suppressed expression of SMYD3 and H3K4me3 along with over expression of HSP 90 and NF-κB. Our study demonstrates that ZYZ-384 is an effective inhibitor targeting SMYD3 which can effectively delay aging.
    Keywords:  Cell proliferation; Chromatin modifier; D-galactose; Senescence
    DOI:  https://doi.org/10.1038/s41598-025-10345-y
  3. Front Aging. 2025 ;6 1621808
    The lifespan-extending MEK1 inhibitor trametinib promotes regulation of de novo lipogenesis enzymes by chaperone-mediated autophagy.
    Jiexian Chen, Joshua Berg, Calvin M Burns, Hanyi Jia, Xinna Li, Richard A Miller, S Joseph Endicott, Gonzalo Garcia.
      The availability of multiple slow-aging mice allows a search for possible shared mechanisms that affect the rate of aging. Previous work has shown downregulation of the MEK1-ERK-MNK kinase cascade, which regulates protein translation through eIF4E, in response to four anti-aging drugs. Here we show that decreased protein abundance of enzymes involved in hepatic de novo lipogenesis (DNL) is characteristic of mice exposed to two anti-aging drugs that modulate glucose homeostasis (acarbose and canagliflozin), as well as in calorically restricted mice and in two long-lived mutant models. The same pattern of changes in the de novo lipogenesis enzymes can be produced, in cultured cells or in intact mice, by trametinib, a drug that inhibits the MEK-ERK kinase cascade, and which has been shown to extend mouse lifespan. The trametinib effect on DNL enzymes is, unexpectedly, not related to transcriptional changes, but depends on selective protein degradation through chaperone-mediated autophagy. Our data support models in which chaperone-mediated proteomic alterations, triggered through the MEK1-ERK-MNK kinase pathway, may collaborate with mTORC1 changes to slow aging and extend mouse lifespan.
    Keywords:  aging; chaperone-mediated autophagy (CMA); extracellular signal-regulated kinase (ERK); lifespan; longevity; signal transduction; transcriptional response
    DOI:  https://doi.org/10.3389/fragi.2025.1621808
  4. Front Aging. 2025 ;6 1628187
    Rapamycin for longevity: the pros, the cons, and future perspectives.
    Kelley M Roark, Philip H Iffland.
      Rapamycin, an antibiotic discovered in the 1970s from Streptomyces hygroscopicus on Easter Island (Rapanui), has become a critical tool in biomedical research. Initially recognized for its potent antifungal and immunosuppressive properties, rapamycin has recently gained significant attention for anti-aging therapy and seizure treatment via mTOR pathway inhibition. The mechanistic target of the rapamycin (mTOR) pathway is an evolutionarily conserved metabolic signaling cascade that regulates cell division, growth, and survival. There is growing evidence that mTOR pathway activity accelerates aging and the development of age-related diseases including cancer, atherosclerosis, diabetes, and declining immune function. Therefore physicians and "biohackers" are using mTOR inhibition via rapamycin (and rapamycin analogs) off-label for prevention of age-related conditions despite not being widely recognized as a treatment by the broader clinical community. Currently, rapamycin (i.e., sirolimus and everolimus) is FDA approved for the prevention of transplant organ rejection and for anti-seizure therapy in Tuberous Sclerosis Complex (TSC; caused by variants in TSC1 or 2). We aim to summarize the mTOR pathway, the impact rapamycin has on the mTOR pathway, and the state of rapamycin use in the field of aging and longevity. Importantly, we will discuss the gaps in knowledge, pitfalls, and potential for the use of rapamycin to prevent aging/age-related disease and discuss the lessons learned from achieving FDA approval of evirolimus for TSC-related seizures after many years of off-label use.
    Keywords:  aging; epilepsy; everolimus; mTOR; sirolimus
    DOI:  https://doi.org/10.3389/fragi.2025.1628187
  5. NPJ Aging. 2025 Jul 10. 11(1): 62
    p300 inhibition delays premature cellular senescence.
    Elisabetta Di Fede, Esi Taci, Silvia Castiglioni, Stefano Rebellato, Silvia Ancona, Paolo Grazioli, Chiara Parodi, Elisa Adele Colombo, Clara Bernardelli, Elena Lesma, Ian Daniel Krantz, Stefania Corti, Alberto Priori, Grazia Fazio, Cristina Gervasini, Valentina Massa, Antonella Lettieri.
      Cellular senescence represents a permanent state of cell cycle arrest, also observed in neurodegenerative disorders. As p300 has been identified as an epigenetic driver of replicative senescence, we aimed to investigate whether in vitro p300 inhibition could rescue the stress-induced premature senescence (SIPS) phenotype. We exploited 2D and 3D (brain organoids) in vitro models of SIPS using two different stressor agents. In addition, we combined the treatment with a p300 inhibitor and validated p300 role in SIPS by analyzing different senescence markers and the transcriptome in our models. Interestingly, p300 inhibition can counteract the DNA damage and SIPS phenotype, detecting a dysregulation of gene expression and protein translation associated with the senescence program. These findings highlight both the molecular mechanisms underlying senescence and p300 as a possible pharmacological target. Thus, targeting p300 and, by extension, senescent cells could represent a promising therapeutic strategy for age-related diseases such as neurodegenerative disorders.
    DOI:  https://doi.org/10.1038/s41514-025-00251-y
  6. NPJ Aging. 2025 Jul 08. 11(1): 55
    Psilocybin treatment extends cellular lifespan and improves survival of aged mice.
    Kosuke Kato, Jennifer M Kleinhenz, Yoon-Joo Shin, Cristian Coarfa, Ali J Zarrabi, Louise Hecker.
      Psilocybin, the naturally occurring psychedelic compound produced by hallucinogenic mushrooms, has received attention due to considerable clinical evidence for its therapeutic potential to treat various psychiatric and neurodegenerative indications. However, the underlying molecular mechanisms remain enigmatic, and few studies have explored its systemic impacts. We provide the first experimental evidence that psilocin (the active metabolite of psilocybin) treatment extends cellular lifespan and psilocybin treatment promotes increased longevity in aged mice, suggesting that psilocybin may be a potent geroprotective agent.
    DOI:  https://doi.org/10.1038/s41514-025-00244-x
  7. Zhonghua Yi Xue Za Zhi. 2025 Jul 08. 105(25): 2072-2082
    [Expert consensus on the treatment of aging related to growth hormone deficiency].
    Pubertal Development and Gonadal Disorders Committee from Chinese Aging Well Association
      The secretion of growth hormone progressively decreases with advancing age, and some of the elderly develop age-related growth hormone deficiency. Physiological concentration of growth hormone is crucial for the regulation of material metabolism and the maintenance of organ and systemic functions in adults. Clinically, adult growth hormone deficiency manifests as a complex constellation of symptoms including obesity, fatty liver, sarcopenia, osteoporosis, diminished sexual function, reduced physical performance, and depression, which are partially analogous to the clinical phenotypes of aging. For patients with clearly identified causes or those with age-related growth hormone deficiency, physiological doses of growth hormone supplementation therapy can significantly improve the aforementioned symptoms. Consequently, adult growth hormone deficiency is considered as one of the endocrine causes for certain aging symptoms. Currently, clinicians have insufficient awareness of this issue. Age-related growth hormone deficiency should logically be an integral part of adult growth hormone deficiency, yet it has not received sufficient clinical attention and emphasis. The Pubertal Development and Gonadal Disorders Committee from Chinese Aging Well Association and Society of Endocrinology and Metablic Disease, China National Health Association organized 34 domestic experts from fields including endocrinology, nutrition, geriatric medicine, and sports medicine. Based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system for clinical evidence levels, they formulated expert consensus and proposed coping strategies centered around key scientific issues related to growth hormone therapy for anti-aging, including the target population for treatment, treatment risks and benefits, and the duration of treatment courses. By integrating the evaluation opinions from the Delphi method, 16 recommendation statements aiming to standardize the application of growth hormone therapy on anti-aging were finally determined. And in response to various issues in the field of growth hormone anti-aging therapy, the future research directions have been proposed.
    DOI:  https://doi.org/10.3760/cma.j.cn112137-20250307-00555
  8. Stem Cell Rev Rep. 2025 Jul 10.
    Advances in Photobiomodulation: Effects on Mesenchymal Stem Cells and their Paracrine Factors.
    Zhuojun Shi, Sining Chen, Wenkai Cai, Wei Chen, Yong Tang.
      Mesenchymal stem cells (MSCs) have emerged as pivotal tools in biomedical engineering, owing to their remarkable capacity for tissue repair and regeneration. Photobiomodulation (PBM), a non-invasive and safe physical stimulation technique, has demonstrated significant potential in enhancing MSCs' cellular activity, osteogenic differentiation, and therapeutic efficacy. Despite these promising findings, several challenges hinder the clinical translation of PBM, including the optimization of irradiation parameters to maximize therapeutic outcomes and the standardization of protocols to ensure reproducibility and reliability. This review explores the current advancements in PBM technology and its application in MSC research, with a focus on understanding its mechanisms and therapeutic potential. By delving into the fine-tuning of PBM parameters, including cell factor secretion dynamics, signal transduction pathways, and cell-cell interaction networks, we aim to illuminate how PBM modulates the paracrine functions of MSCs. Additionally, the integration of PBM with biomaterials and engineering technologies presents exciting opportunities for bone tissue engineering and cell therapy. Future research should focus on uncovering the mechanisms by which PBM influences MSC behavior, optimizing its therapeutic parameters, and evaluating its safety and long-term benefits. Such efforts will pave the way for PBM's seamless integration into clinical applications, including complex bone defect repair, thereby advancing its role in precision medicine.
    Keywords:  Bone tissue engineering; Cell therapy; Mesenchymal stem cells; Paracrine factors; Photobiomodulation
    DOI:  https://doi.org/10.1007/s12015-025-10934-4
  9. bioRxiv. 2025 Jul 03. pii: 2025.03.28.645957. [Epub ahead of print]
    Elimination of senescent cells with senolytic host-directed therapy reduces tuberculosis progression in mice.
    Somnath Shee, Yazmin B Martinez-Martinez, Benjamin Koleske, Shivraj Yabaji, Lester Kobzik, Igor Kramnik, William Bishai.
      By eliciting lung necrosis, which enhances aerosol transmission, Mycobacterium tuberculosis ( Mtb ) sustains its long-term survival as a human pathogen. In studying the human-like necrotic granuloma lesions characteristic of Mtb -infected B6.Sst1S mice, we found that lung myeloid cells display elevated senescence markers: cell cycle arrest proteins p21 and p16, the DNA damage marker γH2A.X, senescence-associated β-galactosidase activity, and senescence-associated secretory phenotype (SASP). These markers were also elevated in Mtb -infected aged wild type (WT) mice but not in young WT mice. Global transcriptomics data revealed upregulation of pro-survival (PI3K, MAPK) and anti-apoptotic pathways in Mtb -infected B6.Sst1S macrophages. As senescent cells are terminally growth-arrested yet metabolically active cells that release tissue-damaging, immunosuppressive SASP, we treated Mtb -infected mice with a cocktail of three senolytic drugs (dasatinib, quercetin, and fisetin) designed to kill senescent cells. Senolytic drug treatment prolonged survival and reduced Mtb lung counts in B6.Sst1S and aged WT mice to a greater degree than young WT mice and concomitantly reduced lung senescence markers. These findings indicate that (1) Mtb infection may induce lung myeloid cells to enter a senescent state and that these cells may promote disease progression, and (2) senolytic drugs merit consideration for human clinical trials against tuberculosis (TB).
    Graphical abstract:
    Highlights: Mtb lung infection results in recruitment of both restrictive and permissive myeloid cells to the nascent granuloma. Mtb infection induces certain permissive myeloid cells to enter a senescent state, characterized by cell cycle arrest and they promote local immunosuppression. Treatment with a Senolytic drug cocktail, which kills senescent cells, augments host resistance against Mtb proliferation, lethality and immunopathology.
    DOI:  https://doi.org/10.1101/2025.03.28.645957
  10. Cells. 2025 Jun 20. pii: 942. [Epub ahead of print]14(13):
    Molecular Regulation of SASP in Cellular Senescence: Therapeutic Implications and Translational Challenges.
    Hubert Klepacki, Krystyna Kowalczuk, Natalia Łepkowska, Justyna Magdalena Hermanowicz.
      Cellular senescence is a complex process that significantly contributes to the pathogenesis of various diseases, including cancer and neurodegenerative disorders. It is characterized by permanent cell cycle arrest and morphological changes, such as cell enlargement and a decrease in lamin B levels. As organisms age, a secretory phenotype known as the senescence-associated secretory phenotype (SASP) develops, which produces pro-inflammatory factors that can impact surrounding tissues and promote disease. This article discusses the molecular mechanisms regulating senescence, notably the p53/p21 and p16INK4a/pRb pathways, which are crucial for inducing cell cycle arrest. While increased activity of cyclin inhibitors like p16 and p21 serves as a protective mechanism against cancer, their prolonged activation can lead to pathological effects. Additionally, the article examines therapies involving senolytics and senomorphics, which aim to eliminate senescent cells. Current research suggests that targeting senescence may represent a promising strategy for treating various diseases, improving health outcomes, and enhancing the overall quality of life as we age.
    Keywords:  senescence; senescence-associated secretory phenotype (SASP); senolytics; senomorphics
    DOI:  https://doi.org/10.3390/cells14130942
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