bims-caglex 2026-06-07 papers

Mol Cells. 2026 Jun 04. pii: S1016-8478(26)00069-5. [Epub ahead of print] 100378

Oxidative Stress Drives Liver Failure During In Vivo Partial Reprogramming.

Hee-Ji Eom, Beom-Ki Jo, Jumee Kim, Hyuk-Jin Cha.

In vivo reprogramming using the Yamanaka factors (OCT4, SOX2, KLF4, and c-MYC; OSKM) enables tissue regeneration but raises major safety concerns when factor expression is sustained. Here, using a doxycycline-inducible OSKM mouse model, we show that prolonged systemic OSKM induction causes early lethality associated with hepatocyte dedifferentiation and oxidative stress, in the absence of tumor formation. Single-nucleus RNA sequencing revealed activation of reactive oxygen species (ROS), oxidative stress, and NRF2 signaling pathways in hepatocytes. Increased ROS production in hepatocytes, together with the higher resistance of female mice and sex-dependent differences in antioxidant response programs, implicates oxidative stress as a primary driver of mortality during sustained OSKM expression. Importantly, antioxidant treatment with N-acetylcysteine (NAC) alleviated oxidative stress and significantly improved survival without impairing reprogramming-associated cellular plasticity. These findings establish oxidative stress as a key driver of liver failure during sustained in vivo reprogramming and provide a mechanistic rationale for cyclic induction strategies.

Keywords: N-acetyl-cysteine; in vivo reprogramming; liver failure; oxidative stress; reactive oxygen species

DOI: https://doi.org/10.1016/j.mocell.2026.100378

Signal Transduct Target Ther. 2026 Jun 01. pii: 202. [Epub ahead of print]11(1):

Insights into the therapeutic strategies for aging and aging-associated diseases.

Ruifang Dong, Qiming Wu, Juntao Kan, Caili Fu, Vincenzo Sorrentino, Ashley Chow, Yanan Lei, Di Wu, Zhenzhen Xu, Jun Du, Dejian Huang.

Aging is a complex biological process characterized by progressive functional decline, driving the incidence of age-related diseases such as neurodegeneration, metabolic disorders, and cardiovascular diseases. Therapeutic strategies targeting aging hallmarks can delay aging and mitigate disease risk. Emerging interventions focus on modulating core aging mechanisms, including cellular senescence, metabolic dysfunction, epigenetic alterations, and mitochondrial impairment, etc. Recent advances have focused on three strategies: senolytics (eliminating senescent cells, e.g., dasatinib + quercetin), senomorphics (inhibiting the senescence-associated secretory phenotype, e.g., rapamycin), and senoreversion (rejuvenating senescent cells via epigenetic reprogramming). Additionally, metabolic interventions such as caloric restriction mimetics (e.g., spermidine, α-ketoglutarate, ergothioneine) enhance mitochondrial function, activate autophagy, and reprogram energy metabolism, demonstrating lifespan extension and healthspan improvement in preclinical models. Collectively, these approaches hold promise for delaying aging and alleviating age-related pathologies, facilitating the transition to precision longevity medicine. Concurrently, artificial intelligence (AI) accelerates discovery by integrating multiomics data, predicting candidate compounds, identifying biomarkers, and enabling personalized interventions. Despite advancements, challenges remain in target specificity, off-target effects, and clinical translation. The convergence of AI, multitarget strategies, and precision medicine signals a transformative era in extending healthspan and combating aging-associated diseases. This review systematically summarizes current breakthroughs, clinical landscapes, and future directions in aging therapeutics, underscoring interdisciplinary strategies to redefine healthy aging.

DOI: https://doi.org/10.1038/s41392-026-02662-z

Mol Ther. 2026 Jun 02. pii: S1525-0016(26)00469-7. [Epub ahead of print]

AAV-mediated FGF21 gene therapy promotes healthspan extension by whole-body tissue-specific adaptations.

Veronica Jimenez, Victor Sacristan, Miquel Garcia, Claudia Jambrina, Estefania Casana, Sergio Muñoz, Laia Vilà, Ignasi Grass, Maria Luisa Jaén, Carles Roca, Xavier León, Sara Marcó, Maria Molas, Albert Ribera, Ivet Elias, Jordi Rodó, Tura Ferré, Fatima Bosch.

The decline of organ function during aging limits healthspan. Despite the potential of lifestyle interventions to improve health, sustained maintenance of healthspan is challenging, and no gerotherapeutic drugs have been approved. Here, we demonstrated that aged and geriatric male and female mice treated with muscle-directed adeno-associated viral (AAV) vector-mediated fibroblast growth factor 21 (FGF21) gene therapy extended healthspan and lifespan with sustained organ benefits. This treatment normalized body weight and adiposity, improved insulin sensitivity and glucose homeostasis, preserved hepatic detoxification capacity, counteracted age-related kidney disease, promoted cardiac health, and muscular function, and enhanced cognition. Transcriptomic and histopathological analyses indicated improved whole-body energy homeostasis and cellular fitness, which were mediated by tissue-specific adaptations, including enhanced mitochondrial function, restored proteostasis, and reversion of inflammation, fibrosis and amyloidosis. AAV-FGF21 treatment also activated AMPK signaling. These results highlight FGF21 gene therapy as a potential strategy to promote healthspan and delay age-related deterioration.

DOI: https://doi.org/10.1016/j.ymthe.2026.05.025

Int J Oral Sci. 2026 Jun 03. pii: 44. [Epub ahead of print]18(1):

OCT4-driven PER1 activation promotes odontogenic differentiation in senescent SCAP spheres.

Changfang Li, Zibin Zhang, Zhuoxin Yang, Tingjie Liu, Xiaoning He, Bei Li, Wei Wang.

Mesenchymal stem cells (MSCs) hold significant promise for applications in regenerative medicine, yet their therapeutic potential is often limited by replicative senescence. Identifying effective strategies to reverse replicative senescence in MSCs and elucidating the underlying molecular mechanisms are essential steps in advancing their clinical use. Here, this study demonstrated that the pluripotency regulator octamer-binding transcription factor 4 (OCT4) promoted odontogenic differentiation by activating period circadian regulator 1 (PER1) in replicative senescent stem cells from apical papilla (SCAP) spheres. Specifically, OCT4 overexpression significantly alleviated cell cycle arrest, reduced senescence-associated β-galactosidase activity, and downregulated the expression of senescence-related markers, including CDKN2A/P16, CDKN1A/P21, and TP53/P53. Moreover, this approach markedly enhanced the proliferation and odontogenic differentiation potential of SCAP spheres in vitro and promoted the formation of regenerative pulp-like tissue in vivo. Mechanistically, we demonstrated that OCT4 transcriptionally activated PER1 through direct binding to its promoter, thereby restoring the odontogenic differentiation capacity of replicative senescent SCAP. Collectively, our findings establish the OCT4-PER1 axis as a critical regulatory pathway that counteracts replicative senescence in SCAP. These insights suggest new therapeutic strategies targeting senescence-associated signaling pathways to enhance MSC-based regenerative outcomes.

DOI: https://doi.org/10.1038/s41368-026-00444-5