bims-caglex 2026-01-25 papers

Nat Aging. 2026 Jan;6(1): 6-22

Past, present and future perspectives on the science of aging.

Fabrisia Ambrosio, Maxim N Artyomov, Steven N Austad, Nir Barzilai, Juan Carlos Izpisua Belmonte, Daniel W Belsky, Bérénice A Benayoun, Anne Brunet, Handan Melike Dönertaş, Dena B Dubal, Evandro F Fang, Jerome N Feige, Linda P Fried, David Furman, Xu Gao, Vadim N Gladyshev, Vera Gorbunova, Myriam Gorospe, Jing-Dong J Han, Oskar Hansson, Eiji Hara, Steve Horvath, Nancy Y Ip, George A Kuchel, Matt Kaeberlein, Dudley W Lamming, Becca R Levy, Guang-Hui Liu, Jinkook Lee, Terrie E Moffitt, Tohru Minamino, Linda Partridge, Parminder Raina, Thomas A Rando, John W Rowe, Michal Schwartz, Andrew J Scott, Felipe Sierra, David A Sinclair, Charlotte E Teunissen, Bruno Vellas, Eric Verdin, Keenan A Walker, Ashley E Webb, Tony Wyss-Coray, Ming Xu, Jin-Tai Yu, Alex Zhavoronkov, Yahyah Aman, Anna Kriebs, Qingzhong Ren, Hannah Walters, Sebastien Thuault.

DOI: https://doi.org/10.1038/s43587-025-01046-2

Aging Cell. 2026 Feb;25(2): e70352

A Novel Human Cellular System for Studying Normal Aging and for Anti-Aging Discovery.

Zhen Feng, Cheuk Shuen Li, Haifeng Fu, Wenxin Jiang, Weiyu Zhang, Yingzhang Huang, Yunying Huang, Timothy Theodore Ka Ki Tam, Yang Li, Fang Liu, Liming Lu, Yin Lau Lee, William Shu Biu Yeung, Gordon Dougan, Pentao Liu.

Aging studies using animal and cellular models have uncovered key proteins and pathways central to organismal aging. However, these models differ genetically and physiologically from human aging, posing challenges in translating discoveries to human contexts. In this study, we present a human normal cell aging model based on the development of cytotrophoblasts (CTBs) to syncytiotrophoblasts (STBs) in the placenta. The in vitro-derived STBs from human trophoblast stem cells (hTSCs) recapitulate the maturation and major cellular aging features of in vivo CTB-STB, including multinucleation, hormone secretion, cell cycle arrest, genome instability, epigenetic changes, activation of endogenous transposable elements, and senescence-associated secretory phenotypes (SASPs). Notably, the progressive senescence in the trophoblast system closely matches the predicted aging trajectory of other human tissue stem cells. Known anti-aging molecules, such as mTOR inhibitors and senolytics, attenuate senescence signals in STBs. The established CGA-EGFP reporter hTSC line enables scalable and quantitative screening and identified candidates with it can be further extended to other context-specific aging processes like that of skin fibroblasts. The hTSC-STB system represents a novel physiologically accelerated cellular aging model, bridges the gap between fundamental aging research and interventions, and prioritizes anti-aging candidates for clinical development.

DOI: https://doi.org/10.1111/acel.70352

Adv Biol (Weinh). 2026 Jan;10(1): e00468

Introducing Cellular Senescence in Human Induced Pluripotent Stem Cells and Differentiated Neural Lineage for Modeling of Age-Associated Diseases.

Kashfia Neherin, Kristopher Holloway, Yingduo Song, Andrew Houston, Feng Chen, Li Ding, Hong Zhang.

Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) resets the epigenetic landscapes that mark the aging clock, and consequently cells differentiated from iPSCs resemble fetal cells rather than adult or aged cells. The lack of proper cellular aging in cells differentiated from iPSCs presents a unique challenge in iPSC-based modeling of age-associated diseases such as neurodegeneration. To address this challenge, we seek to introduce cellular senescence, a hallmark of aging, into iPSC-based models in a robust and temporally controlled manner. An inducible CRISPR interference (CRISPRi) is used to suppress the expression of TERF2, a key component of the telomere protecting Shelterin complex. We demonstrate that suppression of TERF2 robustly activates the DNA damage response, p53/p21 signaling, and cellular senescence in iPSCs in a highly homogeneous and synchronous manner. Applying this inducible CRISPRi-TERF2 system to differentiation of iPSCs to neural progenitor cells (NPCs), we show efficient activation of senescence-associated phenotypes in NPCs. This inducible cell model allows isogenic comparisons of the same cell populations over the course of differentiation with or without the activation of cellular senescence in a synchronous and homogeneous manner, and has broad applications in investigating the role of cellular senescence in the progression of age-related diseases.

Keywords: aging; cellular senescence; disease modeling; neurodegeneration; telomere dysfunction

DOI: https://doi.org/10.1002/adbi.202500468

Nat Commun. 2026 Jan 19.

OTX2 inhibits human pluripotent stem cell reprogramming toward 8-cell-like and morula-like states.

Xi Kong, Nan Jiang, Shaowei Chen, Xingyou Zhang, An Huang, Li Hu, Simeng Yi, Shigang Yin, Jianhua Peng, Yong Jiang, Huangfan Xie, Bingqing Xie.

In human embryos, major zygotic genome activation (ZGA) initiates at the 8-cell (8C) blastomere stage, marking the start of the ontogenesis program. Recent advancements have shown that primed human pluripotent stem cells (hPSCs) can be reprogrammed to 8C-like cells (8CLCs) with totipotent characteristics in vitro. However, the key regulators driving this transition remain largely unexplored. In this study, we identify OTX2 as a key factor that establishes a repressive barrier to the induction of 8CLCs from primed hPSCs. Our findings reveal that OTX2 deletion greatly enhances the generation of TPRX1-EGFP+ 8CLCs, which closely resemble the transcriptomic profiles and epigenetic landscape of 8C/morula embryos. Notably, these OTX2-deleted 8CLCs exhibit improved bidirectional differentiation potential and contribute to both embryonic and extraembryonic tissues in chimeric embryos. Mechanistically, OTX2 regulates both naive and totipotent state transition, but exerts its predominant effect on the latter by binding to loci of key 8C-specific regulators. Collectively, our findings define a critical role for OTX2 in regulating totipotency and establish a foundational framework for generating 8CLCs from primed hPSCs in vitro, offering significant insights for stem cell biology and regenerative medicine.

DOI: https://doi.org/10.1038/s41467-026-68388-2

Nat Commun. 2026 Jan 17.

Coiled-coil heterodimer-mediated split base editing systems enable flexible and robust nucleotide substitutions.

Shuangshuang Mu, Qianru Li, Menglong Chen, Ziqi Li, Yuke Ma, Yuqi Li, Yiran Song, Shuangying Hou, Yuting Ding, Jialu Ju, Yue Lin, Jian Zhang, Yuanxi Yang, Xue Ren, Nan Li, Qin Jin, Liangxue Lai, Kepin Wang, Hui Shi.

Base editors (BEs) enable precise base substitutions, but their size exceeds the packaging capacity of adeno-associated virus (AAV), impeding in vivo applications. Here we design a split BE system that recruits deaminases to Cas9 nickase via coiled-coil heterodimers, resulting in various coiled-coil heterodimers-mediated base editors (CC-BEs), including cytidine base editor (CC-CBE), adenine base editor (CC-ABE), and their derivatives. We reveal that CC-BEs maintain and even improve the editing efficiency of the original unsplit BEs across various cell types and editing scopes, achieving maximum enhancements of 9.6-fold in human immortalized cells and 12.4-fold in primary somatic cells for CC-CBE. Using CC-ABE, we validate in vivo editing efficiency and successfully achieve A-to-G conversion in the Pcsk9 and Dmd genes via dual-AAV vectors in mice. Altogether, we develop a simple and universal strategy to address the challenges posed by the large size of BEs without compromising editing efficiency for base substitutions in vivo.

DOI: https://doi.org/10.1038/s41467-026-68469-2