bims-caglex 2026-01-11 papers

Ageing Res Rev. 2026 Jan 03. pii: S1568-1637(26)00001-2. [Epub ahead of print]115 103009

The epigenetic rejuvenation promise: Partial reprogramming as a therapeutic strategy for aging and disease.

Reprogramming of somatic cells into induced pluripotent stem cells through the introduction of transcription factors Oct3/4, Sox2, Klf4, and c-Myc (OSKM) represents a landmark advance in regenerative biology. Building on this foundation, partial reprogramming can help reset epigenetic age. It further opens opportunities to treat degenerative diseases without the tumorigenic risks associated with full pluripotency. The review advances the field in three ways: it links lineage-preserving partial reprogramming to quantifiable rejuvenation endpoints; defines mesenchymal drift as an age- and disease-associated trajectory amenable to reversal; and maps strategies beyond OSKM, including small-molecule programs and CRISPR-based control circuits. Convergent phenotypes are surveyed in nervous, metabolic, musculoskeletal, and craniofacial systems, with emphasis on improved tissue repair and regeneration. A translational checklist is proposed that emphasizes schedule, delivery, and safety pharmacology to guide rigorous preclinical studies and de-risk early clinical entry points for partial reprogramming therapies.

Keywords: Aging; Cellular plasticity; Epigenetic rejuvenation; Partial reprogramming; Regenerative medicine

DOI: https://doi.org/10.1016/j.arr.2026.103009

Cell Stem Cell. 2026 Jan 08. pii: S1934-5909(25)00445-X. [Epub ahead of print]33(1): 13-28

Anti-aging strategies and ex vivo organ rejuvenation.

Monika Haoui, Pradeep Reddy, Juan Carlos Izpisua Belmonte.

Aging is characterized by a progressive decline in physiological function, driven by interconnected molecular hallmarks that increase the risk of chronic diseases. To extend health span, interventions targeting these hallmarks, including lifestyle modifications, pharmacological agents, and genetic strategies, have been developed. Among these, partial reprogramming, the transient expression of Yamanaka factors, has emerged as a powerful approach to reverse age-related cellular damage and restore youthful epigenetic and transcriptional signatures without erasing cell identity. This perspective highlights the therapeutic possibilities arising from the convergence of partial reprogramming with the innovative technology of ex vivo machine perfusion. These platforms offer a unique opportunity to apply rejuvenation therapies directly to suboptimal donor organs outside the body before transplantation. Combining these strategies could significantly improve organ quality, expand the donor pool, enhance transplantation outcomes, and advance regenerative medicine.

DOI: https://doi.org/10.1016/j.stem.2025.12.011

Proc Natl Acad Sci U S A. 2026 Jan 13. 123(2): e2515183123

Systematic identification of single transcription factor perturbations that drive cellular and tissue rejuvenation.

Janine Sengstack, Jiashun Zheng, Turan Aghayev, Gregor Bieri, Michael Mobaraki, Jue Lin, Changhui Deng, Saul A Villeda, Hao Li.

Cellular rejuvenation through transcriptional reprogramming is an exciting approach to counter aging. Using a fibroblast-based model of human cell aging and Perturb-seq screening, we developed a systematic approach to identify single transcription factor (TF) perturbations that promote rejuvenation without dedifferentiation. Overexpressing E2F3 or EZH2, and repressing STAT3 or ZFX, reversed cellular hallmarks of aging-increasing proliferation, proteostasis, and mitochondrial activity, while decreasing senescence. EZH2 overexpression in vivo rejuvenated livers in aged mice, reversing aging-associated gene expression profiles, decreasing steatosis and fibrosis, and improving glucose tolerance. Mechanistically, single TF perturbations led to convergent downstream transcriptional programs conserved in different aging and rejuvenation models. These results suggest a shared set of molecular requirements for cellular and tissue rejuvenation across species.

Keywords: Perturb-seq screening; liver aging; rejuvenation; replicative aging

DOI: https://doi.org/10.1073/pnas.2515183123

BMC Genomics. 2026 Jan 08.

A transcriptome-based tool for assessing skin aging reveals the ameliorative effect of stem cell-derived extracellular vesicles on UVB-induced aging.

Quantifying biological aging is essential for understanding functional decline and evaluating anti-aging interventions. We present SkinAGE, a fast and resource-efficient transcriptome-based aging clock built using a deep neural network (DNN) trained on gene expression profiles of human dermal fibroblasts. SkinAGE accurately predicts cellular aging status across independent cohorts and a UVB-induced photoaging model. In 23rd-passage HFF-1 cells, the model assigned an average age score of 44, which increased by 24 units after UVB exposure, indicating enhanced transcriptomic senescence. Treatment with human embryonic stem cell-derived extracellular vesicles (hESC-EVs) reduced this score by an average of 21.2 units, suggesting a potent ameliorative effect on cellular aging. Transcriptomic analysis supported this, showing restoration of aging-related gene expression, including enrichment of cell cycle progression and p53 signaling pathways. Overall, SkinAGE provides a scalable, accurate, and cost-effective framework for quantifying cellular aging and assessing rejuvenation strategies.

Keywords: Cellular senescence; Deep learning; Extracellular vesicles; Stem cell; Transcriptomics

DOI: https://doi.org/10.1186/s12864-025-12469-x

bioRxiv. 2025 Dec 29. pii: 2025.12.28.696721. [Epub ahead of print]

Rejuvenation of white adipose tissue in a longitudinal heterochronic transplantation model.

Alibek Moldakozhayev, Alexander Tyshkovskiy, Pasquale Nigro, Cecília G de Magalhães, Kejun Ying, Alec W Eames, Jesse R Poganik, Albina Tskhay, Bohan Zhang, Stanislav Tikhonov, Praju Vikas Anekal, Nicholas P Carbone, Michael F Hirshman, Laurie J Goodyear, Jeremy M Van Raamsdonk, Vadim N Gladyshev.

Exposure to a younger system can induce organismal rejuvenation, yet whether all tissues can be rejuvenated and by what mechanisms remains understudied. We performed heterochronic and isochronic transplantation of subcutaneous white adipose tissue (WAT) between young and old mice and longitudinally tracked changes in biological age. Transplantation accelerated tissue aging, and the molecular age of grafts shifted toward that of the host. Most importantly, old WAT was rejuvenated in a young body. Epigenetic and transcriptomic clocks revealed a reduction of predicted age, accompanied by coordinated activation of canonical and previously unrecognized thermogenic pathways. Molecular rejuvenation was further supported by architectural changes toward a youthful state, including reduced lipid droplet size and decreased cellular heterogeneity. Mitochondrial abundance and morphology remained unchanged, while collagen deposition increased. These results demonstrate that WAT biological age is partially reversible and identify molecular and cellular features underlying its rejuvenation.

DOI: https://doi.org/10.64898/2025.12.28.696721

Biomed Pharmacother. 2026 Jan 06. pii: S0753-3322(25)01113-8. [Epub ahead of print]194 118919

Folate- and aCD47-functionalized lipid nanoparticles efficiently deliver mRNA and remodel pancreatic tumor microenvironment.

Marta Parés, Javier Martínez-Latorre, Vicente Candela-Noguera, Paula M Soriano-Teruel, Alba García-Fernández, Víctor Pallaruelo-Santamaría, Elena Aznar, Ramón Martínez-Máñez, Cristina Fillat.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive and treatment-resistant malignancies, with limited efficacy to conventional treatments such as surgical resection or chemotherapy. This clinical scenario underscores the need for novel therapeutic strategies. The development of multifunctional platforms capable of targeting tumors through multiple mechanisms offers an innovative strategy to overcome this challenge. Lipid nanoparticles (LNPs) offer a versatile platform capable of efficiently delivering genetic material. Moreover, through surface functionalization it is feasible to improve LNP performance optimizing therapeutic outcomes in a single formulation. Here, we explored a dual functionalization strategy of the LNP for tumor targeting and tumor remodeling to improve treatment efficacy. LNPs were designed for delivering reporter DNA plasmid or mRNA into the PDAC cellular models Capan-2 and PANC-1. The DNA plasmid contains a pancreatic cancer-specific chimeric promoter for transcriptional specificity to PDAC cells. Besides, LNPs were functionalized with folate and an anti-CD47 antibody to both target the folate receptor in PDAC cells and block CD47-mediated immune evasion. Both pDNA and mRNA LNPs targeted PDAC cells in a dose-dependent manner, with mRNA-LNPs demonstrating more efficient transfection. Notably, LNPs functionalized with the anti-CD47 antibody increased phagocytosis in vitro, and promoted an inflammatory phenotype of M1-like macrophages in mouse Capan-2 xenografts. This combinatorial design of the formulated LNP represents an innovative therapeutic strategy and opens future perspectives in the search for effective treatments for PDAC.

Keywords: ACD47; Folate; Immunotherapy; Lipid nanoparticles; Macrophages; Pancreatic cancer

DOI: https://doi.org/10.1016/j.biopha.2025.118919