bims-minfam 2025-07-06 papers

Issue of 2025–07–06
five papers selected by
Ayesh Seneviratne, McMaster University

Cell Stem Cell. 2025 Jul 03. pii: S1934-5909(25)00225-5. [Epub ahead of print]32(7): 1036-1037

From symbiote to bad neighbor: The intestinal microbiome as a driver of CHIP.

Hematopoietic stem cells (HSCs) with mutations that can cause clonal hematopoiesis of indeterminate potential (CHIP) accumulate during aging. Agarwal et al.1 demonstrate in Nature that intestinal barrier permeability increases with age and enables the microbial metabolite ADP-heptose to reach the bone marrow, thus driving the expansion of DNMT3A-mutant HSCs.

DOI: https://doi.org/10.1016/j.stem.2025.06.003

Nat Aging. 2025 Jun 30.

A TFEB-TGFβ axis systemically regulates diapause, stem cell resilience and protects against a senescence-like state.

Tim J Nonninger, Jennifer Mak, Birgit Gerisch, Valentina Ramponi, Kazuto Kawamura, Roberto Ripa, Klara Schilling, Christian Latza, Jonathan Kölschbach, Manuel Serrano, Adam Antebi.

Diapause is a long-lived state of resilience that allows organisms to outlast adversity. Caenorhabditis elegans can endure months in a fasting-induced adult reproductive diapause (ARD) and, upon refeeding, regenerate and reproduce. Here we find that mutants of ARD master regulator hlh-30/TFEB arrest in a senescence-like state during ARD and refeeding, in which germline stem cells are characterized by DNA damage, nucleolar expansion, cell cycle arrest and mitochondrial dysfunction, alongside dysregulated immune and growth metabolic signatures, elevated senescence-associated β-galactosidase and premature aging at the organismal level. Forward genetic screens reveal a TFEB-TGFβ signaling axis that systemically controls diapause, stem cell longevity and senescence, aligning nutrient supply to proper metabolism and growth signaling. Notably, TFEB's vital role is conserved in mouse embryonic and human cancer diapause. Thus, ARD offers a powerful model to study stem cell longevity and senescence in vivo, directly relevant to mammals.

DOI: https://doi.org/10.1038/s43587-025-00911-4

Nat Aging. 2025 Jun 30.

Clusterin drives myeloid bias in aged hematopoietic stem cells by regulating mitochondrial function.

Ninghe Sun, Chun-Hsin Lin, Michelle Y Li, Yuting Wang, Danyang Chen, Xiangle Ren, Feng Zhang, Yi Zhang.

Aged hematopoietic stem cells (HSCs) exhibit diminished self-renewal and myeloid-biased differentiation with a decline in hematopoiesis and adaptive immune function. However, the molecular regulation of this impaired function remains largely unknown. Here, through an in vivo CRISPR-Cas9-based screen, we uncovered clusterin (Clu) as a driver of biased differentiation. Clu is upregulated in aged HSCs, and its knockout diminishes biased differentiation. Clu promotes mitochondrial hyperfusion by interacting with Mfn2 in aged HSCs, and its ablation attenuates oxidative phosphorylation, improves mitophagy, and reverses myeloid-biased differentiation via the OXPHOS-p38-Cebpb axis. Transplantation of Clu-depleted aged HSCs into middle-aged mice results in balanced hematopoiesis and improved physical functions. Together, our data identify Clu as a critical regulator of aging-associated myeloid bias and reveal an Mfn2-OXPHOS-p38-Cebpb axis as the mechanism underlying how Clu upregulation in aged HSCs leads to myeloid-biased differentiation, providing a target for rejuvenation of aged hematopoietic and immune systems.

DOI: https://doi.org/10.1038/s43587-025-00908-z

Nature. 2025 Jul 01.

How fast are you ageing? Ordinary brain scans reveal the pace.

Heidi Ledford.

Keywords: Ageing; Brain; Imaging; Neuroscience

DOI: https://doi.org/10.1038/d41586-025-02086-9