bims-caglex 2026-03-15 papers

Proc Natl Acad Sci U S A. 2026 Mar 17. 123(11): e2533687123

Histone modification clocks for robust cross-species biological age prediction and elucidating senescence regulation.

Zhixin Niu, Chang Liu, Yurong Fan, Lei Gu.

Histone modifications represent an untapped resource for biological age prediction that overcomes limitations of traditional DNA methylation-based epigenetic clocks. Here, we developed and validated histone modification-based epigenetic clocks by systematically analyzing publicly available ChIP-seq datasets spanning six tissue types and six histone marks. We identified age-associated loci and constructed 36 tissue-specific epigenetic clocks that demonstrated strong resilience to technical and biological noise, with performance comparable to established DNA methylation clocks. Our models successfully detected biological age acceleration in leukemia samples and captured age reversal following therapeutic interventions. Importantly, we found that many aging-associated loci follow nonlinear trajectories with peak modification levels at midlife, revealing previously unrecognized dynamics in epigenetic aging. We observed age-related fragmentation of super enhancer regions, suggesting progressive chromatin disorganization during aging. Functional validation of a model-selected H3K27ac peak near IGF2BP3 confirmed its causal role in cellular senescence through regulation of TRA2A expression. Extending beyond mammals, we demonstrated the applicability of histone-based clocks in Drosophila melanogaster, a species lacking DNA methylation, highlighting the evolutionary conservation and broader utility of histone modifications as aging biomarkers. Our findings establish histone modifications as accurate, biologically meaningful, and robust indicators of biological age with potential applications in aging research, disease monitoring, and therapeutic development across diverse species.

Keywords: aging; epigenetics; histone modification

DOI: https://doi.org/10.1073/pnas.2533687123

Commun Biol. 2026 Mar 11.

NAD+ controls circadian rhythmicity during cardiac aging.

Bryce J Carpenter, Margaux Lecacheur, Yannick N Mangold, Kai Cui, Stefan Günther, Marit W Vermunt, Pieterjan Dierickx.

Disruption of the circadian clock as well as reduced NAD+ levels are both hallmarks of aging. While circadian rhythms and NAD+ metabolism have been linked in heart disease, their relationship during cardiac aging is less clear. Here, we show that aging leads to disruption of diurnal gene expression in the heart. Long-term supplementation with the NAD+ precursor nicotinamide riboside (NR) boosts NAD+ levels, reprograms the diurnal transcriptome, and reverses naturally occurring cardiac enlargement in aged female mice. In addition, drastic reduction of NAD+ levels in cardiomyocytes impairs PER2::luc oscillations, which is rescued by NR supplementation. Finally, we demonstrate that changes to the cardiac transcriptome due to NR treatment partially depend on the activity of SIRT1. These findings reveal an essential role for NAD+ in regulation of the cardiac circadian clock upon aging, which opens up new avenues to counteract age-related cardiac disorders.

DOI: https://doi.org/10.1038/s42003-026-09818-1

J Adv Res. 2026 Mar 09. pii: S2090-1232(26)00227-4. [Epub ahead of print]

Rejuvenation of THY1+ nucleus pulposus-derived stem cells promotes intervertebral disc regeneration through FGF10-FGFR1-CREB pathway and mitochondrial fission.

Haoxin Zhai, Zexin Wang, Shaoyi Wang, Zhicheng Liu, Dawang Zhao, Yiming Zhang, Kaiwen Liu, Xiangzhen Kong, Qunbo Meng, Hanwen Gu, Lin Chen, Yuanqiang Zhang, Lei Cheng.

INTRODUCTION: Intervertebral disc degeneration (IVDD), a major cause of low back pain, is primarily characterized by compromised regeneration ability of nucleus pulposus-derived stem cells (NPSCs) owing to their senescence. The role of NPSCs as major regenerative cells in IVDD is garnering attention. However, the drivers and mechanisms of NPSCs reactivation and regeneration are poorly understood, limiting the development of targeted therapies. The fibroblast growth factor (FGF) family has shown increasing promise in tissue regeneration; however, the key factors involved in IVDD remain unclear.
OBJECTIVES: To elucidate the regenerative driver of NPSCs and the underlying anti-senescence mechanism to provide a potential therapeutic strategy.
METHODS: Single cell RNA sequencing (scRNA-seq) and bulk RNA sequencing were performed to identify the key NPSCs clusters and regenerative drivers in IVDD. Clinical IVDD samples were collected to determine the alterations in the NPSCs subset proportion and the expression of regeneration factors. Further, NPSCs senescence and in vivo models were used to investigate the specific mechanisms and therapeutic effects.
RESULTS: Thy-1 membrane glycoprotein (THY1)+ NPSCs, which are depleted in IVDD, were the key cells involved in intervertebral disc degeneration based on scRNA-seq. THY1+ NPSCs exhibited stemness and regeneration potential. The RNA-seq analysis of senescent THY1+ NPSCs indicated fibroblast growth factor 10 (FGF10) as a pivotal rejuvenation factor. Multiplex fluorescence staining demonstrated diminished FGF10 expression in IVDD. FGF10 mitigated THY1+ NPSCs senescence by interacting with fibroblast growth factor receptor 1 (FGFR1). The FGF10-FGFR1 axis inhibited CREB phosphorylation and further alleviated ARG2-DRP1-related mitochondrial fission, reversing THY1+ NPSC senescence. Inhibition of CREB and downregulation of ARG2 regulate cellular senescence via modulation of mitochondrial fission. The transplantation of FGF10-overexpression NPSCs prominently alleviated nucleus pulposus degeneration and demonstrated regeneration potential in vivo.
CONCLUSION: Our findings elucidate the pivotal roles of THY1+ NPSCs and FGF10 in intervertebral disc regeneration and NPSCs activation, respectively, contributing to the development of regenerative therapeutic strategies for IVDD.

Keywords: Cellular senescence; FGF10; Intervertebral disc degeneration; Regeneration; THY1(+) nucleus pulposus-derived stem cells

DOI: https://doi.org/10.1016/j.jare.2026.03.008