The FOXO-aging axis: Epigenetic insights and chromatin mechanisms

IF 15.5 1区医学 Q1 CELL BIOLOGY

Ageing Research Reviews Pub Date : 2027-01-01 Epub Date: 2026-10-16 DOI:10.1016/j.arr.2026.103421

Tongfeng Fang, Ruihan Ke, Hongyu Ming, Siqi Ye, Dan He, Tao Chen, Yingying Wu

{"title":"The FOXO-aging axis: Epigenetic insights and chromatin mechanisms","authors":"Tongfeng Fang, Ruihan Ke, Hongyu Ming, Siqi Ye, Dan He, Tao Chen, Yingying Wu","doi":"10.1016/j.arr.2026.103421","DOIUrl":null,"url":null,"abstract":"<div><div>Aging is frequently accompanied by profound alterations in the chromatin landscape, leading to widespread changes in transcriptional programs and cellular functions. Forkhead box O (FOXO) proteins, traditionally viewed as downstream effectors of insulin and stress-response signaling, are now emerging as dynamic chromatin regulators that integrate metabolic cues with epigenetic remodeling during aging. In this review, we first outline the major epigenetic and chromatin alterations associated with aging and then examine the emerging role of FOXO proteins as chromatin regulators in this context. We discuss evidence for FOXO pioneer activity and the structural features that facilitate chromatin engagement, followed by FOXO-mediated regulation through ATP-dependent chromatin remodeling and histone modifications, and consider how these mechanisms may shape age-associated chromatin states and cellular senescence. Finally, we discuss the current FOXO-targeting therapeutic strategies and the challenges of achieving isoform- and chromatin context-specific FOXO modulation. Collectively, this review provides a chromatin-centered perspective on the FOXO-aging axis and offers a conceptual framework for future translational and therapeutic studies.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"123 ","pages":"Article 103421"},"PeriodicalIF":15.5000,"publicationDate":"2027-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Ageing Research Reviews","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1568163726004137","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/10/16 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Aging is frequently accompanied by profound alterations in the chromatin landscape, leading to widespread changes in transcriptional programs and cellular functions. Forkhead box O (FOXO) proteins, traditionally viewed as downstream effectors of insulin and stress-response signaling, are now emerging as dynamic chromatin regulators that integrate metabolic cues with epigenetic remodeling during aging. In this review, we first outline the major epigenetic and chromatin alterations associated with aging and then examine the emerging role of FOXO proteins as chromatin regulators in this context. We discuss evidence for FOXO pioneer activity and the structural features that facilitate chromatin engagement, followed by FOXO-mediated regulation through ATP-dependent chromatin remodeling and histone modifications, and consider how these mechanisms may shape age-associated chromatin states and cellular senescence. Finally, we discuss the current FOXO-targeting therapeutic strategies and the challenges of achieving isoform- and chromatin context-specific FOXO modulation. Collectively, this review provides a chromatin-centered perspective on the FOXO-aging axis and offers a conceptual framework for future translational and therapeutic studies.

查看原文本刊更多论文

foxo老化轴：表观遗传学见解和染色质机制。

衰老通常伴随着染色质景观的深刻改变，导致转录程序和细胞功能的广泛变化。叉头盒O （FOXO）蛋白，传统上被认为是胰岛素和应激反应信号的下游效应器，现在作为动态染色质调节剂出现，在衰老过程中将代谢线索与表观遗传重塑结合起来。在这篇综述中，我们首先概述了与衰老相关的主要表观遗传和染色质改变，然后研究了FOXO蛋白在这方面作为染色质调节因子的新作用。我们讨论了FOXO前驱活性的证据和促进染色质接合的结构特征，随后FOXO通过atp依赖的染色质重塑和组蛋白修饰介导的调节，并考虑了这些机制如何影响与年龄相关的染色质状态和细胞衰老。最后，我们讨论了目前针对FOXO的治疗策略以及实现异构体和染色质上下文特异性FOXO调节的挑战。总的来说，这篇综述提供了以染色质为中心的foxo衰老轴的观点，并为未来的翻译和治疗研究提供了一个概念框架。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Ageing Research Reviews 医学-老年医学

CiteScore

19.80

自引率

2.30%

发文量

216

审稿时长

55 days

期刊介绍： With the rise in average human life expectancy, the impact of ageing and age-related diseases on our society has become increasingly significant. Ageing research is now a focal point for numerous laboratories, encompassing leaders in genetics, molecular and cellular biology, biochemistry, and behavior. Ageing Research Reviews (ARR) serves as a cornerstone in this field, addressing emerging trends. ARR aims to fill a substantial gap by providing critical reviews and viewpoints on evolving discoveries concerning the mechanisms of ageing and age-related diseases. The rapid progress in understanding the mechanisms controlling cellular proliferation, differentiation, and survival is unveiling new insights into the regulation of ageing. From telomerase to stem cells, and from energy to oxyradical metabolism, we are witnessing an exciting era in the multidisciplinary field of ageing research. The journal explores the cellular and molecular foundations of interventions that extend lifespan, such as caloric restriction. It identifies the underpinnings of manipulations that extend lifespan, shedding light on novel approaches for preventing age-related diseases. ARR publishes articles on focused topics selected from the expansive field of ageing research, with a particular emphasis on the cellular and molecular mechanisms of the aging process. This includes age-related diseases like cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. The journal also covers applications of basic ageing research to lifespan extension and disease prevention, offering a comprehensive platform for advancing our understanding of this critical field.