Master controller of aging and development uncovered

New insights into transcription factors and chromatin remodeling reveal potential for improving age-related health outcomes.

Researchers from the University of Queensland have made significant strides in understanding the molecular mechanisms underpinning aging and development, highlighting the crucial role of gene regulatory elements and their interaction with transcription factors. The study, published in Cell Metabolism, offers a comprehensive analysis of chromatin changes across various cell types in both mice and humans, revealing common pathways that govern the transition from youth to old age.

Longevity.Technology: Research into the molecular processes of aging holds significant promise for advancing longevity and improving health outcomes; by dissecting the ways in which gene activity shifts over time, scientists can develop targeted interventions aimed at mitigating age-related diseases and enhancing healthspan. Understanding these underlying mechanisms not only propels geroscientific research, but fosters the development of therapies that can potentially delay or reverse detrimental aging processes.

Overture and beginners

Led by Dr Christian Nefzger, Group Leader, Cellular reprogramming and ageing at UQ, the study employed multi-omic analyses to explore chromatin and transcriptional changes across 22 types of mouse cells, further augmented by existing datasets on human and mouse maturation. The researchers identified a distinct transcription factor binding site (TFBS) signature that is shared between developmental and aging processes, and which is characterized by early-life candidate cis-regulatory elements (cCREs) losing accessibility as organisms mature, while other cCREs gain accessibility through life due to increased levels of Activator Protein 1 (AP-1) [1].

Nefzger noted that the mechanisms by which gene activity shifts from birth through adulthood and into old age have remained largely unknown until now.

“By analyzing molecular datasets from both people and mice and then comparing different age groups over time, we investigated the activity of genes involved in both developmental and ageing processes,” he explained. “Master controller genes regulate which genes are turned on or off in each of our cells, making sure that each cell does its specific job, just as a conductor directs musicians to produce different sounds [2].”

AP-1: The Master Regulator

AP-1 emerged as a pivotal factor in this research, demonstrating its role in progressively activating adult genes while ‘dialing down’ the activity of early-life genes.

This activity, shared across various cell types, illustrates a fundamental mechanism of aging, and Dr Marina Naval-Sanchez, a Postdoctoral Research Fellow in UQ’s Institute for Molecular Bioscience, added that the study showed this cellular process to be predictable across various life stages as individuals mature.

“It was ongoing in adulthood, likely because AP-1 is also activated by a number of stress and inflammatory processes as well as by a protein in our blood that increases with age,” she explained. “This further dampens genes most active early in life, which may drive many of the predictable changes of aging [2].”

The study posits that the redistribution of transcription factors such as AP-1, alongside mild downregulation of cell identity transcription factors, prompts chromatin remodeling that alters developmental and metabolic gene expression [1]. This mechanism can be triggered by elevated AP-1 activity or depletion of repressive H3K27me3,  an epigenetic modification to a DNA packaging protein histone, something that highlights the nuanced interplay of genetic and epigenetic factors in aging.

Implications for Age-Related Diseases

The research holds potential for addressing age-related diseases such as Alzheimer’s, metabolic disorders, and stroke. Dr Ralph Patrick, also a PDRF in the Institute for Molecular Bioscience, explained that to these diseases, it is essential for researchers to first comprehend the underlying processes that cause bodies to age.

“By pinpointing AP-1 as a master controller linked to aging across cell types, we can now study the effects of drugs that reduce its activity to extend quality of life,” he said [2]. Targeting AP-1 and its associated pathways could lead to interventions that slow down or even prevent the onset of these diseases, marking a significant advancement in geriatric medicine.

Nefzger added that the aim is to prevent age-related diseases from escalating or – even better – occurring in the first place by addressing the underlying aging process, thereby enabling people to age in better health.

By focusing on the fundamental processes that drive aging, researchers aim to develop strategies that enhance healthspan, the period of life spent in good health, rather than merely extending lifespan. As the understanding of aging at the molecular level continues to evolve, future research will likely explore additional transcription factors and regulatory elements involved in this process, hopefully paving the way for innovative therapeutic approaches that address the challenges of aging.

[1] https://www.sciencedirect.com/science/article/pii/S1550413124002316?via%3Dihub
[2] https://www.uq.edu.au/news/article/2024/06/revealing-master-controller-of-development-and-ageing