Srujan Ponnapalli
This piece was contributed by Srujan, an intern in the News and Careers Department, as part of the JYI Summer Internship program in 2023.
The timeless quest for a cure for aging has captivated the human imagination for millenia. From ancient legends to modern science fiction, the dream of halting the relentless march of time and achieving healthier aging has been a constant desire of humankind. In recent years, however, this dream has gradually shaped into reality.
Through centuries of medical, agricultural, and scientific progress, nearly 20 percent of the global population of 9 billion will be over the age of 60 by 2050. With this rise of an aging population comes the unshakeable reality that a large majority of humans who live long lifespans must undergo the negative effects associated with aging, from heart disease to dementia. Recent research may suggest otherwise, however. In the past decades, the field of aging research has risen from the backwaters of medical science to being more prominent than ever before. From studying yeast cells to selectively killing senescent cells, countless studies have made the tantalizing possibility to cure aging all the more a reality.
In a groundbreaking discovery at The University of Queensland, Associate Professor Steven Zuryn and Dr. Michael Dai have uncovered a clue hidden within the intricate web of our cellular machinery in their manuscript “ATFS-1 counteracts mitochondrial DNA damage by promoting repair over transcription” published in the journal Nature Cell Biology. Meet ATSF-1, the newfound protein protagonist in the story of extending the human lifespan.
Before delving into how ATSF-1 plays a critical role in a cell’s aging process, it’s important to take a step back and examine how a cell ages in the first place. Mitochondria are often referred to as the "powerhouses" of our cells because they play a crucial role in generating energy. They have their own unique DNA, separate from the DNA found in the cell nucleus, which is passed down from generation to generation through the maternal lineage. Mitochondria utilize oxygen to convert nutrients from the food we consume into adenosine triphosphate (ATP), a molecule that serves as the primary energy currency of our cells. This process, known as oxidative phosphorylation, is essential for fueling various biological functions, from muscle contractions to nerve signaling and everything in between.
However, as mitochondria diligently carry out their energy-producing duties, they also produce harmful by-products known as reactive oxygen species (ROS) or free radicals. These ROS can damage cellular components, including DNA, proteins, and lipids. Over time, the accumulation of this damage contributes to cellular aging and has been linked to various age-related diseases.
This is where ATSF-1 steps in as a crucial regulator. Through their groundbreaking research, Associate Professor Steven Zuryn and Dr. Michael Dai have discovered that ATSF-1 plays a pivotal role in maintaining the balance between two critical processes: mitochondrial creation and repair. In times of cellular stress or when mitochondrial DNA is damaged, ATSF-1 takes charge and prioritizes the repair of the mitochondria over other cellular processes. By promoting mitochondrial repair, ATSF-1 helps to mitigate the harmful effects of ROS and maintain cellular health, potentially slowing down the rate at which cells age.
In essence, ATSF-1 emerges as a key player in the intricate dance between cellular energy production and cellular preservation. Its ability to prioritize mitochondrial repair is like a cellular mechanic, ensuring that the powerhouses of our cells continue to function optimally while minimizing the long-term wear and tear that comes with aging. Understanding ATSF-1's role could pave the way for interventions aimed at preserving mitochondrial health and promoting healthier aging in the years to come.
The researchers aimed to study the role of ATSF-1 in aging by enhancing its cellular function in C. elegans, or roundworms. This was achieved by expressing a modified version of the protein that localizes to the mitochondria instead of the nucleus. This version of ATFS-1, called ATFS-1mit, interferes with mitochondrial transcription and promotes mitochondrial DNA repair. The researchers used different methods to express ATFS-1mit in C. elegans, such as CRISPR genome editing, tissue-specific promoters and transgenic constructs. The researchers quickly found that enhancing the function of the protein promoted cellular health and allowed the worms to become more agile for longer periods of time. While the protein did not make them live longer, it did allow for the worms to remain healthier as they aged.
The discovery of ATSF-1's role in maintaining cellular health sheds light on the intricate mechanisms that underlie the aging process. By targeting mitochondrial repair, researchers may be able to develop strategies to mitigate the harmful effects of reactive oxygen species and slow down the rate at which cells age. Mitochondrial dysfunction is often the root of many human conditions associated with aging, such as dementia and Parkinson’s Disease. Dr. Zuryn and Dr. Dai’s findings may give way to new drugs that capitalize the unique function of ATSF-1 to allow for healthier aging without the mitochondrial diseases associated with growing old.
Additionally, the study's focus on C. elegans as a model organism offers a valuable platform for future research. While the worms' lifespan was not extended, the fact that they exhibited improved cellular health and agility as they aged presents an exciting prospect for understanding the relationship between cellular health and longevity. Translating these findings to mammalian models, including humans, may hold the key to unlocking the secrets of healthy aging and ultimately extending the human lifespan.
As scientists delve deeper into the intricacies of ATSF-1 and its impact on cellular function, collaboration between diverse fields of research is vital. Understanding how cellular health and aging intersect requires a multidisciplinary approach, bringing together experts in genetics, molecular biology, biochemistry, and gerontology. Collaborative efforts will be essential to fully comprehend the complexities of aging and translate these findings into tangible therapies that benefit human health. One day, the fabled fountain of youth may indeed become a reality.
References:
Zhou, Z., et al. (2023) 'Engineering longevity—design of a synthetic gene oscillator to slow cellular aging.' Science, 380, 376-381. https://doi.org/10.1126/science.add7631 [accessed July 19, 2023].
Chang, J., Wang, Y., Shao, L. et al. (2016) 'Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice.' Nature Medicine, 22, 78–83. https://doi.org/10.1038/nm.4010 [accessed July 19, 2023].
Dai, C. Y., Ng, C. C., Hung, G. C. C. et al. (2023) 'ATFS-1 counteracts mitochondrial DNA damage by promoting repair over transcription.' Nature Cell Biology. https://doi.org/10.1038/s41556-023-01192-y [accessed July 19, 2023].