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Aging and Genetic Modifications: Insights from 5hmC

This article explores how aging affects gene regulation and cellular function.

― 6 min read


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Aging is a natural process that affects all living things. As we grow older, our body undergoes several changes. One of the critical aspects of aging is the decline in the ability of our cells to function properly. This decline can lead to various health problems. Scientists have been studying how our genes, the instructions that guide our body's functions, change as we age.

Changes in Gene Regulation

As we age, the way our genes are regulated can change significantly. This means that the control mechanisms that decide when genes are turned on or off may be altered. These changes often lead to adaptations that can affect our health. Certain changes in the structure of our DNA can impact Gene Expression, which is crucial for maintaining proper cell function.

The Role of DNA Modifications

One important area of research focuses on special modifications to DNA that can affect how genes behave. One such modification is known as DNA hydroxymethylation (5hmC). This process involves adding a chemical group to certain parts of DNA. This added group can help regulate gene activity, which is essential for normal cellular processes.

Scientists found that 5hmC is most commonly formed from another modification called 5-methylcytosine (5mC). Various factors in our environment can influence the formation of 5hmC. For example, some nutrients like vitamin C can encourage its formation, while Oxidative Stress can also have an impact.

Aging and 5hmC Levels

Recent studies have shown that 5hmC levels tend to increase in certain organs as we age. For instance, researchers found that older mice had higher levels of 5hmC in their livers compared to younger mice. This increase in 5hmC may be partly due to a lack of cell division in the liver as animals age. With fewer cells dividing, the accumulated 5hmC remains, which is interesting because it suggests that the body's environment and cellular activity can greatly influence these modifications.

When examining gene expression in older organs, scientists observed that genes associated with liver metabolism showed increased 5hmC levels. This suggests that these modifications may play an important role in how our liver functions as we age.

The Importance of Specific Genes

Furthermore, it was noted that genes which remain stable in expression over time usually have higher levels of 5hmC. In contrast, genes that exhibit significant changes in expression often have lower levels of this modification. This finding suggests that 5hmC is involved in preventing excessive changes in gene activity, which could be beneficial for maintaining balance in the liver.

A closer look at the types of genes affected by age-related changes in 5hmC revealed that many of them are crucial for specific functions, especially metabolic processes. This highlights the importance of understanding how these genes are regulated throughout life.

The Relationship Between 5hmC and Gene Expression

Researchers explored how 5hmC may serve to limit the extent of changes in gene expression during aging. They found that higher levels of 5hmC in gene bodies often correlated with more stable gene activity. In contrast, genes that showed dramatic changes in activity tended to have less 5hmC.

By conducting experiments to measure gene expression, scientists were able to confirm the idea that 5hmC helps maintain steady gene activity. This is particularly important for liver function, which is essential for our overall health.

Understanding Alternative Splicing

Another fascinating aspect is the concept of alternative splicing. This is a process where a single gene can lead to multiple protein forms, contributing to the complexity of gene function. Researchers discovered that higher levels of 5hmC were linked to increased alternative splicing events in aged tissues, indicating that 5hmC might not only be regulating gene expression but also influencing how genes produce their corresponding proteins.

How Aging Affects Cellular Function

Aging often leads to reduced energy production in cells. In experiments, when researchers induced a quiescent state in liver cells, they noticed a drop in energy levels. This drop was associated with increased levels of 5hmC. The quiescent state mimics the prolonged resting state of cells as seen in aging tissues, where cells are less active and divide infrequently.

On the other hand, conditions that promote cell division, such as liver regeneration after surgical removal of part of the liver, led to a reduction in 5hmC levels. This suggested that active cell division can help moderate the accumulation of these modifications.

Exploring the Mechanisms Behind 5hmC Accumulation

Despite the knowledge gained, there remain many questions about how 5hmC levels increase with age. Some factors known to influence 5hmC formation were evaluated, but no significant changes in the expression of related genes were observed. This led scientists to explore alternate explanations, including the possibility that the increase in 5hmC may stem from environmental influences rather than simply from modifications at the gene level.

The Role of Stress and Nutrition

The impact of nutrients and oxidative stress on 5hmC levels is an area of active research. While some studies have suggested that increased oxidative stress may lead to higher 5hmC, ongoing investigations have shown mixed results. For instance, introducing antioxidants like vitamin C demonstrated a significant increase in 5hmC levels in cultured liver cells, showing that dietary elements can affect gene regulation.

Analyzing Human Tissues

Interestingly, researchers also wanted to know if what they discovered in mice applies to humans. By examining human tissues, they found that the modifications of 5hmC in genes remained consistent with age, suggesting that this mechanism might be conserved across species. They analyzed various human tissues, including the brain, heart, and liver, to further understand how these modifications influence gene expression.

Conclusion: Implications for Aging and Health

The findings from studying 5hmC provide valuable insight into the aging process and highlight the importance of gene regulation. By understanding how 5hmC levels change with age and how these changes influence gene activity, scientists hope to pave the way for potential therapeutic strategies to address age-related diseases.

Efforts to manipulate these modifications could lead to new approaches for promoting healthy aging, thereby improving the quality of life as we grow older. Understanding the delicate balance of gene expression, the role of cellular activity, and the influence of our environment on these processes remains a critical focus for ongoing research.

The relationship between age, gene regulation, and health is complex but essential for grasping the fundamental mechanisms of biology. Future studies will continue to explore this intricate landscape, as it holds the potential to unlock new avenues for promoting longevity and vitality.

Original Source

Title: Gene body DNA hydroxymethylation restricts the magnitude of transcriptional changes during aging

Abstract: DNA hydroxymethylation (5hmC), the most abundant oxidative derivative of DNA methylation, is typically enriched at enhancers and gene bodies of transcriptionally active and tissue-specific genes. Although aberrant genomic 5hmC has been implicated in age-related diseases, its functional role in aging remains unknown. Here, using mouse liver and cerebellum as model organs, we show that 5hmC accumulates in gene bodies associated with tissue-specific function and restricts the magnitude of gene expression changes with age. Mechanistically, 5hmC decreases the binding of splicing associated factors and correlates with age-related alternative splicing events. We found that various age-related contexts, such as prolonged quiescence and senescence, drive the accumulation of 5hmC with age. We provide evidence that this age-related transcriptionally restrictive function is conserved in mouse and human tissues. Our findings reveal that 5hmC regulates tissue-specific function and may play a role in longevity.

Authors: Payel Sen, J. R. Occean, N. Yang, Y. Sun, M. S. Dawkins, R. Munk, C. Belair, S. Dar, C. Anerillas, L. Wang, C. Shi, C. Dunn, M. Bernier, N. L. Price, J. S. Kim, C.-Y. Cui, J. Fan, M. Bhattacharyya, S. De, M. Maragkakis, R. d. Cabo, S. Sidoli

Last Update: 2024-07-03 00:00:00

Language: English

Source URL: https://www.biorxiv.org/content/10.1101/2023.02.15.528714

Source PDF: https://www.biorxiv.org/content/10.1101/2023.02.15.528714.full.pdf

Licence: https://creativecommons.org/publicdomain/zero/1.0/

Changes: This summary was created with assistance from AI and may have inaccuracies. For accurate information, please refer to the original source documents linked here.

Thank you to biorxiv for use of its open access interoperability.

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