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The Role Of HDAC4 In Maintaining Epigenome Identity

The Role Of HDAC4 In Maintaining Epigenome Identity

A new study explores the role of HDAC4 in cellular senescence and aging. Read on to learn more.

In this article:

  1. What is Senescence?
  2. How Does Senescence Impact Aging?
  3. What Are Histones?
  4. What Did the Researchers Do?
  5. What Is HDAC4?
  6. What Role Does HDAC4 Play in Cellular Senescence?
  7. How Do These Findings Contribute to Epigenetics?

HDAC4 Sheds New Light on Cellular Senescence and Aging


What is Senescence?

Senescence is an irreversible cellular state. Epigenetic reprogramming triggers cells to go into a state where they are no longer dividing, but not dying either. 

Researchers often characterize it as a state of arrest where the cell cycle stops, and cells can no longer grow. Senescence offers a few evolutionary benefits like suppressing the proliferation of damaged cells (including cancer cells), but there’s also a downside. 


How Does Senescence Impact Aging?

Cellular senescence and aging are not the same things, but they’re indeed intertwined. In fact, cellular senescence can be seen as a hallmark of aging. Over time, the accumulation of senescent cells can contribute to cellular dysfunction and aging

Mitochondrial dysfunction, DNA damage, epigenetic dysregulation, and telomere damage can trigger senescence. Senescent cells can then cause inflammation and cell exhaustion, both of which contribute to the aging process. 


What Are Histones?

Illustration showing the formation of an animal cell from dna and chromosomes | Histones | The Role of HDAC4 in Maintaining Epigenome Identiy

Histones play a role in a cell’s cycle progression, conversion of DNA to RNA, and other developmental events. Structurally, DNA, and histones are wrapped together. 

Histone deacetylases (HDAC) are enzymes that regulate how tight or loose histones are wrapped around DNA. Functionally, it also plays a role in DNA expression regulation. 

Since HDAC plays a role in regulating a cell’s cycle progression, a group of nine researchers wanted to understand its role in regulating senescence and the aging process. After conducting a series of experiments, they published their results in bioRxiv in June 2020. 


What Did the Researchers Do?

In their study, the researchers evaluated different class IIa HDAC expressions in different senescence and aging models. They examined the HDAC levels in skin and liver cells of 4-month old mice (young) and 25-month old mice (old). 

They also examined the effects of knocking out the different HDAC in cells. From all of the HDACs, they found that HDAC4 plays a role in senescence regulation. 


What Is HDAC4?

Histone deacetylase 4 (HDAC4) is a protein from class IIa of HDAC. Rather than binding with DNA directly, HDAC4 interacts with DNA through transcription factors. 


What Role Does HDAC4 Play in Cellular Senescence?

After testing different HDACs, they found that HDAC4 is downregulated in all of the senescence and aging models. This prompted the researchers to explore further. 

They didn’t only examine the presence and absence of HDAC4 but also examined the sequential effects of low HDAC4 levels. Here are some of their other findings:

  • HDAC4 levels decrease in older cells (compared to younger cells). 
  • HDAC4 levels trigger the appearance of specific senescence markers and cell-cycle arrest. Including harmful cells, like melanoma cells. 
  • After HDAC4 removal, DNA damage increases in the first 48 hours and then more rapidly in the next 24 hours. 
  • HDAC4 removal inhibits cell proliferation. In their sample, most of the cells without HDAC4 did not launch the second mitosis.
  • HDAC4 absence increases DNA lesion accumulation during replication. When replication occurs before the DNA lesions are repaired, it could lead to a DNA mutation. 
  • Low levels of HDAC4 activates retroviral origin (ERV) transcripts. ERV transcripts involve RNA, which can change the DNA genome by inserting copies of its genome. 

Overall, an HDAC4 knock-out can lead to:

  • Accumulation of replication stress and DNA damage
  • Expression of inflammatory genes

These events may trigger senescence prematurely. Because of these findings, the research team believes that HDAC4 may actually play a role in maintaining the genome integrity and epigenome identity of cells. 

In the absence of HDAC4, senescence can begin in both pre-transformed and transformed cells. They believe that HDAC4 can safeguard a cell’s integrity by preventing the activation of senescent genes and regulating the expression of inflammatory genes.


How Do These Findings Contribute to Epigenetics?

Understanding HDAC4’s role in maintaining epigenome identity broadens medical professionals’ understanding of aging and cellular senescence, especially in the field of epigenetics. Epigenetics focuses on changes in gene expression. 

It also factors in external variables like lifestyle and its impact on gene expression, aging, and disease. These new findings on HDAC4 may hold the key to understanding age-related changes in gene expression.

If you want to learn more about epigenetics and the science of aging, contact Tru Diagnostic today


What do you think of these new findings? Share your thoughts with us in the comments section below. 

Aerobic Glycolysis: How An Increased Demand For NAD+ Can Boost It

Aerobic Glycolysis: How An Increased Demand For NAD+ Can Boost It

A recent study sheds light on aerobic glycolysis and cellular proliferation. Read on to learn more. 


In this article:

  1. What Is Glycolysis?
  2. What Is Aerobic Glycolysis?
  3. What Did The Researchers Do?
  4. What Were the Results of Their Experiments?
  5. What Did They Discover About Aerobic Glycolysis?

Understanding Aerobic Glycolysis in Proliferating Cells

What Is Glycolysis?

Glycolysis is a metabolic pathway. This pathway involves the conversion of food into energy. Cells use the energy released from glycolysis to make: 

  • Adenosine triphosphate (ATP) 
  • Nicotinamide adenine dinucleotide (NADH). 

ATP is a molecule that stores and transfers energy for different cellular processes. On the other hand, when NADH is oxidized, it becomes NAD+. NAD+ helps transport electrons to the cell's mitochondria. This helps turn nutrients into energy.

The presence or absence of oxygen can impact metabolic processes. When oxygen is available, most cells reduce oxygen to water through respiration. Respiration supports the oxidation reactions cells use to extract energy from nutrients.

Cells use an alternative metabolic process when there isn't enough oxygen available. Instead of respiration, most cells will ferment carbohydrates.

The fermentation process in cells creates lactate or ethanol. Cells use lactate and ethanol to help extract energy from nutrients.

Some rapidly proliferating cells use the fermentation process even if there is more than enough oxygen present. This metabolic phenotype is Aerobic glycolysis. 


What Is Aerobic Glycolysis?

Aerobic glycolysis is a type of glycolysis. It is a cellular condition where glucose converts to lactate in the presence of oxygen. It is also called the Warburg effect.

The Warburg effect is more commonly associated with tumors and cancer cells. However, it is also present in non-cancer cells. For example, yeast cells, bacteria cells, lymphocytes, and fibroblasts engage in aerobic glycolysis. 

There are a few non-proliferative cells that also engage in aerobic glycolysis, such as pigmented epithelial cells in mammals' eyes.

Even though a variety of cells engage in aerobic glycolysis, researchers cannot fully explain its mechanisms. They also don't completely understand how it relates to cellular proliferation. 

Researchers ran a series of experiments on yeast and mammal cells to understand aerobic glycolysis better. They examined the consequences of increasing mitochondrial oxidation in cells.


What Did The Researchers Do?

Acetyl-coA biochemical, molecular model. Atoms are represented as spheres with conventional color coding | What Did The Researchers Do? | The Role Of HDAC4 In Maintaining Epigenome Identity

Through a series of experiments, the researchers suppressed fermentation in cells. To do this, they increased pyruvate dehydrogenase complex (PDH) activity in cells. PDH is a multi-enzyme that catalyzes the transformation of pyruvate to acetyl-CoA.  

Acetyl-CoA plays a delivery role that facilitates the Krebs cycle. So PDH plays a vital role in regulating aerobic glycolysis in cells. 


What Were the Results of Their Experiments?

After running their experiment, the researchers found:

  • PDH activation limits aerobic glycolysis and cellular proliferation. 
  • PDH activation decreases NAD+/NADH in ratios in cells, so it decreases cellular proliferation.
  • Increasing pyruvate oxidation limits NAD+ availability for the oxidation reaction. This impairs the proliferation of cells. 
  • Altering NAD+/NADH impacts PDH activation, so it impacts cellular metabolism. 
  • They can restore cellular proliferation by regenerating NAD+ (even after activating PDH). 
  • Reducing NAD+/NADH ratios impede mitochondrial electron transport and NAD+ regeneration. 
  • NAD+ regeneration is more dependent on mitochondrial complex when PDH is activated. 
  • When pyruvate dehydrogenase kinases (PDK) is inhibited, excess ATP limits NAD+ regeneration. 
  • In proliferating cells, NAD+ regeneration demands can supersede the ATP requirement. 
  • Separating ATP synthesis and electron transport increases NAD+ regeneration through respiration.
  • When PDH is activated, increasing ATP consumption decreases cellular proliferation.
  • NAD+ availability in cells determines aerobic glycolysis in cells.  
  • Giving cells another way of regenerating NAD+ suppresses aerobic glycolysis in yeast and mammal cells. This alternative way of regenerating NAD+ doesn't impact cellular proliferation. 

Overall, the findings suggest that aerobic glycolysis occurs when the demand for NAD+ is more than the demand for ATP. Oxidizing pyruvate (rather than fermenting it), increases the demand for NAD+ regeneration. This regeneration happens through mitochondrial respiration.  


What Did They Discover About Aerobic Glycolysis?

Aerobic glycolysis is a cellular process seen in many species, so it is essential to understand the conditions that trigger it. Maintaining a high AT/ADP ratio is essential for the survival of many cells. That is why the oxidation of nutrients is linked to ATP production. 

Mitochondrial respiration can't keep up with NAD+ regeneration when the demand for NAD+ is more than the demand for ATP. This triggers aerobic glycolysis. 

NAD+ plays a vital role in cells. It helps cells create the energy they need for optimal functioning. Some researchers also believe that NAD+ levels can impact aging because its levels decrease as you age. 

Understanding the role of NAD+ in aerobic glycolysis is useful in the field of epigenetics. If you are interested in learning more about the science of aging and epigenetics, visit the Tru Diagnostic website today.


What do you think of these new findings? Share your thoughts with us in the comments section. 

The World's Most Accurate Biological Age Test: It's In Your Genes

The World's Most Accurate Biological Age Test: It's In Your Genes

A biological age test is an excellent health investment. Read on to learn all about it.


In this article:

  1. Provides a More Comprehensive Understanding of Aging
  2. Spotlights Epigenomes
  3. Predicts a Variety of Health Outcomes
  4. Gives You Insight on the Effects of Your Lifestyle
  5. Has Exciting Applications in the Future
  6. Bonus: Uses Quick and Easy Testing Procedures

5 Reasons to Get a Biological Age Test


Provides a More Comprehensive Understanding of Aging

Many people think of age as the number of years they've spent alive, but that just refers to their chronological age. The biological age test, as its name suggests, will provide you with your biological age. 

What is biological age? It refers to how much your cells and body have changed. It also describes how well your body functions. 

So people who have the same chronological age may not have the same biological age. For example, two forty-year-olds could have drastically different biological ages because of a variety of factors. 

All of your tissues and organs have their biological age because some organs will function better than others. Most tests will be able to inform you of your average biological age, which will give you some insight into your body's overall level of functioning. 

Once you have your biological age, you'll be able to calculate your cumulative rate of aging. Your cumulative rate of aging is your biological age relative to your chronological age. 

This is important because many won't have the same chronological and biological ages. So it'll tell you how quickly (or slowly) you're aging. 


Spotlights Epigenomes

Biological age tests focus on your epigenomes and not just your genomes. Genomes refer to your complete DNA. 

Many genetic tests provide information about your unique DNA sequence that makes up your genome. It can be useful, but your genome and DNA will essentially stay the same. 

The advantage of getting a biological age test is that it analyzes your epigenome as well. Your epigenomes are proteins and chemical compounds attached to DNA. 

They help regulate DNA activity. Your epigenomes can activate (or deactivate) DNA, change the way DNA reads messages, and regulate protein development. 

Epigenetic compounds don't change DNA structure, but they can impact its activity. It sheds more light on your true age because your epigenome can change over time. 

In biological age tests, they measure DNA methylation to describe the changes brought on by epigenetic compounds. It provides a more transparent and more nuanced picture of aging across your genome. 


Predicts a Variety of Health Outcomes

Mature woman doing sports at home on a Mat, healthy lifestyle concept | Predicts a Variety of Health Outcomes |

The information you get from a biological age test can shed light on various aging and health outcomes. Studies show that biological age is a useful tool in predicting mortality and age-related diseases such as:

  • Alzheimer's disease
  • Heart disease
  • Diabetes
  • Cancer

Chronological age can also predict health outcomes to a certain extent, but a biological age test can provide more insight across thousands of genome sites. When doctors administer and interpret biological age tests, they can help identify DNA methylation patterns that have an impact on health outcomes. 


Gives You Insight on the Effects of Your Lifestyle

The beauty of biological age tests is that they look at your epigenome, which can change with age. When it comes to epigenetics, you're not only gaining information about your predisposition, but it'll also tell you how your body responds to your lifestyle. 

Your health habits and lifestyle can have an impact on your epigenetic mechanisms. Here are a few lifestyle factors that can influence your epigenome:

  • Diet and nutrition
  • Psychological stress
  • Physical activity
  • Working habits
  • Smoking
  • Alcohol consumption 

Apart from lifestyle factors, environmental factors can also modify epigenetic patterns. For example, chronic exposure to environmental pollutants may cause epigenetic changes, which increase the possibility of developing certain diseases. 

Unlike genetics, there are things you can do to change these lifestyle and environmental factors. A biological age test can help point out the changes you can make to reach your health goals.


Has Exciting Applications in the Future

The scientist have test and researching in laboratory | Has Exciting Applications in the Future | The World's Most Accurate Biological Age Test: It's In Your Genes

Scientists are learning more about epigenetics every day. They barely scratched the surface when it comes to its applications. 

In the future, scientists hope to make biological age tests more and more specific. If they find a convenient way to collect samples from specific organs, they'll be able to offer a biological age for different parts of your body. 

Mimetics is another exciting application of the biological age test. Scientists understand that different behaviors can have an impact on longevity. 

With the help of epigenetics, scientists can try to match these behaviors with their effects on your body. If they can find out what these behaviors are doing and how they help improve body function, they can try to make therapeutics that mimic those effects. 

For example, exercise benefits body function in a variety of ways. If scientists can figure out how to mimic the effects of exercise, then this could benefit people with disabilities who are unable to exercise in the same way.


Bonus: Uses Quick and Easy Testing Procedures

The best thing about the biological age test is how convenient it is! Tru Diagnostic's biological age test is called TruAge

TruAge can be administered by a doctor, but you can also do it all by yourself in the comfort of your own home! The TruAge kit will require a blood sample because blood provides accurate and useful results.

Some tests use saliva and urine samples, but the results from these samples are limited. Studies show that DNA methylation percentages are lower in saliva samples than blood samples so that a saliva sample may miss out on important markers of aging.  

A simple blood test can give you the information you need to optimize your health. Isn't that amazing? 

As you age, the gap between your chronological age and biological age becomes wider. A biological age test gives you the information you need to bridge that gap. If you're interested in learning more about biological age tests, visit Tru Diagnostic's website.


Would you take a biological age test? Share your thoughts with us in the comments section below. 

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