Tag Archives: methylation

Study on mice: Exercising later in life can keep your muscles young

Exercising can not only make you feel younger, but it can also actually keep you younger as well. A study on mice suggests that exercising, even later in life, can do wonders for your muscles. In addition to underscoring the importance of staying active, the study could also help us uncover some of the secrets of rejuvenation.

Even though some diseases are inherited, we can still improve our overall health through lifestyle choices such as diet and exercise. Still, whatever the reason, the genes related to some of these conditions must be expressed for them to develop. So how does this happen?

A new study has brought us closer to an answer by mapping the genetic changes involved in rejuvenating the muscle cells of elderly mice put on an exercise program.

Turning genes on and off

The analysis centers on DNA, the “blueprint” for our bodies. DNA consists of four bases, called cytosine, guanine, adenine, and thymine, and the process used to help manage these massive helixes: a methyl molecule composed of one carbon and three hydrogen atoms. These atoms attach themselves to one of the four bases (cytosine) to form what’s known as a CpG site.

When this occurs, the CpG becomes methylated and the site produces proteins to regulate something in the body — whatever that something may be. In contrast, the region becomes unmethylated when you lose that methyl group, turning that gene off. In this way, a process called DNA methylation can promote or inhibit the expression of specific genes — whether it’s stopping a tumor, preventing cancer, or activating genes responsible for causing wrinkles in old age. This process is constant, occurring billions of times a second in every cell throughout the body, and we’re just starting to understand it.

DNA methylation is one of the many mechanisms of epigenetics, where inborn or acquired changes in DNA don’t touch the actual sequence – meaning a person can potentially reverse things like fat deposits through diet or exercise. More and more studies are starting to suggest that this is an unharnessed and robust process, linked to longevity and the regulation of lifespan in most organisms on earth.

The current study attempts to further this theory using lifestyle interventions such as exercise to roll back genetic aging in skeletal muscle – measuring the animal’s ‘epigenetic clock’ for accuracy. This clock is measured via methylation levels in the blood to reflect exposures and disease risks independent of chronological age, providing an early-warning system and a true representation of a period of existence.

Kevin Murach, an assistant professor at the University of Arkansas, says, “DNA methylation changes in a lifespan tend to happen in a somewhat systematic fashion. To the point, you can look at someone’s DNA from a given tissue sample and with a fair degree of accuracy predict their chronological age.”

Using exercise to turn back the clock

The study design was relatively simple: mice nearing the end of their natural lifespan, at 22 months, were given access to a weighted exercise wheel to ensure they built muscle. They required no coercion to run on the wheel, with older mice running from six to eight kilometers a day, mostly in spurts, and younger mice running up to 10-12 kilometers.

Results from the elderly mice after two months of weighted wheel running suggested they were the epigenetic age of mice eight weeks younger, compared to sedentary mice of the same maturity.

The team also used the epigenetic clock to map a multitude of genes involved in the formation and function of muscles, including those affected by exercise. Blood work indicated that the genes usually over methylated (hypermethylated) in old age resumed normal methylation in the active aged mice, unlike those mapped in their sedentary counterparts.

For instance, the rbm10 gene is usually hypermethylated in old age, disrupting the production of proteins involved in motor neuron survival, muscle weight & function, and the growth of striated muscle. Here it was shown to undergo less methylation in older mice who exercised, improving its performance. Normal methylation levels also resumed across the Timm8a1 gene, keeping mitochondrial function and oxidant defense at workable levels – even where neighboring sites exhibited dysfunctional epigenetic alterations.

More work is needed to harness DNA methylation

Murach notes that when a lifespan is measured incrementally in months, as with this mouse strain, an extra eight weeks — roughly 10 percent of that lifespan — is a noteworthy gain, further commending the importance of exercise in later life.

He adds: that although the connection between methylation and aging is clear, methylation and muscle function are less clear. Despite these sturdy results, Murach will not categorically state that the reversal of methylation with exercise is causative for improved muscle health. “That’s not what the study was set up to do,” he explained. However, he intends to pursue future studies to determine if “changes in methylation result in altered muscle function.”

And, “If so, what are the consequences of this?” he continued. “Do changes on these very specific methylation sites have an actual phenotype that emerges from that? Is it what’s causing aging or is it just associated with it? Is it just something that happens in concert with a variety of other things that are happening during the aging process? So that’s what we don’t know.”

He summarizes that once the medical community has mapped the mechanics of dynamic DNA methylation in muscle, their work could provide modifiable epigenetic markers to improve muscle health in the elderly. 

Gene cutting.

Second gene-silencing mechanism found, could lead to viable clones and safer in vitro

A new cellular gene-silencing mechanism has been identified and could hold the key to safer in vitro fertilization, even the cloning of animals.

Gene cutting.

Image credits Arek Socha.

We each inherit two working copies of most genes from our parents, one from the maternal and one from the paternal side. But for a tiny minority of genes, or allele, only one copy can be allowed to function while the other remains inactivated from inception until the moment we die. This mechanism is called imprinting, and faulty imprinting can cause a host of genetic syndromes, such as Angelman’s (too much imprinting, so both genes are inactivated) or Beckwith-Wiedemann syndrome (too little imprinting, so both alleles are expressed).

Imprinting is why a lion and a tiger can have two types of offspring. If the female is lion, the couple will sire a tigon, which generally-speaking are smaller than both the parent species. But if the female is a tiger, they will sire a liger — which is much larger in general than any of the initial two. The differences in size and appearance come down, in part, to imprinting differences in maternal- and paternal-inherited genes.Usually, imprinting takes place naturally during inception, through a process called methylation — basically, methyl groups are added to a gene to shut it down.

But in artificial fertilization methods, such as in vitro for humans or straight-up cloning of mammals, imprinting can sometimes be faulty or bypassed altogether. However, a new discovery from the Howard Hughes Medical Institute might hold the key to reversing faulty imprinting. The team, whose correspondent author is Investigator Yi Zhang, found another mechanism cells can use to silence imprinted genes — by attaching specially-modified proteins called histones to the problematic alleles.

These genes are histone-y

The researchers succeeded in shutting down the activity of some imprinted genes in mice by modifying a histone known as H3K27 to carry methyl groups. They also identified 76 genes in mice that likely belong to the imprinted gene group, which is a pretty big number: until now, roughly 150 imprinted genes have been found in mice and roughly half that in humans.

There’s still a lot of work to be done on imprinting, Zhang says, but finding a second mechanism underpinning it just goes to show how important imprinting is from evolution’s point of view. It’s possible that the one the team describes in their paper evolved as a back-up to catch any improperly-imprinted alleles before they can cause any damage.

Imprinting disorders seem to develop more often in children conceived in vitro or through similar methods, the paper notes. It’s still unclear as to why. It could be that imprinting problems are inherently tied to infertility itself, or it may well be that these procedures somehow interfere with imprinting and we just don’t know it yet. But Zhao thinks their findings could give hope to couples who’re having difficulties conceiving and are pursuing assisted reproductive technologies that their child will be healthy.

Furthermore, improper imprinting could be why we’ve had so little success in cloning a healthy animal. Usually, the process requires that imprinting marks be scrapped in the precursor cells and then re-added in the eggs and sperm. Previous research lends weight to the idea that even minor bugs in this erase-rewrite phase can have dramatic effects on the development of clone embryos.

“The new imprinting mechanism may eventually offer a target for treating such developmental failures,” Zhang concludes.

The paper “Maternal H3K27me3 controls DNA methylation-independent imprinting” has been published in the journal Nature.

Woman's workout

Exercising triggers chemical changes in DNA

A remarkable research whose findings recently published in the journal Cell, concludes that intense physical exercise leads to chemical alteration of the DNA, turning certain genes on and off. In fact, individuals which lead a relatively sedentary lifestyle changed the DNA in their muscle fibers almost immediately, after a strenuous 35 minute work-out.

Woman's workout  It’s important to note that the genetic code itself wasn’t altered, only the chemical tags. Genes, such as the one responsible for energy production, can be turned on and off through a process called methylation, in which a methyl group is added to a gene. When this happens, the chemical blueprint which instructs the production of certain proteins is modified. This might well explain why cells benefit from exercise, but begs an even more interesting question – “Do we carry some consequence of whether our parents were active or not?” asks study coauthor Romain Barrès of the University of Copenhagen.

Unfortunately, this questions wasn’t addressed in this particular research, which instead sought to track immediate chemical changes in the DNA and how other proteins recognize it, and thus regulate the production of specific proteins to support higher growth and the breakdown of sugar and fats with exercise.

The study focused on two groups of volunteers – those who had completed low- and high-impact cycling workouts. Biopsied cells from the volunteers’ thigh tissue was analyzed and revealed that muscle cells had fewer methyl groups attached to DNA and higher levels of blueprints for energy-regulating proteins after a hard work-out, compared with cells that had undergone a low-impact workout. What’s the bare minimum? According to the researchers, running or biking at a level of exertion where it’s hard to carry on a conversation for about 35 minutes.

“What this likely suggests is that if you did this early in life, while muscles were being developed, that might actually program the muscle,” says Michael Skinner, a researcher at Washington State University in Pullman.

The second leg of their study was at least as interesting. Calcium has been known to biologists for decades that it’s an inter-cellular signaling molecule, which informs muscles when they need to contract. The researchers bathed rat muscle cells into caffeine, which an agent that releases calcium from calcium-storage sites within muscle cells. What happened next was t the muscles were being tricked into think they were exercised. Also, it was observed that caffeine exposure also results in fewer methyl groups and more protein blueprints produced.

The researchers findings will most likely offer new insightful regarding the role of methylation muscle function and development, as well as hopefully motivate people to exercise more often. Hopefully, the researches will continue for where their left off and study whether these kind of DNA chemical modifications are transmissible to offsprings.

Dr. Eric Vilain. (c) UCLA

Scientists predict age using only a saliva sample

Dr. Eric Vilain. (c) UCLA

Dr. Eric Vilain. (c) UCLA

In a recently patented research, UCLA geneticists have shown and demonstrated how they’ve accurately been able to predict a person’s age just by analyzing a saliva sample. The research could possibly find highly welcomed applications in crime scene investigation, as a forensics tool for pinpointing a suspect’s age.

“Our approach supplies one answer to the enduring quest for reliable markers of aging,” said principal investigator Dr. Eric Vilain, a professor of human genetics, pediatrics and urology at the David Geffen School of Medicine at UCLA. “With just a saliva sample, we can accurately predict a person’s age without knowing anything else about them.”

To achieve this, scientists used a process called methylation – a chemical modification of one of the four building blocks that make up our DNA.

“While genes partly shape how our body ages, environmental influences also can change our DNA as we age,” Vilain said. “Methylation patterns shift as we grow older and contribute to aging-related disease.”

In the first round of testing, researchers sampled saliva from 34 pairs of identical male twins, aged between 21 and 55, whose genome was then analyzed. Scientists identified 88 sites on the DNA that strongly correlated methylation to age. In the second round, they replicated their findings after extending to a general population of 31 men and 29 women between the ages of 18 and 70.

Using two of the three genes with the strongest age-related linkage to methylation, scientists constructed a predictive model which helped them tell the age of a study participant within a range of 5 years, an incredible approximation by today’s standard.

“Methylation’s relationship with age is so strong that we can identify how old someone is by examining just two of the 3 billion building blocks that make up our genome,” said first author Sven Bocklandt, a former UCLA geneticist now at Bioline.

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In some people, methylation does not correlate with chronological age. This is because a person’s age is measured in both chronological age and bio-age, which is the true age of a subject. Using data from this particular reserach, scientists might be able to lay the forefront for future accurate bio-age measurements. Medical applications would be both numerous and highly advantageous.

“Doctors could predict your medical risk for a particular disease and customize treatment based on your DNA’s true biological age, as opposed to how old you are,” Vilain said. “By eliminating costly and unnecessary tests, we could target those patients who really need them.”

The UCLA team is currently exploring whether people with a lower bio-age live longer and suffer less disease. They also are examining if the reverse is true — whether a higher bio-age is linked to a greater rate of disease and early death.
The findings can be read in more detail in the June 22 edition of PLoS One, an online journal of the Public Library of Science.