Tag: epigenetics

Categories : AgeingTags :

Cells in Mice Partially Reset to More Youthful States

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Mouse
Photo by Kanasi on Unsplash

Scientists have shown that they can safely and effectively reverse the epigenetic markers of age in middle-aged and elderly mice by partially resetting their cells to more youthful states – reducing many signs of ageing as they do so.

As organisms age, their cells have different epigenetic markers on their DNA compared to younger ones. It is known that adding a mixture of reprogramming molecules, also known as ‘Yamanaka factors’, to cells can reset these epigenetic marks to their original patterns. This approach enables researchers to turn back the clock for adult cells, developmentally speaking, into stem cells.

“We are elated that we can use this approach across the life span to slow down aging in normal animals. The technique is both safe and effective in mice,” said Juan Carlos Izpisua Belmonte, co-corresponding author, professor at the Salk Institute. “In addition to tackling age-related diseases, this approach may provide the biomedical community with a new tool to restore tissue and organismal health by improving cell function and resilience in different disease situations, such as neurodegenerative diseases.”

The Salk Institute research lab reported in 2016 that, for the first time, they were able use the Yamanaka factors to counter the signs of aging and increase life span in mice with a premature ageing disease. More recently, the lab found that the Yamanaka factors can accelerate muscle regeneration even in younger mice. Building on these studies, other scientists have used the same approach to improve the function of other tissues like the heart, brain and optic nerve.

In the new study, the researchers tested variations of the cellular rejuvenation approach in healthy animals as they aged. One group of mice received regular doses of the Yamanaka factors from the time they were 15 months old until 22 months, approximately equivalent to age 50 through 70 in humans. Another group was treated from 12 through 22 months, approximately age 35 to 70 in humans. And a third group was treated for just one month at age 25 months, similar to age 80 in humans.

“What we really wanted to establish was that using this approach for a longer time span is safe,” said Pradeep Reddy, study co-first author. “Indeed, we did not see any negative effects on the health, behaviour or body weight of these animals.”

No blood cell alterations or neurological changes were seen in the mice treated with the Yamanaka factors compared to control mice. Additionally, no cancers were observed in any of the groups of animals.

In terms of normal signs of ageing, the treated mice resembled younger animals in a number of ways. In both the kidneys and skin, the epigenetics of treated animals more closely resembled epigenetic patterns seen in younger animals. When injured, the skin cells of treated animals had a greater ability to proliferate and were less likely to form permanent scars, unlike normal older animals. Metabolic molecules also did not reflect normal age-related changes.

This youthfulness was observed in the animals treated for seven or 10 months with the Yamanaka factors, but not the animals treated for just one month. What’s more, when the treated animals were analysed midway through their treatment, the effects were not yet as evident. This suggests that the treatment is not simply pausing aging, but actively turning it backwards–- although more research is needed to differentiate between the two.

The team is now planning future research to analyse how specific molecules and genes are changed by long-term treatment with the Yamanaka factors. They are also developing new ways of delivering the factors.

“At the end of the day, we want to bring resilience and function back to older cells so that they are more resistant to stress, injury and disease,” said Reddy. “This study shows that, at least in mice, there’s a path forward to achieving that.”

The study was published in Nature Aging.

Source: Salk Institute

Categories : Obstetrics & Gynaecology Substance Use UncategorizedTags :

Effects of Fathers’ Prenatal Alcohol Exposure Manifests in Offspring

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Researchers have discovered that males exposed to alcohol in utero later pass on those effects to their offspring during foetal development, through reduced placental efficiency. The study appears in FASEB Journal.

Dr Michael Golding, an associate professor at Texas A&M University has spent years investigating the father’s role, with regard to drugs and alcohol, in foetal development. Studies have shown that males pass down more than just their genetics, Dr Golding said, but exactly how that process works and the its consequences are still largely unknown.

“When you look at the data from throughout human history, there’s clear evidence that there’s something beyond just genetics being inherited from the male,” Dr Golding said. “So, if that data is solid, we’ve got to start looking more at male behaviour.

“Say you had a parent who was exposed to starvation – they could pass on what you might call a ‘thriftiness,’ where their kids can derive more nutrition from less food,” he said. “That could be a positive if they grow up in a similar environment, or they could grow up in a time when starvation isn’t an issue and they might be more prone to obesity or metabolic syndromes. That kind of data is clearly present in clinical data from humans.”

Epigenetics, which is Dr Golding’s area of study of how things beyond genes, such as behaviour and environment, affect development is called. One of the big questions in the search for answers on how male prenatal behaviour can impact foetal growth has been the way these epigenetic factors manifest.

The team has shown that prenatal exposure to alcohol in males can manifest in the placenta: in mice, offspring of fathers exposed to alcohol have a number of placenta-related difficulties, including increased foetal growth restriction, enlarged placentas, and decreased placental efficiency.

“The placenta supplies nutrients to the growing foetus, so foetal growth restriction can be attributed to a less efficient placenta. This is why placental efficiency is such an important metric; it tells us how many grams of foetus are produced per gram of placenta,” said Thomas, a graduate student at Texas A&M. “With paternal alcohol exposure, placentas become overgrown as they try to compensate for their inefficiency in delivering nutrients to the foetus.”

However,while these increases happened frequently in male offspring, the frequency varied greatly based on the mother; however, the same increases were far less frequent in female offspring. Dr Golding thinks that although information is passed from the father, the mother’s genetics and the offspring’s sex are also involved.

“This is a novel observation because it says that there’s some complexity here,” Dr Golding said. “Yes, men can pass things on to their offspring beyond just genetics, but the mom’s genetics can interpret those epigenetic factors differently, and that ultimately changes the way that the placenta behaves.”

These results don’t draw a clear line in how drinking in human males prior to conception impacts foetal development, but they continue to at least point to it being a question that needs to be explored. 

Dr Golding is hoping that more questions will be asked about male prenatal behaviour so that there’s more data from which to work.

“The thing that I want to ultimately change is this stigma surrounding the development of birth defects,” Dr Golding said. “There’s information coming through in sperm that is going to impact the offspring but is not tied to the genetic code; it’s in your epigenetic code, and this is highly susceptible to environmental exposures, so the birth defects that we see might not be the mother’s fault; they might be the father’s or both, equally.”

Source: Texas A&M University

Categories : AgeingTags :

Muscles may Stay Younger at an Epigenetic Level through Exercise

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While the benefits of exercise in ageing have been well established, such as lowering risk of cardiovascular disease, a new study that used mice demonstrated that exercise in aged individuals could help muscles stay younger at an epigenetic level.

Despite generating a wealth of data, the study, which was published in Aging Cell, made use of a relatively straightforward experiment. Lab mice nearing the end of their natural lifespan, at 22 months, were allowed access to a weighted exercise wheel. Mice generally run voluntarily, without any coercion. Older mice will run anywhere from six to eight kilometres a day, mostly in spurts, while younger mice may run up to 10 to 12 kilometres. The weighted wheel ensured they built muscle. While there isn’t a direct analogue to most human exercise routines, first author Kevin Murach, assistant professor at the University of Arkansas, likened it to “a soldier carrying a heavy backpack many miles.”

When the mice were examined after two months of progressive weighted wheel running, it was determined that they were the epigenetic age of mice eight weeks younger than sedentary mice of the same age – 24 months. Murach noted that while the specific strain of mice and their housing conditions can impact lifespans, “historically, they start dropping off after 24 months at a significant rate.” Needless to say, when your lifespan is measured in months, an extra eight weeks – roughly 10 percent of that lifespan – is a noteworthy gain.

The science behind this hinges largely on DNA methylation, where methyl groups attach to DNA, altering their function. As the body ages, there tends to be increased DNA methylation, or even hypermethylation, at promoter sites on genes in muscle. “DNA methylation changes in a lifespan tend to happen in a somewhat systematic fashion,” Murach explained, “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.” Due to this, researchers can use one of a number of “methylation clocks” to determine the age of a DNA sample.

While the paper strengthens the case for exercise, much work remains to be done. Though there is a clear connection between methylation and ageing, the relationship between methylation and muscle function is less clear. Murach is not yet prepared to say that the reversal of methylation with exercise causes 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.”

Source: University of Arkansas

Categories : GeneticsTags :

Briefly Quitting Cannabis Can Reduce its Genetic Effects in Sperm

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While cannabis use may impact some autism-linked genes in men’s sperm, briefly quitting cannabis over time may significantly lower many of those effects, according to a new study.

This study, published online in Environmental Epigenetics, followed several other studies at Duke University that linked cannabis use to epigenetic changes (alteration of expression without changing genes) present in sperm, including genes in early development.

This new study aimed to find out if cannabis abstinence could reduce such epigenetic changes. The results showed marijuana users who stopped using cannabis for 77 days produced sperm lacking most of the significant changes found when the men were actively using cannabis.
Study author Susan Murphy, PhD, associate professor in the Department of Obstetrics & Gynecology at Duke University School of Medicine, said the results may suggest that marijuana abstinence could result in washout of sperm with the drug’s epigenetic effects. More research is needed for lingering epigenetic effects after abstinence, but there are immediate implications for some.

“Stopping cannabis use for as long as possible – at least for a 74-day period before trying to conceive – would be a good idea,” she said. “If someone is really serious about that, I would say to stop cannabis use for as long as possible prior to conception – meaning multiple spermatogenic cycles.”

“Is it going to fix everything? Probably not,” Prof Murphy said. “We know there are other epigenetic changes that emerged in the ‘after’ sample that we don’t understand yet – and some of those changes are troubling, like an enrichment of other genes related to autism. But it does appear that the things that were the most severely affected in the ‘before’ sample seem to be mitigated by the abstinence period in the ‘after’ samples.”

The study took a baseline sperm sample from marijuana users and non-marijuana users, then followed both groups as the marijuana-using group abstained from cannabis for 77 days – a period spanning the average time it takes for a sperm to mature, which is 74 days. Researchers collected a second sample from both groups after the 77-day period.

During baseline tests, the marijuana-consuming group produced sperm with changes in line with previous studies, which showed altered epigenetic information, including changes in genes linked to early development and neurodevelopmental disorders. With a 77-day abstinence period, this same group was able to produce sperm that had far less altered epigenetic information at the same genes.

The post-abstinence sample was also much more in line with the samples produced by the non-cannabis-using control group.

Prof Murphy says further research is needed to see if the remaining epigenetic changes observed in the sperm of cannabis consumers, when they abstain, carry over into development after fertilisation.

“We don’t know yet whether the alterations that we’re seeing are at genes that have a stable characteristic,” she said, “or if they are in genes that get reprogrammed and really are going to be of no consequence to the child.”

In any case, Prof Murphy says this work is not about legalisation, rather about giving people the power to make informed decisions for themselves.

“I think that we deserve to know what the biological consequences are so that if you are planning to have a child, or even for your own health, you can make an informed decision about whether you want to use it and when, and that’s not really an option right now because we don’t know what it does,” Prof Murphy said.

Source: Duke University