A new study published in Life Science Alliance revealed how aberrant epigenetic regulation contributes to the development of atypical teratoid/rhabdoid (AT/RT) tumours, which mainly affect young children. There is an urgent need for more research in this area as current treatment options are ineffective against these highly malignant tumours.
Most tumours take a long time to develop as harmful mutations gradually accumulate in cells’ DNA over time. AT/RT tumours are a rare exception, because the inactivation of one gene gives rise to this highly aggressive form of brain cancer.
AT/RT tumours are rare central nervous system embryonic tumours that predominantly affect infants and young children.
On average, 73 people are diagnosed with AT/RT in the USA each year. However, AT/RT is the most common central nervous system tumour in children under one years old and accounts for 40-50% of diagnoses in this age group. The prognosis for AT/RT patients is grim, with a postoperative median survival of only 11-24 months.
The collaborative study conducted by Tampere University and Tampere University Hospital examined how aberrant DNA methylation distorts cellular developmental trajectories and thereby contributes to the formation of AT/RT. DNA methylation is a normal process of controlling expression whereby methyl groups are added to the DNA strand, adding epigenetic information.
The new study showed that DNA methylation interferes with the activity of multiple regulators, which usually regulate the differentiation and maturation of central nervous system cells during brain development. Disrupted cell differentiation promotes the abnormal, uncontrolled proliferation of cells that eventually form a tumour.
The study also found several genes that regulate cell differentiation or inhibit tumour development and are silenced in AT/RT together with increased DNA methylation.
“These results will provide deeper insights into the development of AT/RTs and their malignancy. In the future, the results will help to accelerate the discovery of new treatments for this aggressive brain tumour,” says senior author Docent Kirsi Rautajoki from Tampere University.
Researchers from Institut Pasteur have discovered that the immune impacts of smoking can last for many years, leaving smokers with effects on some of their bodies’ defence mechanisms acquired while smoking. These findings, which for the first time reveal a long-term memory of the effects of smoking on immunity, are published in the journal Nature.
Individuals’ immune systems vary significantly in terms of how effectively they respond to microbial attacks. But how can this variability be explained? What factors cause these differences? “To answer this key question, we set up the Milieu Intérieur cohort comprising 1000 healthy individuals aged 20 to 70 in 2011,” explains Darragh Duffy, Head of the Translational Immunology Unit at the Institut Pasteur and last author of the study. While certain factors such as age, sex and genetics are known to have a significant impact on the immune system, the aim of this new study was to identify which other factors had the most influence.”
The scientists exposed blood samples taken from individuals in the Milieu Intérieur cohort to a wide variety of microbes and observed their immune response by measuring levels of secreted cytokines(1). Using the large quantities of data gathered for individuals in the cohort, the team then determined which of the 136 investigated variables (body mass index, smoking, number of hours’ sleep, exercise, childhood illnesses, vaccinations, living environment, etc) had the most influence on the immune responses studied. Three variables stood out: smoking, latent cytomegalovirus infection(2) and body mass index. “The influence of these three factors on certain immune responses could be equal to that of age, sex or genetics,” points out Darragh Duffy.
As regards smoking, an analysis of the data showed that the inflammatory response, which is immediately triggered by infection with a pathogen, was heightened in smokers, and moreover, the activity of certain cells involved in immune memory was impaired. In other words, this study shows that smoking disrupts not only innate immune mechanisms, but also some adaptive immune mechanisms. “A comparison of immune responses in smokers and ex-smokers revealed that the inflammatory response returned to normal levels quickly after smoking cessation, while the impact on adaptive immunity persisted for 10 to 15 years,” observes Darragh Duffy. “This is the first time it has been possible to demonstrate the long-term influence of smoking on immune responses.”
Basically, the immune system appears to have something resembling a long-term memory of the effects of smoking. But how? “When we realised that the profiles of smokers and ex-smokers were similar, we immediately suspected that epigenetic processes were at play(3),” says Violaine Saint-André, a bioinformatician in the Institut Pasteur’s Translational Immunology Unit and first author of the study. “We demonstrated that the long-term effects of smoking on immune responses were linked to differences in DNA methylation(4) – with the potential to modify the expression of genes involved in immune cell metabolism – between smokers, ex-smokers and non-smokers.” It therefore appears that smoking can induce persistent changes to the immune system through epigenetic mechanisms.
“This is a major discovery elucidating the impact of smoking on healthy individuals’ immunity and also, by comparison, on the immunity of individuals suffering from various diseases,” concludes Violaine Saint-André.
Notes:
(1) proteins secreted by a large number of immune cells to communicate among themselves and participate in immune defense.
(2) a virus in the herpes family that is often asymptomatic though dangerous to foetuses.
(3) changes in DNA that affect how genes are expressed, i.e. how they are used by cells.
(4) methylation is a type of chemical modification. Methyl groups position themselves on DNA, changing the way in which the genome is read in the cell.
The journey a cell makes from healthy to metastatic cancer is mostly driven by epigenetic changes, according to a new computational study that has been recently published in the journal Nature.
Every cell makes its own proteins by accessing its genetic information, but genetic mutations may ruin the function of the affected proteins. In oncology, this is regarded as the genetics of cancer. The last decades, however, have seen the rise of a new field: the epigenetics of cancer.
Epigenetic modifications do not change the information but temporarily modify the cell’s ability to read some of its own genes and produce the associated proteins instead. This forms a vast epigenetic program that controls general cell functions and, when altered, it may put it at the starting line of malignant transformation. Is there a way to track these changes and understand the epigenetics of cancer transition?
Now an international team of researchers has made headway towards this goal. They analysed 1.7 million cells from 225 samples from primary and metastatic origin, from 205 patients of 11 different cancer types. For each cell, the team obtained the full transcriptome, exome and epigenome. This covers virtually all gene mutations, gene accessibility and its consequences. With the help of enormous computational resources, they were able deduce the whole functional status of each analysed cell and link it to its particular cancer type.
The results of the work demonstrate that many regions in the DNA are differentially activated or inactivated in a cancer-specific manner, creating a signature for each tumour. These differences are relevant for cancer progression and many correspond to already identified hallmarks of cancer, the steps a cell must undergo to become malignant. Dr Eduard Porta, group leader at the Josep Carreras Leukaemia Research Institute (IJC-CERCA), is part of the team and contributed with his experience in the analysis of large amounts of biological data.
Epigenetic changes at the DNA level stand out as an underlying cause of cancer, according to the new publication. Particularly, the accessibility of enhancer regions, a kind of master regulator acting upon many genes at once. Taken together, the results converges into a short list of genes that can be used as markers for good or poor prognosis, valuable information for the clinical management of patients.
The analysis has also identified the cellular pathways of these important genes, making it possible to track their distant interactions. Sometimes, the affected genes are so fundamental that is impossible to drug them directly without side effects but, knowing the full pathway, researchers may develop strategies to target the weakest link in the chain, maximising the therapeutic benefits while minimising undesirable effects.
A susceptibility to gain weight may be written into the epigenetic information of human cells, a Washington State University study indicates.
The proof-of-concept study with a set of 22 twins found an epigenetic signature in buccal cells appearing only for the twins who were obese compared to their thinner siblings. The findings could lead to the development of a simple cheek swab test for an obesity biomarker and enable earlier prevention, the researchers said.
“Obesity appears to be more complex than simple consumption of food. Our work indicates there’s a susceptibility for this disease and molecular markers that are changing for it,” said Michael Skinner, a WSU professor of biology and corresponding author of the study published in the journal Epigenetics.
The study focused on twins to help eliminate the role of genetics and instead focus on epigenetics, molecular processes which are separate from DNA but influence how genes are expressed. The fact that the epigenetic signature was found in cheek cells rather than fat cells also suggests that the obesity signature is likely found throughout the human system.
The signature’s systemic nature also suggests that something may have occurred early in one twin’s life that triggered obesity susceptibility, Skinner added. It’s also possible that it was inherited by one twin and not the other.
For this study, Skinner worked with lead author Glen Duncan, director of the Washington State Twin Registry based at WSU, to identify 22 twin pairs, both identical and fraternal, who were discordant for obesity: one sibling had a body mass index (BMI) of 30 or higher, the standard for obesity defined by the Centers of Disease Control and Prevention, while the other sibling was in the normal range of 25 and below.
The research team analysed cells from cheek swabs provided by the twins. In the cells from the twin siblings who were obese, they found similar epigenetic changes to DNA methylation regions, areas where molecular groups made of methane attach to DNA, regulating gene expression or turning genes on or off.
The study would need to be replicated with larger groups of people to develop a biomarker test for obesity, the authors said.
The goal would be able to identify people earlier in life before they become obese so health care providers might help create interventions such as lifestyle changes, medication or both, said Duncan.
“Ultimately we would like to have some kind of preventative measure instead of our usual approach which is treatment,” he said. “It’s a simple fact that it’s better to prevent a disease, then try to treat it after you have it.”
A new study suggests boys who smoke in their early teens risk damaging the genes of their future children, increasing their chances of developing asthma, obesity and low lung function.
This research, published in Clinical Epigenetics, is the first human study to reveal the biological mechanism behind the impact of fathers’ early teenage smoking on their children.
Researchers from the University of Southampton and the University of Bergen in Norway investigated the epigenetic profiles of 875 people, aged 7 to 50, and the smoking behaviours of their fathers.
They found epigenetic changes at 19 sites mapped to 14 genes in the children of fathers who smoked before the age of 15. These changes in the way DNA is packaged in cells (methylation) regulate gene expression (switching them on and off) and are associated with asthma, obesity and wheezing.
“Our studies in the large international RHINESSA, RHINE and ECRHS studies have shown that the health of future generations depends on the actions and decisions made by young people today – long before they are parents – in particular for boys in early puberty and mothers/grandmothers both pre-pregnancy and during pregnancy,” says Professor Cecilie Svanes from the University of Bergen and Research Director of the RHINESSA study. “It is really exciting that we have now been able to identify a mechanism that explains our observations in the cohorts.”
‘Unique markers’
“Changes in epigenetic markers were much more pronounced in children whose fathers started smoking during puberty than those whose fathers had started smoking at any time before conception,” says co-lead author of the paper Dr Negusse Kitaba, Research Fellow at the University of Southampton. “Early puberty may represent a critical window of physiological changes in boys. This is when the stem cells are being established which will make sperm for the rest of their lives.”
The team also compared the paternal preconception smoking profiles with people who smoked themselves and those whose mothers smoked before conception.
“Interestingly, we found that 16 of the 19 markers associated with fathers’ teenage smoking had not previously been linked to maternal or personal smoking,” says Dr Gerd Toril Mørkve Knudsen from the University of Bergen and co-lead author of the study. “This suggests these new methylation biomarkers may be unique to children whose fathers have been exposed to smoking in early puberty.”
Teenage vaping ‘deeply worrying’
The number of young people smoking has fallen in the UK in recent years. But co-author Professor John Holloway, from the University of Southampton and the NIHR Southampton Biomedical Research Centre, is concerned about children taking up vaping.
“Some animal studies suggest that nicotine may be the substance in cigarette smoke that is driving epigenetic changes in offspring,” says Professor Holloway. “So it’s deeply worrying that teenagers today, especially teenage boys, are now being exposed to very high levels of nicotine through vaping.
“The evidence from this study comes from people whose fathers smoked as teenagers in the 60s and 70s, when smoking tobacco was much more common. We can’t definitely be sure vaping will have similar effects across generations, but we shouldn’t wait a couple of generations to prove what impact teenage vaping might have. We need to act now.”
The new findings have significant implications for public health. They suggest a failure to address harmful exposures in young teenagers today could damage the respiratory health of future generations, further entrenching health inequalities for decades to come.
The biology underpinning a rare genetic mutation that allows its carrier to feel almost no pain, heal faster and had reduced anxiety and fear, has been uncovered in a new study published in Brain.
Though it may sound like the stuff of superheroes, the carrier of the genetic mutation is an ordinary Scottish woman named Jo Cameron, who was first referred to pain geneticists at University College London in 2013, after her doctor noticed that she experienced no pain after major surgeries on her hip and hand. In 2019, they identified a new gene that they appropriately named FAAH-OUT, which had a rare genetic mutation. In combination with another, more common mutation in FAAH, it was found to be the cause of Jo’s unique characteristics.
The new research describes how the mutation in FAAH-OUT ‘turns down’ FAAH gene expression, as well as the knock-on effects on other molecular pathways linked to wound healing and mood. It is hoped the findings will lead to new drug targets and open up new avenues of research in these areas.
The area of the genome containing FAAH-OUT had previously been assumed to be ‘junk’ DNA that had no function, but it was found to mediate the expression of FAAH, a gene that is part of the endocannabinoid system and that is well-known for its involvement in pain, mood and memory.
In this study, the team from UCL sought to understand how FAAH-OUT works at a molecular level, the first step towards being able to take advantage of this unique biology for applications like drug discovery.
This included a range of approaches, such as CRISPR-Cas9 experiments on cell lines to mimic the effect of the mutation on other genes, as well as analysing the expression of genes to see which were active in molecular pathways involved with pain, mood and healing.
The team observed that FAAH-OUT regulates the expression of FAAH. When it is significantly turned down as a result of the mutation carried by Jo Cameron, FAAHenzyme activity levels are significantly reduced.
Dr Andrei Okorokov (UCL Medicine), a senior author of the study, said: “The FAAH-OUT gene is just one small corner of a vast continent, which this study has begun to map. As well as the molecular basis for painlessness, these explorations have identified molecular pathways affecting wound healing and mood, all influenced by the FAAH-OUT mutation. As scientists it is our duty to explore and I think these findings will have important implications for areas of research such as wound healing, depression and more.”
The authors looked at fibroblasts taken from patients to study the effects of the FAAH-OUT-FAAH axis on other molecular pathways. While the mutations that Jo Cameron carries turn down FAAH, they also found a further 797 genes that were turned up and 348 that were turned down. This included alterations to the WNT pathway that is associated with wound healing, with increased activity in the WNT16 gene that has been previously linked to bone regeneration.
Two other key genes that were altered were BDNF, which has previously been linked to mood regulation and ACKR3, which helps to regulate opioid levels. These gene changes may contribute to Jo Cameron’s low anxiety, fear and painlessness.
Senior study author Professor James Cox said: “The initial discovery of the genetic root of Jo Cameron’s unique phenotype was a eureka moment and hugely exciting, but these current findings are where things really start to get interesting. By understanding precisely what is happening at a molecular level, we can start to understand the biology involved and that opens up possibilities for drug discovery that could one day have far-reaching positive impacts for patients.”
Van Andel Institute scientists have pinpointed a key driver of low bone density, a discovery that may lead to improved treatments with fewer side effects for women with osteoporosis. Their findings appear in the journal Science Advances.
Their research reveals that loss of an epigenetic modulator, KDM5C, preserves bone mass in mice. KDM5C works by altering epigenetic ‘marks’, switches that ensure the instructions written in DNA are read in the right time and place.
Several medications are approved to treat osteoporosis but fears of rare, severe side effects often are a barrier for their use. Treatments that leverage the hormone oestrogen also are available, but are only recommended for low-dose, short-term use due in part to associations with cancer risk.
It is well-established that women experience disproportionately lower bone mass than men throughout their lives. Loss of bone mass accelerates with menopause, increasing the risk of osteoporosis and associated fractures for women as they age.
To figure out why this happens, VAI Associate Professors Connie M. Krawczyk, PhD, and Tao Yang, PhD, and their teams looked at the differences in the ways bone is regulated in male and female mice, which share many similarities with humans and are important models for studying health and disease. They focused on osteoclasts, which help maintain bone health by breaking down and recycling old bone.
“Osteoporosis is a common disease that can have debilitating outcomes,” Yang said. “KDM5C is a promising target to treat low bone mass in women because it is highly specific. We’re hopeful that our findings will contribute to improved therapies.”
The researchers found reducing KDM5C disrupted cellular energy production in osteoclasts, which slowed down the recycling process and preserved bone mass. Importantly, KDM5C is linked to X chromosomes, which means it is more active in females than in males.
“Lowering KDM5C levels is like flipping a switch to stop an overactive recycling process. The result is more bone mass, which ultimately means stronger bones,” Krawczyk said. “We’re very excited about this work and look forward to carrying out future studies to refine our findings. At the end of the day, we hope these insights make a difference for people with osteoporosis.”
An international study demonstrates for the first time that degradation in epigenetic information can drive ageing in an organism, independently of changes to the genetic code itself. Published in the journal Cell, the work shows that a breakdown in epigenetic information causes mice to age and that restoring the integrity of the epigenome reverses those signs of ageing.
“We believe ours is the first study to show epigenetic change as a primary driver of ageing in mammals,” said the paper’s senior author, David Sinclair, professor of genetics at Harvard Medical School.
The team’s extensive series of experiments provide long-awaited confirmation that DNA changes are not the only, or even the main, cause of ageing. Rather, the findings show, chemical and structural changes to chromatin contribute ageing without changing the genome.
“We expect the findings will transform the way we view the process of ageing and the way we approach the treatment of diseases associated with ageing,” said co-first author Jae-Hyun Yang, research fellow in genetics in the Sinclair lab.
Since it is easier to manipulate epigenetics than DNA, this could lead to a whole new avenue of research. Studies in nonhuman primates are currently underway.
“We hope these results are seen as a turning point in our ability to control aging,” said Sinclair. “This is the first study showing that we can have precise control of the biological age of a complex animal; that we can drive it forwards and backwards at will.”
Beyond mutations
A reigning, decades-old theory of ageing was that it arises from an accumulation of changes to DNA, primarily genetic mutations, which over time prevent more and more genes from functioning properly. Over time, researchers began finding contradictory evidence: in some human and mice, high mutation rates was not accompanied by premature ageing, while many types of aged cells lacked mutations. Some researchers believed that epigenetics could be the true culprit.
A component of epigenetics is the physical structures such as histones that bundle DNA into tightly compacted chromatin and unspool portions of that DNA when needed. Bundled up, genes are inaccessible when but are available to be copied and used to produce proteins when they’re unspooled. Thus, epigenetic factors regulate which genes are active or inactive in any given cell at any given time.
By acting as a toggle for gene activity, these epigenetic molecules help define cell type and function. Since each cell in an organism has basically the same DNA, it’s the on-off switching of particular genes that differentiates a nerve cell from a muscle cell from a lung cell.
“Epigenetics is like a cell’s operating system, telling it how to use the same genetic material differently,” said Yang, who is co-first author with Motoshi Hayano, a former postdoctoral fellow in the Sinclair lab who is now at Keio University School of Medicine in Tokyo.
In the late 1990s and early 2000s, Sinclair’s lab and others showed in yeast and mammals that epigenetic changes were associated with ageing but could not determine whether they caused it or were caused by it. At least, this new study let the scientists disentangle epigenetic causes from genetics.
ICE mice
The team’s main experiment involved creating temporary, fast-healing cuts in the DNA of lab mice, which mimicked those breaks chromosomes that mammalian cells receive on a daily basis from things like breathing, exposure to sunlight and cosmic rays, and contact with certain chemicals. This let the researchers simulate a sped-up life.
Most of the breaks did not happen in the DNA’s coding regions, so did not cause mutations. Rather, the breaks altered the way DNA is folded.
Sinclair and colleagues called their system ICE, short for inducible changes to the epigenome.
At first, epigenetic factors paused their normal job of regulating genes and moved to the DNA breaks to coordinate repairs. Afterward, the factors returned to their original locations.
But as time passed, things changed. The researchers noticed that these factors got ‘distracted’ and did not return home after repairing breaks. The epigenome grew disorganised and began to lose its original information. Chromatin got condensed and unspooled in the wrong patterns, a hallmark of epigenetic malfunction.
As the mice lost their youthful epigenetic function, they began to look and act old. The researchers saw a rise in biomarkers that indicate ageing. Cells lost their identities as, for example, muscle or skin cells. Tissue function faltered. Organs failed.
The team used a tool recently developed by Sinclair’s lab to measure how biologically old the mice were, based on how many sites across the genome lost the methyl groupsnormally attached to them. Compared to untreated mice born at the same time, the ICE mice had aged significantly more.
Young again
Next, the researchers gave the mice a gene therapy that reversed the epigenetic changes they’d caused, which Sinclair likened to rebooting a malfunctioning computer.
The therapy delivered a trio of genes (Oct4, Sox2, and Klf4, together named OSK) that are active in stem cells and can help rewind mature cells to an earlier state. (Sinclair’s lab used OSK to restore sight in blind mice in 2020.)
The ICE mice’s organs and tissues resumed a youthful state.
The therapy “set in motion an epigenetic program that led cells to restore the epigenetic information they had when they were young,” said Sinclair. “It’s a permanent reset.”
How exactly OSK treatment achieved that remains unclear.
At this stage, Sinclair says the discovery supports the hypothesis that mammalian cells maintain a kind of backup copy of epigenetic software that, when accessed, can allow an aged, epigenetically scrambled cell to reboot into a youthful, healthy state.
For now, the extensive experiments led the team to conclude that “by manipulating the epigenome, aging can be driven forwards and backwards,” said Yang.
From here
The ICE method offers researchers a new way to explore the role of epigenetics in ageing and other biological processes.
Because signs of ageing developed in the ICE mice after only six months rather than toward the end of the average mouse life span of two and a half years, the approach also saves time and money for researchers studying aging.
Yang said that researchers can also look beyond OSK gene therapy to other methods such as drugs, to determine how lost epigenetic information might be restored in aged organisms.
Watch the team describe their research in the video below.
New research suggests that epigenetic information, which turns DNA sections on or off, and is normally reset between generations, is more frequently carried from mother to offspring than previously thought. The findings were published in Nature Communications.
Despite not directly altering the DNA sequence, epigenetic mechanisms can regulate gene expression through chemical modifications of DNA bases and changes to the chromosomal superstructure in which DNA is packaged.
These epigenetic changes can be induced through various such as diet and stress. While epigenetic modifications are reversible, it was thought that they rarely remain through generations in humans despite persisting through multiple cycles of cell replication.
Epigenetic changes can be influenced by environmental variations such as our diet, but these changes do not alter DNA and are normally not passed from parent to offspring.
The new research reveals that the supply of a specific protein in the mother’s egg can affect the genes that drive skeletal patterning of offspring.
Chief investigator Professor Marnie Blewitt said the findings initially left the team surprised.
“It took us a while to process because our discovery was unexpected,” Professor Blewitt said.
“Knowing that epigenetic information from the mother can have effects with life-long consequences for body patterning is exciting, as it suggests this is happening far more than we ever thought.
“It could open a Pandora’s box as to what other epigenetic information is being inherited.”
The research examined the protein SMCHD1, an epigenetic regulator discovered by Prof Blewitt in 2008, and Hox genes, which control the identity of each vertebra during embryonic development in mammals. The epigenetic regulator prevents these genes from being activated too soon.
In this study, the researchers discovered that the amount of SMCHD1 in the mother’s egg affects the activity of Hox genes and influences the patterning of the embryo. Without maternal SMCHD1 in the egg, offspring were born with altered skeletal structures.
First author and PhD researcher Natalia Benetti said this was clear evidence that epigenetic information had been inherited from the mother, rather than just DNA.
“While we have more than 20 000 genes in our genome, only that rare subset of about 150 imprinted genes and very few others have been shown to carry epigenetic information from one generation to another,” Benetti said.
“Knowing this is also happening to a set of essential genes that have been evolutionarily conserved from flies through to humans is fascinating.”
The research showed that SMCHD1 in the egg, which only persists for two days after conception, has a life-long impact.
SMCHD1 variants are linked to developmental disorder Bosma arhinia microphthalmia syndrome (BAMS) and facioscapulohumeral muscular dystrophy (FSHD), a form of muscular dystrophy. The researchers say their findings could have implications for women with SMCHD1 variants and their children in the future.
Research is underway on using on SMCHD1 to design novel therapies to treat developmental disorders, such as Prader Willi Syndrome and the degenerative disorder FSHD.
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.”
