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Dark matter secrets of the human genome



Dark matter secrets of the human genome
Dark matter secrets of the human genome. Only two percent of our genome consists of protein-coding sequences. Scientists are understanding the function of the rest of the human genome and investigating its role in diseases.

Dark matter secrets of the human genome

In this article, we’re going to read about the dark matter secrets of the human genome. Twenty years ago, a massive scientific effort showed that the human genome contains 20,000 protein-coding genes, but they make up only 2% of our DNA. The rest of the genome was considered useless or redundant DNA, but we now realize it plays an important role.

When it was announced in April 2003 that the 13-year effort to sequence the entire book of life encoded within the human genome was complete, there were high expectations. There was hope that the $3 billion Human Genome Project would lead to cures for chronic diseases and provide insights into everything in our lives that is determined by genetics.

But even as press conferences were being held to announce this achievement, this guide to human life surprised scientists.

At the time, the prevailing belief was that most of the human genome consisted of instructions for building proteins, the building blocks of living organisms, which play various roles within and between our cells, writes the BBC.

With more than 200 different types of cells in the human body, it seemed logical that each would have its own set of genes to perform its essential functions. The emergence of unique sets of proteins was thought to be critical to the evolution of our species and our cognitive powers.

Instead, it turns out that less than two percent of the three billion letters in the human genome are devoted to proteins. Only about 20,000 distinct protein-coding genes were found in the long string of molecules known as base pairs that make up our DNA sequences.

Geneticists were surprised to find that the number of protein-making genes in humans is similar to that of some of the simplest organisms on Earth. Suddenly, the world of science was faced with the unpleasant reality that perhaps most of our understanding of what makes us human has been wrong.

Humans have a total of about 19,000 protein-making genes, while worms have about 20,000, and fruit flies have about 13,000 protein-making genes.

“I remember that unbelievable shock,” says Samir Onezin, a molecular biologist and CEO of Haya Therapeutics, which is trying to use insights from studying human genetics to develop new treatments for cardiovascular disease, cancer, and other chronic diseases“At that moment, people began to think that maybe our understanding of biology was wrong.”

The remaining 98 percent of our DNA is known as “dark matter” or the “dark genome.” At first, some geneticists proposed that the dark genome was the junk DNA or garbage dump of human evolution and the remnants of defective genes that had long since lost their significance.

Although it was obvious to others that the dark genome was vital to our understanding of being human. “Evolution has absolutely no tolerance for junk,” says Kari Stefansson, CEO of the Icelandic company that decodes genetics, which has sequenced more of the entire human genome than any other institution in the world. “There must be an evolutionary reason to maintain this genome size.”

Read More: Scientists discovered the secret of DNA’s X shape

Dark matter secrets of the human genome

Now, two decades later, we have our first insights into the role of the dark genome. It seems that the main function of the dark genome is to regulate the decoding process or the expression of protein-making genes. This part of the genome helps control how our genes behave in response to all the environmental pressures our bodies face throughout our lives, from diet and stress to pollution, exercise, and sleep.

Dark matter secrets of the human genome

Onezin sees proteins as the hardware components of life, while the dark genome is software that processes and responds to external information. As a result, the more we learn about the dark genome, the more we understand the complexity of humans and how we become human. “If we think of ourselves as a species, we see that we are adaptive to the environment at every level,” says Onezin. This adaptation is information processing. “When you go back to the question of what makes us different from a fly or a worm, we find that the answers lie in the dark genome.”

Dark matter secrets of the human genome

When scientists first began poring over the Book of Life in the mid-2000s, one of the biggest challenges was that the non-protein-coding regions of the human genome appeared to be full of repetitive DNA sequences called transposons. These repetitive sequences are so abundant that they make up almost half of the entire genome of all living mammals. “Even reconstructing the first human genome was more difficult with these repetitive sequences,” says Jeff Boke, who directs the Dark Matter Project at New York University’s Langone Medical Center. “If the sequence is unique, it’s easier to analyze.”

At first, geneticists ignored transposons. Most genetic studies have focused solely on the exome (the small protein-coding region in the genome). But in the past decade, the advent of advanced DNA sequencing technologies has allowed geneticists to study the dark genome in greater detail.

An experiment in which researchers deleted a specific transposon fragment in mice, causing half the pups to die before birth, showed that some transposon sequences may be critical to our survival.

Perhaps the best explanation for why transposons are present in our genomes is that they are very old, dating back to the earliest life forms, Bocke says. Other scientists have suggested that transposons come from viruses that invaded our DNA throughout human history and then gradually repurposed in the body to find useful targets.

“In most cases, transposons are pathogens that infect us, and they can infect germline cells, the cells that we pass on to the next generation,” says Dirk Hockmeyer, assistant professor of cell biology at the University of California, Berkeley. “They can then be inherited and permanently integrated into the genome.” Bokeh describes the dark genome as something that acts like a living fossil record of vital changes in our DNA that occurred long ago in ancient history.

One of the most interesting properties of transposons is that they can jump from one part of the genome to another and cause mutations that sometimes have significant consequences.

The movement of a transposon to a different gene may have caused the loss of the tail in the family of large copies, which led to our species gaining the ability to walk upright. “This unique event had a great impact on evolution and gave rise to a lineage of large replicas, including humans,” says Boke.

But as our growing understanding of the dark genome continues to shed more light on evolution, the dark genome could also provide insights into how diseases arise.

Onezin points out that if you look at genome-wide association studies (GWAS), most of the genetic sequences associated with chronic diseases such as Alzheimer’s, diabetes, and heart disease are not in protein-coding regions, but in the dark genome. Genome-wide association studies examine genetic variation in large numbers of individuals to identify genetic variants associated with diseases.

Dark matter secrets of the human genome

The dark genome and diseases

Panay Island in the Philippines is famous for its sparkling white sands and constant influx of tourists, but this amazing place hides a sad secret.

This island has the highest frequency of incurable movement disorder called X-linked parkinsonism dystonia, abbreviated as XDP. Like Parkinson’s disease, people with XDP experience a range of symptoms that affect the ability to walk as well as the ability to react quickly to different situations.

Since XDP was first discovered in the 1970s, the disorder has so far only been seen in people of Filipino descent. The reason for this was a mystery for a long time until geneticists realized that all these people had a unique variant of a gene called TAF1.

The onset of symptoms appears to be driven by a transposon in the middle of this gene, which can alter its function in ways that damage the body over time. This gene variant is thought to have appeared for the first time about two thousand years ago and then became fixed in the population. “The TAF1 gene is an essential gene, meaning that it is needed for the growth and reproduction of all types of cells,” Boke says. “When you change its expression, you end up with this very specific defect that appears in this horrible form of parkinsonism.”

The above case is a simple example of why some DNA sequences in the dark genome can control the function of different genes or activate or suppress the process of converting genetic information into protein in response to environmental signals.

The dark genome also carries instructions for making different types of molecules known as non-coding RNAs. Non-coding RNA molecules have different roles such as helping to form proteins, inhibiting the protein production process, or helping to regulate gene activity. “The RNAs produced by the dark genome act like conductors, directing how the DNA responds to the environment,” Onezin says.

Non-coding RNA is now increasingly considered as a link between the dark genome and various chronic diseases.

The common thinking is that if we continuously give the dark genome the wrong signal (eg, through a smoking lifestyle, poor diet, and inactivity), the RNA molecules that are produced can put the body into a disease state and alter gene activity in some way. which increases inflammation in the body or causes cell death.

Some non-coding RNAs are thought to affect the activity of a gene called p53, which normally acts to prevent the formation of tumors. In complex diseases such as schizophrenia or depression, the unfavorable set of non-coding genes may act in concert to decrease or increase the expression of some genes.

Our growing understanding of the importance of the dark genome has now led to new approaches to treat these diseases. While the pharmaceutical industry usually focuses on proteins, some believe that trying to disrupt the non-coding RNAs that control the genes responsible for these processes may be a more effective approach.

In the field of cancer vaccines, where companies genetically sequence a patient’s tumor sample to identify a suitable target for the immune system to attack, most approaches have focused only on protein-coding regions. However, the German pharmaceutical company Curroc is pioneering an approach in which it also analyzes non-coding regions of proteins in the hope of finding a target that can disrupt the source of cancer.

Onezin’s company, Haya Therapeutics, is pursuing a drug development program that targets a set of non-coding RNAs that cause scar tissue, or fibrosis, in the heart. The formation of scar tissue in the heart can lead to heart failure.

Researchers hope that this approach can minimize the side effects of many common drugs. “The problem with protein-based medicine is that there are only about 20,000 proteins in the body, and most of them are expressed in different cells and in pathways unrelated to disease,” Onezin says. However, the dark genome is very specific in its activity. “There are non-coding RNAs that regulate fibrosis only in the heart, so with a drug based on those, you might get a very safe drug.”

Dark matter secrets of the human genome

We know very little about what geneticists describe as ground rules: how these non-coding sequences interact to regulate gene activity. And how do these complex chains of interactions manifest themselves over time in the form of disease and, for example, cause the neurodegeneration seen in Alzheimer’s disease?

Dark matter secrets of the human genome

“Right now, we’re at the beginning of the journey,” Hockmeyer says. The next 15 to 20 years will be important. In the coming years, researchers will work on identifying specific behaviors in cells that can lead to disease, as well as identifying parts of the dark genome that can play a role in modifying these behaviors. “We now have tools to explore this that we didn’t have access to before.”

One of these tools is gene editing. By cloning the TAF1 gene transposon in the mouse genome, Boke and his team are trying to learn more about how XDP symptoms develop. In the future, a more ambitious version of the project could try to find out how non-coding DNA sequences regulate genes by making pieces of DNA and transferring them to mouse cells.

“We’re currently working on two projects where we’re taking a large piece of non-functional DNA and then trying to insert these elements into it,” says Boke. We insert a gene into that sequence, then we insert a neutralizing sequence right in front of it and another sequence further away from it, and we study how the gene behaves. “We now have the tools to make pieces of the dark genome and study and understand it.”

Hackmeier predicts that as we gain more knowledge, just like when the first genome was sequenced 20 years ago, the Book of Life will continue to yield unexpected surprises. “There are so many questions,” he says: “Is our genome still evolving?” Can we fully decipher it? “We are still in this unknown space and we are exploring it and there are some very interesting discoveries that we can make.”


Making a small version of the intestine in the laboratory




Making a small version of the intestine in the laboratory

Making a small version of the intestine in the laboratory. A lab-grown small intestine could help provide personalized treatment for Crohn’s disease.

Making a small version of the intestine in the laboratory

Scientists have found a way to reveal the severity of intestinal diseases through epigenetic changes, which could help develop a new treatment plan for patients.

For decades, biomedical researchers have been looking for ways to develop a standard treatment for patients with Crohn’s disease and irritable bowel disease (IBD).

Now, scientists at the University of Cambridge have discovered a way to grow a small intestine in the lab from cells taken from a patient for more precise and personalized treatments.

Professor Matthias Zilbauer, professor of pediatric gastroenterology at the University of Cambridge and Cambridge University Hospitals, explained: “The actual model of this small intestine was made more than a decade ago by a scientist named Hans Clovers. Together with a group of scientists, he discovered structural units called intestinal epithelial stem cells.

He added that the scientists combined this with what is needed for cells to continue growing and dividing after they leave the gut.

Focusing on children with Crohn’s disease

Inspired by this model that grows organoids from humans, researchers in this new study found specific epigenetic findings in patients, especially children and adolescents, with Crohn’s disease.

Crohn’s disease is a chronic inflammatory bowel disease whose cases are increasing worldwide, especially among children. This disease significantly affects the quality of life of patients and can lead to severe complications.

A new pathway called major histocompatibility complex class I (MHC class I) was observed, which appears to be regulated by changes in epigenetic programming.

Scientists have discovered a way to reveal the severity of diseases through epigenetic changes, which could help develop a new treatment plan for patients.

“What we found was that patients with significant epigenetic changes had a more severe disease course,” says Seelbauer.

Drug treatment for the small intestine in vitro before administration to the patient

Scientists hope to develop new drugs that can be tested on this small lab intestine before being given to a patient.

Conventional treatments are only effective 60% of the time, so the vast majority of patients may not respond to them and may even be exposed to severe side effects.

In the future, scientists hope to grow these organoids from patients for drug testing and, if a drug works on the small intestine, administer it to the patient.

The study found that the cells that make up the inner lining of the intestine in patients with Crohn’s disease show increased activity of major histocompatibility complex class I, which are proteins found on the surface of nearly all nucleated cells in the body and are critical for the immune response.

Read more: Artificial intelligence identifies cancer killer cells

This high activity can lead to inflammation by activating immune cells to more easily recognize antigens such as toxins or other foreign substances. Antigens may include molecules from food or gut microbiota that trigger an immune response and contribute to the inflammation characteristic of Crohn’s disease. This is the first time that stable epigenetic changes have been shown to explain intestinal epithelial abnormalities in Crohn’s patients.

The team of researchers is currently working on finding drugs that can modify this pathway.

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How to rejuvenate an aging immune system?




immune system
Scientists succeeded in rejuvenating the immune system of old mice with a new therapeutic approach.

How to rejuvenate an aging immune system?

After scientists reduced abnormal stem cells in old animals, mice’s immune systems became more youthful. This technique enhanced the response of old rodents to viral infection and reduced signs of inflammation. In this method, published March 27 in the journal Nature, old mice are treated with an antibody to reduce a population of stem cells that give rise to other types of cells, such as those involved in inflammation.

Excessive inflammation can wreak havoc on the body, and pro-inflammatory stem cells proliferate during aging in mice and humans.

Imbalanced immune system

For decades, researchers in Irving Weissman’s group at Stanford University in California have closely followed the fate of blood stem cells. These cells replenish the supply of red blood cells (which carry oxygen from the lungs to all parts of the body) and white blood cells (which are key components of the immune system).

Balancing the blood stem cell population can rejuvenate the immune system

In 2005, Weissman and colleagues found that as mice age, their blood stem cell population changes. In young mice, there is a balance between two types of blood stem cells, each contributing to a different branch of the immune system. The adaptive compartment produces antibodies and T cells that target specific pathogens. The innate part produces general responses such as inflammation against infection.

However, in old mice, the balance between the two parts of the immune system is skewed towards the production of more pro-inflammatory innate immune cells. Similar changes have been reported in the blood stem cells of aging humans, and researchers speculate that this could lead to a reduced ability to produce new antibodies and T-cell responses. This may explain why the elderly are more susceptible to serious infections from pathogens such as influenza viruses and SARS-CoV-2, and why their response to vaccination is weaker than that of younger people.

Restore the balance of the immune system

If the researchers’ conclusions are correct, restoring balance to the blood stem cell population could also rejuvenate the immune system.

The researchers tested this hypothesis by producing antibodies that bind to blood stem cells, which mainly produce innate immune cells. They then injected these antibodies into old mice with the hope that their immune systems would destroy the stem cells attached to the antibodies.

Antibody treatment rejuvenated the immune system of treated mice. They showed a stronger reaction to the vaccination than the old mice that did not receive the treatment and were better at warding off the viral infection. The treated mice also had lower levels of proteins associated with inflammation, which the authors say shows how different populations of blood stem cells affect the aging of the immune system.

It is possible that the effect of antibody treatment is more than affecting the blood stem cell population. Antibody therapy may also affect the environment in which blood stem cells can live. On the other hand, the said treatment can clear other old cells from the body or stimulate immune responses, thus affecting how mice respond to vaccines and viruses.

It will be years before Weissman and his colleagues’ approach can be tested in humans, but many aspects of the stem cell biology that underlies the production of immune cells are similar in mice and humans.

Weissman’s team is working on a similar approach to rebalance the blood stem cells of elderly people. He believes that even if there is sufficient funding and no unexpected obstacles arise, it will take at least three to five years before they can test their method on humans. In the meantime, the researchers will continue to study the mice to learn more about other effects of the antibody therapy, such as whether it affects the rate of cancer or inflammatory diseases. “The blood-forming system of young and old blood is very different,” says Weissman. “The difference is not just in the bone marrow, but throughout the body.”

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How can hacking the immune system help slow aging?




immune system
Our immune system weakens over time and this could explain the negative effects of aging. Manipulation of the immune system may alter the aging process.

How can hacking the immune system help slow aging?

Stem cell researcher Carolina Florian couldn’t believe what she was seeing. His old laboratory mice began to look younger. They were more lively and their fur was shinier. However, all he had done was a short treatment a few weeks earlier with a drug that modified the organization of proteins in a type of stem cell.

Stem cell researcher Carolina Florian couldn’t believe what she was seeing. His old laboratory mice began to look younger. They were more lively and their fur was shinier. However, all he had done was a short treatment a few weeks earlier with a drug that modified the organization of proteins in a type of stem cell.

When technicians repeating Florian’s experiment in two other laboratories reached the same conclusion, Florian became more confident that the treatment in question would rejuvenate the animals. In two papers in 2020 and 2022, his team explained how this process extended the lifespan of mice and kept them in good physical condition into old age.

The purpose of Florian Elixir is the immune system. The immune cells he targeted are called hematopoietic stem cells, which give rise to mature immune cells. By circulating the blood, a mixture of these cells enters all the organs and affects all the functions of the body. However the molecular composition of hematopoietic stem cells changes during aging, and this upsets the balance of the immune cells that these stem cells produce.

Florian, who works at the Bleuge Biomedical Research Institute in Barcelona, ​​says reversing the misalignment that occurs over time appears to reverse many of the problems of aging, not only in the immune system but in the rest of the body as well.

Health and agingDescription Researchers think the immune system could be the key to healthy aging.

In a paper published in March in the journal Nature, researchers show that restoring the balance between two key types of immune cells rejuvenates the immune system of aging mice and improves the animals’ ability to respond to vaccines and ward off viral infections.

Other scientists have used different experimental methods to reach a similar conclusion: Rejuvenating the immune system rejuvenates many organs in animals, at least in mice. More interestingly, evidence shows that aging of the immune system may cause aging of those organs.

The potential of the findings to help people stay healthy in old age is tantalizing. But applying this knowledge and using it in clinics will be challenging. Tampering with the immune system can be dangerous. Therefore, researchers initially aimed at low-risk goals such as improving the response of the elderly to vaccination and improving the efficacy of cancer immunotherapy.

Vittorio Sebastiano, a stem cell scientist at the Stanford School of Medicine in California, says the prospect that reversing aging might curb age-related diseases is enticing, but we proceed with caution.

Weakened immunity

The human immune system is a complex system whose many cellular and molecular components work together to help a person grow, protect him from infection, help heal wounds, and destroy cells that are becoming cancerous. But along with aging and changing the composition of the system, its efficiency decreases. In old age, people become susceptible to a wide range of infectious and non-infectious diseases and become more resistant to the protective power of vaccines.

Aging of the immune system may cause aging of different body parts

The immune system has two main components: the innate system, which indiscriminately destroys invading pathogens, and the more precise adaptive immune system, whose components learn to recognize and produce antibodies against specific foreign bacteria and viruses.

Hematopoietic stem cells in the bone marrow produce both arms of the immune system. They differentiate into two main types (lymphoid cells and myeloid cells), which then undergo further differentiation.

Lymphoid cells are primarily responsible for adaptive immunity and include B cells that produce antibodies, T cells that help attack invaders and coordinate immune responses and natural killer cells that kill infectious cells. Myeloid cells comprise a group of cell types that are mainly involved in innate immunity.

protein inside cellsProteins in stem cells that produce immune cells become more symmetrical as they age (right).

One of the first changes in the immune system during aging is the shrinking of the thymus, which begins after puberty. The thymus is where T cells mature, but much of this tissue turns to fat by the third decade of life, reducing the production of new T cells and weakening the immune system.

In addition, the function of T cells changes with age and they are not as specialized in detecting infectious agents as before. The ratio of different types of immune cells in the circulation also changes. The ratio of myeloid to lymphoid cells is significantly skewed toward myeloid cells and this can cause inflammation. In addition, an increasing number of immune cells become senescent, meaning that they stop replicating but do not die.

Aging cells usually occur when they undergo mutations. When cells are in this condition, they begin to release inflammatory signals and mark themselves for destruction.

An important anti-cancer and wound-healing mechanism works best when young. But when too much damage accumulates with age and the immune cells themselves age, this mechanism is disrupted. Senescent immune cells, attracted by inflammatory signals from senescent tissues, secrete their own inflammatory molecules. Therefore, they are not cleared properly but instead, add to the inflammation that also damages the surrounding healthy tissues. This phenomenon is known as inflammatory aging. This turns into a terrible positive feedback loop, says Aran Akbar, an immunologist at University College London. Evidence shows that this feedback loop is initiated by the immune system.

Laura Niedernhofer from the University of Minnesota in Minneapolis has shown in a series of experiments in mice that the aging of immune cells causes the aging of other tissues. He says these cells are very dangerous.

His team used genetic methods to delete an important DNA repair enzyme in the immune system of mice. The animals remained healthy until adulthood, but after that, they were no longer able to correct the accumulated mutations, and different types of immune cells began to age.

A few months later, an increasing number of cells in organs such as the liver and kidney were also senescent, and signs of organ damage appeared. When the scientists gave old mice immune cells from the spleens of young, healthy mice, all of these effects were reversed. All of this suggests that modifying the aging properties of the immune system could help prevent or reduce age-related diseases, Niederenhofer says.

Fight against aging

Many scientists are trying to do this from very different angles. Many approaches suggest that very short treatment of the immune system may have long-term effects and minimize side effects.

One of the ways to deal with aging immune cells is to use drugs to remove or inhibit the inflammatory factors that these cells release. Aging immune cells in humans can be changed, Niederenhofer says. If you smoke, they increase and if you exercise, they decrease.

Modifying the immune system can help prevent or reduce aging-related diseases

Some drugs, such as dasatinib, which is approved for the treatment of certain cancers, and quercetin, which is marketed as an antioxidant dietary supplement but not approved as a drug, slow cellular aging, and several trials are testing their effects on aging-related diseases.

Niederneuhofer is conducting a small clinical trial in elderly people with sepsis. Sepsis is a condition that becomes more deadly with age. His team is also conducting experiments to assess which types of immune cells are most involved in aging in the body, and their results could help design more precise treatments. Two types of cells (T cells and natural killer cells) are emerging as the main contenders, he says. He plans to examine natural products and approved drugs for their ability to interact with these types of immune cells during aging.

Akbar thinks targeting inflammation may be just as effective as targeting senescent cells. He and his colleagues conducted a study in healthy volunteers using the investigational compound lozepimod, which inhibits an enzyme involved in the production of a type of inflammatory molecule called cytokines. They treated volunteers with this drug for four days and then measured their skin’s response to an injection of the chickenpox virus over the course of a week. Most people are exposed to this virus during their life and this virus often stays in the body.

As people age, they lose their immunity to the chicken pox virus, and this time it can appear as shingles. The drug restored the immune response in the skin of older volunteers to a level similar to that of young volunteers. Akbar has found in unpublished studies that the same strong results persist up to three months later. Temporarily inhibiting inflammation in this way to keep the immune system functioning may similarly enhance the response of older patients to flu vaccinations, he says.

Boosting the immune system

The value of priming the elderly immune system prior to vaccination has been demonstrated in a series of clinical trials led by Joanne Mannick, CEO of Boston, Massachusetts-based Tornado Therapeutics. The trials tested analogs of the drug rapamycin and other drugs with similar mechanisms that target the immune system and are approved to prevent organ transplant rejection and to treat certain cancers.

The mentioned drugs inhibit an enzyme called mTOR, which is vital for many physiological functions and whose function is impaired in aging. Participants were treated with doses of the drug that were low enough to avoid side effects for several weeks before receiving the flu vaccine. This treatment regimen improved their response to the vaccine and increased their immune system’s ability to resist viral infections.

vaccinationVaccines are less effective in older people, but new approaches could increase their potency.

However the drug rapamycin can increase susceptibility to infection and affect metabolism, so Manick is planning trials with similar drugs that could be safer. “There are different ways to improve the immune system,” he notes.

Another way is to try to restore thymus function to maintain the production of new T cells. Jarrod Dudakoff, an immunologist at the Fred Hutchinson Cancer Center in Seattle, is studying the basic biology of thymus cells to understand how they regenerate after bouts of stress. Dudakov says it’s a little early to see how our understanding of this can be applied in the clinic. But he thinks it’s important to preserve the ability of the thymus to produce T cells.

Others try to fight aging by producing thymus tissue from powerful stem cells and then transplanting it. But Greg Fahey, chief scientific officer at Intervene Immune in Torrance, Calif., says there’s no need to wait to achieve those long-term prospects because synthetic growth hormone regenerates thymus tissue. He is conducting small studies in healthy volunteers using growth hormones as part of a mixture of compounds.

Preliminary results show that the amount of functional thymus tissue in the participants increased and their epigenetic clock (a biomarker of aging) was reversed by several years. Fahey is conducting further testing to see if the drug combination also improves the physical condition of the participants.

Turn back the clock

Another approach that has yet to reach the clinic is reprogramming immune cells to try to turn back the clock on cells that have aged. This procedure involves temporarily placing the cells in a dish exposed to a combination of transcription factors that induce a pluripotent state in mature cells.

Sebastiano and colleagues have shown in human cells that this corrects the epigenetic changes that accompany aging. He has founded a startup to use this technique to tackle a type of cancer treatment called CAR T, in which T cells are engineered outside the body to target and destroy a person’s cancer. However, the T cells may age before they are returned to the person. Rejuvenating them makes production faster and more powerful, says Sebastiano.

One of the challenges of aging studies is the inability to measure aging accurately

Florian’s approach also aims to produce healthier immune cells within the body. Hematopoietic stem cells in the blood develop epigenetic changes and their environment also changes with age. This causes the proteins to arrange themselves in a more symmetrical way in the cells (a process known as polarization), which shifts the balance of differentiation of stem cells towards myeloid cells.

In his studies, Florian used a four-day treatment with a compound called CASIN, which inhibited part of this process to correct polarization and help the mice live longer. When hematopoietic stem cells from aged mice that had received CASIN were transplanted into aged mice that had not received the treatment, the same life-extending effects were seen. Florian hopes to turn his results into a practical method in the clinic. He thinks his drug may help rebuild the immune system after receiving cancer chemotherapy.

The challenge of measuring aging

Research on immune aging faces major challenges. One of the challenges in aging studies of all organs is the inability to measure aging accurately. “We don’t know in a quantitative, measurable, predictable way what aging means at the molecular level in different cell types,” says Sebastiano. “Without these metrics, it is very difficult to demonstrate rejuvenation.”

Another challenge is the difficulty in determining the characteristics that make an immune cell unique. Until recently, it was difficult to show where each of the immune cell subsets lived and how they changed over time. But technologies such as single-cell RNA sequencing, which quantitatively measures genes expressed in single cells, have made the analysis more challenging. For example, a large study of immune cells in the blood of humans and mice across a range of ages, published last November, revealed 55 subpopulations. Only 12 subpopulations of cells changed with age.

By collaborating with different research areas, scientists hope to prove that the immune system plays an important role in healthy aging. Don’t expect an elixir of youth anytime soon, says Florian. Aging research will take a long time, but it can help design tools that will be transformative.

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