One researcher’s journey to understand the molecular basis of aging, using blood

Image by Cliker-Free-Vector-Images
Image by Cliker-Free-Vector-Images

Hanadie Yousef, PhD, studies how the body ages — first as a graduate student at UC Berkeley and currently as a postdoctoral research fellow at Stanford with her mentor, Tony Wyss-Coray, PhD, professor of neurology.

Her current anti-aging research is based on a pivotal study performed at Stanford in the laboratory of Thomas Rando, MD, PhD, professor of neurology and neurological sciences. In this 2005 study, researchers surgically connected the circulatory systems of a young and old mouse. Within a few weeks, the young mouse’s blood began rejuvenating the tissues in the old mouse. Specifically, the young blood rejuvenated organ stem cells in the brain, muscle and liver of the old mouse. When activated, these adult stem cells fend off aging by replenishing depleted cells and regenerating damaged tissues. 

Subsequent studies by the Wyss-Coray lab and others have shown that organ stem cells retain their regenerative capacity, but the biochemical cues that control their function change with age — causing the abandonment of tissue maintenance and repair in the elderly. This can be overcome by injecting young blood to enhance the adult stem cells’ environment.

“In graduate school, I became fascinated with the idea that adult tissues could be rejuvenated by their tissue-specific stem cells, which severely decline in function as we grow old,” said Yousef. “So I wanted to understand the molecular mechanisms underlying this decline.”

Specifically, Yousef examined a molecule called transforming growth factor-beta 1 (TGF-β1). “In young people, TGF-β1 exists at lower levels around stem cells and helps regulate tissue regeneration. However, elevated levels of TGF-β1 in the stem cell microenvironment in older people promotes inflammation and prevents stem cell activity, causing decline in tissue function,” Yousef said.

As a graduate student, to help find a potential treatment, she tested a cancer drug called Alk-5 kinase inhibitor, which decreased the levels of TGF-β1 signaling to stem cells, increasing stem cell activity —when systematically injected into aged mice.

“The control old mice had extensive scar tissue following muscle injury, while the old mice that got the Alk-5 inhibitor were systematically able to generate new muscle fibers almost as well as young animals,” Yousef said. “Additionally, we saw that the inhibitor could cross the blood brain barrier and act locally on neural stem cells to enhance the formation of new adult neurons in the hippocampus, the part of the brain important for learning and memory function that severely declines with age.”

The Berkeley scientists are now considering ways to evaluate the drug’s efficacy in humans. The hope is to be able to inject a drug, like the Alk-5 inhibitor, to prevent the onset of multiple diseases associated with aging, including Alzheimer’s.

And Yousef continues her anti-aging research at Stanford. “I now study the opposite effect: what does old blood do to young brain function?” Yousef said. “We’ve seen that aged blood plasma is more pro-inflammatory than young blood plasma, and it contributes to increased brain inflammation and inhibited neural stem cell function with aging.”

So young blood improves brain function, whereas old blood impairs it. Does this mean that young blood can be injected into older patients to treat degenerative brain disorders like Alzheimer’s? According to Yousef, the answer is:

Potentially, yes! In our lab, my colleagues have shown that young blood can improve brain function in Alzheimer’s mice models, and their results will be published soon. Based on these studies, there is an ongoing clinical trial at Stanford, called the Plasma for Alzheimer’s Symptom Amelioration study, in which Alzheimer’s patients receive young blood transfusions to see if this can reduce the severity of disease progression.

A lot of research is needed before a successful treatment is found for Alzheimer’s, but understanding the rejuvenating factors in young blood may be a key step. “We’re working intensively to find out what those factors might be and from exactly which tissues they originate,” said Wyss-Coray in an earlier news release.

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

A tiny fish helps solve how genes influence longevity

Photograph of the Nothobranchiius furzeri killifish, by Ugua
Photograph of the Nothobranchiius furzeri killifish, by Ugua

A tiny, short-lived fish may help solve one of the largest mysteries: how do genes influence longevity?

The African turquoise killifish has evolved as the shortest-lived known vertebrate — driven by its survival in the hot climate of Mozambique and Zimbabwe in seasonal ponds that only exist for a few months during the wet season. This compressed life span makes the killifish an ideal organism for genetic studies on aging and longevity.

To help researchers study this intriguing animal model, Stanford geneticist Anne Brunet, PhD, and her colleagues have now fully mapped the genome of the African turquoise killifish. Their initial insights into the genetic determinants of the killifish’s life span were published today in Cell.

Brunet’s team sequenced short segments of the killifish DNA and then assembled them using specialized software to create a complete map of the turquoise killifish genome.

Brunet explains in a news release:

The range of life spans seen in nature is truly astonishing, and really we have very little insight into how this has evolved or how this works. By having the genome of this fish and comparing it to other species, we start seeing differences that could underlie life span differences both between species and also within a species.

In the article, the researchers report on their initial study of genes unique to the short-lived killifish, which were identified by comparison to longer-lived species, such as killifish that were mated with longer-lived fish. Surprisingly, they found that the genes associated with life span differences between various killifish strains are clustered on the sex chromosomes, so its short life span likely co-evolved with sex determination. They also identified some unusual aging genes in both killifish and other long-lived fish, raising the question of what role these aging genes play in the determination of life span.

To uncover all of the killifish’s traits, Brunet’s group will have help: They have created a user-friendly website, which provides other researchers with free access to the data.

Brunet explained in the news release, “They can go to our website, enter their favorite gene of interest, and then zoom in on the killifish equivalent.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Oxytocin May Help Rejuvenate Old Muscles


muscle cells of old and young mice
The left image shows healthy muscle tissue from a young mouse. The middle image demonstrates that the efficiency of muscle repair mechanisms decreases with age, resulting in a lower density of muscle fibers and increased scar tissue in an old mouse. Injecting oxytocin rapidly rejuvenates the old tissue, as shown on the right image. (Wendy Cousin and Christian Elabd)

From birth until about the age of 30, your muscles continue to grow larger and stronger. But at some point in your 30s, you begin to lose muscle mass and strength which in turn affects your coordination. As part of the natural aging process, this disease, sarcopenia, is most commonly seen in inactive people but it also affects those who remain physically active throughout their lives.

Now UC Berkeley researchers have discovered that oxytocin – the “trust hormone” associated with maternal nurturing, social attachments, childbirth and sex – may combat this age-related muscle wasting. Their new study was recently published in Nature Communications.

Role in Muscle Regeneration

Led by associate professor of bioengineering Irina Conboy, the researchers found in mice that oxytocin is required to maintain healthy muscles, but the level of oxytocin in the blood and the number of oxytocin receptors in muscle stem cells naturally reduce with age. For instance, old (18 to 24 months) mice were found to have 3 times lower circulating levels of oxytocin than young (2 to 4 months) mice.

The research team performed a series of experiments using young and old mice to better understand oxytocin’s role in muscle repair. They injected the mice daily with oxytocin (or a control solution) under the skin for nine consecutive days, while causing a muscle injury midway on day 4. The researchers found that the old mice that received the oxytocin were able to repair their muscle injury at a level comparable to the young mice – far better than the old control group that didn’t get oxytocin. Systemic administration of oxytocin appears to rapidly improve muscle regeneration by enhancing aged muscle stem cell proliferation.

In contrast, the young mice already had sufficient levels of oxytocin and efficient muscle regeneration, so the oxytocin injections had no significant effect. This is important since most molecules that boost tissue repair are also associated with an increased risk of cancer.

“This is good because it demonstrates that extra oxytocin boosts aged tissue stem cells without making muscle stem cells divide uncontrollably,” explained Wendy Cousin, a senior scientist in Conboy’s lab, in a press release.

The researchers also performed similar experiments using mice with an inactivated gene for oxytocin and control mice. At the young age of 3 months, the two groups of mice appeared to have comparable muscle mass and repair efficiency after a muscle injury. However, muscle atrophy and a significant decline in muscle regeneration were observed for the 1-year old adult mice with the disabled oxytocin gene, signifying premature aging due to a lack of oxytocin.

It is unclear how long it will take the researcher to move beyond mice studies to human use. However, oxytocin is already approved by the FDA for clinical use in humans for other applications. For instance, oxytocin is commonly used to help increase contractions and control bleeding during childbirth. So getting approval for human studies should be straightforward once the researchers are ready.

Conboy’s research team is ultimately interested in applications beyond just maintaining healthy muscles. For instance, they are also investigating whether oxytocin could become a viable alternative to hormone replacement therapy to impede the symptoms of male and female aging. They also believe that aging is the underlying cause of a number of chronic diseases, including Parkinson’s and Type 2 diabetes.

Oxytocin Hype

In fact, researchers around the world are studying the use of oxytocin for seemingly every condition imaginable, including using oxytocin nasal spray to alleviate symptoms associated with mental disorders such as autism, schizophrenia and dementia. However, this research currently demonstrates mixed and inconsistent results, particularly regarding oxytocin’s influence on social skills.

The current excitement about oxytocin, particularly as a remedy for autism, could lead to a dangerous situation given the widespread availability of oxytocin supplements – as an accelerator spray, sublingual liquid that is absorbed under the tongue, pills and mouth lozenges. It is important to consult with your doctor before taking oxytocin.

This is a repost of my KQED Science blog.

How Damaged Is Your DNA?

Summary of the factors that cause DNA damage and the associated diseases. (Courtesy of Sylvain Costes)
Summary of the factors that cause DNA damage and the associated diseases. (Courtesy of Sylvain Costes)

DNA stores the genetic information in each living cell, so its integrity and stability is essential to life.

DNA is constantly being damaged by environmental factors like exposure to ionizing radiation, ultraviolet light and toxins. DNA replication is also prone to error during normal cell division. So your body is busy constantly repairing damaged DNA. However, sometimes this normal DNA repair process fails, causing DNA damage and genetic mutations to accumulate which leads to serious health problems like cancer, immunological disorders and neurological disorders.

If your annual checkup included a simple blood test to determine how much DNA damage you have in your body, you may be able to optimize your long-term health by taking action to minimize DNA damage due to your diet, exercise and environment.

A start-up company called Exogen Biotechnology wants to provide the public with a way to monitor their DNA health, so they can act to reduce their DNA damage. Exogen has developed technology that can rapidly quantify a type of DNA damage called double-strand breaks.

“DNA double-strand breaks are when the two strands of the DNA are cut, so they can move apart,” explained Sylvain Costes, a Staff Scientist at Lawrence Berkeley National Laboratory and co-founder of Exogen.  “This is linked to mutation and chromosome rearrangement, so it’s a big deal – it’s the dangerous type of DNA damage. That’s what we look at.”

Exogen’s DNA damage measurement is based on technology developed over 15 years ago called immunocytochemistry – a technique that uses a primary antibody that recognizes the protein that is repairing the DNA break, along with a secondary fluorescent antibody that binds to the primary antibody. This creates bright spots in the microscope image where there are double-strand DNA breaks, so scientists can take a picture and count the breaks.

Exogen is moving this technique out of the laboratory to make it publicly available. They have significantly improved the technology, so that it’s feasible to rapidly test small blood samples for the level of DNA double-strand breaks. A customer collects tiny blood samples using an in-home kit, combines the blood samples with a fixative solution to preserve them, logs on to the Exogen website to register the samples and complete the questionnaire, and mails the samples to Exogen for analysis.

Exogen tested their new technology in two pilot studies with a total of 97 people. They observed a significant increase in the level of DNA damage with age, where 70 year olds had double the number of DNA double-strand breaks compared to 20 year olds. The four people who had suffered from cancer also had a higher level of DNA damage compared to others in their age group.

“When we did the first pilot study, we saw the excitement of the people,” said Costes. “They realized that this is something totally new; something we know in the research field, but that’s never been given to the people.”

Inspired by the initial pilot studies, Exogen wants to build a large database of DNA damage levels for research purposes so they can better understand the meaning of an elevated level of DNA damage and how certain factors affect DNA health. Of course, their data collection process and database are secure, encrypted and fully HIPAA compliant.

In order to get the necessary blood samples, they are currently running a crowdfunding campaign on Indiegogo. People that donate $99 receive a kit to safely collect three blood samples at home, and then they receive a report on their current level of DNA damage. Exogen is calling the campaign a “citizen science project” since volunteers also fill out questionnaires about their medical history and lifestyle. They’ve already collected $76,000 and the crowdfunding campaign runs through March 26. They plan to spend the money on a microscope and liquid handler, which will allow them to fully automate their system so they can analyze up to 400 blood samples per day.

Currently, Exogen can’t interpret the results or give people advice about how to lower their DNA damage, because the Food and Drug Administration (FDA) hasn’t approved them as a diagnostic test. The goal of the crowdfunding campaign is to collect blood samples from 1000 people so they can go to the FDA.

“Once we have FDA approval, we can start counseling,” said Costes. “Primary care doctors can start engaging and testing it further with their patients, because we’ll provide a guideline to help them understand what it means.”

Costes stressed that their test is very different from genetic testing provided by companies like 23andme. Exogen isn’t looking at the genetic makeup. Instead, they are looking at a physiological response, so they compare it to a cholesterol test.

“To me this is identical to cholesterol,” clarified Costes. “Your genetics places you in a certain range, but your lifestyle can change where you are within that range. In contrast to genetic testing, we feel like this test can bring hope because you have a way to act.”

One of their applications is to determine how DNA damage is affected by lifestyle factors like diet.  Exogen plans to study a group of people for a long time to better understand how DNA damage correlates with specific diseases and with health improvements due to people’s actions. They want to evaluate whether people can improve their DNA health by changing their lifestyle or environment, instead of their fate being driven entirely by genetics.

However, none of the exciting applications can happen until Exogen collects data from a larger number of people. “We need your help to make it happen,” Costes concludes. “We can’t do it alone.”

This is a repost of my KQED Science blog.

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