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Behavioral Science, Chronic Disease, Mental Health, Neuroscience, Research, Stanford News

Can Alzheimer’s damage to the brain be repaired?

Can Alzheimer's damage to the brain be repaired?

repair jobIn my recent Stanford Medicine article about Alzheimer’s research, called “Rethinking Alzheimer’s,” I chronicled a variety of new approaches by Stanford scientists to nipping Alzheimer’s in the bud by discovering what’s gone wrong at the molecular level long before more obvious symptoms of the disorder emerge.

But Stanford neuroscientist Frank Longo, MD, PhD, a practicing clinician as well as a researcher, has another concern. In my article, I quoted him as saying:

Even if we could stop new Alzheimer’s cases in their tracks, there will always be patients walking in who already have severe symptoms. And I don’t think they should be forgotten.

A study by Longo and his colleagues, which just went into print in the Journal of Alzheimer’s Disease, addresses this concern. Longo has pioneered the development of small-molecule drugs that might be able to restore nerve cells frayed by conditions such as Alzheimer’s.

Nerve cells in distress can often be saved from going down the tubes if they get the right medicine. Fortunately, the brain (like many other organs in the body) makes a number of its own medicines, including ones called growth factors. Unfortunately, these growth factors are so huge that they won’t easily cross the blood-brain barrier. So, the medical/scientific establishment can’t simply synthesize them, stick them into an artery in a patient’s arm and let them migrate to the site of brain injury or degeneration and repair the damage. Plus, growth factors can affect damaged nerve cells in multiple ways, and not always benign ones.

The Longo group’s study showed that – in mice, at least -  a growth-factor-mimicking small-molecule drug (at the moment, alluded to merely by the unromantic alphanumeric LM11A-31) could counteract a number of key Alzheimer degenerative mechanisms, notably the loss of all-important contacts (called synapses) via which nerve cells transmit signals to one another.

Synapses are the soldier joints that wire together the brain’s nerve circuitry. In response to our experience, synapses are constantly springing forth, enlarging and strengthening, diminishing and weakening, and disappearing.They are crucial to memory, thought, learning and daydreaming, not to mention emotion and, for that matter, motion. So their massive loss — which in the case of Alzheimer’s disease is a defining feature – is devastating.

In addition to repairing nerve-cells, the compound also appeared to exert a calming effect on angry astrocytes and  microglia, two additional kinds of cells in the brain that, when angered, can produce inflammation and tissue damage in that organ. Perhaps most promising of all, LM11A-31 appeared to help the mice remember where things are and what nasty things to avoid.

Previously: Stanford’s brightest lights reveal new insights into early underpinnings of Alzheimer’s, Stanford neuroscientist discusses the coming dementia epidemic and Drug found effective in two mouse models of Huntington’s disease
Photo by Bruce Turner

Cancer, Research, Stanford News, Surgery, Women's Health

Breast cancer patients are getting more bilateral mastectomies – but not any survival benefit

Breast cancer patients are getting more bilateral mastectomies - but not any survival benefit

woman looking out window2The most common cancer diagnosis you or a woman you love is likely to receive is early stage breast cancer, probably after detection by mammogram. One would think that given the regularity with which it’s diagnosed, treatment options for early stage breast cancer would be streamlined. Unfortunately, this isn’t the case.  There’s a staggeringly large menu of potential surgeries and treatments from which a patient and her doctor must choose, each with their own risks and benefits. Not including all of the different hormone blocking and chemotherapies, patients must pick one of three surgeries, shown here in order of escalating invasiveness and risk of complication:

  • Breast-conserving surgery (removal of the tumor only), followed by radiation
  • Single mastectomy (removal of the entire affected breast and any affected lymph nodes)
  • Bilateral mastectomy (the above plus the the unaffected breast)

One also would assume that the medical evidence base providing the benefits to the risk/benefit equations for each surgery would be large and up-to-date. Surprisingly, it is not. The randomized trials comparing lumpectomy and single mastectomy were conducted 30 years ago, and they showed similar risks of death. There has not been (and probably will never be) a randomized trial comparing bilateral mastectomy to one of the less invasive choices for healthy women. Angelina Jolie and other women positive for the breast cancer genes (BRCA1 and BRCA2) are in a different situation. For these women, clinical studies have observed a survival benefit after prophylactic mastectomy. For the 99 percent of women without mutations in these or other high-risk genes, existing trial data do not speak to current trends.

Even after accounting for [numerous factors], we found no evidence of lower mortality for women who had bilateral mastectomy in comparison to breast-conserving surgery

The complexity of choosing a breast cancer surgery – and how evidence should play into that choice – has been a hot topic in the last two months, after the publication of a large study calculating (based on predictive models) that bilateral mastectomy ultimately provides little to no improvement  in life expectancy as compared to a single mastectomy. Soon thereafter, on the New York Times’ opinion page, journalist Peggy Orenstein discussed the emotional reasons why women remove their remaining healthy breast, but firmly labeled bilateral mastectomy as  the wrong approach to breast cancer, saying, “It’s hard to imagine… that someone with a basal cell carcinoma on one ear would needlessly remove the other one ‘just in case’ or for the sake of ‘symmetry’.” Other journalists shared why they chose bilateral mastectomy knowing that it wouldn’t necessarily save their life.

To improve the evidence regarding outcomes after the three surgery types, our team at the Stanford Cancer Institute and the Cancer Prevention Institute of California used one of the largest cancer databases available: the cancer registry for the entire state of California. We tracked all 189,734 women diagnosed with stages 0-III breast cancer from 1998-2011 to learn which surgeries they were undergoing for breast cancer treatment and how long they survived afterwards.  These are all women who should have been eligible for breast conserving surgery with radiation. Our results were published today in the Journal of the American Medical Association today and have already received media attention.

We found that bilateral mastectomy for early stage breast cancer increased from 2 percent in 1988 to more than 12 percent in 2011.  The rate of increase was fastest among women younger than age 40 at diagnosis, among whom over one-third of those diagnosed in 2011 had a bilateral mastectomy. Bilateral mastectomy was more often chosen by non-Hispanic white women, those with private insurance, and those who received care at a National Cancer Institute-designated cancer center; while unilateral mastectomy was more often chosen by non-white women and those with public/Medicaid insurance. Even after accounting for characteristics of the women themselves, their tumor types, and their hospitals, we found no evidence of lower mortality for women who had bilateral mastectomy in comparison to breast-conserving surgery. Surprisingly, we found that women who underwent unilateral mastectomy had higher mortality than those who had the other two surgery types. We concluded that despite the growing popularity of bilateral mastectomy, it likely does not provide a better outcome than a less invasive procedure.

These data and the public response to them underscore the need for more updated and more personalized information regarding outcomes after common surgeries. Ideally, these would be accessible real-time by patients and their doctors in easily-understood formats.

Christina A. Clarke, PhD, is a Research Scientist and Scientific Communications Advisor for the Cancer Prevention Institute of California, and a member of the Stanford Cancer Institute.

Previously: At Stanford event, cancer advocate Susan Love talks about “a future with no breast cancer”, Exploring the reasons behind choosing a double mastectomy and Researchers unsure why some breast cancer patients choose double mastectomies
Photo by Alex

Nutrition, Obesity, Research, Stanford News

When it comes to weight loss, maintaining a diet is more important than diet type

When it comes to weight loss, maintaining a diet is more important than diet type

bathroom_scaleSelecting a weight-loss plan can be tricky. Everywhere you look, media reports bombard you with stories about how Jennifer Hudson lost 80 pounds by joining Weight Watchers, Sharon Osbourne shed 23 pounds on the Atkins diet, and other A-listers slimmed down on the Zone Diet. And then there’s that close friend who dropped three dress sizes after following the South Beach Diet. How do you determine which dieting plan is the most effective?

To answer this question, Edward Mills, PhD, a visiting associate professor at Stanford, and colleagues completed a network meta-analysis of 48 randomized trials of brand-name diets, which included a total of more than 7,200 overweight or obese adults. In addition to those mentioned above, researchers also evaluated six other diets: Ornish, Vulumetrics, Jenny Craig, Rosemary Conley, Biggest Loser and Nutrisystem. The diets were divided into three categories —  low-carb, low-fat and moderate macronutrient.

The diet that a person can maintain for the long term, or for as long as possible, is the most effective weight-loss plan

Overall, the study showed that if people stuck to their diets (no matter the type) they lost weight, but ultimately the “weight-loss differences between individual diets were minimal and largely unimportant,” according to Mills. The study authors concluded that the diet that a person can maintain for the long term, or for as long as possible, is the most effective weight-loss plan. They also found that exercise and behavioral support can enhanced weight loss.

Interested to know more about the research, I reached out to Mills, who explained how the evidence failed to support recommending a specific diet and discussed the potential of being able to combine diets to achieve lasting weight loss without having to maintain strict eating habits.

Why did you and your colleagues complete a comparison study of popular diets?

There is a massive weight-loss industry that promotes different diets that are marketed in different ways. Some diets are promoted as being more medical, such as the Ornish diet, while others target people according to lifestyle, for example the South Beach diet. With all the promotion of different diets occurring and people discussing what they believe works or does not work, we wanted to examine whether the clinical trial evidence demonstrated superiority of any particular diet, a strategy we are calling “evidence-based dieting.”

In the study, individuals on a low-carb and low-fat diet lost the most weight (8 kg over six months), compared to those who were not on any diet. Why are these diets not considered to be the most effective of those studied?

These diets do appear to offer the largest weight-loss benefits, but the difference between the different diets was so small that other issues begin to be more important. We looked at the diets using two different analyses. First, we grouped diets according to their type of diet, called a class, and then examined whether the individual diet resulted in different outcomes. Although we found differences according to the classes of diets, these were not really observed when we examined the individual diets. So at this point, we can’t recommend any particular diet over another. But those that are low carb or low fat are preferable.

What did you find most surprising about the study results?

What is most surprising about the results is that the individual diet a person chooses doesn’t seem to be the most important aspect of dieting, instead maintaining a diet is. Some people have a lot of difficulty adhering to a diet because they find the particular diet too difficult to maintain, such as avoiding carbs if they’re trying the Atkin’s diet. It appears that if all diets offer more or less the same benefits, then people should be able to switch between diets when they need to. This approach may be really helpful in adhering to dieting in general.

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Events, Medicine X, Stanford News, Technology

Countdown to Medicine X: 3D printing takes shape

Countdown to Medicine X: 3D printing takes shape

3D printed handFrom customizing lab equipment to assisting in surgical planning to developing models of proteins and pathogens, 3D printing is helping to reshape biomedical research and health care. This year, Medicine X (which kicks off one week from today) will explore the transformative force of the technology during a range of panels and demonstrations in the “3D Printing and the Future of Medicine” session.

During the session, attendees will have the opportunity to learn more about health-care related 3-D printing applications at the “3-D Experience Zone,” which will showcase technologies from leading manufacturers. Attendees can learn about surgical applications of 3D printing from 3D Systems; find out how 3D Hubs is creating a global community by connecting owners of 3D printers with those who want to utilize the technology; and see how Occipital’s 3D scanning hardware for the iPad is supporting patient care. Additionally, they can discover how Artec creates a 3D full-body scan in a mere 12 seconds and enjoy chocolate and candy from the ChefJet food printer.

The session will also feature two Saturday-afternoon panels titled “Diverse Distributed & Design-Driven” and “Innovation Implementation,” with the latter exploring:

…some of the challenges and issues to consider in this brave new world. Will the FDA approve printed food, pharmaceuticals, and medical devices? How can 3D printing startups include patients in their design process? What are the public health implications when almost anyone can print biomaterials from the comfort of their own home? And once we ensure public safety, how can we make 3D printing affordable and accessible for all?

Darrell Hurt, PhD, computational biologist and project lead for the National Institutes of Health 3D Print Exchange, is among the panelists, and Monika Wittig, director and co-founder of Live Architecture Network, will moderate the discussions.

“As a designer, I am thrilled that this conference continues to widen the view of valuable cross-disciplinary collaborations. This is decidedly the aspect that I found most profound during my first Medicine X experience,” said Wittig. “My hope is attendees leave this session feeling a heightened awareness of 3D design and production technologies and the many realms of potential engagement in health sectors including prototyping, globally-distributed production and mass-customized design.”

More news about Stanford Medicine X is available in the Medicine X category.

Previously: Countdown to Medicine X: Specially designed apps to enhance attendees’ conference experience, Countdown to Medicine X: Global Access Program provides free webcast of plenary proceedings, Countdown to Medicine X: How to engage with the “no smartphone” patient and Medicine X symposium focuses on how patients, providers and entrepreneurs can ignite innovation
Image of 3D printed hand from Medicine X

Medical Education, Medical Schools, Stanford News

Medical students start “transformational” journey

Medical students start "transformational" journey

With the help of Lars Osterberg MD, MPH, and Dr. Neil Gesundheit, MD. they give Brandon Turner  his official white coat at at the Stanford Medicine White Coat and Stethoscope Ceremony on Friday, August 22, 2014,at Stanford School of Medicine.  ( Norbert von der Groeben / Stanford School of Medicine )

The new school year has begun for students across the country, including Stanford’s 90 first-year medical students – who started class on Monday and spent last week at orientation activities anxious and excited for the  journey to finally begin.

To help the students prepare, faculty talked to them about the emotional and academic challenges of medical school and emphasized that it can be metamorphic and, not surprisingly, somewhat stressful. “They are seeing life and death,” said one faculty member at orientation, who added that medical school “is a transformational time the likes of which I don’t think you see in any other level of education.”

The week of preparation concluded with the traditional stethoscope ceremony, which I wrote about in an article published online today. The ceremony symbolizes the importance of the personal connection between doctor and patient, and during the event each student walks across the stage to accept their stethoscopes. As Laurie Weisberg, MD, president of the medical center alumni association, told the students:

The great thing about the stethoscope is you have to be close to your patient to use it. This is your chance to truly interact with the patient. You are listening to what the patient has to tell you.

In his address to the students, Dean Lloyd Minor, MD, told them the four-year, or longer, journey would change the way they see the world and that they “will learn some of life’s most valuable lessons from your patients.” He also highlighted some of the demographics of the new class:

Fifty-one percent of you are women; 15 percent of you are from communities underrepresented in medicine; 21 of you were born outside of the U.S., coming from China, Columbia, India, Vietnam, just to name a few. You come from a diverse and wide range of universities — 10 of you from Stanford, 13 from the Stanford of the East [Harvard]. Eighteen of you already have a master’s or a doctorate, and many of you have already published research, participated in varsity athletics, shined in the arts and contributed to your community.

Previously: Abraham Verghese urges Stanford grads to always remember the heritage and rituals of medicine, Top 10 reasons I’m glad to be in medical school and “Something old and something new” for Stanford medical students
Photo, of Brandon Turner receiving his official white coat at a ceremony last Friday, by Norbert von der Groeben

Applied Biotechnology, Parenting, Pediatrics, Research, Sleep, Stanford News, Technology

Biodesign fellows take on night terrors in children

Biodesign fellows take on night terrors in children

baby on bed

Standing in the Clark Center’s grand courtyard, gazing upward at scientists ascending an outdoor staircase and traversing the exterior corridors on the top two floors, one senses that big ideas take shape here. But how?

Prototyping, say Andy Rink, MD, and Varun Boriah, MS, who spent the last year as Biodesign fellows. Part of Stanford’s Bio-X community, the Biodesign Program trains researchers, clinicians and engineers to be medical-technology innovators during its year-long fellowship. Fellows learn the Biodesign Process, which could be likened to design thinking for health care. On teams of two or four, the fellows identify a substantial health-care need and generate ideas to solve it using medical-device innovation.

Though most Biodesign projects take root after fellows complete a “clinical immersion” shadowing health-care workers in a hospital to observe problems, Rink found his inspiration when visiting family and waking up to a 3-year-old relative’s screams from recurring night terrors. The problem was not so much that it affected the child – pediatricians may advise that children will likely outgrow the condition – but that it affected the parents, Rink saw.  The parent’s lost sleep and anxiety over their child’s well being had huge effects on their quality of life. (In some cases, these are so severe that Xanax and Valium may be prescribed to the children as a last-ditch effort.) What if a treatment could be found that involved no medication and no parental intervention, offering everyone a solid night’s sleep?

The physician and engineer are working with School of Medicine sleep researchers Christian Guilleminault, MD, professor of psychiatry and behavioral sciences, and Shannon Sullivan, MD, clinical assistant professor of psychiatry and behavioral sciences, on a clinical method to treat night terrors in children. In a first-floor room of the Clark Center, they’re protoyping an under-mattress device that senses how deeply a child is sleeping and is able to prevent the nightly episodes from occurring, creating a healthier sleep cycle for the children.  This relieves the parent’s anxiety, and helps the entire family sleep better.

Faculty and students from more than 40 departments across Stanford’s campus, including the schools of medicine, business, law, engineering and humanities and sciences, play a role in Biodesign, as do experts from outside the university. Fellows work closely with the Institute of Design at Stanford, attending – and then teaching – the school’s d.bootcamp. They also have access to the d.school’s facilities and consult regularly with their faculty. Some of the d.school’s methods – focusing on big problems, encouraging radical collaboration, prototyping early and user-testing before focusing on functionality – guide the trajectory of Biodesign projects.

Physicians who are Biodesign fellows often work outside their specialty, and engineers bring a mix of academic and industry experience to the design table. While faculty mentors may simply provide advice to fellows, Guilleminault and Sullivan have become invested in the course of the research as lead investigators on the study. For their involvement, they were both honored with the Biodesign Specialty Team Mentorship Award.

Fellow Boriah noted that medical-device innovation is moving from products like catheters to systems such as health IT, mobile health and software. A former CEO and co-founder of a wearable patient blood-diagnostics device, he said the Biodesign program has provided valuable “access to clinical reality.” Rink, a surgical resident at Northwestern University, said that as a fellow, he’s been “exposed to a side you don’t see in a hospital.”

The researchers are currently recruiting participants ages 2-12 for their study. Rink and Boriah are also working with the Stanford-supported StartX to see their project into the next stage of development.

Previously: Sleep, baby, sleep: Infants’ sleep difficulties could signal future problemsStudying pediatric sleep disorders an “integral part” of the future of sleep medicine and At Med School 101, teens learn that it’s “so cool to be a doctor” 
Photo by MissMayoi

Big data, Evolution, Genetics, In the News, Research, Science, Stanford News

Flies, worms and humans – and the modENCODE Project

Flies, worms and humans - and the modENCODE Project

It’s a big day in comparative biology. Researchers around the country, including Stanford geneticist Michael Snyder, PhD, are publishing the results of a massive collaboration meant to suss out the genomic similarities (and differences) among model organisms like the fruit fly and the laboratory roundworm. A package of four papers, which describe how these organisms control how, when and where they express certain genes to generate the cell types necessary for complex life, appears today in Nature.

From our release:

The research is an extension of the ENCODE, or Encyclopedia of DNA Elements, project that was initiated in 2003. As part of the large collaborative project, which was sponsored by the National Human Genome Research Institute, researchers published more than 4 million regulatory elements found within the human genome in 2012. Known as binding sites, these regions of DNA serve as landing pads for proteins and other molecules known as regulatory factors that control when and how genes are used to make proteins.

The new effort, known as modENCODE, brings a similar analysis to key model organisms like the fly and the worm. Snyder is the senior author of two of the papers published today describing some aspects of the modENCODE project, which has led to the publication, or upcoming publication, of more than 20 papers in a variety of journals. The Nature papers, and the modENCODE project, are summarized in a News and Views article in the journal (subscription required to access all papers).

As Snyder said in our release, “We’re trying to understand the basic principles that govern how genes are turned on and off. The worm and the fly have been the premier model organisms in biology for decades, and have provided the foundation for much of what we’ve learned about human biology. If we can learn how the rules of gene expression evolved over time, we can apply that knowledge to better understand human biology and disease.”

The researchers found that, although the broad strokes of gene regulation are shared among species, there are also significant differences. These differences may help explain why humans walk, flies fly and worms slither, for example:

The wealth of data from the modENCODE project will fuel research projects for decades to come, according to Snyder.

“We now have one of the most complete pictures ever generated of the regulatory regions and factors in several genomes,” said Snyder. “This knowledge will be invaluable to researchers in the field.”

Previously: Scientists announce the completion of the ENCODE project, a massive genome encyclopedia

Pain, Research, Stanford News

New painkiller could tackle pain, without risk of addiction

New painkiller could tackle pain, without risk of addiction

painkillersThose suffering from chronic pain, take note: A new pain-reliever may soon be on the scene that lacks the “high” of opioids and the cardiac-risk of non-steroidal anti-inflammatory (NSAIDs) drugs such as aspirin. The compound reduced inflammatory pain in mice, according to research by a team of Stanford scientists led by Daria Mochly-Rosen, PhD, a professor of chemical and systems biology.

Mochly-Rosen discovered the compound, called Alda-1, more than five years ago while searching for the reason moderate alcohol use can decrease the severity of heart attacks. She found an enzyme, called aldehyde dehydrogenase 2, that breaks down a family of alcohol byproducts, called aldehydes. Aldehydes also cause pain in mice and Alda-1 relieves the pain, Mochly-Rosen said.

“I’m not a pain expert,” Mochly-Rosen says in our release on the Science Translational Medicine paper. “We hit this enzyme for a completely different reason. Hopefully this will help people who have pain.”

Alda-1 — coincidentally, Alda is also the name of Mochly-Rosen’s 87-year-old mother — works by knocking aldehyde dehydrogenase 2 into high gear. Say goodbye to the aldehydes, and goodbye to the pain.

Mochly-Rosen’s discovery of the link between pain and Alda-1 is a big deal for many reasons, including the suffering of thousands addicted to opioids such as Oxycontin. It’s also particularly meaningful for the millions in the Han Chinese ethnic group who suffer from alcohol flush.  They have a mutation in aldehyde hydrogenate 2, which makes it uncomfortable to drink alcohol and causes sufferers to turn red.

The inflammation is caused by the build-up of aldehydes, which are byproducts of alcohol. Alcohol-flush syndrome, as it’s sometimes called, has been recognized for decades.

The researchers created a mouse with a mutation akin to the enzyme mutation in humans. When they injected aldehydes into the mice, the mice with the mutation felt more pain than the other mice. And Alda-1 also relieved their pain.

Dribbles of evidence suggest some Asians are more sensitive to pain. Now, Mochly-Rosen and her team plan to investigate if the susceptibility stems from the enzyme mutation.

Becky Bach is a former park ranger who now spends her time writing, exploring, or practicing yoga. She’s currently a science writing intern in the medical school’s Office of Communication & Public Affairs.

Previously: Another big step toward building a better aspirin tablet, Blocking addiction risks of morphine without reducing its pain-killing effects, Patients’ genetics may play a role in determining side effects of commonly prescribed painkillers, and Stanford’s Sean Mackey discusses recent advances in pain research and treatment
Photo by Michelle Tribe/Wikimedia Commons

Applied Biotechnology, Ophthalmology, Public Health, Stanford News, Technology

Stanford-developed eye implant could work with smartphone to improve glaucoma treatments

Stanford-developed eye implant could work with smartphone to improve glaucoma treatments

eyeGlaucoma, caused by rising fluid pressure in the eyes, is known as the silent thief of sight. Catching the disease in the early stages is critical because if detected too late it leads to blindness. Regular monitoring and controlling of the disease once detected is invaluable.

Now, Stephen Quake, PhD, professor of bioengineering at Stanford, and Yossi Mandel, MD, PhD, an applied physics and ophthalmologist at Bar-Ilan University in Israel, have developed a tiny eye implant that would allow patients to take daily or hourly measurements of eye pressure from home.

A recent Stanford Report article explains how the device works:

It consists of a small tube – one end is open to the fluids that fill the eye; the other end is capped with a small bulb filled with gas. As the [internal optic pressure] increases, intraocular fluid is pushed into the tube; the gas pushes back against this flow.

As IOP fluctuates, the meniscus – the barrier between the fluid and the gas – moves back and forth in the tube. Patients could use a custom smartphone app or a wearable technology, such as Google Glass, to snap a photo of the instrument at any time, providing a critical wealth of data that could steer treatment. For instance, in one previous study, researchers found that 24-hour IOP monitoring resulted in a change in treatment in up to 80 percent of patients.

“For me, the charm of this is the simplicity of the device. Glaucoma is a substantial issue in human health. It’s critical to catch things before they go off the rails, because once you go off, you can go blind. If patients could monitor themselves frequently, you might see an improvement in treatments,” Quake added.

The full report (subscription required) is published in the current issue of Nature Medicine.

Previously: What I did this summer: Stanford medical student investigates early detection methods for glaucomaTo maintain good eyesight, make healthy vision a priority and Instagram for eyes: Stanford ophthalmologists develop low-cost device to ease image sharing
Photo by Magmiretoby

Aging, Autoimmune Disease, Immunology, Infectious Disease, Research, Stanford News

Our aging immune systems are still in business, but increasingly thrown out of balance

Our aging immune systems are still in business, but increasingly thrown out of balance

business as usual

Stanford immunologist Jorg Goronzy, MD, told me a few years ago that a person’s immune response declines slowly but surely starting at around age 40. “While 90 percent of young adults respond to most vaccines, after age 60 that response rate is down to around 40-45 percent,” he said. “With some vaccines, it’s as low as 20 percent.”

A shaky vaccine response isn’t the only immune-system slip-up. With advancing age, we grow increasingly vulnerable to infection (whether or not we’ve been vaccinated), autoimmune disease (an immune attack on our own tissues) and cancer (when a once well-behaved cell metamorphoses into a ceaselessly dividing one).

A new study led by Goronzy and published in Proceedings of the National Academy of Sciences, suggests why that may come about. The culprit he and his colleagues have fingered turns out not to be the most likely suspect: the thymus.

This all-important organ’s job is to nurture an army of specialized  immune cells called T cells. (The “T” is for “Thymus.”) T cells are capable of recognizing and mounting an immune response to an unbelievably large number of different molecular shapes, including ones found only on invading pathogens or on our own cells when they morph into incipient tumor cells.

Exactly which feature a given T cell recognizes depends on the structure of a receptor molecule carried in abundance on that T cell’s surface.  Although each T cell sports just one receptor type, in the aggregate the number of different shapes T-cells recognize is gigantic, due to a high rate of reshuffling and mutation in the genes dictating their receptors’ makeup. (Stanford immunologist Mark Davis, PhD, perhaps more than any other single individual,  figured out in the early 1980s how this all works.)

T cells don’t live forever, and their generation from scratch completely depends on the thymus. Yet by our early teens the organ,  situated  in front of the lungs at the midpoint of our chest, starts shriveling up and replaced by (sigh – you knew this was coming)  fat tissue.

After the thymus melts away,  new T-cells come into being only when already-existing ones undergo cell division, for example to compensate for the attrition of their neighbors in one or another immune-system dormitory (such as bone marrow, spleen or a lymph node).

It’s been thought that the immune-system’s capacity to recognize and mount a response to pathogens (or incipient tumors) fades away because with age-related T-cell loss comes a corresponding erosion of diversity:  We just run out of T-cells with the appropriate receptors.

The new study found otherwise.  “Our study shows that the diversity of the human T-cell receptor repertoire is much higher than previously assumed, somewhere in the range of one billion different receptor types,” Goronzy says. “Any age-associated loss in diversity is trivial.” But the study also showed an increasing imbalance, with some subgroups of T cells (characterized by genetically identical  receptors)  hogging the show and other subgroups becoming vanishingly scarce.

The good news is that the players in an immune response are all still there, even in old age. How to restore that lost balance is the question.

Previously: How to amp up an aging immune response, Age-related drop in immune responsiveness may be reversible and Deja vu: Adults’ immune systems “remember” microscopic monsters they’ve never seen before
Photo by Lars Plougmann

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