In the first evidence of a natural intervention triggering stem cell-based regeneration of an organ or system, a study in the June 5 issue of the Cell Press journal Cell Stem Cell shows that cycles of prolonged fasting not only protect against immune system damage — a major side effect of chemotherapy — but also induce immune system regeneration, shifting stem cells from a dormant state to a state of self-renewal.
In both mice and a Phase 1 human clinical trial, long periods of not eating significantly lowered white blood cell counts. In mice, fasting cycles then “flipped a regenerative switch”: changing the signaling pathways for hematopoietic stem cells, which are responsible for the generation of blood and immune systems, the research showed.
The study has major implications for healthier aging, in which immune system decline contributes to increased susceptibility to disease as we age. By outlining how prolonged fasting cycles — periods of no food for two to four days at a time over the course of six months — kill older and damaged immune cells and generate new ones, the research also has implications for chemotherapy tolerance and for those with a wide range of immune system deficiencies, including autoimmunity disorders.
“We could not predict that prolonged fasting would have such a remarkable effect in promoting stem cell-based regeneration of the hematopoietic system,” said corresponding author Valter Longo, the Edna M. Jones Professor of Gerontology and the Biological Sciences at the USC Davis School of Gerontology, and director of the USC Longevity Institute.
“When you starve, the system tries to save energy, and one of the things it can do to save energy is to recycle a lot of the immune cells that are not needed, especially those that may be damaged,” Longo said. “What we started noticing in both our human work and animal work is that the white blood cell count goes down with prolonged fasting. Then when you re-feed, the blood cells come back. So we started thinking, well, where does it come from?”
Prolonged fasting forces the body to use stores of glucose, fat and ketones, but also breaks down a significant portion of white blood cells. Longo likens the effect to lightening a plane of excess cargo.
During each cycle of fasting, this depletion of white blood cells induces changes that trigger stem cell-based regeneration of new immune system cells. In particular, prolonged fasting reduced the enzyme PKA, an effect previously discovered by the Longo team to extend longevity in simple organisms and which has been linked in other research to the regulation of stem cell self-renewal and pluripotency — that is, the potential for one cell to develop into many different cell types. Prolonged fasting also lowered levels of IGF-1, a growth-factor hormone that Longo and others have linked to aging, tumor progression and cancer risk.
“PKA is the key gene that needs to shut down in order for these stem cells to switch into regenerative mode. It gives the ‘okay’ for stem cells to go ahead and begin proliferating and rebuild the entire system,” explained Longo, noting the potential of clinical applications that mimic the effects of prolonged fasting to rejuvenate the immune system. “And the good news is that the body got rid of the parts of the system that might be damaged or old, the inefficient parts, during the fasting. Now, if you start with a system heavily damaged by chemotherapy or aging, fasting cycles can generate, literally, a new immune system.”
Prolonged fasting also protected against toxicity in a pilot clinical trial in which a small group of patients fasted for a 72-hour period prior to chemotherapy, extending Longo’s influential past research: “While chemotherapy saves lives, it causes significant collateral damage to the immune system. The results of this study suggest that fasting may mitigate some of the harmful effects of chemotherapy,” said co-author Tanya Dorff, assistant professor of clinical medicine at the USC Norris Comprehensive Cancer Center and Hospital. “More clinical studies are needed, and any such dietary intervention should be undertaken only under the guidance of a physician.”
“We are investigating the possibility that these effects are applicable to many different systems and organs, not just the immune system,” said Longo, whose lab is in the process of conducting further research on controlled dietary interventions and stem cell regeneration in both animal and clinical studies.
- Chia-Wei Cheng, Gregor B. Adams, Laura Perin, Min Wei, Xiaoying Zhou, Ben S. Lam, Stefano Da Sacco, Mario Mirisola, David I. Quinn, Tanya B. Dorff, John J. Kopchick, Valter D. Longo. Prolonged Fasting Reduces IGF-1/PKA to Promote Hematopoietic-Stem-Cell-Based Regeneration and Reverse Immunosuppression. Cell Stem Cell, 2014; 14 (6): 810 DOI:1016/j.stem.2014.04.014
Surgeons in Cambridgeshire have performed the first heart transplant in Europe using a non-beating heart.
Donor hearts are usually from people who are brain-stem dead, but whose hearts are still beating. In this case, the organ came from a donor after their heart and lungs had stopped functioning, so-called circulatory death. Papworth hospital says the technique could increase the number of hearts available by at least 25%. The recipient Huseyin Ulucan, 60, from London, had a heart attack in 2008. He said: “Before the surgery, I could barely walk and I got out of breath very easily, I really had no quality of life.” He said he was “delighted” with the improvement in health since the transplant. “Now I’m feeling stronger every day, and I walked into the hospital this morning without any problem,” he said.
There have been 171 heart transplant in the past 12 months in the UK. But demand exceeds supply, and some patients have to wait up to three years for a suitable organ. Many patients die before an organ becomes available. Non-beating-heart donors provide kidneys, livers and other organs, but until now it has not been possible to use the heart because of concerns it would suffer damage. The new procedure involved re-starting the heart in the donor five minutes after death and perfusing it and other vital organs with blood and nutrients at body temperature. The lead transplant surgeon, Stephen Large, said: “We had the heart beating for about 50 minutes, and by monitoring its function were able to tell that it was in very good condition.”
The organ was then removed and transferred to a heart-in-a-box machine, where it was kept nourished and beating for a further three hours before the transplant surgery at Papworth. The organ care system is also used for maintaining lung, liver and kidneys outside the body. The standard method for transporting hearts and other organs for transplant is to pack them in ice, but some organs can be damaged by this process. The Papworth team said that restoring the heartbeat after death and keeping the organ nourished had helped reduce damage in the heart muscle. Last year surgeons in Australia performed the world’s first transplant using a non-beating heart, also using the heart-in-a-box technology.
TransMedics, the US company that makes the organ care machine, said each unit cost £150,000 plus £25,000 per patient transplanted. Papworth and Harefield hospitals are the only two heart transplant units in the UK who use the device. Prof James Neuberger, associate medical director for organ donation and transplantation at NHS Blood and Transplant, said: “Sadly, there is a shortage of organs for transplant across the UK and patients die in need of an organ. “We hope Papworth’s work and similar work being developed elsewhere will result in more hearts being donated and more patients benefiting from a transplant in the future. “We are immensely grateful to the donor’s family, and we hope they are taking great comfort in knowing that their relative’s organs have saved lives and have also made an important contribution to heart transplantation in the UK.”
Dr. S is a young surgeon who graduated shortly after the outbreak of the crisis in Syria. He now works in a makeshift hospital in a semi-rural neighbourhood located to the east of Damascus. This is a facility that received dedicated MSF support and supplies throughout the period of siege, support that continues on a regular monthly basis to this day. He tells the story of his medical journey – an experience that parallels the war in the country.
A temporary truce that death could not penetrate
There was a pregnant woman who was trapped during the time we were under full siege. She was due to deliver soon. All negotiation attempts to get her out failed. She needed a cesarean operation, but there was no maternity hospital we could get her to, and I had never done this operation before.
A few days before the expected delivery date, I was trying to get a working internet connection to read up information on doing a C-section. The clock was ticking and my fear and stress started to peak. I wished I could stop time, but the woman’s labour started. The atmosphere was tense already, with mad shelling hammering the area. The bombardments had reached a deafening level. We brought the woman into the operating theatre and I did the operation. Joy overwhelmed me when we knew the baby girl was healthy, and her mother too.
In this madness, our work as surgeons is to save as many lives as we can. Sometimes we succeed, and sometimes we fail. It is as if we repair the damage that the war left. But this operation was not the usual damage repair; it helped bring new life to this earth. It was a magical moment; a temporary truce that death could not penetrate.
I chose a deserted school as my hospital
I graduated as a surgeon shortly after the crisis started in Syria. In the Summer of 2011, with the acceleration of events and medical needs increasing, I started working in small private hospitals. A few months later, I was arrested, as were many of my colleagues. At the beginning of 2012 I was out, and I returned to treat people and carry on my general surgery specialization. I was working in improvised field hospitals, operating in conditions that were largely unsuitable for medical work. We worked in the east of Damascus and then in the Ghouta area, where the medical need was urgent.
At the end of 2012, a semi-rural neighbourhood located to the east of Damascus witnessed violent clashes. The area was packed with displaced people at the time, without any medical centre to treat wounded people. I went there and decided to set up a field hospital. Following a search, I chose a deserted school that had previously been hit. The upper floors were damaged, but the ground floor, as well as the basement, were in a good shape. Despite the daily, continuous shelling on the area, and the constant fear and stress, the medical team with which I worked managed to provide tremendous medical care to those who needed it the most.
One day in July 2013, around 10:00 am, the hospital was hit by a rocket. The massive explosion turned the place upside down and its pressure tore out the wooden walls. Medical tools and people were thrown in all directions. Soon a dust cloud settled over the building and made it impossible to see. The explosion was like nothing before. I thought that worse could follow and this explosion might be only the beginning of something very bad. Indeed, shells rained on the area and we could hear the clashes getting worse.
As we were getting over the shock, one of the hospital workers collapsed. She lived near the hospital. Her young boy was at home and the area was coming under heavy shelling. She could not keep it together and she wanted to save her child. A medic offered to go out and look for the child. I did not like the idea because we did not know what was going on outside. As soon as the medic was out of the hospital door, he saw a tank with its gun facing towards him. A healthy man walked out, and few moments later, he came back with shards of metal in his body. It was only then that we realized the severity of the situation outside. We decided to evacuate the hospital – two medics per patient to carry them – and we got out of the back door.
It was apocalyptic! We tried to walk fast towards a small medical centre not far from there. Shelling was hammering the fields around us. I was expecting the worst with every shell we heard. We managed to arrive at our destination unharmed. It was like a miracle. We had left our equipment in the evacuated hospital, but we did not dare to go back there. Over the next days, we heard that the fighting was moving away from the area around the hospital. Under heavy bombardment, we decided to go back and bring our equipment. We had to do that to be able to treat people. Taking turns to do the trip, we managed to retrieve as much as possible after ten days.
From then, we were under siege – impossible to get in and out of there. This was also true for medical supplies. We received a flow of injured people since the first day of the siege. I often operated on two people at once. We worked around the clock. Sleeping and resting were an impossible luxury. We managed to stop for few moments before dawn to eat some food and drink some water, before getting back to work. Most days heavy shelling and raging fighting brought us more injured people, leaving us no chance to rest. The numbers of injured people were way beyond what we could handle, and that forced us to make painful clinical decisions.
After the siege
We were under siege for eight months, up until February 2014. Eight months of suffering and stress, followed by a ceasefire, during which many people managed to go back to their homes. It became easier to get hold of supplies, and that helped us to continue providing medical care to people in need. Nevertheless, the humanitarian situation remained bad. There were still often clashes at the edges of the this area and the shelling was still frequent. This formal ceasefire did not change the nature of our work, but we finally found enough time to expand the hospital. People returning to the neighbourhood meant an increase in the needs, thus more pressure on us. We setup an obstetrics department and clinics to provide basic medical care and chronic diseases management. We could start doing bone, internal and urinary surgeries; all operations we could not perform before because we had suffered critical shortages of supplies and we had been prioritizing life-saving operations.
MSF continued to provide us with much of what we needed. We even received laboratory kit, which allowed us to carry out diagnostic tests. And we received an incubator for the obstetrics unit. Little by little, we could start to respond to all the basic general medical needs for the people in the area.
It has to stop, one day
Three years of non-stop surgery under tough circumstances – I have maxed out. I’ve had enough of scenes of misery. I was on the phone recently with my surgery professor and he said: “regardless of the operating conditions, your work during these three years matches my whole 30 years’ experience as a doctor. You have reached retirement in just three years.” And indeed, every moment of every day I feel I have had enough, but we have no other choice. People here need us. They are in desperate need of all kinds of medical care, from the most simple to the most complicated. We cannot add another reason for the deterioration of this already disastrous situation.
Today, I am almost certain that, when the war is over, I will quit medicine. Any human being would make that decision after living what I have lived through. I look forward to the end of this war. It has to stop, one day. Then, I can choose what to do. Only then, will we be truly alive again.
At some point in your life, you’ve probably been labeled a “right-brain thinker” (you’re so creative!) or a “left-brain thinker” (you’re so logical). Maybe this has shaped the way you see yourself or view the world.
“This is an idea that makes no physiological sense,” she says.
Blakemore believes that the concept of “logical, analytical, and accurate” thinkers favoring their left hemisphere and “creative, intuitive, and emotional” thinkers favoring their right hemisphere is the misinterpretation of valuable science. She thinks it entered pop culture because it makes for snappy self-help books. And of course people love categorizing themselves.
In the ’60s, ’70s, and ’80s, the renowned cognitive neuroscientist Michael Gazzaniga led breakthrough studies on how the brain works. He studied patients who — and here’s the key — lacked a corpus callosum, the tract that connect the brain’s hemispheres. During this time doctors had experimented on patients suffering from constant seizures due to intractable epilepsy by disconnecting the hemispheres.
Gazzaniga could thus determine the origins in the brain of certain cognitive and motor functions by monitoring the brains of these patients.
He found, for example, that a part of the left brain he dubbed “The Interpreter” handled the process of explaining actions that may have begun in the right brain.
He discovered “that each hemisphere played a role in different tasks and different cognitive functions, and that normally one hemisphere dominated over the other,” Blakemore explains.
This was breakthrough research on how parts of the brain worked. But in a normal human being, the corpus callosum is constantly transmitting information between both halves. It’s physically impossible to favor one side.
Blakemore thinks that this misinterpretation of the research is actually harmful, because the dichotomous labels convince people that their way of thinking is genetically fixed on a large scale.
“I mean, there are huge individual differences in cognitive strengths,” Blakemore says. “Some people are more creative; others are more analytical than others. But the idea that this has something to do with being left-brained or right-brained is completely untrue and needs to be retired.”
You can listen to Blakemore and many other experts taking down their least favorite ideas in the Freakonomics Radio episode “This Idea Must Die,” hosted by “Freakonomics” co-author Stephen J. Dubner.
The outlook used to be pretty bleak for those who had lost movement in their limbs due to severe nerve damage, but over the last year or so, some incredible advances have been made that are restoring shattered hope for many.
The amazing breakthroughs include spinal cord stimulation that allowed paralyzed men to regain some voluntary control of their legs, a brain implant that enabled a quadriplegic man to move his fingers, and a system that allowed a paralyzed woman to control a robotic armusing her thoughts. Science has definitely been on a roll, but this winning streak isn’t showing any signs of slowing down. Now, the world’s first “bionic reconstructions” have been performed on three Austrian men to help them regain hand function. This technique enabled the newly amputated patients to control prosthetic hands using their minds, allowing them to perform various tasks that most people take for granted.
The men that underwent the procedure had all suffered serious nerve damage as a result of car or climbing accidents, which left them with severely impaired hand function. The nerves that suffered injury were those within a network of fibers supplying the skin and muscles of the upper limbs, known as the brachial plexus. As lead researcher Professor Oskar Aszmann explains in a news release, traumatic events that sever these nerves are essentially inner amputations, irreversibly separating the limb from neural control. While it is possible to operate, Aszmann says the techniques are crude and do little to improve hand function. However, his newly developed procedure is quite different, and is proving to be a success.
Before the men could be fitted with their prosthetic hands, the researchers had to do some preliminary surgical work in which leg muscle was grafted into their arms in order to improve signal transmission from the remaining nerves. After a few months, the fibers had successfully innervated the transplanted tissue, meaning it was time to start the next stage: brain training.
Using a series of sensors placed onto the arm, the men slowly began to learn how to activate the muscle. Next, they mastered how to use electrical nerve signals to control a virtual hand, before eventually moving on to a hybrid hand that was affixed to their non-functioning hand. After around nine months of cognitive training, all of the men had their hand amputated and replaced with a robotic prosthesis that, via sensors, responds to electrical impulses in the muscles.
A few months later, the men had significantly improved hand movement control, which was highlighted by a test of function known as the Southampton Hand Assessment Procedure. As reported in The Lancet, before the procedure, the men scored an average of 9 out of 100, which soared to 65 using the prosthetic. Furthermore, the men reported less pain and a higher quality of life. For the first time since their injuries, they were able to perform avariety of tasks such as picking up objects, slicing food and undoing buttons with both hands.
“So far, bionic reconstruction has only been done in our center in Vienna,” said Aszmann. “However, there are no technical or surgical limitations that would prevent this procedure from being done in centers with similar expertise and resources.”
Think of it as interval training for the dinner table.University of Florida Health researchers have found that putting people on a feast-or-famine diet may mimic some of the benefits of fasting, and that adding antioxidant supplements may counteract those benefits.
Fasting has been shown in mice to extend lifespan and to improve age-related diseases. But fasting every day, which could entail skipping meals or simply reducing overall caloric intake, can be hard to maintain.
“People don’t want to just under-eat for their whole lives,” said Martin Wegman, an M.D.-Ph.D. student at the UF College of Medicine and co-author of the paper recently published in the journal Rejuvenation Research. “We started thinking about the concept of intermittent fasting.”
Michael Guo, a UF M.D.-Ph.D. student who is pursuing the Ph.D. portion of the program in genetics at Harvard Medical School, said the group measured the participants’ changes in weight, blood pressure, heart rate, glucose levels, cholesterol, markers of inflammation and genes involved in protective cell responses over 10 weeks.
“We found that intermittent fasting caused a slight increase to SIRT 3, a well-known gene that promotes longevity and is involved in protective cell responses,” Guo said.
The SIRT3 gene encodes a protein also called SIRT3. The protein SIRT3 belongs to a class of proteins called sirtuins. Sirtuins, if increased in mice, can extend their lifespans, Guo said. Researchers think proteins such as SIRT3 are activated by oxidative stress, which is triggered when there are more free radicals produced in the body than the body can neutralize with antioxidants. However, small levels of free radicals can be beneficial: When the body undergoes stress — which happens during fasting — small levels of oxidative stress can trigger protective pathways, Guo said.
“The hypothesis is that if the body is intermittently exposed to low levels of oxidative stress, it can build a better response to it,” Wegman said.
The researchers found that the intermittent fasting decreased insulin levels in the participants, which means the diet could have an anti-diabetic effect as well.
The group recruited 24 study participants in the double-blinded, randomized clinical trial. During a three-week period, the participants alternated one day of eating 25 percent of their daily caloric intake with one day of eating 175 percent of their daily caloric intake. For the average man’s diet, a male participant would have eaten 650 calories on the fasting days and 4,550 calories on the feasting days. To test antioxidant supplements, the participants repeated the diet but also included vitamin C and vitamin E.
At the end of the three weeks, the researchers tested the same health parameters. They found that the beneficial sirtuin proteins such as SIRT 3 and another, SIRT1, tended to increase as a result of the diet. However, when antioxidants were supplemented on top of the diet, some of these increases disappeared. This is in line with some research that indicates flooding the system with supplemental antioxidants may counteract the effects of fasting or exercise, said Christiaan Leeuwenburgh, Ph.D., co-author of the paper and chief of the division of biology of aging in the department of aging and geriatric research.
“You need some pain, some inflammation, some oxidative stress for some regeneration or repair,” Leeuwenburgh said. “These young investigators were intrigued by the question of whether some antioxidants could blunt the healthy effects of normal fasting.”
On the study participants’ fasting days, they ate foods such as roast beef and gravy, mashed potatoes, Oreo cookies and orange sherbet — but they ate only one meal. On the feasting days, the participants ate bagels with cream cheese, oatmeal sweetened with honey and raisins, turkey sandwiches, apple sauce, spaghetti with chicken, yogurt and soda — and lemon pound cake, Snickers bars and vanilla ice cream.
“Most of the participants found that fasting was easier than the feasting day, which was a little bit surprising to me,” Guo said. “On the feasting days, we had some trouble giving them enough calories.”
Leeuwenburgh said future studies should examine a larger cohort of participants and should include studying a larger number of genes in the participants as well as examining muscle and fat tissue.
- Martin P Wegman, Michael Guo, Douglas M Bennion, Meena N Shankar, Stephen M Chrzanowski, Leslie A Goldberg, Jinze Xu, Tiffany A Williams, Xiaomin Lu, Stephen I Hsu, Stephen D Anton, Christiaan Leeuwenburgh, Mark L Brantly.Practicality of Intermittent Fasting in Humans and its Effect on Oxidative Stress and Genes Related to Aging and Metabolism.Rejuvenation Research, 2014; 141229080855001 DOI: 1089/rej.2014.1624