Fasting triggers stem cell regeneration of damaged, old immune system

In the first evidence of a natural intervention triggering stem cell-based regeneration of an organ or system, a study 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 involving patients receiving chemotherapy, 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.

Learn more: Fasting-mimicking diet

• A low-calorie fasting-like diet, plus chemotherapy, enables the immune system to recognize and kill skin and breast cancer cells, according to a new USC-led study on mice.

• Evidence is mounting that a diet mimicking the effects of fasting has health benefits beyond weight loss, with a new USC-led study indicating that it may reduce symptoms of multiple sclerosis.

• A diet that mimics fasting appears to slow againt.

The study has major implications for healthier aging, in which immune system decline contributes to increased susceptibility to disease as people 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.

“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?”

Fasting cycles

Prolonged fasting forces the body to use stores of glucose, fat and ketones, but it 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 OK 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 of the study. “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.

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New machine can preserve donor livers for 1 week

Researchers in Switzerland have built a perfusion machine that can preserve human livers for transplantation for a week or more, potentially slashing the number of donor livers that must be discarded due to time-related deterioration.

Existing perfusion technology can preserve a donor liver for up to 24 hours.

The team of surgeons, biologists and engineers at University Hospital Zurich said their liver perfusion machine integrates core physiological functions, including automated glucose and oxygen management, waste-product removal and hematocrit control. The research is part of the Wyss Zurich “Liver4Life” project, and the study was published in the journal Nature Biotechnology.

The machine continuously moves the liver in an effort to mimic diaphragm oscillations. It is also fully automated, obviating the need for constant presence of personnel. The researchers first tested the machine on pig livers, then on 10 severely injured human livers that had been rejected by all European transplant centers, according to the study. After a seven-day perfusion, six of the human livers were producing bile, synthesizing coagulation factors, maintaining cellular energy and remained intact. They even healed from injuries and inflammation that occurred before or at the beginning of the perfusion process, the study said.

The researchers posited that such long-term perfusion may one day enable:

        Repair of severely fatty livers.
        Lowered odds of organ rejection.
        Chemotherapy that would be too toxic for the rest of a patient’s body.
        Long-distance transportation of organs to improve worldwide organ-sharing and transplantation logistics.
        Liver regeneration, with a donor liver split into several anatomic segments to regrow in the machine.

“Recent surgical procedures have shown that massive liver regeneration in humans can occur within 6 (days) of major tissue loss,” the researchers wrote. “If feasible, such an approach could double or even triple the availability of organs for transplantation. We may also imagine the use of partial grafts for auto-transplantation in patients with liver cancer, obviating the need for immune suppression.

“With further testing to demonstrate its use with injured livers and long-term transplantation success, this machine may provide an avenue for providing more patients with liver grafts,” they concluded.

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Scientists discover new breakthrough in treatment for cancer hair loss

Scientists have determined a new way to protect the hair follicle from chemotherapy in an effort to prevent hair loss as a result of cancer treatments.

Researchers have discovered a new strategy for how to protect hair follicles from chemotherapy, which could lead to new treatments that prevent chemotherapy-induced hair loss—arguably one of the most psychologically distressing side effects of modern cancer therapy.

The study describes how damage in the hair follicle caused by taxanes, cancer drugs which can cause permanent hair loss, can be prevented.

To do this, scientists have exploited the properties of a newer class of drugs called CDK4/6 inhibitors, which blocks cell division and are already medically approved as so-called "targeted" cancer therapies.

The lead author on the study explains: "Although at first this seems counter-intuitive, we found that CDK4/6 inhibitors can be used temporarily to halt cell division without promoting additional toxic effects in the hair follicle. When we bathed organ-cultured human scalp hair follicles in CDK4/6 inhibitors, the hair follicles were much less susceptible to the damaging effects of taxanes"

Taxanes are very important anti-cancer drugs commonly used to treat, for example, patients with breast or lung carcinoma and particularly cause anxieties among breast cancer patients for the very distressing and sometimes long-lasting hair loss taxanes can induce. (Thousands of patients in the US are currently suing pharmaceutical company Sanofi over a lack of warning of the risk of permanent hair loss after treatment with the taxane drug Taxotere.)

Dr. emphasizes: "A pivotal part of our study was to first get to grips with how exactly hair follicles responded to taxane chemotherapy, and we found that the specialized dividing cells at the base of the hair follicle that are critical for producing hair itself, and the stem cells from which they arise, are most vulnerable to taxanes. Therefore, we must protect these cells most from undesired chemotherapy effects—but so that the cancer does not profit from it."

The team hope that their work will support the development of externally applicable medicines that will slow or briefly suspend cell division in the scalp hair follicles of patients undergoing 
chemotherapy to mitigate against chemotherapy-induced hair damage. This could complement and enhance the efficacy of existing preventive approaches i.e. scalp cooling devices. 

The researchers underscore that more work is desperately needed in this lamentably under-funded field of cancer medicine, where patients have waited for so long to see real breakthroughs in pharmacological hair loss prevention.

Dr.  said: "Despite the fact that taxanes have been used in the clinic for decades, and have long been known to cause hair loss, we're only now scratching the surface of how they damage the human hair follicle."

He added: "We also don't really know why some patients show greater hair loss than others even though they get the same drug and drug-dose, and why it is that certain chemotherapy regimens and drug combinations have much worse outcomes than others"

"We need time to further develop approaches like this to not only prevent hair loss, but promote hair follicle regeneration in patients who have already lost their hair due to chemotherapy." 

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Study fnds mechanism to heal injured nerve fibres

Researchers found new mechanisms that enable the regeneration of nerve fibers, which could open up new treatment approaches for the brain, optic nerve and spinal cord injuries.

The brain, spinal cord and optic nerves are referred to collectively as the central nervous system. The nerve fibers called axons are unable to grow back following injury meaning that damage is permanent.

It is possible to partially restore the regenerative capacity of nerve cells in the central nervous system by eliminating the inhibiting protein PTEN. However, a knockout of this kind also triggers many different reactions in the cells at the same time, which often lead to cancer, explained a Prof.

As a result, the direct inhibition of this protein is not suitable for therapeutic approaches in humans. What's more, the originally postulated mechanism underlying the renewed regenerative capacity following PTEN knockout could not be confirmed in further studies, causing the researchers to seek alternative explanations.

While investigating this as-yet unclear mechanism, the researchers were able to show for the 1st time that PTEN knockout significantly inhibits an enzyme called glycogen synthase kinase 3, GSK3 for short.

This enzyme, in turn, blocked another protein called collapsin response mediator protein 2, CRMP2.
this meant that the PTEN knockout prevents CRMP2 from being inhibited by GSK3.

If we directly prevent this 2nd step, i.e., stop the inhibition of CRMP2, we can also achieven the regeneration-promoting effect in a more specific manner, explained the researcher.

The activation of CRMP2 itself is not known to have any carcinogenic effect.

Although we have so far only shown these effects in genetically modified mice using gene therapy approaches, these findings open up various possibilities for the development of new drug approaches, explained the neuropharmacologist.

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Researchers discover new therapy target for drug-induced liver failure

A new research from a mouse study has suggested that treatments that increase levels of the protein thrombospondin-1 could help the liver recover from an overdose of acetaminophen.

According to the research presented at a meeting, Acetaminophen, a commonly used pain reliever, and fever reducer is the leading cause of quickly developing, or acute, liver failure in the United States.

“The only treatment available now for acetaminophen overdose must be administered early before significant liver injury occurs,” said the researcher.

“We are working to identify new drug targets to improve treatment options and reduce the need for liver transplantation, which is often the only option for patients with acute liver failure due to drug toxicity,” he added.

Researchers found that mice with acute liver failure from acetaminophen toxicity had higher levels of thrombospondin-1 than mice with normal liver function.

When they administered acetaminophen to genetically modified mice that lack thrombospondin-1, the liver injury and loss of liver function was more severe compared to unmodified mice.

The researchers also observed impaired liver regeneration and increased cell death in the mice without thrombospondin-1.

“Our study is the first to investigate thrombospondin-1 during acetaminophen toxicity. We were able to identify cell communication pathways that do not work properly during acetaminophen-induced liver injury and thus lead to worse outcomes,” said the researcher.

Next, the researchers plan to give mice different drug treatments that manipulate thrombospondin-1 to find out which treatment might be suited for potential clinical studies.They also plan to examine patients with acetaminophen-induced acute liver failure to determine if their thrombospondin-1 findings from mice hold true in people.

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New material to repair bone defects developed

Using near-infrared (NIR) light irradiation, researchers have developed a bio-material that can accelerate bone healing.

While thermal therapy has been traditionally used to treat bone regeneration, it has been proved inefficient in delivering the appropriate amount of heat to the correct part of the patient's body and may cause side effects such as surface burns.

On the other hand, NIR light is electromagnetic radiation with longer wavelengths than those of visible light. Due to higher transmittance through biological tissues, it has been used as a photo-thermal therapy to release heat.

Researchers developed an implantable bio-composite made of black phosphorus nanomaterial and a widely-used tissue-engineering chemical compound to repair bone defects and promote the growth of new bone, researcher reported on Saturday.

Phosphorus is one of the vital elements constituting about 1 per cent of the total human body weight. With the black phosphorus nano-material, the composite has shown a highly-efficient photo-thermal response.

Even when the composite is covered by a tissue barrier as thick as 7 mm, it can still increase the temperature under the NIR light irradiation.

In the experiments conducted on rats, researchers found that the most effective target temperature by the NIR light-trigger is between 39.5 and 40.5 degrees Celsius, only about 3 to 5 degrees higher than the normal human body temperature.

According to lead author, the composite has large clinical potential. It is biodegradable and can produce non-toxic end products such as water and carbon dioxide which can also serve as necessary bone ingredients.

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