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Fasting Activates Autophagy, Which Helps Slow Down Aging Process, Has Positive Impact On Cell Renewal —Yoshinori Ohsumi

The 2016 Nobel Prize in Physiology or Medicine went to Japanese Scientist Yoshinori Ohsumi for a spectacular work in medicine. He discovered that fasting activates a process known as autophagy, which helps to slow down aging process because it has positive impact on cell renewal.

The research revealed that fasting in general is good for fighting cancer and helping to keep humans younger.

He discovered this mechanism by which the human body and cells carry out this process of autophagy, which is simply a process for degrading and recycling cellular components.

Yoshinori Ohsumi

Summary

This year’s Nobel Laureate discovered and elucidated mechanisms underlying autophagy, a fundamental process for degrading and recycling cellular components.

The word autophagy originates from the Greek words auto-, meaning “self”, and phagein, meaning “to eat”Thus,autophagy denotes “self eating”. This concept emerged during the 1960’s, when researchers first observed that the cell could destroy its own contents by enclosing it in membranes, forming sack-like vesicles that were transported to a recycling compartment, called the lysosome, for degradation. Difficulties in studying the phenomenon meant that little was known until, in a series of brilliant experiments in the early 1990’s, Yoshinori Ohsumi used baker’s yeast to identify genes essential for autophagy. He then went on to elucidate the underlying mechanisms for autophagy in yeast and showed that similar sophisticated machinery is used in our cells.

Ohsumi’s discoveries led to a new paradigm in our understanding of how the cell recycles its content. His discoveries opened the path to understanding the fundamental importance of autophagy in many physiological processes, such as in the adaptation to starvation or response to infection. Mutations in autophagy genes can cause disease, and the autophagic process is involved in several conditions including cancer and neurological disease.

Degradation – a central function in all living cells

In the mid 1950’s scientists observed a new specialized cellular compartment, called an organelle, containing enzymes that digest proteins, carbohydrates and lipids. This specialized compartment is referred to as a “lysosome” and functions as a workstation for degradation of cellular constituents. The Belgian scientist Christian de Duve was awarded the Nobel Prize in Physiology or Medicine in 1974 for the discovery of the lysosome. New observations during the 1960’s showed that large amounts of cellular content, and even whole organelles, could sometimes be found inside lysosomes. The cell therefore appeared to have a strategy for delivering large cargo to the lysosome. Further biochemical and microscopic analysis revealed a new type of vesicle transporting cellular cargo to the lysosome for degradation (Figure 1). Christian de Duve, the scientist behind the discovery of the lysosome, coined the term autophagy, “self-eating”, to describe this process. The new vesicles were named autophagosomes.Figure 1:

Our cells have different specialized compartments. Lysosomes constitute one such compartment and contain enzymes for digestion of cellular contents. A new type of vesicle called autophagosome was observed within the cell. As the autophagosome forms, it engulfs cellular contents, such as damaged proteins and organelles. Finally, it fuses with the lysosome, where the contents are degraded into smaller constituents. This process provides the cell with nutrients and building blocks for renewal.

During the 1970’s and 1980’s researchers focused on elucidating another system used to degrade proteins, namely the “proteasome”. Within this research field Aaron Ciechanover, Avram Hershko and Irwin Rose were awarded the 2004 Nobel Prize in Chemistry for “the discovery of ubiquitin-mediated protein degradation”. The proteasome efficiently degrades proteins one-by-one, but this mechanism did not explain how the cell got rid of larger protein complexes and worn-out organelles. Could the process of autophagy be the answer and, if so, what were the mechanisms?

A groundbreaking experiment

Yoshinori Ohsumi had been active in various research areas, but upon starting his own lab in 1988, he focused his efforts on protein degradation in the vacuole, an organelle that corresponds to the lysosome in human cells. Yeast cells are relatively easy to study and consequently they are often used as a model for human cells. They are particularly useful for the identification of genes that are important in complex cellular pathways. But Ohsumi faced a major challenge; yeast cells are small and their inner structures are not easily distinguished under the microscope and thus he was uncertain whether autophagy even existed in this organism. Ohsumi reasoned that if he could disrupt the degradation process in the vacuole while the process of autophagy was active, then autophagosomes should accumulate within the vacuole and become visible under the microscope. He therefore cultured mutated yeast lacking vacuolar degradation enzymes and simultaneously stimulated autophagy by starving the cells. The results were striking! Within hours, the vacuoles were filled with small vesicles that had not been degraded (Figure 2).

The vesicles were autophagosomes and Ohsumi’s experiment proved that authophagy exists in yeast cells. But even more importantly, he now had a method to identify and characterize key genes involved in this process. This was a major break-through and Ohsumi published the results in 1992.Figure 2: In yeast (left panel) a large compartment called the vacuole corresponds to the lysosome in mammalian cells. Ohsumi generated yeast lacking vacuolar degradation enzymes. When these yeast cells were starved, autophagosomes rapidly accumulated in the vacuole (middle panel). His experiment demonstrated that autophagy exists in yeast. As a next step, Ohsumi studied thousands of yeast mutants (right panel) and identified 15 genes that are essential for autophagy.

Autophagy genes are discovered

Ohsumi now took advantage of his engineered yeast strains in which autophagosomes accumulated during starvation. This accumulation should not occur if genes important for autophagy were inactivated. Ohsumi exposed the yeast cells to a chemical that randomly introduced mutations in many genes, and then he induced autophagy. His strategy worked! Within a year of his discovery of autophagy in yeast, Ohsumi had identified the first genes essential for autophagy. In his subsequent series of elegant studies, the proteins encoded by these genes were functionally characterized. The results showed that autophagy is controlled by a cascade of proteins and protein complexes, each regulating a distinct stage of autophagosome initiation and formation (Figure 3).Figure 3:

Ohsumi studied the function of the proteins encoded by key autophagy genes. He delineated how stress signals initiate autophagy and the mechanism by which proteins and protein complexes promote distinct stages of autophagosome formation.

Autophagy – an essential mechanism in our cells

After the identification of the machinery for autophagy in yeast, a key question remained. Was there a corresponding mechanism to control this process in other organisms? Soon it became clear that virtually identical mechanisms operate in our own cells. The research tools required to investigate the importance of autophagy in humans were now available.

Thanks to Ohsumi and others following in his footsteps, we now know that autophagy controls important physiological functions where cellular components need to be degraded and recycled. Autophagy can rapidly provide fuel for energy and building blocks for renewal of cellular components, and is therefore essential for the cellular response to starvation and other types of stress. After infection, autophagy can eliminate invading intracellular bacteria and viruses. Autophagy contributes to embryo development and cell differentiation. Cells also use autophagy to eliminate damaged proteins and organelles, a quality control mechanism that is critical for counteracting the negative consequences of aging.

Disrupted autophagy has been linked to Parkinson’s disease, type 2 diabetes and other disorders that appear in the elderly. Mutations in autophagy genes can cause genetic disease. Disturbances in the autophagic machinery have also been linked to cancer. Intense research is now ongoing to develop drugs that can target autophagy in various diseases.

Autophagy has been known for over 50 years but its fundamental importance in physiology and medicine was only recognized after Yoshinori Ohsumi’s paradigm-shifting research in the 1990’s. For his discoveries, he is awarded this year’s Nobel Prize in physiology or medicine.

Key publications

Takeshige, K., Baba, M., Tsuboi, S., Noda, T. and Ohsumi, Y. (1992). Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. Journal of Cell Biology 119, 301-311

Tsukada, M. and Ohsumi, Y. (1993). Isolation and characterization of autophagy-defective mutants of Saccharomyces cervisiae. FEBS Letters 333, 169-174

Mizushima, N., Noda, T., Yoshimori, T., Tanaka, Y., Ishii, T., George, M.D., Klionsky, D.J., Ohsumi, M. and Ohsumi, Y. (1998). A protein conjugation system essential for autophagy. Nature 395, 395-398

Ichimura, Y., Kirisako T., Takao, T., Satomi, Y., Shimonishi, Y., Ishihara, N., Mizushima, N., Tanida, I., Kominami, E., Ohsumi, M., Noda, T. and Ohsumi, Y. (2000). A ubiquitin-like system mediates protein lipidation. Nature, 408, 488-492

Yoshinori Ohsumi was born 1945 in Fukuoka, Japan. He received a Ph.D. from University of Tokyo in 1974. After spending three years at Rockefeller University, New York, USA, he returned to the University of Tokyo where he established his research group in 1988. He is since 2009 a professor at the Tokyo Institute of Technology.

The Nobel Assembly, consisting of 50 professors at Karolinska Institutet, awards the Nobel Prize in Physiology or Medicine. Its Nobel Committee evaluates the nominations. Since 1901 the Nobel Prize has been awarded to scientists who have made the most important discoveries for the benefit of mankind.

Nobel Prize® is the registered trademark of the Nobel Foundation

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First Scrotum And Penis Transplant Performed |The Republican News

The transplant was carried out by surgeons at John Hopkins university hospital© Other The transplant was carried out by surgeons at John Hopkins University hospital
A man who lost his genitals in a war injury has received the world’s first full penis and scrotum transplant.Surgeons at Baltimore’s John Hopkins University have rebuilt the veteran’s entire pelvic region from the parts of a deceased donor.

It is hoped that the operation will give the injured man full urinary and sexual function within weeks.

In an ambitious March operation lasting 14 hours, surgeons connected tiny nerves, blood vessels, skin, muscles and tendons to rebuild both the man’s penis and extensive surrounding tissue.

While a handful of successful penis transplants have been reported in recent years, this was the first to reconstruct the scrotum as well – making it far more complex and expensive than previous procedures.

The recipient, who wishes to remain anonymous, said he “felt finally more normal” on waking up from the operation.

The operation took 14 hours in total           © Other The operation took 14 hours in total

“It’s a real mind-boggling injury to suffer; it is not an easy one to accept,” he said.

The extent of the patient’s injuries – he had lost his penis, scrotum, and much of his abdominal wall – meant taking an exact replica of what was missing was the most sensible option for the surgeons treating him.

“We’ve really replaced like with like,” surgeon Dr Richard Redett said. “We looked at the defect our patient had and procured the exact same graft from our donor.”

The full transplant is radically different to current procedures – often used in transgender surgery or to treat congenital abnormalities – that use a patient’s own skin to construct a penis.

Such operations require patients to use an implant to achieve an erection, bringing a higher risk of infection than the highly experimental full transplant.

But while they avoid such problems, transplants present new ethical problems in penis surgery.

The families of deceased donors need to give explicit permission for a penis – as parts of the face or hands – to be given for transplant, for example.

This replaces a larger area of genitalia than any previous operation© Other This replaces a larger area of genitalia than any previous operation

It was also decided in this operation that a scrotum transplant should not extend to the donor’s testicles, which would bring the possibility of having children. “We just felt there were too many unanswered ethical questions,” surgeon Damon Cooney said.

Surgeons at John Hopkins described lost penises as “an unspoken injury of war”, suffered in silence by patients who face stigma as well as a loss of sexual intimacy and urinary function.

The US Department of Defense trauma registry has recorded 1,367 male service personnel with having suffered genitourinary injuries between 2001 and 2013, although it is not clear whether how many of those resulted in the loss of all or part of the penis.

Patients can also lose a penis through cancer or accidents. One previous penis transplant, in China, was reversed after psychological problems experienced by the recipient and his wife.

After the surgery in March, however, doctors say the first penis and scrotum recipient is doing well.

(SkyNews)

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