Aging really is ‘in your head’

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Scientists answer hotly debated questions about how calorie restriction delays aging process

Among scientists, the role of proteins called sirtuins in enhancing longevity has been hotly debated, driven by contradictory results from many different scientists. But new research at Washington University School of Medicine in St. Louis may settle the dispute.

Reporting Sept. 3 in Cell Metabolism, Shin-ichiro Imai, MD, PhD, and his colleagues have identified the mechanism by which a specific sirtuin protein called Sirt1 operates in the brain to bring about a significant delay in aging and an increase in longevity. Both have been associated with a low-calorie diet.

The Japanese philosopher and scientist Ekiken Kaibara first described the concept of dietary control as a method to achieve good health and longevity in 1713. He died the following year at the ripe old age of 84—a long life for someone in the 18th century.

Since then, science has proven a link between a low-calorie diet (without malnutrition) and longevity in a variety of animal models. In the new study, Imai and his team have shown how Sirt1 prompts neural activity in specific areas of the hypothalamus of the brain, which triggers dramatic physical changes in skeletal muscle and increases in vigor and longevity.

“In our studies of mice that express Sirt1 in the brain, we found that the skeletal muscular structures of old mice resemble young muscle tissue,” said Imai. “Twenty-month-old mice (the equivalent of 70-year-old humans) look as active as five-month-olds.”

Imai and his team began their quest to define the critical junctures responsible for the connection between dietary restriction and longevity with the knowledge from previous studies that the Sirt1 protein played a role in delaying aging when calories are restricted. But the specific mechanisms by which it carried out its function were unknown.

Imai’s team studied mice that had been genetically modified to overproduce Sirt1 protein. Some of the mice had been engineered to overproduce Sirt1 in body tissues, while others were engineered to produce more of the Sirt1 protein only in the brain.

“We found that only the mice that overexpressed Sirt1 in the brain (called BRASTO) had significant lifespan extension and delay in aging, just like normal mice reared under dietary restriction regimens,” said Imai, an expert in aging research and a professor in the departments of Developmental Biology and Medicine.

The BRASTO mice demonstrated significant life span extension without undergoing dietary restriction. “They were free to eat regular chow whenever they wished,” he said.

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U Of M Research Discovers Way to Regenerate Muscles

B0007267 Muscle Fibers
Using stem cells, U of M researchers have found a way to regenerate muscles in diseased lab mice.

It’s being called breakthrough research by medical journals around the world, and it’s happening at the University of Minnesota.

Using stem cells, U of M researchers have found a way to regenerate muscles in diseased lab mice.

They hope this breakthrough will lead to better treatments for patients fighting Duchenne Muscular Dystrophy, which brings with it learning disabilities, and extreme fatigue.

Researchers were able to essentially correct the gene mutation that causes muscular dystrophy.

Dr. Rita Perlingeiro heads the lab conducting the study. She explains the first step is to remove skin cells from the tail of a mouse with the disease.

“These are skin, simply skin,” she said. “They don’t make muscle.”

Using a molecularly engineered protein, researchers reprogram the cell to make any tissue in the animal’s body.

Next researchers corrected the disease in the reprogrammed cell, and reprogrammed them once again — this time to be muscle stem cells.

“The next step is we specifically instruct them to make skeletal muscle,” she said.

Researchers then measured the results using a device that quantifies muscle function. While the mice weren’t cured, they were able to restore some mobility.

Perlingeiro says there are still many steps to go through before bringing this to humans.

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via CBS Minnesota
 

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Researchers utilize genetically corrected stem cells to spark muscle regeneration

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By injuring the transplanted muscle and watching it repair itself, the researchers demonstrated that the cell transplants endowed the recipient mice with fully functional muscle stem cells.

Researchers at the University of Minnesota‘s Lillehei Heart Institute have combined genetic repair with cellular reprogramming to generate stem cells capable of muscle regeneration in a mouse model for Duchenne Muscular Dystrophy (DMD).

The research, which provides proof-of-principle for the feasibility of combining induced pluripotent stem cell technology and genetic correction to treat muscular dystrophy, could present a major step forward in autologous cell-based therapies for DMD and similar conditions and should pave the way for testing the approach in reprogrammed human pluripotent cells from muscular dystrophy patients.

The research is published in Nature Communications.

To achieve a meaningful, effective muscular dystrophy therapy in the mouse model, University of Minnesota researchers combined three groundbreaking technologies.

First, researchers reprogrammed skin cells into “pluripotent” cells – cells capable of differentiation into any of the mature cell types within an organism. The researchers generated pluripotent cells from the skin of mice that carry mutations in the dystrophin and utrophin genes, causing the mice to develop a severe case of muscular dystrophy, much like the type seen in human DMD patients. This provided a platform that would mimic what would theoretically occur in human models.

The second technology employed is a genetic correction tool developed at the University of Minnesota: the Sleeping Beauty Transposon, a piece of DNA that can jump into the human genome, carrying useful genes with it. Lillehei Heart Institute researchers used Sleeping Beauty to deliver a gene called “micro-utrophin” to the pluripotent cells they were attempting to differentiate.

Much like dystrophin, human micro-utrophin can support muscle fiber strength and prevent muscle fiber injury throughout the body. But one key difference between the two is in how each is perceived by the immune system. Because dystrophin is absent in muscular dystrophy patients, its presence can prompt a devastating immune system response. But in those same patients, utrophin is active and functional, making it essentially “invisible” to the immune system. This invisibility allows the micro-utrophin to replace the dystrophin and progress the process of building and repairing muscle fiber within the body.

The third technology utilized is a method to produce skeletal muscle stem cells from pluripotent cells – a process developed in the laboratory of Rita Perlingeiro, Ph.D., the principal investigator of the latest study.

Perlingeiro’s technology involves giving pluripotent cells a short pulse of a muscle stem cell protein called Pax3. The Pax3 protein pushes the pluripotent cells to become muscle stem cells, and allows them to be expanded exponentially in number. The Pax3-induced muscle stem cells were then transplanted back into the same strain of muscular dystrophy mice from which the pluripotent stem cells were originally derived.

Combined, the platforms created muscle-generating stem cells that would not be rejected by the body’s immune system. According to Perlingeiro, the transplanted cells performed well in the dystrophic mice, generating functional muscle and responding to muscle fiber injury.

“We were pleased to find the newly formed myofibers expressed the markers of the correction, including utrophin,” said Perlingeiro, a Lillehei endowed scholar within the Lillehei Heart Institute and an associate professor in the University of Minnesota Medical School. “However, a very important question following transplantation is if these corrected cells would self-renew, and produce new muscle stem cells in addition to the new muscle fibers.”

By injuring the transplanted muscle and watching it repair itself, the researchers demonstrated that the cell transplants endowed the recipient mice with fully functional muscle stem cells.

This latest project from the U of M provides the proof-of-principle for the feasibility of combining induced pluripotent stem cell technology and genetic correction to treat muscular dystrophy.

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via University of Minnesota Academic Health Center & EurekAlert
 

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VIDEO: Researchers engineer light-activated skeletal muscle

Technique may enable robotic animals that move with the strength and flexibility of their living counterparts.

Many robotic designs take nature as their muse: sticking to walls like geckos, swimming through water like tuna, sprinting across terrain like cheetahs. Such designs borrow properties from nature, using engineered materials and hardware to mimic animals’ behavior.

Now, scientists at MIT and the University of Pennsylvania are taking more than inspiration from nature — they’re taking ingredients. The group has genetically engineered muscle cells to flex in response to light, and is using the light-sensitive tissue to build highly articulated robots. This “bio-integrated” approach, as they call it, may one day enable robotic animals that move with the strength and flexibility of their living counterparts.

The researchers’ approach will appear in the journal Lab on a Chip.

Harry Asada, the Ford Professor of Engineering in MIT’s Department of Mechanical Engineering, says the group’s design effectively blurs the boundary between nature and machines.

“With bio-inspired designs, biology is a metaphor, and robotics is the tool to make it happen,” says Asada, who is a co-author on the paper. “With bio-integrated designs, biology provides the materials, not just the metaphor. This is a new direction we’re pushing in biorobotics.”

Seeing the light

Asada and MIT postdoc Mahmut Selman Sakar collaborated with Roger Kamm, the Cecil and Ida Green Distinguished Professor of Biological and Mechanical Engineering, to develop the new approach. In deciding which bodily tissue to use in their robotic design, the researchers set upon skeletal muscle — a stronger, more powerful tissue than cardiac or smooth muscle. But unlike cardiac tissue, which beats involuntarily, skeletal muscles — those involved in running, walking and other physical motions — need external stimuli to flex.

Normally, neurons act to excite muscles, sending electrical impulses that cause a muscle to contract. In the lab, researchers have employed electrodes to stimulate muscle fibers with small amounts of current. But Asada says such a technique, while effective, is unwieldy. Moreover, he says, electrodes, along with their power supply, would likely bog down a small robot.

Instead, Asada and his colleagues looked to a relatively new field called optogenetics, invented in 2005 by MIT’s Ed Boyden and Karl Deisseroth from Stanford University, who genetically modified neurons to respond to short laser pulses. Since then, researchers have used the technique to stimulate cardiac cells to twitch.

Asada’s team looked for ways to do the same with skeletal muscle cells. The researchers cultured such cells, or myoblasts, genetically modifying them to express a light-activated protein. The group fused myoblasts into long muscle fibers, then shone 20-millisecond pulses of blue light into the dish. They found that the genetically altered fibers responded in spatially specific ways: Small beams of light shone on just one fiber caused only that fiber to contract, while larger beams covering multiple fibers stimulated all those fibers to contract.

A light workout

The group is the first to successfully stimulate skeletal muscle using light, providing a new “wireless” way to control muscles. Going a step further, Asada grew muscle fibers with a mixture of hydrogel to form a 3-D muscle tissue, and again stimulated the tissue with light — finding that the 3-D muscle responded in much the same way as individual muscle fibers, bending and twisting in areas exposed to beams of light.

The researchers tested the strength of the engineered tissue using a small micromechanical chip — designed by Christopher Chen at Penn — that contains multiple wells, each housing two flexible posts. The group attached muscle strips to each post, then stimulated the tissue with light. As the muscle contracts, it pulls the posts inward; because the stiffness of each post is known, the group can calculate the muscle’s force using each post’s bent angle.

Asada says the device also serves as a training center for engineered muscle, providing a workout of sorts to strengthen the tissue. “Like bedridden people, its muscle tone goes down very quickly without exercise,” Asada says.

The light-sensitive muscle tissue exhibits a wide range of motions, which may enable highly articulated, flexible robots — a goal the group is now working toward. One potential robotic device may involve endoscopy, a procedure in which a camera is threaded through the body to illuminate tissue or organs. Asada says a robot made of light-sensitive muscle may be small and nimble enough to navigate tight spaces — even within the body’s vasculature. While it will be some time before such a device can be engineered, Asada says the group’s results are a promising start.

“We can put 10 degrees of freedom in a limited space, less than one millimeter,” Asada says. “There’s no actuator that can do that kind of job right now.”

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via MIT – Jennifer Chu
 

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