Scientists discover key driver of reversing aging process

A study tying the aging process to the deterioration of tightly packaged bundles of cellular DNA could lead to methods of preventing and treating age-related diseases such as cancer, diabetes and Alzheimer's disease, experts say.

A study tying the aging process to the deterioration of tightly packaged bundles of cellular DNA could lead to methods of preventing and treating age-related diseases such as cancer, diabetes and Alzheimer’s disease, experts say.

A study tying the aging process to the deterioration of tightly packaged bundles of cellular DNA could lead to methods of preventing and treating age-related diseases such as cancer, diabetes and Alzheimer’s disease, experts say. In the study, scientists at the Salk Institute and the Chinese Academy of Science found that the genetic mutations underlying Werner syndrome, a disorder that leads to premature aging and death, resulted in the deterioration of bundles of DNA known as heterochromatin.

The discovery, made possible through a combination of cutting-edge stem cell and gene-editing technologies, could lead to ways of countering age-related physiological declines by preventing or reversing damage to heterochromatin.

“Our findings show that the gene mutation that causes Werner syndrome results in the disorganization of heterochromatin, and that this disruption of normal DNA packaging is a key driver of aging,” says Juan Carlos Izpisua Belmonte, a senior author on the paper. “This has implications beyond Werner syndrome, as it identifies a central mechanism of aging–heterochromatin disorganization–which has been shown to be reversible.”

Werner syndrome is a genetic disorder that causes people to age more rapidly than normal. It affects around one in every 200,000 people in the United States. People with the disorder suffer age-related diseases early in life, including cataracts, type 2 diabetes, hardening of the arteries, osteoporosis and cancer, and most die in their late 40s or early 50s.

The disease is caused by a mutation to the Werner syndrome RecQ helicase-like gene, known as the WRN gene for short, which generates the WRN protein. Previous studies showed that the normal form of the protein is an enzyme that maintains the structure and integrity of a person’s DNA. When the protein is mutated in Werner syndrome it disrupts the replication and repair of DNA and the expression of genes, which was thought to cause premature aging. However, it was unclear exactly how the mutated WRN protein disrupted these critical cellular processes.

In their study, the Salk scientists sought to determine precisely how the mutated WRN protein causes so much cellular mayhem. To do this, they created a cellular model of Werner syndrome by using a cutting-edge gene-editing technology to delete WRN gene in human stem cells. This stem cell model of the disease gave the scientists the unprecedented ability to study rapidly aging cells in the laboratory. The resulting cells mimicked the genetic mutation seen in actual Werner syndrome patients, so the cells began to age more rapidly than normal. On closer examination, the scientists found that the deletion of the WRN gene also led to disruptions to the structure of heterochromatin, the tightly packed DNA found in a cell’s nucleus.

This bundling of DNA acts as a switchboard for controlling genes’ activity and directs a cell’s complex molecular machinery. On the outside of the heterochromatin bundles are chemical markers, known as epigenetic tags, which control the structure of the heterochromatin. For instance, alterations to these chemical switches can change the architecture of the heterochromatin, causing genes to be expressed or silenced.

The Salk researchers discovered that deletion of the WRN gene leads to heterochromatin disorganization, pointing to an important role for the WRN protein in maintaining heterochromatin. And, indeed, in further experiments, they showed that the protein interacts directly with molecular structures known to stabilize heterochromatin–revealing a kind of smoking gun that, for the first time, directly links mutated WRN protein to heterochromatin destabilization.

“Our study connects the dots between Werner syndrome and heterochromatin disorganization, outlining a molecular mechanism by which a genetic mutation leads to a general disruption of cellular processes by disrupting epigenetic regulation,” says Izpisua Belmonte. “More broadly, it suggests that accumulated alterations in the structure of heterochromatin may be a major underlying cause of cellular aging. This begs the question of whether we can reverse these alterations–like remodeling an old house or car–to prevent, or even reverse, age-related declines and diseases.”

Izpisua Belmonte added that more extensive studies will be needed to fully understand the role of heterochromatin disorganization in aging, including how it interacts with other cellular processes implicated in aging, such as shortening of the end of chromosomes, known as telomeres. In addition, the Izpisua Belmonte team is developing epigenetic editing technologies to reverse epigenetic alterations with a role in human aging and disease.

 

Source:  sciencedaily.com

Scientists Grow Human Brain

Scientists Grow Human Brain From Stem Cells:

Scientists Grow Human Brain From Stem Cells

Scientists Grow Human Brain From Stem Cells

Ear, eye, liver, windpipe, bladder and even a heart. The list of body parts grown from stem cells is getting longer and longer. Now add to it one of the most complex organs: the brain.

A team of European scientists has grown parts of a human brain in tissue culture from stem cells. Their work could help scientists understand the origins of schizophrenia or autism and lead to drugs to treat them, said Juergen Knoblich, deputy scientific director at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences and one of the paper’s co-authors.

The advance could also eliminate the need for conducting experiments on animals, whose brains are not a perfect model for humans.

To grow the brain structures, called organoids, the scientists used stem cells, which can develop into any other kind of cell in the body. They put the stem cells into a special solution designed to promote the growth of neural cells. Bits of gel interspersed throughout the solution gave the cells a three-dimensional structure to grow upon. In eight to 10 days, the stem cells turned into brain cells. After 20 days to a month, the cells matured into a size between three and four millimeters, representing specific brain regions such as the cortex and the hindbrain.

Growing brain tissue this way marks a major advancement because the lab-grown brain cells self-organized and took on growth patterns seen in a developing, fetal brain.

Currently, the organoids are limited on how big they can get because they do not have a circulatory system to move around nutrients.

Knoblich’s team didn’t stop at growing the brain organoids, though. They went a step further and used the developing tissue to study microcephaly, a condition in which the brain stops growing. Microcephalic patients are born with smaller brains and impaired cognitive development. Studying microcephaly in mice doesn’t help because human and mouse brains are too different.

For this part of the study, the researchers used stem cells from a microcephalic patient and grew neurons in a culture. They found that normal brains have progenitor stem cells that make neurons and can do so repeatedly. In microcephalic brains, the progenitor cells differentiate into neurons earlier, said Madeline A. Lancaster, the study’s lead author. The brain doesn’t make as many neurons and a child is born with a much smaller brain volume.

Yoshiki Sasai, a stem-cell biologist at the Riken Center for Developmental Biology in Kobe, Japan, garnered headlines last year by growing the precursors to a human eye.

“The most important advancement is that they combined this self-organization culture with disease-specific cells to model a genetic disease of human brain malformation,” he said.

“Everything we have done with other organs starts with this stage,” said Dr. Anthony Atala, the director of the Wake Forest Institute for Regenerative Medicine, who has done years of research on using 3D printers to build organs. Atala was not involved in this study, but he noted that before he could build organs, he needed to grow the pieces in order to get the cells to differentiate in just the right way. So though it’s unlikely anyone will print brains the way he did a kidney, this kind of experiment is where organ regeneration starts.

Knoblich said the next step is studying other brain disorders, but it will take some time to grow enough brain tissue. One factor is maximum size and how far the brain can develop in the culture. Brain cells develop in layers, and there are several by the time a baby is born. The cortical cells Knoblich’s team grew only had one such layer. Another factor is getting blood vessels inside the tissue. That problem could be solved some time in the future, though he said he couldn’t predict when.

It is tempting to think one day there will be whole brains in vats, but that isn’t likely to happen.

“Aside from the severe ethical problem, I do not think this will be possible,” Knoblich said. To form actual functioning neural circuits, a brain needs sensory input. “Without any sensory input, the proper organization may not happen.”