Aging ⯀  

Researchers have found that stem cells in the brain’s hypothalamus govern how fast aging occurs in the body. The finding, made in mice, could lead to new strategies for warding off age-related diseases and extending lifespan. 

In the brain, the hypothalamus is known to regulate important processes including growth, development, reproduction and metabolism. In a 2013 Nature paper, scientists made the surprising finding that the hypothalamus also regulates aging throughout the body.

Now, the researchers at the Albert Einstein College of Medicine have precisely identified the cells in the hypothalamus that control aging: a tiny population of adult neural stem cells, which were known to be responsible for forming new brain neurons.

The team's work has been published in the journal Nature.

"Our research shows that the number of hypothalamic neural stem cells naturally declines over the life of the animal, and this decline accelerates aging."

"Our research shows that the number of hypothalamic neural stem cells naturally declines over the life of the animal, and this decline accelerates aging," says senior author Dongsheng Cai, M.D., Ph.D., professor of molecular pharmacology at the school. "But we also found that the effects of this loss are not irreversible. By replenishing these stem cells or the molecules they produce, it’s possible to slow and even reverse various aspects of aging throughout the body."

The researchers first looked at the fate of those cells as healthy mice got older to see if stem cells in the hypothalamus held the key to aging. The number of hypothalamic stem cells began to diminish when the animals reached about 10 months, which is several months before the usual signs of aging start appearing. "By old age—about two years of age in mice—most of those cells were gone," says Dr. Cai.

Next, the researchers wanted to learn whether this progressive loss of stem cells was actually causing aging and was not just associated with it. They observed what happened when they selectively disrupted the hypothalamic stem cells in middle-aged mice. "This disruption greatly accelerated aging compared with control mice, and those animals with disrupted stem cells died earlier than normal," says Dr. Cai.

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The team hypothesized that adding stem cells to the hypothalamus could counteract aging. To test that experiment, the researchers injected hypothalamic stem cells into the brains of middle-aged mice whose stem cells had been destroyed as well as into the brains of normal old mice. In both groups of animals, the treatment slowed or reversed various measures of aging.

Dr. Cai and his colleagues found that the hypothalamic stem cells appear to exert their anti-aging effects by releasing molecules called microRNAs (miRNAs). They are not involved in protein synthesis but instead play key roles in regulating gene expression. miRNAs are packaged inside tiny particles called exosomes, which hypothalamic stem cells release into the cerebrospinal fluid of mice.

The researchers extracted miRNA-containing exosomes from hypothalamic stem cells and injected them into the cerebrospinal fluid of two groups of mice: middle-aged mice whose hypothalamic stem cells had been destroyed and normal middle-aged mice.

This treatment significantly slowed aging in both groups of animals as measured by tissue analysis and behavioral testing that involved assessing changes in the animals’ muscle endurance, coordination, social behavior and cognitive ability.

Dr. Cai and his team are now trying to identify the particular populations of microRNAs and perhaps other factors secreted by these stem cells that are responsible for these anti-aging effects—a first step toward possibly slowing the aging process and treating age-related diseases.

SOURCE  Albert Einstein College of Medicine

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 Neuroscience  

Researchers have announced they are now able to 'film' a brain as it forms memories. The feat was accomplished by using mRNA molecules, which are crucial to forming memories, fluorescent "tags", so they could be watched more easily.

In two studies in the January 24 issue of Science, researchers at Albert Einstein College of Medicine of Yeshiva University used advanced imaging techniques to provide a window into how the brain makes memories.

These insights into the molecular basis of memory were made possible by a technological tour de force never before achieved in animals: a mouse model developed at Einstein in which molecules crucial to making memories were given fluorescent "tags" so they could be observed traveling in real time in living brain cells.

The research has been published in two articles, "Visualization of Dynamics of Single Endogenous mRNA as Labeled in Live Mouse," and "Single Beta-actin mRNA Detection in Neurons Reveals a Mechanism for Regulating Its Translatability," in the journal Science.

Efforts to discover how neurons make memories have long confronted a major roadblock: Neurons are extremely sensitive to any kind of disruption, yet only by probing their innermost workings can scientists view the molecular processes that culminate in memories. To peer deep into neurons without harming them, Einstein researchers developed a mouse model in which they fluorescently tagged all molecules of messenger RNA (mRNA) that code for beta-actin protein – an essential structural protein found in large amounts in brain neurons and considered a key player in making memories. mRNA is a family of RNA molecules that copy DNA's genetic information and translate it into the proteins that make life possible.

Robert Singer, Ph.D. Image Source: Albert Einstein College of Medicine

Robert Singer, Ph.D., is the senior author of both papers and professor and co-chair of Einstein's department of anatomy & structural biology and co-director of the Gruss Lipper Biophotonics Center at Einstein.

In the research described in the two Science papers, the Einstein researchers stimulated neurons from the mouse's hippocampus, where memories are made and stored, and then watched fluorescently glowing beta-actin mRNA molecules form in the nuclei of neurons and travel within dendrites, the neuron's branched projections. They discovered that mRNA in neurons is regulated through a novel process described as "masking" and "unmasking," which allows beta-actin protein to be synthesized at specific times and places and in specific amounts.

Singer states, "we know the beta-actin mRNA we observed in these two papers was ‘normal' RNA, transcribed from the mouse's naturally occurring beta-actin gene and attaching green fluorescent protein to mRNA molecules did not affect the mice, which were healthy and able to reproduce."

Neurons come together at synapses, where slender dendritic "spines" of neurons grasp each other, much as the fingers of one hand bind those of the other. Evidence indicates that repeated neural stimulation increases the strength of synaptic connections by changing the shape of these interlocking dendrite "fingers." Beta-actin protein appears to strengthen these synaptic connections by altering the shape of dendritic spines.

Memories are thought to be encoded when stable, long-lasting synaptic connections form between neurons in contact with each other.

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The first paper describes the work of Hye Yoon Park, Ph.D., a postdoctoral student in Dr. Singer's lab. Her research was instrumental in developing the mice containing fluorescent beta-actin mRNA—a process that took about three years.

Dr. Park stimulated individual hippocampal neurons of the mouse and observed newly formed beta-actin mRNA molecules within 10 to 15 minutes, indicating that nerve stimulation had caused rapid transcription of the beta-actin gene. Further observations suggested that these beta-actin mRNA molecules continuously assemble and disassemble into large and small particles, respectively. These mRNA particles were seen traveling to their destinations in dendrites where beta-actin protein would be synthesized.

In the second paper, lead author and graduate student Adina Buxbaum of Dr. Singer's lab showed that neurons may be unique among cells in how they control the synthesis of beta-actin protein.

These findings suggest that neurons have developed an ingenious strategy for controlling how memory-making proteins do their job. "This observation that neurons selectively activate protein synthesis and then shut it off fits perfectly with how we think memories are made," said Dr. Singer. "Frequent stimulation of the neuron would make mRNA available in frequent, controlled bursts, causing beta-actin protein to accumulate precisely where it's needed to strengthen the synapse."

To gain further insight into memory's molecular basis, the Singer lab is developing technologies for imaging neurons in the intact brains of living mice. Since the hippocampus resides deep in the brain, they hope to develop infrared fluorescent proteins that emit light that can pass through tissue. Another possibility is a fiberoptic device that can be inserted into the brain to observe memory-making hippocampal neurons.




SOURCE  Albert Einstein College of Medicine

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