It is something of an eternal question: Can we slow or even reverse the aging process? Even though genetic manipulations can, in fact, alter some cellular dynamics, little is known about the mechanisms of the aging process in living organisms.

Now scientists from the Florida campus of The Scripps Research Institute (TSRI) have found in animal models that a single gene plays a surprising role in aging that can be detected early on in development, a discovery that could point toward the possibility of one day using therapeutics, even some commonly used ones, to manipulate the aging process itself.

“We believe that a previously uncharacterized developmental gene known as Spns1 may mediate the aging process,” said Shuji Kishi, a TSRI assistant professor who led the study.

Using various genetic approaches to disturb Spns1 during the embryonic and/or larval stages of zebrafish—which have emerged as a powerful system to study diseases associated with development and aging—the scientists were able to produce some models with a shortened life span, others that lived long lives.

While most studies of “senescence”—declines in a cell’s power of division and growth—have focused on later stages of life, the study is intriguing in exploring this phenomenon in early stages. “Mutations to Spns1 both disturbs developmental senescence and badly affects the long-term bio-chronological aging process,” Kishi said.

The new study shows that Spns1, in conjunction with another pair of tumour suppressor genes, beclin 1 and p53 can, influences developmental senescence through two differential mechanisms: the Spns1 defect was enhanced by Beclin 1 but suppressed by ‘basal’ p53. In addition to affecting senescence, Spns1 impedes autophagy, the process whereby cells remove unwanted or destructive proteins and balance energy needs during various life stages.

Building on their insights from the study, Kishi and his colleagues noted in the future therapeutics might be able influence aging through Spns1. He noted one commonly used antacid, Prilosec, has been shown to temporarily suppress autophagic abnormality and senescence observed in the Spns1 deficiency.

Scientists at the Salk Institute for Biological Studies have identified a gene that regulates sleep and wake rhythms.

The discovery of the role of this gene, called Lhx1, provides scientists with a potential therapeutic target to help night-shift workers or jet lagged travellers adjust to time differences more quickly. The results can point to treatment strategies for sleep problems caused by a variety of disorders.

“It’s possible that the severity of many dementias comes from sleep disturbances,” says Satchidananda Panda, a Salk associate professor who led the research team. “If we can restore normal sleep, we can address half of the problem.”

Every cell in the body has a “clock” – an abundance of proteins that dip or rise rhythmically over approximately 24 hours. The master clock responsible for establishing these cyclic circadian rhythms and keeping all the body’s cells in sync is the suprachiasmatic nucleus (SCN), a small, densely packed region of about 20,000 neurons housed in the brain’s hypothalamus.

More so than in other areas of the brain, the SCN’s neurons are in close and constant communication with one another. This close interaction, combined with exposure to light and darkness through vision circuits, keeps this master clock in sync and allows people to stay on essentially the same schedule every day. The tight coupling of these cells also helps make them collectively resistant to change. Exposure to light resets less than half of the SCN cells, resulting in long periods of jet lag.

In the new study, researchers disrupted the light-dark cycles in mice and compared changes in the expression of thousands of genes in the SCN with other mouse tissues. They identified 213 gene expression changes that were unique to the SCN and narrowed in on 13 of these that coded for molecules that turn on and off other genes. Of those, only one was suppressed in response to light: Lhx1.

“No one had ever imagined that Lhx1 might be so intricately involved in SCN function,” says Shubhroz Gill, a postdoctoral researcher and co-first author of the paper. Lhx1 is known for its role in neural development: it’s so important, that mice without the gene do not survive. But this is the first time it has been identified as a master regulator of light-dark cycle genes.

By recording electrical activity in the SCN of animals with reduced amounts of the Lhx1 protein, the researchers saw that the SCN neurons weren’t in sync with one another, despite appearing rhythmic individually.

“It was all about communication–the neurons were not talking to each other without this molecule,” says Ludovic Mure, a postdoctoral researcher and an author on the paper. A next step in the work will be to understand exactly how Lhx1 affects the expression of genes that creates this synchronicity.

Studying a mouse version of jet lag–an 8-hour shift in their day-night cycle–the scientists found that those with little or no Lhx1 readjusted much faster to the shift than normal mice. This suggests that because these neurons are less in sync with one another, they are more easily able to shift to a new schedule, though it is difficult for them to maintain that schedule, Panda says.

These mice also exhibited reduced activity of certain genes, including one that creates vasoactive intestinal peptide or Vip, a molecule that has important roles in development and as a hormone in the intestine and blood. In the brain, Vip affects cell communication, but nobody had known that Lhx1 regulated it until now, Panda says. Interestingly, the team also found that adding Vip restored cell synchrony in the SCN.

“This approach helped us to close that knowledge gap and show that Vip is a very important protein, at least for SCN,” Panda says. “It can compensate for the loss of Lhx1.”

On the other hand, cutting back on Vip could be another way to treat jet lag. Vip could be an even easier drug target compared with Lhx1 because Vip is secreted from cells rather than inside cells, Panda says. “If we find a drug that will block the Vip receptor or somehow break down Vip, then maybe that will help us reset the clock much faster,” he adds. Salk Institute for Biological Studies

Autopsies have revealed that some individuals develop the cellular changes indicative of Alzheimer’s disease without ever showing clinical symptoms in their lifetime.
Vanderbilt University Medical Center memory researchers have discovered a potential genetic variant in these asymptomatic individuals that may make brains more resilient against Alzheimer’s.
‘Most Alzheimer’s research is searching for genes that predict the disease, but we’re taking a different approach. We’re looking for genes that predict who among those with Alzheimer’s pathology will actually show clinical symptoms of the disease,’ said principal investigator Timothy Hohman, Ph.D., a post-doctoral research fellow in the Center for Human Genetics Research and the Vanderbilt Memory and Alzheimer’s Center.
The researchers used a marker of Alzheimer’s disease found in cerebrospinal fluid called phosphorylated tau. In brain cells, tau is a protein that stabilises the highways of cellular transport in neurons. In Alzheimer’s disease tau forms ‘tangles’ that disrupt cellular messages.
Analysing a sample of 700 subjects from the Alzheimer’s Disease Neuroimaging Initiative, Hohman and colleagues looked for genetic variants that modify the relationship between phosphorylated tau and lateral ventricle dilation — a measure of disease progression visible with magnetic resonance imaging (MRI). One genetic mutation (rs4728029) was found to relate to both ventricle dilation and cognition and is a marker of neuroinflammation.
‘This gene marker appears to be related to an inflammatory response in the presence of phosphorylated tau,’ Hohman said.
‘It appears that certain individuals with a genetic predisposition toward a ‘bad’ neuroinflammatory response have neurodegeneration. But those with a genetic predisposition toward no inflammatory response, or a reduced one, are able to endure the pathology without marked neurodegeneration.’
Hohman hopes to expand the study to include a larger sample and investigate gene and protein expression using data from a large autopsy study of Alzheimer’s disease.
‘The work highlights the possible mechanism behind asymptomatic Alzheimer’s disease, and with that mechanism we may be able to approach intervention from a new perspective. Future interventions may be able to activate these innate response systems that protect against developing Alzheimer’s symptoms,’ Hohman said. EurekAlert

A study led by Yale Cancer Center may provide clues to how some aggressive cancers turn off, or silence, genes critical to suppressing tumours. The findings suggest that this gene silencing process could be interrupted to increase the chances that aggressive tumours will respond to treatment.

As cancer develops, it often outstrips its blood supply and receives less oxygen than normal tissue. This low-oxygen environment, called hypoxia, is associated with aggressive tumours of all types that are more likely to progress despite chemotherapy and radiation therapy.

The study, which used colon cancer tissue, found that hypoxia also triggers the silencing of a critical tumour-suppressing gene called MLH1.

The team also identified an enzyme, LSD1 (lysine specific demethylase), associated with MLH1 that could be a target to reverse or block the silencing process. Since LSDI is an enzyme, it is possible to target it with small molecules to inhibit its activity.

“We’ve long known that hypoxic tumours are associated with worse prognoses, but the idea that hypoxic tumours could silence genes was an unexpected finding,” said senior author Dr. Peter M. Glazer, the Robert H. Hunter Professor and chair of therapeutic radiology, and professor of genetics at Yale School of Medicine. “Now that we know how big a role hypoxia plays, we have a new and clinically-relevant path to explore in terms of circumventing this process. The next step is to determine how hypoxia affects other tumor-suppressing genes.” Yale School of Medicine

Newly developed test can identify sickle cell disease in minutes and could be used in rural clinics around the globe
Within minutes after birth, every child in the U.S. undergoes a battery of tests designed to diagnose a host of conditions, including sickle cell disease. Thousands of children born in the developing world, however, aren’t so lucky, meaning many suffer and die from the disease each year.

A.J. Kumar hopes to put a halt to at least some of those deaths.

A Post-Doctoral Fellow in Chemistry and Chemical Biology working in the lab of George Whitesides, the Woodford L. and Ann A. Flowers University Professor, Kumar and colleagues, including other co-authors, have developed a new test for sickle cell disease that provides results in just 12 minutes and costs as little as 50 cents – far faster and cheaper than other tests.

‘The tests we have today work great, they have a very high sensitivity,’ Kumar said. ‘But the equipment needed to run them costs in the tens of thousands of dollars, and they take hours to run. That’s not amenable to rural clinics, or even some cities where the medical infrastructure isn’t up to the standards we see in the U.S. That’s where having a rapid, low-cost test becomes important and this paper shows such a test can potentially work.’

When run against more than 50 clinical samples – 26 positive and 26 negative – the new test showed good sensitivity and specificity for the disease, Kumar said, so the early evidence is promising, but additional testing will be needed to determine whether the test is truly accurate enough to use in the field.

The test designed by Kumar is deceptively simple, and works by connecting two ideas scientists have understood for decades.

The first is the notion that blood cells affected by the disease are denser than normal cells, and the second is that many polymers, when mixed in water, automatically separate into layers ordered by density.

Conventional methods to separate cells by density relied on layering liquids with different density by hand. The insight, arrived at by Charles Mace (now at Tufts) and Kumar, was that the self-forming layers could be used to separate cells, such as red blood cells, by density.

‘When you mix the polymers with water, they separate just like oil and water,’ he said. ‘Even if you mix it up, it will still come back to those layers.’

It wasn’t until a chance meeting with Dr. Thomas Stossel, however, that Kumar believed the technology might have a real impact on sickle cell disease.

‘Initially, we started off working on malaria, because we thought when parasites invaded the cells, it would change their density,’ he said. ‘But when I met Tom Stossel on a panel at the Harvard Medical School, he said, ‘You need to work on sickle cell.’ He’s a haematologist by training and has been working with a non-profit in Zambia for the past decade, so he’s seen the need and the lack of a diagnostic tool.’

When Kumar and colleagues ran tests with infected blood, their results were unmistakable. While healthy red blood cells settled in the tubes at specific levels, the dense cells from blood infected with sickle cell settled in a band significantly lower. The band of red cells could clearly be seen by eye.

Just showing that the test worked, however, wasn’t enough.

‘We wanted to make the test as simple as possible,’ Kumar explained. ‘The idea was to make it something you could run from just a finger prick. Because these gradients assemble on their own, that meant we could make them in whatever volume we wanted, even a small capillary tube.’

The design the team eventually settled on is barely larger than a toothpick. In the field, Kumar said, running the test is as simple as uncapping the tube, pricking a patient’s finger and allowing the blood to wick into the tube.

While further study is needed to determine how accurate and effective the test may be, Kumar said stopping even a few sickle-cell-related deaths would EurekAlert