Posts Tagged ‘aging’


Illustration of how pH imbalance inside endosomes may contribute to Alzheimer’s disease

Johns Hopkins Medicine scientists say they have found new evidence in lab-grown mouse brain cells, called astrocytes, that one root of Alzheimer’s disease may be a simple imbalance in acid-alkaline—or pH—chemistry inside endosomes, the nutrient and chemical cargo shuttles in cells.

Astrocytes work to clear so-called amyloid beta proteins from the spaces between neurons, but decades of evidence has shown that if the clearing process goes awry, amyloid proteins pile up around neurons, leading to the characteristic amyloid plaques and nerve cell degeneration that are the hallmarks of memory-destroying Alzheimer’s disease.

The new study, described online June 26 in Proceedings of the National Academy of Sciences, also reports that the scientists gave drugs called histone deacetylase (HDAC) inhibitors to pH-imbalanced mice cells engineered with a common Alzheimer’s gene variant. The experiment successfully reversed the pH problem and improved the capacity for amyloid beta clearance.

HDAC inhibitors are approved by the U.S. Food and Drug Administration for use in people with certain types of blood cancers, but not in people with Alzheimer’s. They cautioned that most HDAC inhibitors cannot cross the blood-brain barrier, a significant challenge to the direct use of the drugs for brain disorders. The scientists say they are planning additional experiments to see if HDAC inhibitors have a similar effect in lab-grown astrocytes from Alzheimer’s patients, and that there is the potential to design HDAC inhibitors that can cross the barrier.

However, the scientists caution that even before those experiments can happen, far more research is needed to verify and explain the precise relationship between amyloid proteins and Alzheimer’s disease, which affects an estimated 50 million people worldwide. To date, there is no cure and no drugs that can predictably or demonstrably prevent or reverse Alzheimer’s disease symptoms.

“By the time Alzheimer’s disease is diagnosed, most of the neurological damage is done, and it’s likely too late to reverse the disease’s progression,” says Rajini Rao, Ph.D., professor of physiology at the Johns Hopkins University School of Medicine. “That’s why we need to focus on the earliest pathological symptoms or markers of Alzheimer’s disease, and we know that the biology and chemistry of endosomes is an important factor long before cognitive decline sets in.”

Nearly 20 years ago, scientists at Johns Hopkins and New York University discovered that endosomes, circular compartments that ferry cargo within cells, are larger and far more abundant in brain cells of people destined to develop Alzheimer’s disease. This hinted at an underlying problem with endosomes that could lead to an accumulation of amyloid protein in spaces around neurons, says Rao.

To shuttle their cargo from place to place, endosomes use chaperones—proteins that bind to specific cargo and bring them back and forth from the cell’s surface. Whether and how well this binding occurs depends on the proper pH level inside the endosome, a delicate balance of acidity and alkalinity, or acid and base, that makes endosomes float to the surface and slip back down into the cell.

Embedded in the endosome membrane are proteins that shuttle charged hydrogen atoms, known as protons, in and out of endosomes. The amount of protons inside the endosome determines its pH.

When fluids in the endosome become too acidic, the cargo is trapped within the endosome deep inside the cell. When the endosome contents are more alkaline, the cargo lingers at the cell’s surface for too long.

To help determine whether such pH imbalances occur in Alzheimer’s disease, Johns Hopkins graduate student Hari Prasad scoured scientific studies of Alzheimer’s disease looking for genes that were dialed down in diseased brains compared with normal ones. Comparing a dataset of 15 brains of Alzheimer’s disease patients with 12 normal ones, he found that 10 of the 100 most frequently down-regulated genes were related to the proton flow in the cell.

In another set of brain tissue samples from 96 people with Alzheimer’s disease and 82 without it, gene expression of the proton shuttle in endosomes, known as NHE6, was approximately 50 percent lower in people with Alzheimer’s disease compared with those with normal brains. In cells grown from people with Alzheimer’s disease and in mouse astrocytes engineered to carry a human Alzheimer’s disease gene variant, the amount of NHE6 was about half the amount found in normal cells.

To measure the pH balance within endosomes without breaking open the astrocyte, Prasad and Rao used pH sensitive probes that are absorbed by endosomes and emit light based on pH levels. They found that mouse cell lines containing the Alzheimer’s disease gene variant had more acidic endosomes (average of 5.37 pH) than cell lines without the gene variant (average of 6.21 pH).

“Without properly functioning NHE6, endosomes become too acidic and linger inside astrocytes, avoiding their duties to clear amyloid beta proteins,” says Rao.

While it’s likely that changes in NHE6 happen over time in people who develop sporadic Alzheimer’s disease, people who have inherited mutations in NHE6 develop what’s known as Christianson syndrome in infancy and have rapid brain degeneration.

Prasad and Rao also found that a protein called LRP1, which picks up amyloid beta proteins outside the astrocyte and delivers them to endosomes, was half as abundant on the surface of lab grown mouse astrocytes engineered with a human gene variant called APOE4, commonly linked to Alzheimer’s disease.

Looking for ways to restore the function of NHE6, Prasad searched databases of yeast studies to find that HDAC inhibitors tend to increase expression of the NHE6 gene in yeast. This gene is very similar across species, including flies, mice and humans.

Prasad and Rao tested nine types of HDAC inhibitors on cell cultures of mouse astrocytes engineered with the APOE4 gene variant. Broad-spectrum HDAC inhibitors increased NHE6 expression to levels associated with mouse astrocytes that did not have the Alzheimer’s gene variant. They also found that HDAC inhibitors corrected the pH imbalance inside endosomes and restored LRP1 to the astrocyte surface, resulting in efficient clearance of amyloid beta protein.

More information: Hari Prasad et al. Amyloid clearance defect in ApoE4 astrocytes is reversed by epigenetic correction of endosomal pH, Proceedings of the National Academy of Sciences (2018). DOI: 10.1073/pnas.1801612115

https://medicalxpress.com/news/2018-08-ph-imbalance-brain-cells-contribute.html

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by SUKANYA CHARUCHANDRA

Even when Parkinson’s patients don’t have mutations in a gene called LRRK2, more of the active enzyme the gene generates is present in their brains than in healthy brains, researchers reported last week (July 25) in Science Translational Medicine. The finding suggests that LRRK2 inhibitors could help to reduce harmful effects of the enzyme in the vast majority of Parkinson’s patients.

“This is the really interesting bit of data … the demonstration that when you look in the brains of individuals with idiopathic Parkinson’s [where the cause is unknown], that there’s evidence that LRRK2 is activated,” says Patrick Lewis, who studies Parkinson’s disease at University College London and the University of Reading in the UK. He has collaborated with one of the paper’s coauthors but was not involved in this study.

Ten percent of Parkinson’s cases have known genetic causes. Three percent of cases are due to a mutation in LRRK2, the gene encoding the LRRK2 enzyme. The enzyme is highly active in Parkinson’s patients with a mutated LRRK2 gene, and the increased enzyme activity has been linked to the development of the disease.

In the new study, Timothy Greenamyre, a professor of neurology at the University of Pittsburgh, and his team wanted to look at the level of active LRRK2 in patients without an LRRK2 mutation. “Because [LRRK2] is a low-abundance protein, people have had difficulty detecting it,” Greenamyre says. To spot active LRRK2, the researchers first developed two versions of an assay: the first detects the active enzyme and the second, the inactive enzyme. In the first detection method, researchers used two different antibodies, one that binds to a specific subunit that acts as a known indicator of the active enzyme and another that binds to a different proximal portion of it. When both antibodies bind successfully, their close contact generates a fluorescent signal—a sign of active LRRK2. The second method detects a protein known to regulate LRRK2 activity. Higher levels of this protein indicate lower levels of available active LRRK2.

The team used the assay on postmortem brain tissue from Parkinson’s disease patients and from healthy individuals. The researchers observed higher levels of the active LRRK2 enzyme in substantia nigra dopamine-producing neurons—the death of which indicate neurodegenerative disease—in the brain tissue of Parkinson’s patients’ with no mutation in the LRRK2 gene than in healthy brain tissue.

“We have been wondering for a very long time whether LRRK2 plays a role in sporadic Parkinson’s disease,” says Mark Cookson, who studies the neurodegenerative disorder in the National Institutes of Health’s Laboratory of Neurogenetics. He has collaborated with Greenamyre before but was not involved in this work. According to Cookson, this study provides “defensive evidence” of LRRK2’s role in the disease, even in patients without a mutation in the gene.

In the next set of experiments, Greenamyre and his colleagues wanted to see if active LRRK2 turned up in two rat models of Parkinson’s disease. In the first rodent model, the animals were given the toxin rotenone to induce symptoms of the disease. Even without a mutation in the LRRK2 gene, the rats had higher levels of active LRRK2 protein. In the rats’ brains, the active LRRK2 enzymes were linked with clumps of another protein, α-synuclein. The clumps eventually help form Lewy bodies, a characteristic feature of Parkinson’s brains. In the second rodent model, the researchers overexpressed wildtype α-synuclein in the rats’ substantia nigra, which caused levels of active LRRK2 to rise. When the group treated the rotenone-rodent model with a drug that inhibited the LRRK2 protein, the number of clumps and Lewy bodies dropped.

The team also observed higher levels of reactive oxygen species (ROS)—chemically responsive molecules such as peroxides—in the brains of both rat models of Parkinson’s disease. As a result, Greenamyre and his colleagues wanted to see if directly increasing ROS led to more active LRRK2. In a third set of experiments, the team dosed healthy human cell lines with hydrogen peroxide and found the addition of the ROS increased the levels of LRRK2. A spike in ROS levels, the researchers suggest, activates LRRK2, which in turn aids in the development of some classic Parkinson’s features. Blocking the production of ROS resulted in a drop in active LRRK2. The result gives clues to an environmental cause for Parkinson’s disease.

Pharmaceutical companies are already developing LRRK2 inhibitors that can help the small percentage of Parkinson’s patients that have a mutation in the LRRK2 gene. “The inhibitors may benefit patients not only with the mutation but also patients who have idiopathic diseases—they’re much more common,” says coauthor Dario Alessi, a professor who studies signaling pathways in neurodegenerative disorders at the University of Dundee in the UK.

LRRK2 inhibitors, the researchers note, cause mild, yet reversible side effects, in the lungs and kidneys.

R.D. Maio et al., “LRRK2 activation in idiopathic Parkinson’s disease,” Science Translational Medicine, doi:10.1126/scitranslmed.aar5429, 2018.

https://www.the-scientist.com/news-opinion/key-enzyme-active-in-brains-of-patients-without-parkinsons-mutation-64599

by Bob Yirka

A team of researchers from several institutions in Iceland and the U.S. has conducted a unique blood serum investigation and discovered multiple protein networks that are involved in the aging process. In their paper published in the journal Science, the group describes their study and what they found.

Prior research has shown that when older mice have their blood systems connected to younger mice, the older mice experience improvements in age-related organ deterioration. This finding has led scientists to suspect that aging might be caused by something in the blood. In this new effort, the researchers sought to test this idea by studying proteins in the circulatory system.

The study consisted of analyzing blood samples from 5,457 people living in Iceland, all of whom were over the age of 65 and who were participants in an ongoing study called Age, Gene/Environment Susceptibility. The volunteers had also been chosen specifically to represent a cross section of the people living in Iceland. The major part of the blood analysis involved creating a panel of DNA aptamers (short sequences that bind to proteins) that could be used to recognize proteins, both known and unknown. Blood serum from the volunteers was then compared against the panels and the results were analyzed by a computer looking for patterns.

The researchers report that they discovered 27 networks that showed evidence of coordinated pattern expression. These networks, or modules, as the researchers call them, were different from one another in size and form and were made of proteins from both tissue and organs. They also report that many of the modules had expression patterns that have in the past been associated with age-related diseases such as heart disease and metabolic syndrome—and there were some that were also associated with mortality in the years after the samples were taken from the volunteers. The group suggests their findings offer more evidence of the role blood serum plays in the aging process.

The researchers report that they also looked for the means by which the networks they discovered are regulated and found that approximately 60 percent of mechanisms involved are unknown.

More information: Valur Emilsson et al. Co-regulatory networks of human serum proteins link genetics to disease, Science (2018). DOI: 10.1126/science.aaq1327

https://m.medicalxpress.com/news/2018-08-blood-serum-reveals-networks-proteins.html

by Elie Dolgin

There might be no natural limit to how long humans can live — at least not one yet in sight — contrary to the claims of some demographers and biologists.

That’s according to a statistical analysis published Thursday in Science1 on the survival probabilities of nearly 4,000 ‘super-elderly’ people in Italy, all aged 105 and older.

A team led by Sapienza University demographer Elisabetta Barbi and University of Roma Tre statistician Francesco Lagona, both based in Rome, found that the risk of death — which, throughout most of life, seems to increase as people age — levels off after age 105, creating a ‘mortality plateau’. At that point, the researchers say, the odds of someone dying from one birthday to the next are roughly 50:50 (see ‘Longevity unlimited’).

“If there is a mortality plateau, then there is no limit to human longevity,” says Jean-Marie Robine, a demographer at the French Institute of Health and Medical Research in Montpellier, who was not involved in the study.

That would mean that someone like Chiyo Miyako, the Japanese great-great-great-grandmother who, at 117, is the world’s oldest known person, could live for years to come — or even forever, at least hypothetically.

Researchers have long debated whether humans have an upper age limit. The consensus holds that the risk of death steadily increases in adulthood, up to about age 80 or so. But there’s vehement disagreement about what happens as people enter their 90s and 100s.

Some scientists have examined demographic data and concluded that there is a fixed, natural ‘shelf-life’ for our species and that mortality rates keep increasing. Others have looked at the same data and concluded that the death risk flattens out in one’s ultra-golden years, and therefore that human lifespan does not have an upper threshold.

Age rage

In 2016, geneticist Jan Vijg and his colleagues at Albert Einstein College of Medicine in New York City rekindled the debate when they analysed the reported ages at death for the world’s oldest individuals over a half-century. They estimated that human longevity hit a ceiling at about 115 years — 125 tops.

Vijg and his team argued2 that with few, if any, gains in maximum lifespan since the mid-1990s, human ageing had reached its natural limit. The longest known lifespan belongs to Jeanne Calment, a French super-centenarian who died in 1997 at age 122.

Experts challenged the statistical methods in the 2016 study, setting off a firestorm into which now step Barbi and Lagona. Working with colleagues at the Italian National Institute of Statistics, the researchers collected records on every Italian aged 105 years and older between 2009 and 2015 — gathering certificates of death, birth and survival in an effort to minimize the chances of ‘age exaggeration’, a common problem among the oldest old.

They also tracked individual survival trajectories from one year to the next, rather than lump people into age intervals as previous studies that combine data sets have done. And by focusing just on Italy, which has one of the highest rates of centenarians per capita in the world, they avoided the issue of variation in data collection among different jurisdictions.

As such, says Kenneth Howse, a health-policy researcher at the Oxford Institute of Population Ageing in the United Kingdom, “these data provide the best evidence to date of extreme-age mortality plateaus in humans”.

Ken Wachter, a mathematical demographer at the University of California, Berkeley, and an author of the latest study, suspects that prior disputes over the patterns of late-life mortality have largely stemmed from bad records and statistics. “We have the advantage of better data,” he says. “If we can get data of this quality for other countries, I expect we’re going to see much the same pattern.”

Robine is not so sure. He says that unpublished data from France, Japan and Canada suggest that evidence for a mortality plateau is “not as clear cut”. A global analysis is still needed to determine whether the findings from Italy reflect a universal feature of human ageing, he says.

Off limits

The world is home to around 500,000 people aged 100 and up — a number that’s predicted to nearly double with each coming decade. Even if the risk of late-life mortality remains constant at 50:50, the swelling global membership in the 100-plus club should translate into a creep upwards in the oldest person alive by about one year per decade, says Joop de Beer, a longevity researcher at the Netherlands Interdisciplinary Demographic Institute in The Hague.

Many researchers say they hope to better understand what’s behind the levelling off of mortality rates in later life. Siegfried Hekimi, a geneticist at McGill University in Montreal, Canada, speculates that the body’s cells eventually reach a point where repair mechanisms can offset further damage to keep mortality rates level.

“Why this plateaus out and what it means about the process of ageing — I don’t think we have any idea,” Hekimi says.

For James Kirkland, a geriatrician at the Mayo Clinic in Rochester, Minnesota, the strong evidence for a mortality plateau points to the possibility of forestalling death at any age. Some experts think that the very frail are beyond repair. But if the odds of dying don’t increase over time, he says, interventions that slow ageing are likely to make a difference, even in the extremely old.

Not everyone buys that argument — or the conclusions of the latest paper.

Brandon Milholland, a co-author of the 2016 Nature paper, says that the evidence for a mortality plateau is “marginal”, as the study included fewer than 100 people who lived to 110 or beyond. Leonid Gavrilov, a longevity researcher at the University of Chicago in Illinois, notes that even small inaccuracies in the Italian longevity records could lead to a spurious conclusion.

Others say the conclusions of the study are biologically implausible. “You run into basic limitations imposed by body design,” says Jay Olshansky, a bio-demographer at the University of Illinois at Chicago, noting that cells that do not replicate, such as neurons, will continue to wither and die as a person ages, placing upper boundaries on humans’ natural lifespan.

This study is thus unlikely to be the last word on the age-limit dispute, says Haim Cohen, a molecular biologist at Bar-Ilan University in Ramat-Gan, Israel. “I’m sure that the debate is going to continue.”

Psychologists at the University of Sussex have found a link between depression and an acceleration of the rate at which the brain ages. Although scientists have previously reported that people with depression or anxiety have an increased risk of dementia in later life, this is the first study that provides comprehensive evidence for the effect of depression on decline in overall cognitive function (also referred to as cognitive state), in a general population.

For the study, published today, Thursday 24 May 2018, in the journal Psychological Medicine, researchers conducted a robust systematic review of 34 longitudinal studies, with the focus on the link between depression or anxiety and decline in cognitive function over time. Evidence from more than 71,000 participants was combined and reviewed. Including people who presented with symptoms of depression as well as those that were diagnosed as clinically depressed, the study looked at the rate of decline of overall cognitive state – encompassing memory loss, executive function (such as decision making) and information processing speed – in older adults.

Importantly, any studies of participants who were diagnosed with dementia at the start of study were excluded from the analysis. This was done in order to assess more broadly the impact of depression on cognitive ageing in the general population. The study found that people with depression experienced a greater decline in cognitive state in older adulthood than those without depression. As there is a long pre-clinical period of several decades before dementia may be diagnosed, the findings are important for early interventions as currently there is no cure for the disease.

Lead authors of the paper, Dr Darya Gaysina and Amber John from the EDGE (Environment, Development, Genetics and Epigenetics in Psychology and Psychiatry) Lab at the University of Sussex, are calling for greater awareness of the importance of supporting mental health to protect brain health in later life.

Dr Gaysina, a Lecturer in Psychology and EDGE Lab Lead, comments: “This study is of great importance – our populations are ageing at a rapid rate and the number of people living with decreasing cognitive abilities and dementia is expected to grow substantially over the next thirty years.

“Our findings should give the government even more reason to take mental health issues seriously and to ensure that health provisions are properly resourced. We need to protect the mental wellbeing of our older adults and to provide robust support services to those experiencing depression and anxiety in order to safeguard brain function in later life.”

Researcher Amber John, who carried out this research for her PhD at the University of Sussex adds: “Depression is a common mental health problem – each year, at least 1 in 5 people in the UK experience symptoms. But people living with depression shouldn’t despair – it’s not inevitable that you will see a greater decline in cognitive abilities and taking preventative measures such as exercising, practicing mindfulness and undertaking recommended therapeutic treatments, such as Cognitive Behaviour Therapy, have all been shown to be helpful in supporting wellbeing, which in turn may help to protect cognitive health in older age.”

The research paper, ‘Affective problems and decline in cognitive state in older adults’ will be available at: https:// doi.org/10.1017/S0033291718001137 from Thursday 24 May 2018.

http://www.sussex.ac.uk/broadcast/read/44977

by MELISSA BREYER

If there’s a single way of eating that persists in laying claim as one of the healthiest, it’s the Mediterranean diet. Experts continue to sing the praises of eating plenty of olive oil, plant foods, fish and wine.

The latest research — following several years of headline-making studies — makes it hard to argue with them.

Following a Mediterranean diet can protect against the harmful effects of air pollution, according to a 2018 study conducted by New York University. The study analyzed about 550,000 people for 17 years and factored in their level of exposure to pollution. Those who followed the Mediterranean diet compared to those who didn’t had a lower risk of dying from cardiovascular disease and heart attacks.

“Air pollution is hypothesized to cause bad health effects through oxidative stress and inflammation, and the Mediterranean diet is really rich in foods that are anti-inflammatory and have antioxidants that might intervene through those avenues,” said study author Chris Lim on Time.com.

It’s worth noting that the diet doesn’t protect against ozone exposure. (Researchers believe that ozone exposure effects the cardiac system differently.)

Why the hits keep on coming

Researchers have been uncovering the benefits of this particular diet for years. In fact, the diet’s benefits for heart health were so clear in one 2013 study that researchers ended the study early, saying it was unethical to continue.

Research from 2014 added to the accolades. Scientists in Boston looked at the nutritional data from 4,676 women participating in the Harvard Nurses’ Health Study — the well-known ongoing prospective cohort analysis ­— and discovered that those whose food choices most closely followed a Mediterranean diet had longer telomeres. Telomeres are the protective buffers on the ends of chromosomes and can be used as a biomarker of aging; the longer they are, the better.

“We know that having shorter telomeres is associated with a lower life expectancy and a greater risk of cancer, heart disease and other diseases,” said study coauthor Immaculata De Vivo, an associate professor of medicine at Brigham and Women’s Hospital. “Certain lifestyle factors like obesity, sugary sodas, and smoking have been found to accelerate telomere shortening, and now our research suggests the Mediterranean diet can slow this shortening.”

The key is cell aging

The Mediterranean diet isn’t a specific diet plan per se, but rather eating in the traditional style of those living in Mediterranean countries. It’s characterized by consuming a lot of vegetables, fruits, nuts, legumes and unrefined grains. There is plenty of olive oil, but little saturated fat; a moderate intake of fish, but little dairy, meat and poultry. And while cookies and sugar are limited, a regular but moderate dose of wine is involved.

It’s thought that the antioxidants present in the favored foods protect against cell aging. While the researchers didn’t find that any specific food provided the silver bullet, they suggest that it was a combination of the components that predicted telomere length.

The researchers scored each woman’s diet according to how closely it adhered to Mediterranean components. What they found was that each one-point change in their grading system equated to an extra year and a half of life. A three-point change, the study notes, would correspond to an average 4.5 years of aging, which is comparable to the difference between smokers with non-smokers.

The researchers also concluded that women who may have veered slightly from the Mediterranean diet but who still ate a healthy diet — like eating chicken and low-fat dairy products in addition to the Mediterranean basics — also had longer telomeres than those who ate a standard American diet with red meat, saturated fats, sweets and empty calories. Those who followed the Mediterranean diet, however, had the longest telomeres on average.

https://www.mnn.com/food/healthy-eating/stories/mediterranean-diet-could-add-years-to-your-life

Brown University researchers studying the biology of aging have demonstrated a new strategy for stimulating autophagy, the process by which cells rebuild themselves by recycling their own worn-out parts.

In a study published in the journal Cell Reports, the researchers show that the approach increased the lifespans of worms and flies, and experiments in human cells hint that the strategy could be useful in future treatments for Alzheimer’s disease, ALS and other age-related neurodegenerative conditions.

“Autophagy dysfunction is present across a range of age-related diseases including neurodegeneration,” said Louis Lapierre, an assistant professor of molecular biology, cell biology and biochemistry at Brown who led the work. “We and others think that by learning how to influence this process pharmacologically, we might be able to affect the progression of these diseases. What we’ve shown here is a new and conserved entry point for stimulating autophagy.”

Autophagy has become a hot topic in recent years, earning its discoverer the Nobel Prize in Physiology and Medicine in 2016. The process involves the rounding up of misfolded proteins and obsolete organelles within a cell into vesicles called autophagosomes. The autophagosomes then fuse with a lysosome, an enzyme-containing organelle that breaks down those cellular macromolecules and converts it into components the cell can re-use.

Lapierre and his colleagues wanted to see if they could increase autophagy by manipulating a transcription factor (a protein that turns gene expression on and off) that regulates autophagic activity. In order for the transcription factor to switch autophagic activity on, it needs to be localized in the nucleus of a cell. So Lapierre and his team screened for genes that enhance the level of the autophagy transcription factor, known as TFEB, within nuclei.

Using the nematode C. elegans, the screen found that reducing the expression of a protein called XPO1, which transports proteins out of the nucleus, leads to nuclear accumulation of the nematode version of TFEB. That accumulation was associated with an increase in markers of autophagy, including increased autophagosome, autolysosomes as well as increased lysosome biogenesis. There was also a marked increase in lifespan among the treated nematodes of between about 15 and 45 percent.

“What we showed was that by blocking the escape of this transcription factor from the nucleus, we could not only influence autophagy but we could get an increase in lifespan as well,” Lapierre said.

The next step was to see if there were drugs that could mimic the effect of the gene inhibition used in the screening experiment. The researchers found that selective inhibitors of nuclear export (SINE), originally developed to inhibit XPO1 to treat cancers, had a similar effect — increasing markers of autophagy and significantly increasing lifespan in nematodes.

The researchers then tested SINE on a genetically modified fruit fly that serves as a model organism for the neurodegenerative disease ALS. Those experiments showed a small but significant increase in the lifespans of the treated flies. “Our data suggests that these compounds can alleviate some of the neurodegeneration in these flies,” Lapierre said.

As a final step, the researchers set out to see if XPO1 inhibition had similar effects on autophagy in human cells as it had in the nematodes. After treating a culture of human HeLa cells with SINE, the researchers found that, indeed, TFEB concentrations in nuclei increased, as did markers of autophagic activity and lysosomal biogenesis.

“Our study tells us that the regulation of the intracellular partitioning of TFEB is conserved from nematodes to humans and that SINE could stimulate autophagy in humans,” Lapierre said. “SINE have been recently shown in clinical trials for cancer to be tolerated, so the potential for using SINE to treat other age-related diseases is there.”

Future research, Lapierre said, will focus on testing these drugs in more clinically relevant models of neurodegenerative diseases. But this initial research is a proof of concept for this strategy as a means to increase autophagy and potentially treat age-related diseases.

Lapierre is a faculty member in the newly approved Center on the Biology of Aging within the Brown Institute for Translational Science. This center, led by Professor of Biology John Sedivy, studies the biological mechanisms of aging. The center’s mission is to expand biomedical research and education programs in the emerging discipline of biogerontology, and to bring forth scientific discoveries related to aging and associated disorders.