New methods to identify Alzheimer’s drug candidates that have anti-aging properties

From left: Dave Schubert and Pam Maher.
via Salk Institute

Salk research focuses on the development of compounds that may protect against the diseases of aging, such as Alzheimer’s

Old age is the greatest risk factor for many diseases, including Alzheimer’s disease (AD) and cancer. Geroprotectors are a recently identified class of anti-aging compounds. New Salk research has now identified a unique subclass of these compounds, dubbed geroneuroprotectors (GNPs), which are AD drug candidates and slow the aging process in mice.

“The argument for geroprotectors is that if one can extend the lifespan of model organisms, such as mice, and translate this effect to humans, then you should be able to slow down the appearance of many diseases that are associated with aging, such as Alzheimer’s, Parkinson’s, cancer and overall frailty,” says first author Dave Schubert, Salk professor and head of Salk’s Cellular Neurobiology Laboratory.

The study, which appeared in the journal Trends in Pharmacological Sciences, on November 13, 2018, was conducted in collaboration with Salk Senior Staff Scientist Pamela Maher, whose lab is in the Cellular Neurobiology department and who is the study’s senior author.

The team started with two chemicals found in plants that have demonstrated medicinal properties: fisetin, a natural product derived from fruits and vegetables, and curcumin, from the curry spice turmeric. From these, the team synthesized three AD drug candidates based upon their ability to protect neurons from multiple toxicities associated with the aging brain. The lab showed that these three synthetic candidates (known as CMS121, CAD31 and J147), as well as fisetin and curcumin, reduced the molecular markers of aging, as well as dementia, and extended the median lifespan of mice or flies.

Importantly, the group demonstrated that the molecular pathways engaged by these AD drug candidates are the same as two other well-researched synthetic compounds that are known to extend the lifespan of many animals. For this reason, and based on the results of their previous studies, the team says fisetin, curcumin and the three AD drug candidates all meet the definition of being geroneuroprotectors.

The group is now focusing on getting two GNPs into human clinical trials. The fisetin derivative, CMS121, is currently in the animal toxicology studies required for FDA approval to start clinical trials. The curcumin derivative, J147, is under FDA review for allowance to start clinical trials for AD early next year. The group plans to incorporate biochemical markers for aging into the clinical trials to assay for potential geroprotective effects.

“Since we found that the natural products curcumin and fisetin are also GNPs and commercially available as supplements, they could provide some therapeutic benefits right now,” says Maher.

Other studies in the lab are determining whether these compounds have effects on organs outside of the brain. “If these drugs have benefits for other body systems, such as maintaining kidney function and overall muscle health, they could be used in additional ways to treat or prevent the diseases of aging,” Schubert says.

The investigators say that the discovery of these AD drug candidates validates the drug discovery model they have developed as a plausible method for identifying additional GNP compounds that will help promote healthy aging. This could greatly accelerate the pipeline for drugs to treat the diseases of aging for which there are currently no cures.

Learn more: RESEARCHERS REPORT NEW METHODS TO IDENTIFY ALZHEIMER’S DRUG CANDIDATES THAT HAVE ANTI-AGING PROPERTIES

 

 

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Fasting or caloric restriction can have anti-aging effects on the vascular system

via Medical News Today

A molecule produced during fasting or calorie restriction has anti-aging effects on the vascular system, which could reduce the occurrence and severity of human diseases related to blood vessels, such as cardiovascular disease, according to a study led by Georgia State University.

“As people become older, they are more susceptible to disease, like cancer, cardiovascular disease and Alzheimer’s disease,” said Dr. Ming-Hui Zou, senior author of the study, director of the Center for Molecular and Translational Medicine at Georgia State and a Georgia Research Alliance Eminent Scholar in Molecular Medicine. “Age is the most important so-called risk factor for human disease. How to actually delay aging is a major pathway to reducing the incident and severity of human disease.

“The most important part of aging is vascular aging. When people become older, the vessels that supply different organs are the most sensitive and more subject to aging damage, so studying vascular aging is very important. This study is focused on vascular aging, and in old age, what kind of changes happen and how to prevent vascular aging.”

In this study, the research team explores the link between calorie restriction (eating less or fasting) and delaying aging, which is unknown and has been poorly studied. The findings are published in the journal Molecular Cell.

The researchers identified an important, small molecule that is produced during fasting or calorie restriction conditions. The molecule, ?-Hydroxybutyrate, is one type of a ketone body, or a water-soluble molecule that contains a ketone group and is produced by the liver from fatty acids during periods of low food intake, carbohydrate restrictive diets, starvation and prolonged intense exercise.

“We found this compound, ?-Hydroxybutyrate, can delay vascular aging,” Zou said. “That’s actually providing a chemical link between calorie restriction and fasting and the anti-aging effect. This compound can delay vascular aging through endothelial cells, which line the interior surface of blood vessels and lymphatic vessels. It can prevent one type of cell aging called senescence, or cellular aging.”

Senescent cells can no longer multiple and divide. The researchers found ?-Hydroxybutyrate can promote cell division and prevent these cells from becoming old. Because this molecule is produced during calorie restriction or fasting, when people overeat or become obese this molecule is possibly suppressed, which would accelerate aging.

In addition, the researchers found when ?-Hydroxybutyrate binds to a certain RNA-binding protein, this increases activity of a stem cell factor called Octamer-binding transcriptional factor (Oct4) in vascular smooth muscle and endothelial cells in mice. Oct4 increases a key factor against DNA damage-induced senescence, which can keep blood vessels young.

“We think this is a very important discovery, and we are working on finding a new chemical that can mimic the effect of this ketone body’s function,” Zou said. “We’re trying to take the global approach to reducing cardiovascular disease and Alzheimer’s disease. It’s difficult to convince people not to eat for the next 24 hours to increase the concentration of this compound (?-Hydroxybutyrate), and not everybody can do that, but if we can find something that can mimic this effect and people can still eat, it would make life more enjoyable and help fight disease.

“This stem cell factor (Oct4) could be a pharmaceutical or pharmacological target for slowing down or preventing aging. Then, if the vascular system becomes younger, it is less likely to have cardiovascular disease, Alzheimer’s disease and cancer because all of these diseases are age-related.”

In the future, the researchers would like to target senescent cells with the goal of eliminating them and rejuvenating the vascular system to prevent cardiovascular disease.

Learn more: Researchers Identify Molecule With Anti-Aging Effects On Vascular System

 

 

 

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6 new groups of molecules could be the key to delaying aging

Salix alba, more commonly known as white willow bark, is the most potent aging-delaying pharmacological intervention yet described. | Photo via Wikimedia Commons

Salix alba, more commonly known as white willow bark, is the most potent aging-delaying pharmacological intervention yet described. | Photo via Wikimedia Commons

Montreal researchers clear a major hurdle in the fight for longevity

Hearing loss, brittle bones, sagging skin, a deteriorating mind: these are just some of the issues associated with growing old. For millennia, humans have fought the process of aging using everything from fountains of youth to pricey face creams, all to no avail. But a group of Montreal-based researchers is coming ever closer to achieving healthy longevity — armed with the power of science.

In a study recently published in Oncotarget, researchers from Concordia University and Idunn Technologies assess how six previously identified plant extracts can delay aging by affecting different signaling pathways that set the pace of growing old.

Vladimir Titorenko is a biology professor and the study’s senior author. He says that the potential of using these plant extracts for delaying the onset of age-related diseases is underscored by the fact that Health Canada classifies them as safe for human consumption. Five of them are recommended by the federal department as health-improving supplements with clinically proven benefits.

In the study, Titorenko and his co-authors confirmed that one extract is particularly effective: Salix alba, more commonly known as white willow bark, is the most potent aging-delaying pharmacological intervention yet described.

To make this identification, the researchers used yeast to test the effectiveness of the plant extracts. But why yeast? That’s because, at a cellular level, aging progresses similarly in yeast and humans. In both, the pace of aging is defined by a distinct set of chemical reactions arranged into several cascades. These cascades, which scientists call “signalling pathways,” regulate the rate of aging in a wide range of organisms.

Using yeast — the best cellular aging model — Titorenko and his colleagues monitored how the information flowing through each of these signalling pathways was affected by  each of the six aging-delaying plant extracts.

“It’s known that some of these signalling pathways delay aging if activated in response to certain nutrients or hormones,” he says. “These pathways are called ‘anti-aging’ or ‘pro-longevity’ pathways. Other signalling pathways speed up aging if activated in response to certain other nutrients or hormones. These pathways are called ’pro-aging’ or ‘pro-death’ pathways.”

Co-author Éric Simard, CEO of Idunn Technologies, explains that each of the six aging-delaying plant extracts targets a different anti-aging or pro-aging signalling pathway.

It is especially noteworthy that this study revealed the following features of the six plant extracts as potential tools in decelerating chronic symptoms and diseases of old age:

  • They imitate the aging-delaying effects of the caloric restriction diet in yeast
  • They slow yeast aging by eliciting a mild stress response
  • They extend yeast longevity more efficiently than any lifespan-prolonging chemical compound yet described
  • They delay aging through signalling pathways implicated in age-related diseases
  • One of them delays aging via a previously unknown pathway
  • They extend longevity and delay the onset of age-related diseases in organisms other than yeast

“This study is an important step forward for science because these signaling pathways could eventually  delay the onset and progression of chronic diseases associated with human aging,” says Simard, who has recently published a new book on the topic.

“These diseases include arthritis, diabetes, heart disease, kidney disease, liver dysfunction, stroke, neurodegenerative diseases like Parkinson’s, Alzheimer’s and Huntington’s diseases, and many forms of cancer.”

Learn more: 6 new groups of molecules could be the key to delaying aging

 

 

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Experimental drug J147 targeting Alzheimer’s disease shows anti-aging effects

Antonio Currais and David Schubert Image: Courtesy of the Salk Institute for Biological Studies

Antonio Currais and David Schubert
Image: Courtesy of the Salk Institute for Biological Studies

Salk team finds molecule that slows the clock on key aspects of aging in animals

Salk Institute researchers have found that an experimental drug candidate aimed at combating Alzheimer’s disease has a host of unexpected anti-aging effects in animals.

The Salk team expanded upon their previous development of a drug candidate, called J147, which takes a different tack by targeting Alzheimer’s major risk factor–old age. In the new work, the team showed that the drug candidate worked well in a mouse model of aging not typically used in Alzheimer’s research. When these mice were treated with J147, they had better memory and cognition, healthier blood vessels in the brain and other improved physiological features, as detailed November 12, 2015 in the journal Aging.

“Initially, the impetus was to test this drug in a novel animal model that was more similar to 99 percent of Alzheimer’s cases,” says Antonio Currais, the lead author and a member of Professor David Schubert’s Cellular Neurobiology Laboratory at Salk. “We did not predict we’d see this sort of anti-aging effect, but J147 made old mice look like they were young, based upon a number of physiological parameters.”

Alzheimer’s disease is a progressive brain disorder, recently ranked as the third leading cause of death in the United States and affecting more than five million Americans. It is also the most common cause of dementia in older adults, according to the National Institutes of Health. While most drugs developed in the past 20 years target the amyloid plaque deposits in the brain (which are a hallmark of the disease), few have proven effective in the clinic.

“While most drugs developed in the past 20 years target the amyloid plaque deposits in the brain (which are a hallmark of the disease), none have proven effective in the clinic,” says Schubert, senior author of the study.

Several years ago, Schubert and his colleagues began to approach the treatment of the disease from a new angle. Rather than target amyloid, the lab decided to zero in on the major risk factor for the disease–old age. Using cell-based screens against old age-associated brain toxicities, they synthesized J147.

Previously, the team found that J147 could prevent and even reverse memory loss and Alzheimer’s pathology in mice that have a version of the inherited form of Alzheimer’s, the most commonly used mouse model. However, this form of the disease comprises only about 1 percent of Alzheimer’s cases. For everyone else, old age is the primary risk factor, says Schubert. The team wanted to explore the effects of the drug candidate on a breed of mice that age rapidly and experience a version of dementia that more closely resembles the age-related human disorder.

In this latest work, the researchers used a comprehensive set of assays to measure the expression of all genes in the brain, as well as over 500 small molecules involved with metabolism in the brains and blood of three groups of the rapidly aging mice. The three groups of rapidly aging mice included one set that was young, one set that was old and one set that was old but fed J147 as they aged.

The old mice that received J147 performed better on memory and other tests for cognition and also displayed more robust motor movements. The mice treated with J147 also had fewer pathological signs of Alzheimer’s in their brains. Importantly, because of the large amount of data collected on the three groups of mice, it was possible to demonstrate that many aspects of gene expression and metabolism in the old mice fed J147 were very similar to those of young animals. These included markers for increased energy metabolism, reduced brain inflammation and reduced levels of oxidized fatty acids in the brain.

Another notable effect was that J147 prevented the leakage of blood from the microvessels in the brains of old mice. “Damaged blood vessels are a common feature of aging in general, and in Alzheimer’s, it is frequently much worse,” says Currais.

Currais and Schubert note that while these studies represent a new and exciting approach to Alzheimer’s drug discovery and animal testing in the context of aging, the only way to demonstrate the clinical relevance of the work is to move J147 into human clinical trials for Alzheimer’s disease.

“If proven safe and effective for Alzheimer’s, the apparent anti-aging effect of J147 would be a welcome benefit,” adds Schubert. The team aims to begin human trials next year.

Read more: Experimental drug targeting Alzheimer’s disease shows anti-aging effects

 

 

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Mapping the Genes that Increase Lifespan

Budding Yeast via Buck Institute

Budding Yeast via Buck Institute

Following an exhaustive, ten-year effort, scientists at the Buck Institute for Research on Aging and the University of Washington have identified 238 genes that, when removed, increase the replicative lifespan of S. cerevisiae yeast cells. This is the first time 189 of these genes have been linked to aging. These results provide new genomic targets that could eventually be used to improve human health.

The research was published online on October 8th  in the journal Cell Metabolism.

“This study looks at aging in the context of the whole genome and gives us a more complete picture of what aging is,” said Brian Kennedy, PhD, lead author and the Buck Institute’s president and CEO. “It also sets up a framework to define the entire network that influences aging in this organism.”

The Kennedy lab collaborated closely with Matt Kaeberlein, PhD, a professor in the Department of Pathology at the University of Washington, and his team. The two groups began the painstaking process of examining 4,698 yeast strains, each with a single gene deletion. To determine which strains yielded increased lifespan, the researchers counted yeast cells, logging how many daughter cells a mother produced before it stopped dividing.

“We had a small needle attached to a microscope, and we used that needle to tease out the daughter cells away from the mother every time it divided and then count how many times the mother cells divides,” said Dr. Kennedy. “We had several microscopes running all the time.”

These efforts produced a wealth of information about how different genes, and their associated pathways, modulate aging in yeast. Deleting a gene called LOS1 produced particularly stunning results. LOS1 helps relocate transfer RNA (tRNA), which bring amino acids to ribosomes to build proteins. LOS1 is influenced by mTOR, a genetic master switch long associated with caloric restriction and increased lifespan. In turn, LOS1 influences Gcn4, a gene that helps govern DNA damage control.

“Calorie restriction has been known to extend lifespan for a long time.” said Dr. Kennedy. “The DNA damage response is linked to aging as well. LOS1 may be connecting these different processes.”

A number of the age-extending genes the team identified are also found inC. elegans roundworms, indicating these mechanisms are conserved in higher organisms. In fact, many of the anti-aging pathways associated with yeast genes are maintained all the way to humans.

The research produced another positive result: exposing emerging scientists to advanced lab techniques, many for the first time.

“This project has been a great way to get new researchers into the field,” said Dr. Kennedy. “We did a lot of the work by recruiting undergraduates, teaching them how to do experiments and how dedicated you have to be to get results. After a year of dissecting yeast cells, we move them into other projects.”

Though quite extensive, this research is only part of a larger process to map the relationships between all the gene pathways that govern aging, illuminating this critical process in yeast, worms and mammals. The researchers hope that, ultimately, these efforts will produce new therapies.

“Almost half of the genes we found that affect aging are conserved in mammals,” said Dr. Kennedy. “In theory, any of these factors could be therapeutic targets to extend healthspan. What we have to do now is figure out which ones are amenable to targeting.”

Read more: Mapping the Genes that Increase Lifespan

 

 

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