I speak with Ali on Drive, Radio Live, New Zealand.
A recent study examining the diet of an isolated Japanese community provides clues to their increased longevity and lack of neurodegenerative disease.
The Ogimi people on the Japanese island of Okinawa have been the subject of intense study owing to their increased lifespan and apparent lack of neurodegenerative diseases. Okinawan women have an average life expectancy of 85.08 years, exceeding the average Japanese women’s life expectancy of 83.99 years. A suggestion that caloric restriction during world war II resulting in increased longevity has been largely dismissed as an explanation given Europeans also suffered from the same fate without the associated increased longevity.
The major source of calories in the Ogimi diet come from seaweeds and tofu based products which is in contrast to the rest of Japan where rice is the major staple. An analysis of the Ogimi diet shows it is remarkably rich in amino acids, particularly L-serine, of which tofu, edamame, seaweed and pork have the highest L-serine content.
On average, the total L-serine content of the Ogimi diet for women over the age of 70 is in excess of 8 g/day which is about 6 g/day above the daily L-serine intake (2.53 g/day) from all sources consumed by women in the USA and twice the L-serine intake (7.15 g/day) consumed by the 99th percentile of US women age 71+.
Interestingly, the Ogimis also make flour from the seeds of the cycad, a plant that has been directly linked to neurodegenerative diseases owing to the toxic amino acid derived from cyanobacteria – BMAA – that resides in the seeds. Studies examining BMAA toxicity have shown L-serine to be neuroprotective against BMAA in cell cultures, fruit flies, and monkeys.
A recent clinical trial of ALS patients who were supplemented with 30g/day of L-serine showed a slowing of disease progression by 85%.
The unique nature of the Ogimi diet, being rich in seaweeds and tofu, all of which have high serine content, may explain the lack of neurodegenerative disease and increased longevity in this community.
This suggests a diet high in serine or serine supplementation throughout life may be beneficial in preventing progression to neurodegeneration.
The study by Cox and Metcalf is open access and available here
For many years, there have been suggestions that exposure to air pollution increases the risk of getting dementia, and now a study provides compelling evidence in support of this theory.
Most people are not aware that the majority of neurodegenerative illnesses are not purely genetic in nature, but rather require a combination of a faulty gene and some environmental toxin. In Alzheimer’s Disease (AD), the most significant risk factor of all is age, but the most significant genetic risk factor is having the APOE 4 gene. Even so, this gene accounts for less than a 50% heritable risk, suggesting other factors must be involved in triggering disease.
In a study published in January, researchers followed 3647 US women (who had this genetic risk), for more than a decade, and found a significant correlation between exposure to air pollution levels greater than those considered safe by the United States EPA, and cognitive decline. Air pollution was defined as particulate matter of a size less than 2.5 uM (PM2.5) which is a common component of exhaust fumes from traffic pollution.
The gene that is at fault here is called APOE and humans have three types, one of which as been linked to increasing risks for AD as well as heart disease*. APOE ε3 is the most common type, APOE ε2 provides protection against heart disease by lowering levels of the bad cholesterol low-density lipoprotein or LDL, and APOE ε4 is a risk factor since it increases LDL. In this study, the researchers studied women who had either one or two copies of the “risk” gene.
Most people are not aware that the majority of neurodegenerative illnesses are not purely genetic in nature, but rather require a combination of a faulty gene and some environmental toxin.
Apart from excessive levels of air pollution increasing the the risk of dementia, the type of APOE that the women had was also a significant contributor. Women who had 2 copies of APOE ε4 had a greater risk of dementias than those with one APOE ε3 and one APOE ε4 or 2 APOE ε3s. Thus, residing in places with PM2.5 exceeding EPA standards increased the risks for global cognitive decline and all-cause dementia respectively by 81 and 92%, with stronger adverse effects in APOE ε4/4 carriers.
Researchers utilised the Women’s Health Initiative Memory Study (WHIMS), a well characterized, nationwide prospective cohort of older US women. The participants were community-dwelling (>95% in urban areas) across 48 US states, aged 65 to 79 years, and free of dementia when enrolled in 1995–1999. The age of subjects at the beginning of the trial provides evidence for late-life exposure to air pollution as a common environmental factor for developing dementia.
We already have epidemiological evidence associating cognitive deficits with PM2.5 exposures among the elderly, but this is the first study to show a gene-environment interaction and importantly, that the damage occurs later in life. This is important since it gives you an opportunity to reduce your risk by reducing your exposure. All the more reason to make a sea-change to the country later in life, whilst your still have your faculties intact.
Thus, residing in places with PM2.5 exceeding EPA standards increased the risks for global cognitive decline and all-cause dementia respectively by 81 and 92%, with stronger adverse effects in APOE ε4/4 carriers.
Take home message:
• People who lived in high pollution locations had a greater risk of getting dementia.
• This was increased when they also had genetic risk factors
• Moving away from areas of excessive air pollution (ie higher than what the EPA considers safe) will reduce your risk of getting dementia
• These findings provide the first experimental evidence for gene-environment interactions involving airborne particulate matter and a genetic risk factor for Alzheimer’s disease.
*APOE ε4 combined with air pollution is also a risk factor for heart disease, as described here.
Over the past few days, the news has been full of stories about a "breakthrough" in ALS/MND research, thanks to funding provided by the Ice Bucket Challenge.
The announcement concerns the publication of two Nature papers (see here and here) that examined the genomes of several thousand ALS patients and discovered three new genes and linked one already known, to increased susceptibility for contracting ALS.
Before I go any further, I want to make a distinction. There are two kinds of ALS
1) Genetically acquired ALS is called familial and results from the inheritance of a gene from your mother or father. If either of these had the disease, then you have a 50% chance of carrying the same gene (this doesn't necessarily mean you will develop ALS, just that you are at greater risk). This form of ALS, abbreviated to fALS is uncommon, affecting only between 5–10% of all patients.
2) By far the most common form of ALS is sporadic, meaning we don't know why people get it, and there's no genetic cause. This form is abbreviated to sALS and affects approximately 90% of all patients.
Genes provide a clue but are not the only answer.
Whilst over 20 genes have so far been linked to ALS, to date only 4 have been shown to cause the inherited form of the disease. The other genes so far described are unique to ALS patients but the exact roles they play in disease have not been completely elucidated.
The Nature papers describe three more such genes – they have been found in ALS patients but what they do and how they might influence the aetiology of disease requires more research.
A susceptibility gene for sALS?
The other gene included in the Nature studies, called NEK1, was first identified in 2015. This type of gene is of particular interest to me, since a mutated form of it was found in patients with both types of ALS. The researchers report NEK1 increases patients susceptibility to contracting ALS, thus opening up possibilities for interventions.
This is important because even though the two types of ALS I describe above have different names and are contracted in different ways, the pathologies are the same. So to find a common gene amongst fALS and sALS patients is very important, as it might imply similar pathways for disease progression.
More sobering is that only three percent of patients from both groups had the gene mutation, so it's by no means common.
ALS = genes + environment
I'm an environmental ALS researcher, but I'm not naive enough to think environmental trigger(s) alone are enough to trigger the disease. We've always acknowledged that ALS likely requires a combination of genes and some kind of environmental toxin to trigger pathology. And so here we are – with NEK1, a gene that increases people's susceptibility to ALS.
Could this be the key? Well, it's way too early to say and given this gene mutation was only identified in three percent of patients, it's clearly not the only gene involved in sALS.
Nevertheless, this is yet another clue on the long and complex path to unravelling ALS/MND.
I was on ABC Radio Goulburn Valley this morning talking about the current blue green algae bloom. This was in response to reports that people are ignoring warnings and swimming and wake boarding in affected parts of the river.
I then saw a report on ABC News where a farmer said not only is he letting his cattle drink from the river, but he's also drinking the water! This is a very bad idea. When health authorities put out warnings, they don't just do it for shits and giggles.
Dr Rachael Dunlop talks to Tess about the issue of women in science
First time scientists have observed brain tangles in an animal model through exposure to environmental toxin
January 20, 2016 – A new study published today in the science journal Proceedings of the Royal Society B indicates that chronic exposure to an environmental toxin may increase the risk of neurodegenerative illness. The cause of neurodegenerative disease remains largely unknown, and the role of environmental factors in these illnesses is poorly understood. However, scientists have long suspected a link between BMAA, a neurotoxin found in some harmful algal blooms, and neurodegenerative illness.
Brain tangles and amyloid deposits are the hallmarks of both Alzheimer’s disease and an unusual illness suffered by Chamorro villagers on the Pacific Island of Guam, whose diet is contaminated by the environmental toxin BMAA. Pacific Islanders with this unusual condition also suffer from dementia and symptoms similar to Alzheimer’s disease, motor neurone disease (MND) and Parkinson’s disease.
“Our findings show that chronic exposure to BMAA can trigger Alzheimer’s-like brain tangles and amyloid deposits,” said Paul Alan Cox, Ph.D., an ethnobotanist at the Institute for EthnoMedicine, in Wyoming, USA and lead author of the study. “As far as we are aware, this is the first time researchers have been able to successfully produce brain tangles and amyloid deposits in an animal model through exposure to an environmental toxin.”
Researchers conducted two experiments on vervets that lasted for 140 days each. The first group received fruit containing L-BMAA, the second group received fruit containing one-tenth of the regular dose of L-BMAA, the third group received fruit containing equal amounts of L-BMAA and L-serine, and the fourth group received fruit containing a placebo. After 140 days, tangles and amyloid deposits were found in the brain tissues of all of the vervets who consumed BMAA.
“This study takes a leap forward in showing causality—that BMAA causes disease,” said Deborah Mash, Ph.D., director of the University of Miami Brain Endowment Bank and co-author of the study. “The tangles and amyloid deposits produced were nearly identical to those found in the brain tissue of the Pacific Islanders who died from the Alzheimer’s-like disease.”
However, there was a significant reduction in the density of tangles in those that consumed equal amounts of L-serine.
This protective effect of L-serine was first reported by scientists in Sydney Australia in 2013 and led to clinical trials in patients with MND. “Our work showing L-serine was protective against BMAA was conducted in cells, so it’s very exciting to see it extrapolates into animals” said Dr Rachael Dunlop, a Visiting Associate at Macquarie University and member of the worldwide consortium working on this project.
Cox does not advocate patients taking L-serine at this time. "The FDA has not approved its use for the treatment of neurodegenerative illness, and much more research is needed," he said. "However, this new animal model may prove useful in evaluating other potential new Alzheimer's drugs."
The Institute has sponsored FDA-approved human clinical trials to study the effects of the naturally-occurring amino acid L-serine in people with MND, and will soon begin a Phase I human clinical trial of L-serine for patients diagnosed with mild cognitive impairment or early stage Alzheimer's disease.
The full version of the paper can be found at http://dx.doi.org/10.1098/rspb.2015.2397 once the embargo is lifted.
About the Institute for EthnoMedicine
Founded in 2004, the Institute for EthnoMedicine is a non-profit research organization dedicated to discovering new cures for neurodegenerative diseases from studies of indigenous peoples. Based in Jackson Hole, Wyo., the Institute has established a consortium of 50 scientists operating in 28 institutions across 10 countries, allowing for global collaboration through access to the latest technology and state-of-the-art laboratory facilities.
Dr Rachael Dunlop is also a member of the worldwide consortium working on this project and a Visiting Associate at the Faculty of Medicine and Health Sciences, Macquarie University. She is based in Australia and available for media interviews on 0414 184 452 firstname.lastname@example.org email@example.com @DrRachie
A paper published today suggests that chronic exposure to an environmental toxin may increase the risk of neurodegenerative illnesses such as Alzheimer’s disease.
For the first time, researchers have shown that feeding vervets a toxin found in blue green algae resulted in protein deposits in the brain, consistent with those seen in human Alzheimer's.
Whilst the cause(s) of most neurodegenerative disease remains largely unknown, it is expected that a gene/environment interaction will eventually be identified. Around 5-10 % of cases are caused by genes, but the role of environmental factors in these illnesses is poorly understood.
Owing to its role in an unusual illness suffered by Chamorro villagers on the Pacific Island of Guam, an algal toxin called BMAA, (Beta-Methylamino-L-alanine) has been investigated for over 40 years. BMAA was first discovered when scientists were searching for the causes of the fatal illness that had symptoms of Alzheimer’s, motor neurone (MND) and Parkinson’s disease and at its peak, killed over 25% of the male population of one village.
For the first time, researchers have shown that feeding vervets a toxin found in blue green algae resulted in protein deposits in the brain, consistent with those seen in human Alzheimer's.
When efforts to find a genetic link had been exhausted researchers looked for an environmental trigger. They found blue green algae growing in the roots of cycad tress, a staple foodstuff of the Chamorros, and a toxin produced by the algae had concentrated in the seeds of the plant.
The study published today in the Royal Society Proceedings B recreates experimentally the pathology seen in these people by using chronic administration of BMAA in food. Three groups of vervets were fed fruit for 140 days, some with BMAA, some with placebo and some with a known inhibitor of BMAA, an amino acid called L-serine.
In all the animals fed BMAA, tangles and plaques were detected in their brain tissue, but not in the placebo animals. This is the first time researchers have been able to successfully produce brain tangles and amyloid deposits in an animal model through exposure to an environmental toxin.
In all the animals fed BMAA, tangles and plaques were detected in their brain tissue, but not in the placebo animals.... in combination with L-serine showed a highly significant reduction in the number and density of protein tangles
Even more compelling was the vervets fed BMAA in combination with L-serine showed a highly significant reduction in the number and density of protein tangles. L-serine was first reported to block BMAA toxicity in cell culture back in 2013, but this is the first evidence it can prevent the formation of protein deposits in the brain.
The path from dementia to discovery – set backs in implicating BMAA in disease.
The story of BMAA as a neurotoxin has a long and chequered history. In the 1950s, US physicians reported a puzzling neurodegenerative illness in the indigenous Chamorros of Guam that manifested as dementia, Alzheimer’s, Parkinson’s and Motor Neurone Diseases. In the 1960s, Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) was described based on protein tangles in the brain and clinical symptoms which resemble the various symptoms of this disease.
A search for an environmental trigger led to an investigation of cycad flour, as this served as a staple foodstuff by the indigenous people, used to make tortillas, and thicken soups.
The impetus for this stemmed from another neurological disease called Lathyrism which was caused by an unusual amino acid (ODAP) found in legumes of the genus lathyrus sativus. Neurolathyrism manifested as an acute paralysis and may have been implicated in the death of Chris McCandless aka “Alexander Supertramp” whose emaciated corpse was found in the wilderness of Alaska. Whilst it was initially thought he died of starvation it now seems likely the starvation was a result of paralysis caused by eating grass peas meaning he was unable to scavenge for food.
But in order to prove that a substance is a causative agent, it needs to satisfy Koch’s postulates and these include demonstrating that when inoculated into a healthy, susceptible laboratory animal, it can cause the disease.
So, in the 1980s, BMAA was fed to macaques and found to cause acute neurological symptoms , but this finding was discounted when it was argued that an equivalent human dose would require the consumption of more than 1000 kg of cycad seed flour . However, the observation that the majority of BMAA in cycad seeds binds to proteins and cannot be released by washing with water, suggested that the BMAA doses ingested by the Chamorros had been previously underestimated [14,15].
Meanwhile, evidence continued to build for the link between BMAA and neurodegenerative disease with respect to cyanobacterial exposure and epidemiology. For example, it was reported that people who consume large quantities of seafood from waters contaminated with blue green algae had a higher risk of contracting MND.
An elegant study mapping MND patients’ place of residence showed those who lived on the leeward side of water bodies that had regular algal blooms were at a greater risk for disease. This suggests that ingestion is not the only route for exposure but inhalation of BMAA may also play a role. This hypothesis is supported by observations that soldiers who fought in the gulf war also have an increased risk of contracting MND and over 60% of the desert crusts of Qatar contain BMAA. BMAA was found to bioaccumlate up the food chain from crabs, to pelagic fish to sharks.
A key missing puzzle piece was how BMAA might stick to proteins as was seen in the cycad flour. And it was not until 2013 that a plausible explanation was presented. In a paper on which I was first author, we showed that BMAA had a structure similar enough to an amino acid humans already use to make proteins. We showed that BMAA could be swapped for L-serine when cells make proteins, rendering the proteins toxic and causing the cells to commit suicide.
This was a critical discovery because it finally offered an explanation for how BMAA might be stored in the brain. And for this we need to look to brain cells and their renewal. Neurons, unlike other cells in the body, are not turned-over very often, so they are unable to dispose of damaged or toxic proteins as efficiently as say hair or skin cells. This means they might act as a reservoir for BMAA, locking it up inside their proteins, where it can do damage years later.
The findings of today's study are significant – not only because they provide evidence for what we've long suspected – but also because they implicate a ubiquitous toxin in a growing and formidable human health problem. BMAA is made by blue green algae (more accurately known as cyanobacteria) which manifest as characteristic bright green blooms in bodies of water. The problem is these blooms are increasing in size and frequency as global temperatures rise. And Australia is particularly susceptible, historically having had the world's largest ever fresh water algal bloom that occurred in the summer of 1991–92.
So if BMAA is already enriched in the environment, it follows that we've all been exposed to some degree, so why don't we all have neurodegeneration? As previously noted, it's likely that the trigger for the disease is a combination of genes and environmental factors, and also the process probably requires many years. But at least now we have a model to explore ways to prevent or even cure the disease.
What we do know is what we've long suspected – BMAA can cause disease in susceptible individuals.
For many years researchers have been looking for the causes of MND but in the majority of cases, a cause and a cure remain elusive. Although now over 20 different genes have been associated with MND, only 8-10% of cases are genetic (also called familial ALS or fALS) versus more than 90% being sporadic (sALS) or of unknown origin. My work focuses on the environmental causes for MND.
“...8-10% of MND cases are genetic versus more than 90% being sporadic or of unknown origin.”
Several years ago, when I was working in heart research, we were approached by ethnobotanist and a TIME magazine, "Hero of Medicine" from the Institute for Ethnomedicine, in Jackson Hole, Wyoming, Dr Paul Cox. Dr Cox was one of the original researchers to identify a link between blue green algae and MND. With his expertise in plants and ours in cells, he reckoned that together we could figure out a puzzle that had been bugging the research community for years – why did a toxin found in blue green algae called BMAA appear to concentrate up the food chain causing neurodegnerative illnesses in animals and humans?
This had first been observed on Guam when blue green algae was identified at the roots of cycad trees, which concentrated in the seeds of the plant and in even higher concentrations in the fruit bats that fed on the seeds (both of which were food sources for the locals).
The terms motor neurone disease (MND), amyotrophic lateral sclerosis (ALS) and Lou Gehrig's Disease are interchangeable. MND is used in Australia, whilst ALS and Lou Gehrig's are used in the USA.
Dr Cox thought the high levels of algal toxin found in the locals foods, might be linked the the higher than normal levels of neurodegenerative disease seen on the island - a condition known as lytico bodig or ALS/PDC.
He had seen our work showing that the drug used to treat Parkinson's Disease called levodopa (or L-DOPA) could be toxic to cells in certain conditions, owing to a unique structural property. L-DOPA is very similar to a compound humans normally use in the building blocks of their proteins, and thus can trick cells into thinking it's the same one. When cells use it by mistake, they can make damaged proteins that can eventually kill cells.
Since BMAA also mimics human amino acids, Dr Cox's idea was that it may build-up in the food chain via the same mechanism and this may explain the mechanism that triggers MND in susceptible people.
Well he was right, and we recently published this work with Dr Cox and his colleague Dr Sandra Banack. But importantly, not only did we identify the mechanism by which BMAA might be causing toxicity, we also identified which human amino acid it might be exchanging with, and this opens the door to develop preventative medicines.
The research model pioneered by Dr Cox is unique in that he has assembled an international team of cross-discipline scientists all focusing on solving the problem of dementia. As a group working outside the silo, we have been able to make breakthrough much faster than traditional research, going from the bench to clinical trials in just over two years.
Now that we have clues to how BMAA might be triggering MND, we want to work out a) how to stop it and b) is it possible to reverse the damage?
This work is ongoing and we were recently awarded an ARC grant towards this project. However government funding cuts meant we only received 70% of the money we need to see this work to its fruition. If you would like to donate, please click the link to Macquarie University Faculty of Medicine and Health Sciences and select "MND, environmental causes".
In a paper published on March 25th, it’s been revealed that watering wheat seedlings with BMAA contaminated water results in uptake by the plant and incorporation of the neurotoxin into the seeds and roots.
In shoot samples, protein-associated BMAA was detected after only 1 day and the highest amount was found after 28 days.
In roots, protein-associated BMAA was detectable after 5 days, peaking after 14 days. Longer exposure did not cause further accumulation.
There were also large concentrations of free BMAA detected in seedlings watered with 1000 mg/L BMAA.
The authors commented,
“..so little is known about the effects of BMAA on plants, and even less about the risks posed by consumption of crop plants containing BMAA to human health.”
It’s been demonstrated in the laboratory that techniques such as sand and carbon filtration can remove BMAA from water, but these are not routinely used for irrigation water. Even more of a concern are news reports such as the one from 2010 which says, “Murrumbidgee Irrigation says tests on Lake Wyangan have shown the water is suitable for irrigation" in spite of the presence of a toxic algal bloom.
But water is not screened for BMAA in Australia, because quite simply, no test yet exists (we’ve recently submitted a grant to develop one). Most water treatment plants will remove it as a matter of course, but irrigation water is generally not treated before use.
Of course, we must be cautious because this is only one study and it only measured BMAA content out to 28 days. It did not follow the fate of BMAA after this time, so who knows what remains in the plant by the time it hits our dinner tables.
Also, it seems unlikely that a crop would be watered with BMAA-contaminated water for its lifetime, as algal blooms (and BMAA production) are transient. So if BMAA is incorporated into the plant proteins early in life, it might be gone by harvest, as proteins are broken down and recycled. On the other hand, if the plant is exposed to BMAA close to harvest, then BMAA contamination might pose a risk.
We know from several studies now that consuming BMAA contaminated seafood increases the risk of contracting MND. Indeed, if it's true for consuming BMAA-contaminated flour from cycad seeds, then it follows the same would apply for wheat.
But as the authors state, and I agree, we just don’t know enough yet. But..
"Considering that eutrophication and the climate change will most likely increase the appearance of toxin producing cyanobacteria more research in this field is definitively necessary."
And that’s exactly why we’re here.