Asparagus is a vegetable with a remarkably long history of use going back to ancient civilizations such as Egypt, Greece, and Rome.¹ In those times, asparagus was not just consumed as a food, it was also utilized for its medicinal properties.

Modern scientific researchers are now discovering the potential therapeutic benefits of asparagus, particularly its anti-inflammatory and antioxidant effects. This venerable vegetable produces a number of bioactive compounds with the capacity to neutralize the free radicals that contribute to the development of various diseases.

Enzyme-Treated Asparagus Extract (ETAS®) is an extract derived from asparagus stems, usually regarded as inedible.² Research suggests it may help reduce stress and improve sleep. Additionally, ETAS has been shown to improve heart rate variability–a measure of the heart’s ability to respond to stress by balancing parasympathetic and sympathetic nervous system activity.  There is also evidence to suggest it can boost cognitive function and alleviate fatigue.

ETAS stimulates the production of Heat Shock Protein 70 (HSP70), a protective protein.² In its role as a molecular chaperone, HSP70 assists in the proper folding and restructuring of proteins within cells, and shields them from stress. This protein is naturally generated in response to high temperatures, known as heat stress. The ability to stimulate production of HSP70 is key to the positive effects of ETAS.

At the molecular level, ETAS contains hydroxymethylfurfural derivatives, which are unique compounds that can stimulate HSP70 synthesis.² Specifically, one compound called asfural, a derivative of 5-hydroxymethyl-2-furfural (HMF-1), significantly enhances the activity of the gene responsible for HSP70 production. Asfural also possesses several health-promoting properties, including antioxidant effects, protection against myocardial damage, and improved blood circulation.

New studies, including in vitro work, animal studies, and human clinical trials show that ETAS might protect brain cells from harmful molecules associated with Alzheimer’s disease (AD). This could translate into improvements in thinking skills and daily functioning in individuals with dementia. This is particularly relevant for AD, the most common form of dementia.

ETAS Protects Neurons from Stress

In neurodegenerative conditions such as AD, biological stressors like oxidative and inflammatory stress cause widespread damage to and destruction of neurons.

Ten years ago, researchers published the first evidence suggesting that ETAS might be able to mitigate neuronal damage. They looked at the effects of ETAS on a type of lab-made cells called NG108-15 cells which are similar to human neurons, and also on early signs of memory decline in a strain of mice (senescence-accelerated mouse prone 8 (SAMP8)), bred specifically for manifesting symptoms similar to early stages of cognitive decline.³

NG108-15 cells are often used to model primary cells from the central nervous system. In the context of neurodegenerative diseases like Alzheimer’s, NG108-15 cells provide a controlled environment to study the effects of various treatments and interventions.

The study showed that treatment with ETAS increased the production of certain protective factors in NG108-15 cells.³ These factors, including HSP70 and heme oxygenase-1, which are known to protect cells and prevent them from undergoing apoptosis.

Moreover, when NG108-15 cells were subjected to harmful conditions that mimic low oxygen levels (by adding the reagent, cobalt chloride) or high nitric oxide levels (using the nitric oxide donor, sodium nitroprusside), ETAS was able to significantly reduce cell damage.³ This was evidenced by a decrease in the release of lactate dehydrogenase, an indicator of cell damage.

Additionally, the researchers observed that ETAS lessened cognitive impairment in SAMP8 mice.³ Cognitive function was assessed using tests of contextual fear memory. This type of memory relies on the hippocampus, a region of the brain important for learning as it relates to conscious experiences. In humans, the hippocampus is affected early on in AD.

In conclusion, the findings indicate that ETAS protects NG108-15 cells against damage caused by hypoxia and oxidative stress,³ leading the authors to suggest that ETAS would likely protects human neurons from similar types of harm. Furthermore, ETAS appears to alleviate cognitive impairment in SAMP8 mice, which exhibit accelerated aging and age-related cognitive deficits that include memory problems.

Together, these observations suggest that ETAS might have potential as a therapy for neurodegenerative disorders such as Alzheimer’s disease and age-related cognitive decline in humans.

Neutralizing β-Amyloid & Free Radicals

Alzheimer’s disease (AD) is characterized by the buildup of amyloid beta peptide in brain cells, resulting in excessive production of harmful reactive oxygen species (ROS).⁴ These unstable molecules can damage cells throughout the body, and are associated with various disease states.

Recent studies suggest that specific phytochemicals can counteract ROS in animal cells. ETAS is one notable example of this. Researchers at Kyorin University School of Medicine in Tokyo studied ETAS’s effects against cellular damage triggered by amyloid beta using PC12 cells. This is a cell line commonly used in Alzheimer’s research.⁴

They found that treating PC12 cells with ETAS before exposing them to amyloid beta significantly improved cell survival and reduced ROS levels.⁴ The exact mechanism by which ETAS reduces ROS is unclear. One possibility is that it blocks enzymes that make ROS, which are typically generated through accelerated chemical reactions. This is a reasonable theory because ETAS contains 5-hydroxymethyl-2-furfural, known to inhibit an ROS-producing enzyme called xanthine oxidase.

Additionally, 5-hydroxymethyl-2-furfural seems to boost the production of the body’s natural ROS-fighting antioxidant enzymes like glutathione peroxidase and superoxide dismutase.⁴ These enzymes help neutralize and remove harmful ROS from cells.

Thus, ETAS may function through a dual mechanism: firstly, by inhibiting enzymes that elevate ROS production, and secondly, by enhancing the generation of antioxidant enzymes that aid in ROS elimination.⁴ The observed decrease in ROS levels may be especially important for neurons, which are vulnerable to ROS triggered by AD-linked amyloid-beta peptides.

Increased Neuronal Connections, Enhanced Learning

Previous studies have shown that ETAS can help protect against early signs of cognitive decline in SAMP8 mice and reduce the harmful effects of amyloid beta on PC12 cells. There is also research showing that ETAS has several beneficial effects on healthy individuals, such as enhancing sleep and reducing psychological stress.¹

One study examined the effects of ETAS on the regular memory functions of rats and the development of neurites, nerve-like extensions, in PC12 cells.¹ The data revealed that ETAS notably accelerated the learning process, as demonstrated by a significant reduction in the time required for treated rats to complete a water maze task by day two. Additionally, lab tests showed that ETAS fostered the growth of neurites in PC12 cells in a concentration-dependent way.

The study’s authors propose that the beneficial impact of ETAS on learning might be directly associated with its capacity to stimulate neurite development in PC12 cells.¹ In summary, this work suggests that ETAS can enhance memory function in normal rats early in the learning acquisition process, and this is related to ETAS’s ability to stimulate neurite growth.

Improved Memory & Sleep

Cognitive decline and disruptions of circadian rhythms both tend to increase in older adults and in those with AD. A team of researchers in Taiwan looked at the effects of ETAS on these problems in senescence-prone SAMP8 mice.⁵

The study divided three-month-old male SAMP8 mice into groups that received either a control diet or ETAS at doses of 200 or 1000 mg/kg body weight. A group of senescence-accelerated resistant mice (SAMR1) served as a normal control.

After 12 weeks of feeding, the mice given ETAS showed significant improvements in cognitive performance on an active avoidance test.⁵ ETAS also reduced the expression of amyloid-beta precursor protein (APP) and BACE-1 (beta-site amyloid precursor protein cleaving enzyme), two proteins involved in the production of amyloid beta (Aβ). As a result, there was less Aβ buildup in the brain as a whole, and in the hippocampus specifically.

In addition, ETAS significantly increased the number of neurons in the suprachiasmatic nucleus (SCN), a part of the brain that controls circadian rhythms. Note that neuron numbers in the SCN are reduced in the brains of individuals with AD. ETAS also normalized the expression of melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2), proteins that help regulate day-night biological rhythms.⁵

ETAS seems to improve brain function, reduce the buildup of Aβ protein, and regulate circadian rhythms.⁵ This suggests it could help prevent the memory loss and sleep-wake cycle disruptions that are commonly associated with aging and that become more severe in AD.

Preventing Apoptosis

Researchers at McGovern Medical, Houston TX, used genetically modified mice that overproduce a protein called amyloid precursor protein (APP) to test the hypothesis that ETAS®50 (a standardized form of ETAS) could protect brain cells by increasing heat shock proteins (HSPs) and by preventing apoptosis ⁶. ETAS®50 is comprised of two components: 50% elemental ETAS and 50% dextrin.

APP is the precursor to beta-amyloid. Mice that over-express APP are commonly used as animal models of human AD.

The researchers used two types of mice for this study: the genetically modified APP over-producers, and normal wild-type mice. All the animals were 6-8 weeks old and weighed between 20-24 grams.⁶ They were divided into five groups: one group of wild-type mice received ETAS®50 at 1,000 mg/kg. A second wild-type group received a saline control solution. There were three groups of APP-overproducing mice: one group received saline, the second received ETAS®50 at 200 mg/kg, and the third got ETAS at a daily dose of 1,000 mg/kg.

The saline solution served dual purposes: it was used as a vehicle for the ETAS®50, and as a control or placebo when given alone. The animals were treated daily for one month.

The researchers then tested the spatial memory of the mice using a method called the Morris Water Maze.⁶ The observations indicated that the APP mutant mice struggled with memory and cognitive functions compared to WT. Treatment with ETAS®50 led to improved memory in these mice, with the higher dose resulting in greater benefits, suggesting a dose-dependent effect.

When the study ended, the researchers examined the brains of the mice. The brains of the APP-overexpressers showed higher amounts of amyloid β, tau proteins, and caspase-3, all of which are associated with AD. However, treatment with ETAS®50 increased the levels of HSP70 and HSP27, and reduced the harmful levels of amyloid β, tau proteins, and caspase-3.

Overall, the study suggests that ETAS®50 could help protect the brain from AD-associated damage by boosting the body’s stress-response proteins and reducing harmful substances in the brain.⁶ This was confirmed by a significant increase in the expression of the HSP70 gene in the hippocampus.

Easing Dementia Symptoms

In Japan, a country where the population is aging rapidly, dementia is a significant public health concern.⁷ Pharmaceutical therapies are of limited efficacy, and some carry risk of serious potentially life-threatening side effects. As a result, there’s strong interest in finding holistic alternative treatments with a safer side effect profile.

ETAS®50 is one option, and Japanese researchers are studying it in the context of dementia. Previous research shows that ETAS®50 helps regulate the autonomic nervous system, which controls involuntary functions like heartbeat, digestion, and breathing.⁷ It also improves sleep quality and reduces stress, which could help alleviate dementia symptoms.

Takayuki Zenimoto and Mitsuhiko Takahashi at the Institute of Dementia, Japan Healthcare University, Sapporo, conducted a pilot trial to examine the effects of ETAS®50 on patients with mild to moderate dementia.⁷ The trial included 27 patients (mean age: 87.4 ± 11.6 years) and took place from October 2018 to February 2020. The patients were given ETAS®50 for 12 weeks, followed by a placebo for an additional 12 weeks.

To measure dementia symptom severity, the investigators used the Neuropsychiatric Inventory Questionnaire (NPI-Q-a) ⁷. They found significant improvement in symptoms during the ETAS®50 treatment period compared to the placebo period. Specifically, there was a significant reduction in agitation and depression. There was also a noticeable improvement in apathy, although this effect was not statistically significant.

Better Memory, Executive Function & Mood

Another pilot study on human subjects assessed whether ETAS could help people with mild cognitive impairment (MCI) maintain their cognitive abilities.⁸ MCI is often a precursor to development of Alzheimer’s disease (AD).

In this study, 30 participants were randomly divided into two groups.⁸ One group received a daily dose of 1,000 mg of ETAS daily, while the other group received a placebo. This continued for 12 months.

The investigators evaluated cognitive function using various neuropsychological tests, including the Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB), Clock Drawing Test (CDT), and Hospital Anxiety and Depression Scale (HADS). These tests measure cognitive performance, executive (planning and organizing) functions, visuospatial abilities, and levels of anxiety and depression, respectively.

The study subjects also underwent brain MRIs and EEGs, as well as blood tests to assess the participants’ HSP70 protein levels.⁸ This gave the researchers objective indicators of brain structure and function, and biomarkers of efficacy.  

The group receiving ETAS showed significant improvements in their MMSE, FAB, and HADS scores, suggesting better cognitive performance and lower levels of anxiety and depression.⁸ There was also a slight increase in their blood HSP70 levels. This group also maintained normal levels of the CD4/CD8 immune complex, a key factor in immune health. There were no adverse events associated with ETAS during the study.⁸

The researchers concluded that ETAS supplementation could potentially slow down cognitive decline and reduce symptoms of anxiety and depression which are often associated with AD.

Safe and Efficacious

A multi-center Japanese study published in December 2023 assessed the safety of ETAS, particularly regarding the potential for overdose, and the safety of long-term use.⁹ This was a double-blind, placebo-controlled trial involving 92 volunteers, of which 55 were selected after screening.⁹

The participants were divided into two groups: one received a daily dose of 1,500 mg of ETAS50, and the other received a placebo, for 28 days.

At baseline and again after the 28-day intervention, participants underwent blood and urine tests, anthropometric evaluations (measurements of the human body), and surveys.⁹ The effectiveness of ETAS was assessed by measuring blood cortisol levels, which is an indicator of stress.

The final analysis included 23 participants in each group.⁹ None of the participants withdrew from the study due to difficulties in taking the capsules. Importantly, no severe side effects were observed in either group.

In terms of effectiveness, only the placebo group showed significant increases in blood cortisol levels after the intervention, suggesting that the ETAS treatment had a stress-mitigating effect.⁹ The study concluded that ETAS can be safely administered with minimal side effects. Furthermore, it may have stress-relieving effects in healthy individuals.

END

Ari Magill, MD, is a board-certified neurologist, health researcher, and scientist with nearly 20 years of experience in clinical research and patient care. A graduate of the University of Texas Southwestern Medical School, and completed his neurology residency at the University of Arizona. He followed this with a fellowship in movement disorders at the University of Colorado. Dr. Magill has worked as a neurohospitalist and clinical researcher, treating patients with cognitive impairments, including veterans with traumatic brain injuries. He is passionate about cognitive, behavioral, and memory disorders, and functional medicine health coaching. Dr. Magill’s approach considers both eastern medicine’s preventive philosophies and western medicine’s focus on disease and injury treatment. Dr. Magill is a contract writer for Expert Institute, where he provides medical background reports for court cases. He is dedicated to advancing dementia treatment through neuroscience research and promoting comprehensive lifestyle changes supported by the judicious use of supplements..

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