ACEMg, the first clinically proven antioxidant supplement for hearing preservation

A paradigm shift to hearing preventive care in ENT medicine and audiology.

Why are antioxidant supplements popular? 

Google Gemini AI explains the popularity of antioxidants pretty well.

Antioxidant supplements are popular because of the perceived health benefits of fighting free radicals and preventing oxidative stress, which is thought to contribute to various diseases. 

What are antioxidants?
Antioxidants are substances that can prevent or delay some types of cell damage. They are naturally found in many foods, especially fruits and vegetables, and are also available as dietary supplements. 

Why are they considered beneficial?

Fighting free radicals: Free radicals are unstable molecules that can damage cells, proteins, and DNA. Antioxidants neutralize these free radicals, preventing or slowing down the damage they can cause. 

Oxidative stress: When free radicals outnumber antioxidants, it can lead to a state called oxidative stress, which can damage your DNA and other important molecules in your body. Antioxidants help reduce oxidative stress. 

Potential health benefits: Some research suggests that antioxidants may help reduce the risk of chronic diseases, such as heart disease, cancer, and age-related macular degeneration  

Clinical proof of antioxidants is rare

The Google Gemini AI explanation includes a few qualifiers.

“perceived health benefits…. potential health benefits … thought to contribute…. Some research suggests …”

The qualifiers are necessary because even though molecular and cellular biochemistry (life chemistry) on antioxidants is solid, clinical studies demonstrating the specific impact of an antioxidant or combination of antioxidants on human biological cell function are rare. It is not for lack of trying. Clinical research is complicated and most often quite costly.  Antioxidants don’t treat disease, they are preventive by nature, and prevention is difficult to prove. Dietary supplement companies have turned large clinical research problems into a $170 billion global consumer supplements industry aimed at people wanting to stay healthy, with Americans contributing about $50 billion to the total.

This long article examines the general health benefits of antioxidant supplements, then focuses on antioxidants in our area of expertise, hearing biochemistry, and explains how the ACEMg supplement formula was clinically proven to preserve or improve hearing [1].

1. How does hearing work?
2. What are micronutrients?
3. What are free radicals and how do they cause hearing loss?
4. Why are antioxidants at the forefront of auditory neuroscience research?
5. Why it is so hard to collect clinical data on antioxidant supplements?
6. How are real-world evidence studies being used to deliver ACEMg clinical data?

1. How does hearing work?

Sound becomes hearing in the organ of Corti within the cochlea, the inner ear, an auditory system that has evolved over 300 million years. Outer hair cells (OHC) in the organ of Corti are the heart of hearing. OHC convert sound wave energy into electrical signals through auditory transduction. The signals are sent through the auditory nerve to the brain’s auditory cortex within a few microseconds, significantly faster than vision.

OHC are tubular nerve cells with hair-like projections called stereocilia protruding from their tops. The stereocilia are arranged in a staircase pattern, mechanically sensitive to deflections caused by sound waves. OHC are unlike the hair on your head. They do not grow or regenerate, and their biochemical environment and function within the organ of Corti is unique in the human body.

Sound waves reach the fluid-filled inner ear through pulsations of the eardrum. The pulsations initiate a complex metabolic process that starts with the creation of pressure waves in the cochlear fluid that cause OHC stereocilia to bend, opening ion channels embedded in the cell. Ions are electrically charged molecules that change with the loss or gain of electrons. Ion exchange is the root of auditory transduction biochemistry.

In auditory transduction, ions flow into OHC, leading to a change in electrical potential, primarily potassium, K+, where the + indicates a positive charge from the loss of one electron, and calcium, Ca2+,  where 2+ indicates a positive charge from the loss of two electrons. These electrical charges initiate the nerve impulses that travel through the auditory nerve to the brain’s auditory cortex.

2. What are micronutrients?

Micronutrients are small molecules and cofactors, biochemical helper molecules used to create energy in metabolism, the process of cellular respiration. Vitamins and minerals are micronutrients. Their discovery is relatively recent. Most were discovered in the first half of the 20th Century [2]. There are two basic types of micronutrients. Endogenous micronutrients are produced within the body. Exogenous micronutrients originate in food.

Starting in the 1980s, auditory neuroscience research investigated the fundamental role of micronutrients in OHC metabolism. Since then, the investigation of micronutrients in the management of free radicals in OHC function has become a central focus of auditory neuroscientists studying hearing. Free radicals are reactive oxygen species (ROS), highly reactive ionic byproducts of metabolism.

3. What are free radicals and how do they cause hearing loss?

Auditory transduction is a metabolic process requiring a high rate of adenosine triphosphate, ATP, to fuel outer hair cell ion pumps and maintain the electrical charges called ionic gradients. In metabolism, mitochondria, the organelles within OTC, are responsible for producing ATP. Reactive oxygen species, commonly called free radicals are created as byproducts of metabolism. Cells, including OHC, must neutralize free radicals to maintain normal cell functioning. If not neutralized, free radicals create oxidative stress that can damage the cell.

Detoxification of OHC free radicals involves enzymes – proteins that speed up chemical reactions and carry electrons essential for producing ATP in metabolism within mitochondria, the power plant of cells. Micronutrients ensure cells have the molecular resources necessary to maintain ionic gradients, repair damage, and sustain the rapid pace of OHC signal transduction. Disruptions in the balance or availability of nutrients can compromise cell function and increase the risk of damage and dysfunction.

4. Why are antioxidants at the forefront of auditory neuroscience research?

Decades of investigations taught auditory neuroscientists that excess free radicals initiate oxidative stress, contributing to OHCl damage leading to SNHL.  In medical terms, ROS defines the pathogenesis and pathophysiology of SNHL, leading to a general hypothesis: 

Antioxidants can protect OHC by neutralizing excess inner ear free radicals.

Micronutrients, specifically antioxidants, are at the forefront of auditory neuroscience research because they protect inner ear cells from free radical damage, crucial for supporting the biochemical pathways that maintain normal OHC function [3]. 

Cells become vulnerable when antioxidant systems are overwhelmed, either through excessive free radical production, micronutrient deficiency, or a combination of both. Cells have evolved intricate antioxidant defense systems to neutralize free radicals and counteract oxidative stress. This vulnerability is particularly problematic in the auditory system, where the failure to neutralize excess free radicals can result in OHC damage, experienced as hearing loss. Hearing loss is thought to be permanent since OHC do not regenerate.

Exogenous micronutrients, including well-known antioxidant vitamins like A, C, and E, play protective roles in numerous tissues, including the inner ear. Beta carotene is a provitamin A  carotenoid, a group of natural pigments found in plants. Beta carotene, converted into vitamin A in the intestine as the body needs it, is one of the most well-known and abundant of the hundreds of different carotenoids, responsible for the orange-red color of many fruits and vegetables, such as carrots, sweet potatoes, and apricots.

Vitamin C is a potent water-soluble antioxidant that scavenges free radicals and protects cellular components from oxidative damage. Vitamin E is a fat-soluble antioxidant that safeguards lipids – fatty cell components – from free radical damage.

Public health studies, called epidemiological studies, have demonstrated correlations between higher dietary intake of antioxidants and lower levels of hearing loss in older adults. Specifically concerning hearing, these studies have shown that diets rich in carotenoids and vitamins C and E are associated with lower risks of hearing impairment, indicating that diets high in antioxidants may protect the auditory system.

However, public health data also demonstrate that diet alone is insufficient to prevent hearing loss. Lifestyle factors and environmental exposures, primarily noise and high sound pressure levels, or SPL,  accelerate the biological aging process by introducing intense metabolic auditory transduction demands that quickly exceed the storehouse of micronutrients required to maintain ionic gradients and sustain the rapid pace of signal transduction, making micronutrient supplementation, especially antioxidant supplementation, an important area of investigation for auditory health. As it is now understood that free radical-initiated SNHL, mainly from environmental sources, can happen at any age, the traditional distinction between so-called noise-induced hearing loss, or NIHL, and age-related hearing loss, or presbycusis, is disappearing.

In summary, antioxidants are at the forefront of auditory neuroscience research for many reasons.

• Preclinical studies in animals, mainly mice, rats, and guinea pigs, demonstrate that antioxidants can reduce hearing loss from noise and high SPL. Antioxidants directly neutralize free radicals, interrupting the cascade of biological events that lead to OHC damage.
• Exogenous antioxidant supplementation is inherently preventive, reducing the burden of endogenous supplements.
• Many antioxidants have multiple mechanisms of action. They can protect cellular membranes, maintain mitochondrial function, and even modulate inflammatory responses associated with cellular stress.
• Supplements can deliver antioxidants directly to the inner ear through the bloodstream, an appealing non-invasive therapeutic strategy.
• Many antioxidants, particularly those that are naturally present in the diet, have an excellent safety record, making them attractive candidates for long-term use in at-risk populations.
• Antioxidant therapies can be used alongside other treatments. They may enhance the efficacy of anti-inflammatory or ototoxic drugs, or work in synergy with other neuroprotective agents.
• Hearing loss is now understood to be the major controllable risk factor for dementia, mainly Alzheimer’s disease. By inference, mitigating SNHL may reduce dementia risk.

5. Why it is so hard to collect clinical data on antioxidant supplements?

The vast repertoire of around 400 antioxidant compounds presents a tantalizing prospect for protecting OHC from oxidative damage. It also presents a landscape of formidable challenges.

• The unique physiology of outer hair cells, their inaccessibility deep within the cochlea, and the complexity of replicating their natural environment mean that even the most promising antioxidant compounds face significant hurdles before they can be validated as effective therapies in clinical studies.
• Antioxidants may not act on a single target but can influence multiple cellular processes. Their effects might be synergistic or antagonistic when combined with other cellular pathways. This network of interactions makes it nearly impossible to attribute observed changes in outer hair cell function solely to one compound without inadvertently affecting other mechanisms.
• Each of the identified 400-plus naturally occurring exogenous provitamins, vitamins, carotenoids, and polyphenols has a unique chemical structure and works in a specific way, called a mechanism of action, which adds layers of complexity when investigating their biological impact. Testing each of the 400-plus antioxidants individually would require many hundreds of experiments with rigorous controls, randomized groups, and repeated trials. The sheer number of compounds, combined with variations in concentration and interactions, makes such comprehensive screening virtually impossible.
• In vitro experiments, conducted outside a living organism, often fail to replicate the inner ear microenvironment. In randomized controlled studies, including in vivo studies, every variable aside from the one being tested must be kept constant. The inherent dynamic nature of OHC makes the control of noise exposure, oxygen levels, metabolic state, and even genetic variations of animal subjects quite challenging. Moreover, OHC are delicate and highly sensitive to their native conditions. They do not respond well outside the organ of Corti. The hearing systems of mice, rats, and guinea pigs are similar to humans.
• Histology, the examination of tissue microanatomy, which typically relies on destructive analyses, provides a static snapshot of OHC structure after experimental treatment but is generally unable to capture dynamic processes like changes in ion flux or real-time ROS scavenging and might not capture subtle biochemical changes in ROS levels or mitochondrial function. Replication of the in vivo environment is therefore not possible, and neither are predictions from in vivo studies onto humans.

6. How are real-world evidence studies being used to deliver ACEMg clinical data?

SNHL arises from a complex interplay of environmental, lifestyle, and genetic factors. While randomized controlled trials (RCTs) have long been the gold standard in clinical research, they present significant limitations for evaluating antioxidant supplements in hearing preservation.

RCTs require strict controls and a uniform participant pool, conditions that do not easily accommodate the diversity of real-life hearing risks. The combination of multifactorial etiology with typically long latency before measurable hearing loss occurs creates large challenges in designing and conducting RCTs that capture the long-term benefits of antioxidant interventions.

Non-randomized, long-term real-world evidence (RWE) and real-world data (RWD) studies solve these problems by gathering information from everyday settings to offer a more authentic snapshot of how treatments perform across a heterogeneous population. These studies not only produce more accurate data than traditional public health surveys but also reflect the complex interplay of lifestyle, genetics, and environmental factors that influence hearing health.

Importantly, the 21st Century Cures Act of 2016 bolstered the legitimacy of RWE/RWD trials by formally recognizing their value in supporting regulatory decisions, advancing medical research, and improving public health. This legislative endorsement marks a significant shift, encouraging the adoption of RWE/RWD approaches to complement—and in some cases, even supplant—RCTs for conditions like SNHL, where long-term outcomes and real-world variability are critical [4].

An N-of-1 study monitors an individual’s response to a treatment over time. The ACEMg antioxidant formula was demonstrated in a 2-year, non-randomized clinical RWE/RWD study to protect, preserve, and also improve the function of outer hair cells within six months for 75.3% of daily users [5].

Scale-free RWE/RWD studies use the same data-gathering protocol for each participant to create a large-scale, non-randomized dataset. Soundbites is at the forefront of using the scale-free RWE/RWD clinical research design with the 24-week OTIS Study of ACEMg (Soundbites), conducted by participants at home. The OTIS Study aims to validate the hearing preservation or improvement findings from the 2-year RWE/RWD study, and assess its impact on the relief of tinnitus and hyperacusis symptoms. The common protocol enables individual data to be aggregated. Informed consent and data-sharing agreements enable the findings to be published for access by the public and health agencies [6].

References

1. Videos with handouts and supplemental materials explaining the anatomy, physiology, normal and dysfunctional inner ear biochemistry are available at keephearing.org.
2. Nutrition History of modern nutrition science—implications for current research, dietary guidelines, and food policy. https://www.bmj.com/content/361/bmj.k2392
3. Protective effects of vitamins/antioxidants on occupational noise-induced hearing loss: A systematic review, Journal of Occupational Health, https://academic.oup.com/joh/article/63/1/e12217/7249811

4. https://www.fda.gov/regulatory-information/selected-amendments-fdc-act/21st-century-cures-act#

5. Impact of the ACEMg Biomedicine on Sensorineural Hearing Loss and Auditory Function: Analysis of Real-World Clinical Data,  https://doi.org/10.31219/osf.io/uw7tq

6. ACEMg Hearing Preservation and Tinnitus Relief (OTISRWD), https://clinicaltrials.gov/study/NCT06477354?term=NCT06477354&rank=1