RESEARCH

OVER 30 YEARS OF SCIENTIFIC RESEARCH ON HEARING LOSS

R&D
Summary

Noise Induced Hearing Loss (NIHL) was a primary driver of the research and discoveries through empirical observations in animal models of the relevance of free radical formation as the primary underlying mechanism responsible for NIHL. There is a compelling empirical data base in animals and a consensus in the field that free radicals are significantly responsible for NIHL; that blood flow is an additional key factor; and that the ACEMg antioxidants-plus-vasodilator formulation (ACEMg) will provide an effective treatment for many. Specifically:

  • Discovery of formation of free radicals in the inner ear following intense noise;
     

  • Surprising quantification of a 40-fold increase in free radical formation in the inner ear following exposure to intense noise;
     

  • Demonstration that modulation of endogenous antioxidant systems modulate the extent of noise-induced pathology (i.e., down-regulation of endogenous systems increases noise-induced pathology);
     

  • Demonstration that additional exogenous antioxidants decrease noise-induced pathology;
     

  • Identification of the source of free radicals reflecting noise-induced demand for energy resulting in increased free radical formation as part of the mitochondrial respiratory chain;
     

  • Modeling of the biochemical cell death pathway from noise to free radical formation to cell death;
     

  • Demonstration that these findings were similar across a number of different rodent animal models and species;
     

  • Discovery that this model is identical to that across organ systems demonstrating stress-induced free radical formation leading to pathology;
     

  • Discovery that in the inner ear the sequence, pathways and pathology are common to other stress agents. Free radicals define the “common cell death pathway” of drug-induced hearing loss, age-related hearing loss, certain genetic hearing loss, and trauma-induced pathology;
     

  • Identification of a uniquely effective formulation of antioxidants and inner ear vasodilator (ACEMg) preventing stress-induced cell death;
     

  • Finding that in a small sample (N=8) of military officers undergoing “urban warfare” training, requiring firing a high powered rifle in an enclosed space which resulted in a temporary hearing loss, the loss was reduced by 50% when they had taken ACEMg prior to the exercise compared to the hearing loss when they had taken a placebo prior to the exercise.

Josef M. Miller, PhD

Professor Emeritus, University of Michigan
Professor, Karolinska Institute, Stockholm, Sweden
Director, Tissue Engineering Laboratory
Kresge Hearing Research Institute, University of Michigan Medical School
Founder, Hearing Health Science

Dr. Miller was one of the world’s leading research neuroscientists. His work on the biochemistry of free radicals in inner ear pathology changed the way research neuroscientists consider acquired hearing loss. He is the author of more than 350 scholarly articles in peer reviewed academic journals, 283 of which are catalogued here.

ACEMg softgel capsules are a retail OTC nutraceutical and an epidemiological study agent for real world evidence (RWE) studies of NIHL, age-related hearing loss (ARHL) and tinnitus. The softgels are also intended for use as an active and placebo clinical medicine in random control trials (RCT) to treat the ototoxic side effect of aminoglycoside antibiotics. The active and placebo liquid format of ACEMg is intended as an RCT clinical medicine to treat hearing loss caused by the Connexin 26 genetic defect.

Summary of continuing research

Dr. Miller is the lead editor of the definitive work of compiled scholarship in the field, “Free Radicals in ENT Pathology,” (Springer. 2015).

From the publisher’s review:

Assembles comprehensive reviews on a broad variety of ENT pathology, including areas partially covered in current literature, such as the role of nutrition and heavy metals in hearing. Discusses the interrelationship of basic and translational studies. Uniquely outlines a path for future research and development of antioxidant interventions.

Dr. Miller has a record of more than thirty years of biomedical research accomplishments continuously supported by €28 million in grants from the USA National Institutes of Health and the European Commission.

More than 30 basic and translational research papers have been published in leading peer reviewed academic scientific journals by Dr. Miller and a diverse team of colleagues. Author Michael Lewis makes this point about papers in academic journals in his book “The Undoing Project”.

Papers written for social science journals are not intended for public consumption. For a start, they’re instinctively defensive. The readers of academic papers, in the mind’s eye of their authors, are at best skeptical, and more commonly hostile. The writers of these papers aren’t trying to engage their readers, much less give them pleasure. They’re trying to survive them.

The work of Dr. Miller and his team not only survived peer review, their discoveries changed the way scientists understand acquired hearing loss. Their work succeeded in superseding (replacing) more than a century of conventional wisdom that the cause of hearing loss is biomechanical.

Dr. Miller and his team demonstrated that the fundamental, common underlying cause of acquired hearing loss is biochemical. That understanding is now settled science. Dr. Miller and his team were leaders creating the new field and defining its doctrine.

The research by Dr. Miller and his team demonstrated that hearing loss is caused by excess inner ear free radicals triggering oxidative stress and restricted blood flow. Excess free radicals initiate a metabolic stress disorder that disrupts normal cellular function and can damage cells. Damage can end in cell death, which is experienced as hearing loss. Hearing loss is permanent since hearing cells do not regenerate. Hearing damage and hearing loss are often accompanied by tinnitus, or ringing in the ears. The description of tinnitus is somewhat misleading because tinnitus is a neurological disorder; the sound originates in the brain. There is no cure for tinnitus either.

 

Further, Dr. Miller and his team identified a hearing preservation therapeutic, a safe micronutrient cocktail of antioxidant vitamins A, C and E and the vasodilator mineral Magnesium (Mg) – known in the medical literature as ACEMg (say ‘Ace Mag’). ACEMg stops the problem at its source, eliminating excess free radicals, helping protect inner cells from oxidative stress and maintain normal inner ear blood flow.

Dr. Miller’s work on the underlying causes of acquired hearing loss started in 1986. His work in noise-induced formation of free radicals in noise-induced hearing loss (NIHL) and antioxidants to prevent NIHL began in the mid-1990s.

 
 
 
 

2008

Described the genes involved with NIHL: [Yamashita D, Minami SB, Kanzaki S, Ogawa K, Miller JM.: Bcl-2 Genes Regulate Noise-Induced Hearing Loss, J Neurosci Res 86(4):920-928, 2008] PMID: 17943992

2011

Showed that the ACEMg antioxidant formulation given orally in humans increases plasma levels of the antioxidants: Le Prell CG, Johnson AC, Lindblad AC, Skjonsberg A, Ulfendahl M, Guire K, Green GE, Campbell KCM, Miller JM.: Increased vitamin plasma levels in Swedish military personnel treated with nutrients prior to automatic weapon training, Noise Health 13:55, 432-43, 2011] PMID: 22122960

REAL WORLD EVIDENCE STUDY

For the first time, it’s possible to collect environmental, demographic and genetic data, measuring effectiveness of a safe solution to preserve hearing and maintain social vitality throughout life.

The ACEMg real world epidemiological studies are citizen science in the public interest.Ultimately the studies will scale globally.

We’re recruiting pilot tests participants from the dance music scene. Sign up below for the newsletter to keep in touch and if you choose, participate in the study.

HELP YOURSELF AND HELP OTHERS

 

If you sign up for our monthly newsletter then we will keep you informed as to the progress of our Real World Evidence Study. We will also inform you how you can participate in the program. 

Data Protection is very important to us and we will never pass your personal data onto a 3rd party or sell your data.

 

1999

A variety of interventions that reduced free radicals prevented NIHL [Yamasoba T, Schacht J, Shoji F, Miller JM: Attenuation of cochlear damage from noise trauma by an iron chelator, a free radical scavenger and glial cell line-derived neurotrophic factor in vivo, Brain Res 815(2): 317-325, 1999] PMID: 9878807

1998

The antioxidant glutathione prevents NIHL [Yamasoba T, Nuttall AL, Harris C, Raphael Y, Miller JM: Role of glutathione in protection against noise-induced hearing loss, Brain Research 784(1-2): 82-90, 1998] PMID: 9518561


Intense noise upregulated endogenous antioxidant systems [Yamasoba T, Harris C, Shoji F, Lee RJ, Nuttall AL and Miller JM: Influence of intense sound exposure on glutathione synthesis in the cochlea, Brain Research 804(1): 72-78, 1998] PMID: 9729286


Aging increased sensitivity to NIHL [Miller JM, Dolan DF, Raphael Y and Altschuler RA Interactive effects of aging with noise induced hearing loss, Scand Audiol Suppl 48: 53-61, 1998] PMID: 9505298

Researchers seeking access to source articles who do not have access to paid subscriptions through their institutions may request a copy for their personal use by contacting research@hearinghealthscience.com

Research and discoveries leading to ACEMg

2000

Neurotrophins that have antioxidant properties reduce NIHL [Shoji F, Yamasoba T, Magal E, Dolan DF, Altschuler RA, Miller JM: Glial cell line-derived neurotrophic factor protects auditory hair cells in the guinea pig cochlear from noise stress in vivo, Hear Res 142(1-2): 41-55, 2000] PMID: 10748327

 

Not all neurotrophins have similar properties [Shoji F, Miller AL, Mitchell A, Yamasoba T, Altschuler RA, Miller JM: Differential protective effects of neurotrophins in the attenuation of noise-induced hair cell loss, Hear Res 146(1-2): 134-142, 2000] PMID: 10913890

Replicated and extended observation on the protective value of exogenous glutathione for NIHL [Ohinata, Y, Yamasoba, T, Schacht, J and Miller JM: Glutathione limits noise-induced hearing loss, Hear Res 146(1-2): 28-34, 2000] PMID: 10913881

Intense noise causes massive formation of free radicals in inner ear. We identified the underlying mechanism for the decrease in blood flow: Ohinata Y, Miller, JM, Altschuler RA and Schacht J: Intense noise induces formation of vasoactive lipid peroxidation products in the cochlea, Brain Res 878(1-2): 163-173, 2000] PMID: 10996147

2003

Showed that a variety of agents that prevent free radical induced lipid peroxidation prevent NIHL. [Ohinata Y, Miller JM, Schacht J: Protection from noise-induced lipid peroxidation and hair cell loss in the cochlea, Brain Res 966:265-273, 2003. PMID: 12618349

 

Described pathway to cell death induced by noise. [LePrell CG, Dolan DF, Schacht J, Miller JM, Lomax MI, Altschuler RA: Pathways for protection from noise induced hearing loss, Noise & Health 5(20):1-17, 2003] PMID: 14558888

Showed that 8-iso-prostaglandin F(2alpha), a product of noise exposure, reduces inner ear blood flow [Miller JM, Brown JN, Schacht J: Audiol Neurootol 8:207-221, 2003]. PMID: 12811002.

2001

Neurotrophic factors with little antioxidant properties did not protect the inner ear from NIHL. [Yamasoba T, Altschuler RA, Raphael Y., Miller AM, Shoji F, and Miller JM: Absence of hair cell protection by exogenous FGF-1 and FGF-2 delivered to the guinea pig cochlea in vivo, Noise Health 3:65-78, 2001] PMID: 12689449

2004

Described new cell death pathway involved in NIHL [Minami SB, Yamashita D, Schacht J, Miller JM: Calcineurin activation contributes to noise-induced hearing loss, J Neurosci Res 78 383-392, 2004. PMID: 15389832

 

Showed that steroids could attenuate NIHL: [Takemura K, Komeda M, Yagi M, Himeno C, Izumikawa M, Doi T, Kuriyama H, Miller JM, Yamashita T.: Direct inner ear infusion of Dexamethasone attenuates noise-induced trauma in guinea pig, Hear Res 196(1-2): 58-68, 2004. PMID: 15464302

 

Described yet another important pathway to cell death from intense noise: [Yamashita D, Miller JM, Jiang H-Y, Minami SB, Schacht J: AIF and EndoG in noise-induced hearing loss, Neuroreport 15(18): 2719-2722, 2004] PMID: 15597041

Showed that antioxidant treatment following the noise exposure (“morning after pill”) could prevent NIHL: [Yamashita D, Jiang H-Y, Schacht J, Miller JM: Delayed production of free radicals following noise exposure, Brain Res 1019: 201-209, 2004] PMID: 15306254

Yamashita D, Jiang H-Y, LePrell CG, Schacht J, Miller JM: Post-exposure treatment attenuates noise-induced hearing loss, Neurosci 134(2): 633-642, 2005] PMID: 15961244

2014

Showed that elevated intake of the micronutrients ACEMg reduced the risk of hearing loss: Antioxidant vitamins and magnesium and the risk of hearing loss in the US general population, [Yoon-Hyeong Choi, Josef M Miller, Katherine L Tucker, Howard Hu, and Sung Kyun Park, Am J Clin Nutr. 2014 Jan; 99(1): 148–155]

Showed that ACEMg slowed progression of deafness for a boy with GJB2 (CONNEXIN 26) mutations: [Aaron Thatcher, Colleen Le Prell, Josef Miller, Glenn Green, ACEMg supplementation ameliorates progressive Connexin 26 hearing loss in a child, International Journal of Pediatric Otorhinolaryngology, Volume 78, Issue 3, March 2014, Pages 564–566]

2016

Showed that an appropriate conditioning noise exposure may reduce a subsequent noise-induced threshold shift. Preclinical study of ACEMg supported by the EC grant to the ProHearing consortium: [Juan C. Alvarado, Verónica Fuentes-Santamaría, María C. Gabaldón-Ull, Tania Jareño-Flores, Josef M. Miller, and José M. Juiz: Noise-Induced “Toughening” Effect in Wistar Rats: Enhanced Auditory Brainstem Responses Are Related to Calretinin and Nitric Oxide Synthase Upregulation (Front Neuroanat. 2016; 10: 19]

Further to the 2014 Green et al Connexin 26 case study, showed that the ACEMg Diet Supplement Modifies Progression of Hereditary Deafness, [Kari L. Green, Donald L. Swiderski, Diane M. Prieskorn, Susan J. DeRemer, Lisa A. Beyer, Josef M. Miller, Glenn E. Green, and Yehoash Raphael, Sci Rep. 2016; 6: 22690]

2006

Described mechanisms of NIHL and biochemical pathways to cell death induced by noise. [Miller J, Yamashita S, Minami S, Yamasoba T and LePrell C.: Mechanisms and prevention of noise induced hearing loss, Otol Jpn 16 (2):139-153, 2006]

2015

Showed that ongoing administration of ACEMg delayed the onset and reduced the level of age-related hearing loss (ARHL). Findings justified US Patent application 15/272,981 for ACEMg as a therapeutic treatment for ARHL: Juan Carlos Alvarado, Verónica Fuentes-Santamaría, Pedro Melgar-Rojas, María Llanos Valero, María Cruz Gabaldón-Ull, Josef M. Miller, and José M. Juiz, Synergistic effects of free radical scavengers and cochlear vasodilators: a new otoprotective strategy for age-related hearing loss Front Aging Neurosci. 2015; 7: 86]

Showed that the ACEMg dietary supplement can be beneficial for reducing hearing loss due to aminoglycosides and overstimulation: [C. G. Le Prell, C. Ojano-Dirain, E. W. Rudnick, M. A. Nelson, S. J. DeRemer, D. M. Prieskorn, and J. M. Miller: Assessment of Nutrient Supplement to Reduce Gentamicin-Induced Ototoxicity, J Assoc Res Otolaryngol. (JARO) 2014 Jun; 15(3): 375–393

2007

[Le Prell CG, Yamashita D, Minami S, Yamasoba T, Miller JM.: Mechanisms of noise-induced hearing loss indicate multiple methods of prevention, Hear Res 226(1-2):22-43, 2007] PMID: 17141991; PMC1995566 §

 

Identified a new micronutrient formulation of antioxidants and a vasodilator that synergistically and dramatically protected the ear from NIHL. [Le Prell CG, Hughes LF, Miller JM.: Free radical scavengers, vitamins A, C, and E, plus magnesium reduces noise trauma, Free Rad Biol Med 42(9): 1454-1463, 2007]. PMID:17395018; PMCID: PMC1950331

Described additional important cell death pathways, elaborating the mechanisms involved with NIHL. [Minami SB, Yamashita D, Schacht J, and Miller JM.: Creatine and tempol attenuates noise-induced hearing loss, Brain Res 1148:83-89, 2007] PMID: 17359945; PMCID: PMC2680083

2009

Hearing regeneration research has been ongoing since the mid-1980s in parallel with hearing preservation research. The Kresge Hearing Research Institute (KHRI) at the University of Michigan Medical School participates in both lines of research. Dr. J.M. Miller served as Director of KHRI from 1984-2000. Additional information on KRHI is available at https://medicine.umich.edu/dept/khri/about-us/khri

 

Cell replacement therapy is a potentially powerful approach to replace degenerated or severely damaged spiral ganglion neurons. This study aimed at stimulating the neurite outgrowth of the implanted neurons and enhancing the potential therapeutic of inner ear cell implants: [Zhengqing Hu, Mats Ulfendahl, Diane M. Prieskorn, N. Petri Olivius, and Josef M. Miller: Functional evaluation of a cell replacement therapy in the inner ear, Otol Neurotol. 2009 Jun; 30(4): 551–558.