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Presbyacusis, Dietary Restrictions and Antioxidants

Michael D. Seidman, M.D.
Department of Otolaryngology
Head and Neck Surgery
Henry Ford Health System
6777 West Maple Road
West Bloomfield, MI 48323
(248) 661-7211 / (248) 661-6456 FAX
mseidma1@hfhs.org

"Effects of Dietary Restriction and Antioxidants on Presbyacusis,"

Laryngoscope, May, 2000;110:727-738. #35497

Kirk Hamilton: Could you please share with us your educational background and current position?


Michael D. Seidman: I attained my Bachelor of Science in Human Nutrition and Doctor of Medicine from the University of Michigan. After a five year residency in Otolaryngology-Head and Neck Surgery at Henry Ford Health System (HFHS) I completed a fellowship in Otology/Neurotology and Skull Base Surgery at the Ear Research Foundation in Sarasota, Florida. I am currently directing the Division of Otologic/Neurotologic Surgery in the Department of Otolaryngology-Head and Neck Surgery for HFHS. I am the Director of the Otolaryngology Research Laboratory, the Co-Director of the Tinnitus Center and the Medical-Chair of the Complementary/Integrative Medicine Initiative for HFHS. Additionally, I am an active scientist and have extramural funding from the National Institute of Health and other major institutions.

I have expertise in the molecular basis of aging, noise-induced hearing loss, otology/neurotology-skull base surgery and in nutrition/antioxidants and their relationship to health and aging. I have been invited to lecture around the world on such topics, have more than 75 major publications and awards, have a US patent on a supplement that positively effects age-related hearing loss, and several patents pending on aging, mitochondrial function and Alzheimer?s disease.

In 1997, I founded and became the CEO of Body Language Vitamin Company. Our emphasis is to promote health and enhance the lives of everyone through responsible vitamin, mineral, herbal and phytonutrient supplementation as well as dietary modifications, exercise and stress reduction. I am the co-editor for the International Tinnitus Journal and I am on the editorial review board for four major otolaryngology journals and the American Journal of Chinese Medicine. Additionally, I serve on the Scientific or Medical Advisory Board of the Self Help for Hard of Hearing People Inc., the Life Extension Foundation, the Ear Research Foundation, Nutrition Superstores.com, Geltech, Inc. and the American Tinnitus Association.

KH: Why did you think that dietary restriction and antioxidants may be involved in age related hearing loss?

MDS: Aging is a complex process that involves many disciplines including molecular biology, biochemistry, genetics, physiology, etc. There is compelling evidence that aging processes can be attenuated through genetic/molecular manipulation. This has been clearly shown in the earthworm (life span can be increased significantly by altering the expression of specific genes). Additionally, dietary manipulation (caloric restriction of 30% has been demonstrated to increase life span by up to 30% to 50%) and antioxidant manipulation (animals with higher antioxidant defenses/levels have longer life spans have been shown to reduce the effects of aging and extend lifespan).

The supposition that dietary restriction and antioxidants should have an effect on age-related hearing loss seemed almost obvious when considering the literature relating the general "anti-aging" effects of dietary restriction and antioxidants. Dietary restriction can positively affect longevity, and antioxidants appear to reverse or retard some of the age-related increase in reactive oxygen species.

Our laboratory has spent the past 10 to 15 years trying to unlock some of the secrets of aging in the inner ear. It must be emphasized that the processes of aging occurring in the inner ear are also happening in the brain, heart and throughout the entire body. Thus, I firmly believe, and already have significant evidence, that the patent I have developed that has improved age-related hearing loss will also improve aging in general.

In order to understand some inherent properties of aging, I would like to discuss the Membrane Hypothesis of Aging or the Mitochondrial Clock Theory of Aging. The mitochondrion is the cell?s powerhouse. It is responsible for the production of more than 95% of all the energy needed by our bodies. When energy is formed by the mitochondria, there is a by-product formed called a free radical or a reactive oxygen species (ROS). The Membrane Hypothesis of Aging (MHA), also called the Mitochondrial Clock Theory of Aging, is based upon the progressive accumulation of free radical damage, also known as oxidative damage. Oxidative damage is caused by the action of ROS, which are generated in increasing quantities with age. ROS are known to damage deoxyribonucleic acid (DNA) in general and mitochondrial DNA, in specific, as well as cells and tissue. This mitochondrial DNA damage leads to reduced ability for energy production and ultimately causes aging and death. This is the premise for the use of powerful antioxidants to slow the processes of aging.

The mitochondrion is a tiny structure inside a cell and it has its own DNA that determines all the functions of the mitochondria. The mitochondrial DNA (MtDNA) is made up of 16,569 tiny molecules (base pairs) that when completely intact makes energy for the body extremely efficiently. However, if there are subtle changes in the DNA there can be dramatic effects on energy production. Research in our laboratory, as well as several others around the world, has identified a specific deletion (or elimination) in mitochondrial DNA that is known to occur in response to aging. It is called the common aging deletion and consists of 4,977 base pairs. It is not difficult to comprehend that if you remove approximately 1/3 of the mitochondrial DNA you will have significant problems with energy production and cellular function. This deletion can be measured in our bodies and effectively translates to a molecular test for aging, and although not yet commercially available, I have a patent pending on this technology and our laboratory has been studying this deletion in mice, rats and humans for many years. We also know that this deletion can be identified in cells as early as 20 years of age and there are some medical conditions where this deletion can be seen as early as one year of age.

Studies from our laboratory have demonstrated an age-dependent increase in the presence of the common mitochondrial deletion (MtDNA4977)(Seidman et al 2000). Specifically, we identified this common aging deletion in only one of fifteen young rats, while eleven of fourteen aged rats had the MtDNA deletion. The aged rats also had hearing loss and what?s even more interesting is that the three aged rats without the deletion had better hearing when compared to the eleven with the deletion. We were also able to study mitochondrial function in aged rats and humans, as you would predict, it was significantly reduced compared to the young subjects. (Seidman et al 2000). Human studies have revealed the presence of this MtDNA deletion in white blood cells of patients with age-related hearing loss more often that in control patients (Ueda et al 1998). Two other human studies have identified the common aging deletion (MtDNA4977) in patients with age-related hearing loss more than in control subjects (Bai et al 1997, Fischel-Ghodsian et al 1998).

It is known that certain tissues are more susceptible to oxidative damage (damage from free radicals) and reduced energy supply. This is especially true for tissues that no longer make new cells. For example the brain, eye, inner ear and muscle accumulate high amounts of these deletions, making them more susceptible to free radical damage than other tissues. Therefore, increased oxidative damage that is associated with aging preferentially affects these tissues.

Another significant problem that occurs with age is the reduction in enzymes that protect from ROS damage including superoxide dismutase, catalase and glutathione peroxidase (Semsei et al 1982; 1989; Richardson et al 1987). Thus, with aging, we produce less energy, make more free radicals and have fewer mechanisms to protect us from these changes. The cumulative effect contributes to the aging process and to the occurrence of many diseases.

KH: Can you tell us a little about your study and the results?

MDS: The premise of our most recent studies is that the membrane hypothesis of aging (MHA), also known as the mitochondrial clock theory of aging is the basis for presbyacusis. Furthermore, treatment with antioxidants or dietary restriction can attenuate age-related hearing loss. Many studies have demonstrated a reduction in blood flow to specific tissues including the cochlea with aging. Hypoperfusion further leads to the formation of reactive oxygen species (ROS). ROS are highly toxic molecules directly affecting tissues including inner ear structures. Additionally, ROS can damage mitochondrial DNA (MtDNA) resulting in the production of specific MtDNA deletions (MtDNA del49777 {human} or MtDNA del4834 {rat}; also known as the common aging deletion).

This prospective randomized study provides compelling evidence that long-term treatment with compounds that block or scavenge reactive oxygen species attenuate age-related hearing loss and reduce the impact of associated deleterious changes at the molecular level. Additionally, this thesis will present data suggesting that the common aging deletion MtDNA4834 may not only be associated with aging but also with presbyacusis.

130 rats were assigned randomly to one of six groups with appropriate controls. The animals were divided into the following treatment arms, using ten to determine the appropriate caloric restriction:

Group 1) 30% caloric restriction

Group 2) Vitamin E over-treatment supplementation

Group 3) Vitamin C over-supplementation

Group 4) Treatment with melatonin

Group 5) Treatment with Lazaroids

Group 6) Treatment with placebo

All subjects were tested at baseline and every three months until their health failed (range 16-32 months with an average of 25 months). This testing included auditory sensitivity studies, using auditory brainstem responses (ABR) and tissue analysis for MtDNA deletions, using molecular biologic techniques. At the conclusion of the study, the animals underwent a final ABR, were tested for mitochondrial DNA deletions in the brain, liver, skeletal muscle and inner ear tissues. Their opposite ear was used for histologic analysis.

Results indicate that the 30% caloric restricted group maintained the most acute auditory sensitivities, the lowest quantity of MtDNA deletions, and the least amount of outer hair cell loss. The placebo subjects had the poorest auditory sensitivity, the most MtDNA deletions, and the greatest degree of outer hair cell loss. The treatment subjects fared better than the placebo group in the tested parameters but were worse than the diet restricted subjects.

Intervention designed to reduce reactive oxygen species damage, protects against age-related hearing loss specifically and aging generally. This is reflected by the improvement in mitochondrial function as seen in the treated groups and an overall reduction in MtDNA deletions. The data also suggests that the common aging deletion appears to be associated with presbyacusis, as demonstrated by an increased frequency of the MtDNA del4834 in the cochleae with the greatest amount of hearing loss. In conclusion, nutritional and pharmacologic strategies may very well provide rational treatment options that would limit the age-associated increase in ROS generation, reduce or prevent MtDNA damage, improve mitochondrial function, and preserve hearing as the organism advances in age.

KH: Can you tell us if there is any human data which suggests antioxidants and dietary restriction slow the incidence of hearing loss?

MDS: There is extensive evidence that antioxidants and dietary restriction can positively affect aging in animals and humans, although humans are less well studied. In regard to the incidence of age-related hearing loss, the only animal data that exists is the work that we have published in American Journal of Otology in 2000 and the Laryngoscope 2000. This study investigated aged rats with moderate hearing loss in response to placebo, acetyl-L-carnitine or alpha lipoic acid. These two compounds work to improve mitochondrial function and reduce the damaging effects of ROS. The experiments assessed hearing in rats that were 24 months of age, which is equivalent to approximately 80 to 85 human years. The animals were fed either a placebo or one of the two nutrients for six weeks. The findings demonstrated the hearing worsening in the placebo animals, while the treated subjects had a statistically significant improvement in auditory sensitivity. Specifically, the animals fed acetyl-L-carnitine and alpha lipoic acid had improved hearing by 7 dB while the placebo rats lost approximately 5dB of hearing. The Laryngoscope article details the study of 130 rats described above.

Another study from our laboratory, which will be presented soon, revealed that polyunsaturated phosphatidylcholine (PPC), from soy bean extract, protects against age-related hearing loss. A group of rats were fed a placebo (normal) diet while the treatment group received a test diet that was precisely the same as the placebo with the exception of having polyunsaturated phosphatidylcholine (PPC) added to it. The study was completed over six months using 18- to 20-month-old subjects. We were able to study mitochondrial function using a sensitive and complicated series of laboratory tests and identified that the treated subjects had a four-fold higher mitochondrial function than the placebo animals. Additionally, the treated animals experienced only a 10 to 18 dB worsening of their hearing while the placebo group had a 35 to 47 dB drop in their hearing. Collectively, these data support the hypothesis that PPC can preserve and actually enhance mitochondrial function and delay the progression of age-related hearing loss. Studies that have been conducted over the past 10 to 15 years, clearly support the use of nutritional strategies to positively influence the aging process. Human studies clearly need to be done but will require significant resources to conduct. In view of the intense competition for funding at the national level, it is difficult to secure these funds. Additionally, pharmaceutical companies are typically not interested in supporting the studies as patents are not routinely available for such nutritional compounds.

KH: Have you used this approach in your patients and seen results? What is your nutritional supplement and dietary regimen?

MDS: I am a staunch advocate of appropriate lifestyle choices, such as elimination of tobacco use, maintaining appropriate weight, using alcohol in moderation, adhering to an excellent diet, exercise, reducing stress and I always recommend the appropriate use of nutritional supplements including vitamins, minerals, herbs and phytonutrients.

When specifically looking at hearing loss patients, they are treated similarly to my other patients and I strongly advocate excellent lifestyle choices. When asked about supplements that may help hearing, data only exists for our patented formula. A number of patients have reported improvement in hearing. Their hearing was typically improved by 5dB. However, this is within inter-test variability and I must emphasize, that careful clinical studies are warranted. We would be thrilled to do these studies with appropriate funding.

The specific dietary supplements that I recommend are: Body Language Vitamin Co. Multi-vitamin formula (PROPRIETARY) (3 pills/day), Body Language Vitamin Co. Antioxidant formula (PROPRIETARY) (2 pills/day), and Body Language Vitamin Co. Anti-age/Energy formula (PATENTED) (1pill/day). (Body Language Vitamin Co., W. Bloomfield MI. www.bodylangvitamin.com or 877-LIVE-FIT.)

KH: For the supplements you recommend, can you share with us how they might work in protecting DNA and also improve blood flow to the inner ear structures?

MDS: Experimentally and clinically, it is well known that a primary source of ROS generation is through oxidative phosphorylation, ischemia/reperfusion or prolonged hypoperfusion (such as is seen in myocardial infarction), cerebrovascular accidents, aging, possibly sudden sensorineural hearing loss and presbyacusis. It is clear that in the aging cochlea there is a significant reduction of perfusion (Seidman MD, et al 1996) and the ongoing need for energy generation through oxidative phosphorylation. Therefore, these two processes allow for the generation of ROS within the cochlea.

In regard to vascular changes associated with aging, the aging process is clearly linked with alterations in circulatory function. Studies have demonstrated markedly decreased flow within the circulatory system in the elderly population (Gacek et al, 1969; Harkins, 1981; Rosenhall et al, 1986; Haeffding et al, 1987). Prolonged periods of reduced blood flow (hypoperfusion) may lead to decreased oxygen tensions within tissues culminating in the generation of damaging ROS.

Various lines of research have centered around the concept that altered blood flow and/or oxygen delivery results in inner ear hair cell damage and hearing loss. In a human cadaveric study of cochlear vessels, an age related, gradual loss of capillaries in the spiral ligament of the scala vestibuli was observed, with an increase in intravascular strands and avascular channels. Similar, but less pronounced findings were noted in the spiral ligament in the scala tympani (Johnsson and Hawkins, 1972b). Another human cadaver study, using a micro sphere technique to quantify blood flow, found diminished flow in morphometrically normal appearing basal turn capillaries (Prazma et al, 1987). Changes in whole blood viscosity and red cell rigidity have been correlated with high frequency hearing loss in elderly human subjects (Gatehouse and Lowe, 1991). A series of in vivo experiments using intra vital microscopy of the cochlear microvasculature, demonstrated age-dependent statistically significant reductions in mean red blood cell velocity and significant increases in capillary permeability (Seidman et al, 1996). In contrast, Axelsson noted no significant differences in cochlear blood vessels of young and old guinea pigs. However, there were more failures in contrast filling of the older animals' vessels due to frequent ruptures of the vessels (Axelsson, 1971). One might speculate that this may in part be due to increased vascular fragility that is a common feature of aged vasculature. In a personal communication with Dr. Axelsson, he endorsed this speculation. These findings may be secondary to increased vascular permeability which is a common sequelae of ischemic injury.

The effects of cochlear hypoxia on auditory function have been extensively studied. There is a direct correlation between hypoxia and decreased hearing sensitivity. Studies inducing hypoxia by inspiration of 100% nitrogen (Wing, 1959), tracheal clamping and cessation of respiration (Fernandez et al, 1959), chemical agents (Kubayashi et al, 1987), and vessel occlusion (Kimura et al, 1956: Perlman et al, 1957) have all shown significant alterations of compound action potential (CAP), summating potentials (SP), and cochlear micro phonics (CM) (Honrubia et al, 1965: Okumura, 1970: Woolf et al, 1986). If the duration of the hypoxia is short, full recovery of cochlear potentials is observed (Nuttall et al, 1979: Brown et al, 1983: Nuttall, 1984). However, after longer hypoxic states (greater than eight minutes) some or all of the cochlear potentials fail to recover. For example, experimental occlusion of the anterior inferior cerebellar artery (AICA) in guinea pigs for durations of 1 to 60 minutes, led to rapid depression of the CM within two to three seconds of occlusion, and if the duration of occlusion was greater than 16 minutes, the CM often did not recover (Konishi et al, 1961).


KH: Do you think it is reasonable, aside from encouraging a diet rich in fruits and vegetables, to give basic antioxidant supplements to patients? And, if so which supplements?

MDS: In addition to appropriate lifestyle choices including a diet rich in fruits and vegetables, I always recommend appropriate nutritional supplementation as described in question five.

Alpha lipoic acid (ALA) is a coenzyme necessary for normal mitochondrial function and energy production. This vitamin-like substance has been supplemented orally for health benefits and has also been used to treat a variety of liver and brain disorders, as well as mushroom poisoning. Consideration has also been given to the use of ALA in the treatment of diabetes and recent studies in our laboratory have demonstrated improvement in age-related hearing loss (Seidman et al, 2000). Dietary supplementation of ALA successfully prevents the degree of heart damage in response to a heart attack.

Acetyl L-carnitine (ALCAR) is a biological compound, which plays an important role in energy production. Chronic treatment with ALCAR enhances stimulation of antioxidant defenses. It also enhances learning and memory possibly due to its ability to increase the release of acetylcholine. Studies in our laboratory have shown improved hearing in aged subjects compared to controls. Additionally, the treated subjects had improved mitochondrial function, energy production and there was evidence for a reduction in mitochondrial damage (Seidman et al, AJO 2000). ALCAR can restore the integrity of the cardiac mitochondrial membrane altered by aging (specifically the cardiolipin content), and improves the activities of many important enzymes. Collectively, this allowed more efficient energy production and resulted in improved cardiac performance in the aged.

CoEnzyme Q-10 (CoQ-10) is crucial for mitochondrial function and is essential in the generation of energy. It was first recognized in 1957 as a component necessary for oxidative phosphorylation (the process by which the mitochondria makes energy). CoQ-10 functions as an antioxidant and can therefore combat the production of free oxygen radicals. There is evidence supporting an age-related decline of CoQ-10 in humans and other species, thus further supporting the membrane hypothesis of aging. CoQ-10 is currently used alone or in combination as a health/nutritional supplement. It has shown promise in enhancing heart function and has been used medicinally in European countries for this purpose. It is, in this regard, gaining momentum in the USA. It may also be useful in cognitive and other neurologic disorders (i.e. Alzheimer's disease and diseases that produce muscle weakness such as certain muscular dystrophies).

Glutathione (L-K-glutamyl-L-cysteinyl-glycine; GSH) detoxifies reactive oxygen metabolites (it acts as an antioxidant). It is also involved in the breakdown and detoxification of certain drugs. Mitochondrial glutathione is critical to the healthy cell and is important as an antioxidant defense system within the mitochondria. Many studies have demonstrated that alterations of glutathione levels through excess or reduced production have a beneficial or harmful influence on cellular function, respectively. Recent studies have demonstrated an age-associated 86% reduction in glutathione levels in the auditory nerve. Thus, it can be hypothesized that hearing loss may occur in part because of reduction in glutathione levels with age with subsequent increases in ROS production.

In conclusion, senescence appears to be a complex process triggered by a variety of factors, which include decreased blood supply, compromised enzymatic defenses, increased production of ROS, cumulative DNA damage and structural abnormalities at the cellular and subcellular level. The inner ear is not impervious to the effects of senescence and may experience unique events as the organism ages. These may be related, in part, to the local organization and control of the cochlear blood supply. Additionally, because of free radical damage to the mitochondria, DNA deletions occur and the net result is reduced energy production. This reduction in energy production appears to be a general manifestation of senescence, and may also account for presbyacusis.

The results of these studies clearly demonstrate a protective effect of dietary restriction and nutritional over supplementation on age-related hearing loss and MtDNA deletions. This beneficial effect most likely represents a slowing of the mitochondrial clock theory of aging. Specifically, dietary restriction and other mechanisms aimed at reducing the overall burden of ROS provide an internal milieu that is more favorable to the organism. There is compelling evidence that supplementing with more than one antioxidant may be more protective than single antioxidants alone. This makes teleologic sense when considering that nutritional supplements work by a variety of mechanisms. Some stabilize cell membranes, others scavenge ROS molecules, while others enhance the role of different antioxidants. These studies propose an integrated hypothesis of aging and presbyacusis. In addition, presented data provides a framework for the continuing identification and evolution of pharmacological and nutritional strategies designed to attenuate age-associated hearing loss. Finally, those areas of scientific inquiry have also been identified that require further investigation with the ultimate goal of enhancing our understanding of the mechanisms that surround senescence and presbyacusis, both as a phenomenon and an intrinsic biological property.
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