Life Extension Magazine®

Issue: Jan 1997

An inside report form the newsletter of the American Aging Association about a symposium on Dietary Alteration of Mitochondrial Aging.

1995 AGE MEETING Part 2:

We omit the Viewpoint section of AGE News for this issue in order to bring you our second installment of coverage of the last AGE meeting.

Dietary Alteration of Mitochondrial Aging

Summary by Richard Weindruch, Ph.D.

Two types of dietary influence on mitochondrial aging were examined in this section. The first three talks focused on the dietary restriction (DR) paradigm. Here, caloric restriction (CR) imposed without essential nutrient deficiency extends maximum life span and retards both the rate of biological aging and the development of late-life diseases in mice and rats. Presently, there is little agreement on the mechanisms which underlie these outcomes of CR It has been speculated that the beneficial effects of CR may derive from its ability to reduce free radical generation and alter free radical metabolism.

Antioxidant Enzyme Activity Rises As Muscle Mass Declines

Richard Weindruch (Associate Professor of Medicine, University of Wisconsin at Madison) summarized existing knowledge on CR's influence on free radical production and metabolism and described his laboratory's findings in various animal models (rats, mice and rhesus monkeys) subjected to DR. It is clear that the influences of aging and DR on oxidative stress are highly tissue specific. The argument was made that the most consistent and important changes in this regard occur in tissues such as muscle and brain which have a high dependence on oxygen for ATP [biological energy] generation but a low capacity for cellular replacement. Accordingly, most of this talk concerned skeletal muscle where DR was found to oppose age-associated losses in hind limb muscle mass.

Interestingly, muscle mass loss in normally fed rats was accompanied by increases in the activities of the antioxidant enzymes glutathione peroxidase and catalase. It was suggested that these increases could be a response to increased levels of hydrogen peroxide or other oxidants.

Mitochondrial Membrane Lipid Aging Changes Slowed

by DR, B.P. Yu (Professor of Physiology, University of Texas at San Antonio)

DR, B.P. Yu has been a major contributor in this area of inquiry and discussed the rapidly-mounting evidence for an increased stability of mitochondria from restricted rats to resist several changes known to occur with aging. He emphasized the possible importance of age-associated changes in membrane composition, fluidity, and peroxidizability. Further, reactive aldehydic species such as 4-hydroxynonenal (4-HNE) appear to be important modulators of mitochondrial metabolism. Interestingly, 4-HNE is capable of suppressing mitochondrial respiration.

Severe Aging Changes in Mitochondria Partly Blocked by DR

Ritchie Fuers (National Center for Toxicological Research, Jefferson, AR)
communicated findings on the influence of age and DR on the enzyme complexes of the electron transport system (ETS).

[The ETS is where most biological energy is made in living cells and is located in the subcellular organelles known as mitochondria.] ETS activities were measured in gastrocnem-ius muscle from 10 and 20 month old B6C3F, female mice fed either ad libitum (AL) or DR diets. Older (26 month) AL mice were studied for Complex IV [part of the ETS].

Activities of complexes I, III, and IV decreased 50-75% from 10 to 20 months of age in AL mice. At 10 months, activities of complexes I, III, and IV were 30-65% lower in DR mice. The Km for ubiquinol-2 [derived from coenzyme Q10] of complex III increased (i.e., the affinity of the complex for substrate decreased) bY 29% by 20 months of age in AL mice while no change occurred in DR mice. The Vmax (an indicator of the quantity of total enzyme) of Complex IV declined by 90% from 10 to 20 months of age in AL mice but this change was opposed by DR.

Complex IV contains high and low affinity binding sites. (The high affinity sites are places on the enzyme complex that are most important for its function.) The Km for high affinity sites was uninfluenced by age or diet through 20 months of age, but the Km was about 2-fold higher for the 26 months AL mice. The percentage of total binding sites which were of high affinity fell from 68% at 10 months in AL mice to 46% at 20 months [a 32% decline] and was even lower (33%, a 51% decline) at 26 months. This value was 80% for DR mice at 10 and 20 months.

These alterations with aging in mitochondrial ETS capacities may contribute to decreases in skeletal muscle function.

Peroxidizable Fat Protects Hearts

The session's final talk departed from DR and was presented by Salvatore Pepe of the National Institute on Aging's Laboratory of Cardiovascular Science. He discussed work on rat heart mitochondria involving the effects of long-term dietary supplementation with either omega-3 polyunsaturated fatty acids or long chain saturated fatty acids. The outcomes he measured included cardiac performance, cardiac metabolism, and the ability to recover from myocardial ischemia. Dietary lipids produced marked effects on myocardial oxygen demand that were independent of contractile function. When isolated hearts were subjected to ischemia/reperfusion injury, the consequences were more severe in hearts from rats fed a diet rich in saturated fats as compared to those fed a fish oil diet high in omega-3 polyunsaturated fatty acids.

Further, the respiratory control ratio (a measure of mitochondrial function) was increased in mitochondria isolated from the fish oil-fed rats. In sum, dietary fat intake can markedly influence mitochondrial function.

In the past two years, there have been reports on three large, widely publicized trials in which beta carotene was administered to smokers for multiyear periods m an attempt to reduce the incidence of lung cancer.

The Physicians Health Study found no effect on lung cancer incidence or cardiovascular disease either beneficial or harmful, of beta carotene supplementation. The other two studies, the Beta Carotene and Retinol Efficacy Trial (CARET) and the Finnish study on Alphatocopherol and Beta-Carotene (ATBC) reported significantly increased risks of lung cancer in smokers supplemented with beta-carotene. These results have been causing considerable concern that beta carotene supplements might be harmful to smokers. However, a further analysis of the CARET data found that the observation from earlier human epidemiological studies - that individuals with higher blood beta carotene levels have lower risks of cancer and heart disease - held m this study as well. The new analysis of the data indicates that those who were eating diets high in fruits and vegetables from the very start of the study (as indicated by high initial blood levels of beta carotene) did experience a reduced risk of developing lung cancer, irrespective of supplementation.

Furthermore, excess cases of death and disease were not found in those who attained the highest blood beta carotene levels during supplementation, either in CARET or in ATBC.

Reference: Rowe, "Beta Carotene Takes a Collective Beating," The Lancet 347:249, 1996. Warner et al. (1) suggest that both increased lifespan and reduced incidence of cancer induced by caloric restriction might be explained as an increase in apoptosis (programmed cell death).

Although aging is associated with the death of cells as a result of various kinds of damage, it is also associated with a failure of damaged cells to kill themselves through apoptosis. Cancer may be the result of uncontrolled cell proliferation but, increasingly, it also appears to result from an imbalance between cell proliferation and cell death.

Warner et al. cite evidence that senescent human fibroblasts in culture undergo apoptosis much more slowly than presenescent fibroblasts after serum deprivation (removal of growth factors that maintain viability).

They also cite an autoimmune disease in a mouse strain (MRL/lpr) in which certain Iymphocytes fail to die (because of a defect in the fas gene, linked to apoptosis). This leads to an accumulation of defective Iymphocytes in Iymphoid organs. In a recent caloric restriction experiment done on mice of this strain and cited by Warner et al., the accumulation of these defective cells was prevented and lifespan was extended.

Thus, the enhanced apoptosis in Iymphoid cells that occurred may be a mechanism for the beneficial effects of caloric restriction.

We hope that this hypothesis will excite others as much as it does us. We enjoy eating and are not likely to cut down to 60% of normal caloric intake no matter how many caloric restriction (CR) experiments are done that extend rat or mouse lifespan, or even if CR actually works in primates. This promising new hypothesis appears plausible as at least a partial explanation of how CR might work.

If it is true, then we are likely to eventually have an opportunity to obtain the advantage of CR without actually restricting calories. This is the dream of humanity from time immemorial: to have our cake and eat it too!

We hope that CR research money will be used to test this and other plausible mechanisms of the action of CR rather than continuing to be used only to compile ever larger catalogs of expensive measurements that do not tell us how caloric restriction works.

1. Warner, Fernandes, and Wang. A unifying hypothesis to explain the retardation of aging and tumorigenesis by caloric restriction.
J. Gerontol.: Biol. Sci. 50A(3): B107-B109, 1995.

The following pertains to a quote attributed to Dr. Denham Harman in a recent article
(Natural Health Magazine May /June, 1995, pp. 56 and 58):
"Too many antioxidants can leave you feeling very weak. BHT decreases ATP and mitochondrial function." The article concluded "The key, then, is to take enough antioxidants to quench the free radicals that are acting in destructive ways but not so many that you interfere with those that are essential to your body's good health." One reader asked: but how much is really too much?

I believe that a shallow and superficial article of this type on such an important subject does a great disservice to its readers as the issues raised require exploration in much greater depth than the brief treatment given. Such an article can only leave many readers with excessive fears about the potential negative effects of even moderately high antioxidant consumption. I would like to see an in-depth discussion of this subject touching upon whether there are any reports of humans or animals experiencing decreased energy production as a result of anything less than the incredibly huge levels of antioxidants such as the 7.5 lb. per day human equivalent cited in this article. Have you ever observed in yourselves or in individuals you have known, a reduction of energy and endurance levels which could be related to high dose antioxidant consumption?

Donald Loomis, Jersey City, NJ

Sandy and Durk respond: The issue of how much of the antioxidants to take is important. The guy who wrote the magazine article claimed his energy went way up in a day or two after reducing his levels of vitamin E and mixed carotenes. If so, ithad nothing to do with the vitamin E and/or beta carotene, since those are stored in the body and supplies are depleted slowly over a period of days for the vitamin E and months for beta carotene. Other points include:
1) If we are taking "natural" vitamin E and mixed carotenoids, there are lots of other things in there besides the E and the carotenoids in the amounts he was taking. These other things could have been having significant effects. We recommend using synthetic vitamin E and beta carotene.

2) People with faulty skin DNA repair in response to ultraviolet light are typically treated with 500,000 and even up to 1,000,000 units of beta carotene daily; this treatment doesn't cause fatigue.

3) Hoffmann La-Roche did a study in which they gave normal people 55,000 units of vitamin E a day for ten months. Fatigue was not noted (though stickiness was, as the vitamin E oozed out of peoples skin).

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