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LE Magazine February 2001


The evolution of
maximum lifespan in mammals
Each species of mammal has a known Maximum Lifespan Potential (MLSP). An intriguing line of research inspired by the free radical theory of aging suggests that the MLSP of each species corresponds to the level of a free radical called superoxide. Superoxide is a free radical formed from oxygen, especially when electrons leak out from the cellular respiratory chain. The lower the mitochondrial superoxide level in a given species, the longer that species lives. A similar relationship between superoxide and MLSP has also been found in fly species. While this does not necessarily mean that superoxide is a direct cause of aging, it does open up some fascinating lines of inquiry, albeit highly speculative ones.

In order to understand an insight into longevity that this research has provided, it is necessary to consider a fine point of animal physiology. In mammals, CoQ10 exists alongside the related form CoQ9. The proportions of CoQ10 and CoQ9 vary greatly between species. For example, rats and mice have mostly CoQ9, while rabbits, pigs and cows have mostly CoQ10 in heart cell mitochondria.
Antioxidant researchers Rajindar Sohal, Achim Lass and colleagues discovered that the higher the proportion of CoQ9 in a species, the more superoxide is generated in its heart mitochondria. The species with the highest proportions of CoQ10, on the other hand, have the lowest superoxide production in heart mitochondria and live the longest. As Lass and Sohal put it (1999), this finding is “consistent with the speculative notion that longevity co-evolved with a relative increase in the amounts of CoQ10.” In other words, the evolution of longer lifespan in mammals may be connected with the evolution of higher proportions of CoQ10.

There may be no meaningful way to test Sohal's hypothesis experimentally. He and his colleagues did make one attempt in which they altered the natural proportions of CoQ9 and CoQ10 in isolated submitochondrial particles from several species, then measured their rates of superoxide production. At normal physiological concentrations, superoxide levels remained the same; only at higher than normal concentrations did CoQ10 reduce superoxide generation. Thus the role of CoQ10 in evolution remains a thought-provoking though inconclusive hypothesis.

A model of bioenergetic aging

According to the free radical theory of aging, the buildup of oxidative stress and oxidative damage causes age-related degeneration. Since mitochondrial DNA and the cellular respiratory chain are highly susceptible to oxidative damage, this theory complements the bioenergetic theory of aging proposed by Linnane. Figure 2 illustrates how these theories might fit together.

The bioenergetic theory of aging


Figure 1. The series of boxes on the bottom shows how mitochondrial deterioration can hasten aging and degeneration, as proposed by Linnane. Mitochondria are highly susceptible to oxidative stress, which reinforces the other factors.

When Cellular Energy Declines

Figure 2. Cell undergoing programmed cell death.

Programmed cell death is a well-orchestrated process of cellular self-destruction. As the cell shrinks and then fragments, its organelles remain relatively intact and enclosed by membranes. Neighboring cells or macrophages safely digest the fragments. By contrast, in necrotic cell death the cell swells and ruptures, organelles disintegrate, and inflammation tends to occur.

Programmed cell death has been described for decades, but scientists are just beginning to unravel its molecular mechanisms. Programmed cell death is actuated by the opening of a channel in the inner membrane of the mitochondria called the "megachannel" (also called the permeability transition pore, or PTP). When the megachannel opens, the mitochondrial membrane becomes highly permeable and loses its electrical charge. Cell death-promoting factors from the mitochondrial inner membrane space are released into the cell. When this happens in a large enough proportion of the cell's mitochondria, the cell cannot survive. This process can lead either to programmed cell death, or to the more destructive cell death pathway called necrosis. What determines whether the megachannel opens and which path the dying cell takes?

We now know that programmed cell death is controlled by the mitochondria. It is thought that when a sudden bioenergetic catastrophe opens the megachannel before the cell can adapt, the cell undergoes violent necrotic death. On the other hand, when the megachannel opens gradually over a sufficient period of time, an orderly cellular suicide process unfolds instead.

A binding site for the CoQ10 family of compounds has been shown to regulate the opening of the mega-channel in rat liver and muscle cells. Moreover, groundbreaking new laboratory research shows that CoQ10 directly inhibits the opening of the megachannel.

Japanese research shows the visible effect of CoQ10 on cells under stress. Oxidative stress leads to programmed cell death, partly by damaging the cellular respiratory chain. As free radicals degrade the cell's metabolism regulatory mechanisms, DNA and proteins, the cell takes adaptive measures. The mitochondria typically enlarge or fuse to form "megamitochondria." Scientists speculate that this conserves energy or reduces free radical production. If oxidative stress subsides, the cell may return to normal. However, additional oxidative stress brings on programmed cell death.

Japanese scientists found that CoQ10 prevents these pathological changes. They gave one group of rats hydrazine, a drug that stimulates production of free radicals, for 7 to 8 days. They gave another group CoQ10 in addition to hydrazine. Hepatocytes (liver cells) from the hydrazine group showed "remarkably enlarged" mitochondria, while hepatocytes from the hydrazine plus CoQ10 group were only "slightly swollen," as illustrated below. The authors conclude that CoQ10 prevented megamitochondria formation by suppressing lipid peroxidation, and perhaps by preventing degradation of cellular respiration (uncoupling of oxygen consumption from ATP production).

Figure 3. CoQ10 protects rat liver mitochondria from free radical toxicity.


Normal mitochondria from the liver of an untreated rat. Megamitochondria from the liver of a rat given the toxin hydrazine. This remarkable enlargement of the mitochondria often precedes cell death from oxidative stess. Mitochondria from the liver of a rat given CoQ10 along with the toxin. These mitochondria are nearly normal, exhibiting only slight enlargement.

Artist's impression, adapted from Adachi K. et al. (1995).


Adachi K et al. A deletion of mitochondrial DNA in murine doxorubicin-induced cardiotoxicity. 1993. Biochem Biophys Res Comm 195: 945-951.

Adachi K et al. Suppression of the hydrazine-induced formation of megamitochondria in the rat liver by coenzyme Q10. 1995.
Toxicol Pathol 23: 667-676.

Alleva R et al. Supplementation with coenzyme Q10 protects DNA against oxidative damage and enhances DNA repair enzyme activity. 2000.
Free Radic Biol Med 29, Suppl 1: S80.

Ames BN et al. Mitochondrial decay in aging. 1995.
Biochim Biophys Acta 1271: 165-170.

Arbustini E et al. Mitochondrial DNA mutations and mitochondrial abnormalities in dilated cardiomyopathy. 1998.
Am J Pathol 153: 1501-1510.

Cavalli LR et al. Mutagenesis, tumorigenicity, and apoptosis: are the mitochondria involved? 1998.
Mutat Res 398: 19-26.

“Cellular Nutrition for Vitality and Longevity,” LIFE EXTENSION magazine, April 2000, pp. 24-28.

DiMauro S et al. Mitochondria in neuromuscular disorders. 1998.
Biochim Biophys Acta 1366: 199-210.

Esposito LA et al. Mitochondrial disease in mouse results in increased oxidative stress. 1999.
Proc Natl Acad Sci USA 96: 4820-4825.

Fontaine E et al. A ubiquinone-binding site regulates the mitochondrial permeability transition pore. 1998.
J Biol Chem 273: 25734-25740.

Fontaine E et al. Regulation of the permeability transition pore in skeletal muscle mitochondria. 1998.
J Biol Chem 273: 12662-12668.

Geromel V et al. The consequences of a mild respiratory chain deficiency on substrate competitive oxidation in human mitochondria. 1997.
Biochem Biophys Res Comm 236: 643-646.

Karbowski M et al. Free radical-induced megamitochondria formation and apoptosis. 1999.
Free Radic Biol Med 26: 396-409.

Kopsidas G et al. An age-associated correlation between cellular bioenergy decline and mtDNA rearrangements in human skeletal muscle. 1998.
Mutat Res 421: 27-36.

Kovalenko SA et al. Tissue-specific distribution of multiple mitochondrial DNA rearrangements during human aging. 1998.
Ann NY Acad Sci 854: 171-181.

Ku HH et al. Relationship between mitochondrial superoxide and hydrogen peroxide production and longevity of mammalian species. 1993.
Free Radic Biol Med 15: 621-627.

Lass A et al. Mitochondrial ubiquinone homologues, superoxide radical generation, and longevity in different mammalian species. 1997.
J Biol Chem 272: 19199-19204.

Lass A et al. Comparisons of coenzyme Q bound to mitochondrial membrane proteins among different mammalian species. 1999.
Free Radic Biol Med 27: 220-226.

Linnane AW et al. Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. 1989.
Lancet 1: 642-645.

Linnane AW et al. The universality of bioenergetic disease and amelioration with redox therapy. 1995.
Biochim Biophys Acta 1271: 191-194.

Linnane AW et al. The universality of bioenergetic disease. Age-associated cellular bioenergetic degradation and amelioration therapy. 1998.
Ann NY Acad Sci 854: 202-213.

Martinucci S et al. Ca2+-reversible inhibition of the mitochondrial megachannel by ubiquinone analogues. 2000.
FEBS Lett 480: 89-94.

Michikawa Y et al. Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication. 1999.
Science. 286: 774-9.

Ozawa T. Genetic and functional changes in mitochondria associated with aging. 1997.
Physiol Rev 77: 425-464.

Pepe S et al. Coenzyme Q10 normalizes impaired post-ischemic contractile recovery of aged human myocardium in vitro. 1998.
Circulation 98, Suppl: 3602.

Richter C et al. Control of apoptosis by the cellular ATP level. 1996.
FEBS Lett 378: 107-110.

Rosenfeldt FL et al. Response of the human myocardium to hypoxia and ischemia declines with age. 1998.
Ann NY Acad Sci 854: 489-490.

Rowland MA et al. Coenzyme Q10 treatment improves the tolerance of the senescent myocardium to pacing stress in the rat. 1998.
Cardiovasc Res 40: 165-173.

Sohal RS et al. Mitochondrial superoxide and hydrogen peroxide generation, protein oxidative damage, and longevity in different species of flies. 1995.
Free Radic Biol Med 19: 499-504.

Susin SA et al. Mitochondria as regulators of apoptosis: doubt no more. 1998.
Biochim Biophys Acta 1366: 151-165.

Turker MS. Somatic cell mutations: can they provide a link between aging and cancer? 2000.
Mech Ageing Dev 117: 1-19.

Wallace DC. Mitochondrial diseases in man and mouse. 1999.
Science 283: 1482-1488.

Wallace DC et al. Mitochondrial DNA mutations in human degenerative diseases and aging. 1995.
Biochim Biophys Acta 1271: 141-151.

Walter L et al. Three classes of ubiquinone analogs regulate the mitochondrial permeability transition pore through a common site. 2000.
J Biol Chem 275: 29521-29527.

Wei YH. Oxidative stress and mitochondrial DNA mutations in human aging. 1998.
Proc Soc Exp Biol Med 217: 53-63.

Wei YH et al. Simultaneous increase of mitochondrial DNA deletions and lipid peroxidation in human aging. 1996.
Proc NY Acad Sci 786: 24-43.

Zhang C et al. Varied prevalence of age-associated mitochondrial DNA deletions in different species and tissues: a comparison between human and rat. 1997.
Biochem Biophys Res Comm 230: 630-635.

Wolvetang EJ et al. Mitochondrial respiratory chain inhibitors induce apoptosis. 1994.
FEBS Lett 339: 40-44.

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