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LE Magazine February 2001

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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

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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.

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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).

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