Mitochondria and Aging

MITOCHONDRIA AND AGING

As described earlier, cellular senescence and aging can be attributed to oxidative stress. Indeed, many people consider oxidative damage the main culprit in aging. Because the majority of oxidizing radicals are formed by aerobic respiration, the mitochondria play a central role here. In brief, mitochondrial electron transport, which manufactures most of the ATP, uses about 85% of the oxygen. Partial reduction of the O 2 molecule creates highly reactive species including superoxide ions ( • O 2 − ), peroxides (H 2 O 2 ), and hydroxyl radicals (OH•). These reactive oxygen metabolites damage protein, lipid, and DNA nonspecifically ( Fig. 20.5 ).

Mitochondrial DNA (mtDNA) is a main target for ROM because it is not protected by histones and is close to the electron transport chain. If the mtDNA is oxidized, mutations may accumulate in the genes for energy production that are carried on the mtDNA. This may give rise to a defective electron transport chain. Hence the mitochondria produce less energy and cellular processes slow down. Moreover, defective electron transport proteins may produce even more ROM, which damages the mtDNA further, so starting a vicious cycle. Remember that each mitochondrion has multiple copies of its genome, each cell has many mitochondria, and each tissue has many cells. Damage from many events must accumulate for its effects to be noticeable. Cells that are highly metabolically active tend to accumulate oxidative damage faster.

Antioxidant enzymes can alleviate the effects of oxidant stress. There are several of these with varied roles. The two most familiar are superoxide dismutase (SOD) and catalase .

There are two forms of SOD with different metal ions at the active site. Cu/Zn SOD is found primarily in the cytoplasm, whereas Mn SOD is found in the mitochondria. SOD converts superoxide ions to oxygen plus hydrogen peroxide. Catalase converts hydrogen peroxide to oxygen plus water. Superoxide dismutase :

2 • O₂ + 2 H + → O₂ + H₂ O₂

Catalase : 2H₂ O₂ → O 2 + 2 H₂O

If the microscopic transparent worm Caenorhabditis elegans is treated with antioxidants, its mean life span increases significantly—by as much as 54%. These worms did not have a smaller body size or reduced fertility, suggesting there was little nonspecific reduction in metabolism. Other studies with the fruit fly, Drosophila melanogaster , support this view. Adding antioxidants to the diet of Drosophila has varied effects on the average life span. For example, vitamin E (alphatocopherol, a free radical scavenger) increased the life span by 13%, but vitamin C had no effect. Three studies have shown that the antioxidant thioproline increases life span, but the effect was highly variable (6% to 30% increase). Genetically engineered flies with one extra gene for SOD or catalase gene showed no change in life span. However, flies with three copies of SOD and three copies of catalase gained a one-third increase in life span due, presumably, to less oxidative damage.

Because metabolism and oxidation are linked to aging, if the metabolic rate decreases, less damage should accumulate, and the organism should live longer. Decreasing the body temperature lowers the metabolic rate, as seen in cold-blooded or hibernating animals. Such animals are able to survive on their body fat for extended periods of time by lowering the heart rate and slowing metabolism. Decreased physical activity also lowers the metabolic rate, as does limiting the diet. To test this theory, mice were put on a calorie-restricted diet. This decreased blood glucose and insulin levels. The mice also had improved insulin sensitivity and lower body temperature. In support of the theory that calorie restriction limits oxidative damage, the rodents had fewer reactive oxygen metabolites in the mitochondria and accumulated less oxidative damage over their life span. The greatest effect was seen in the brain and skeletal muscle, both tissues with high metabolic rates.

Although these results are promising, the jury is still out on whether antioxidants can lengthen the life span of all organisms. Many factors can contribute to the oxidation ofproteins or DNA and subsequent aging of the organism. Further research must be done to determine the exact role each factor plays.