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Energy, Diet and Aging

By: Peter T. Pugliese, MD
Posted: September 25, 2009, from the October 2009 issue of Skin Inc. magazine.

page 3 of 6

In glycolysis, a single molecule of glucose is metabolized into two molecules of pyruvate, a three-carbon compound generating two ATP and two nicotinamide adenine dinucleotide (NADH) molecules. Pyruvate is converted into acetyl-CoA, generating one molecule of carbon dioxide that enters the Krebs cycle to generate one molecule of ATP and flavin adenine dinucleotide plus hydrogen squared (FADH2), and three molecules of NADH per acetyl-CoA. It is these NADH and FADH2 molecules that serve as electron carriers to transfer electrons generated by glycolysis and later by the Krebs cycle into the ETC.

In the ETC, the inner membrane creates a pH gradient with these electrons across the inner membrane. Next, the membrane proteins pump protons from the inner matrix into the intermembrane space. It is this chemosmotic gradient that serves as an energy reservoir to drive the formation of ATP as protons are pumped back into the inner matrix via a membrane protein called ATP synthase. Each glucose molecule yields 32 ATP via the ETC, in addition to two from the Krebs cycle and two from glycolysis to total 36 ATP molecules generated via aerobic respiration. This is an enormous increase over anaerobic respiration, and it made multicellular life possible.

Aerobic respiration and aging

A continuous stream of molecular oxygen will create plenty of unstable reactive oxygen species (ROS) capable of damaging many types of cellular components, and much of this oxidative damage will accumulate throughout time and play a significant role in aging. Because mitochondrial DNA exists in the inner matrix, and they are closer in proximity to the inner membrane where high energy electrons form unstable compounds, the mtDNA has a high chance of being damaged by ROS-causing mutations of mtDNA that can result in the manufacture of mutant ETC proteins leading to the leaking of more electrons and thus more ROS. This is the basic concept of the defective or damaged mitochondrial theory of aging.

There is a lot of evidence that suggests that mitochondria are implicated in the aging process. Mainly, the loss of the integrity of the mitochondrial genome is thought to be the culprit in aging. One component of DNA replication involves a proofreading ability of mitochondrial DNA to make sure it is normal before it is reproduced. The agent responsible for this is mitochondrial polymerase and in one study it was removed in mice models. The mtDNA mutations that were reproduced caused the development of a mouse that resembled the physical signs seen in premature aging.4 It may be that the accumulation of mtDNA mutations might be the result of a more fundamental process that can bring about aging changes rather than the actual defects in mitochondrial genome causing aging.

Diet, energy and aging

It has been known for more than 70 years that dietary restriction can increase life span, although scientists are still not certain about how this is achieved. It was first suggested that calorie restriction (CR) exerts its beneficial effects by slowing carbohydrate use, respiration and the rate of damage produced by ROS. This may not be the case, however. A careful examination of the physiology of CR has shown that rather than slowing respiration, CR actually increases mitochondrial function. Also, CR appears to be a regulated—rather than a passive—process, requiring protein, such as sirtuins, to regulate and exert its effects.5 Sirtuins comprise nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylases that increase life span in yeast, the worm Caenorhabditis elegans and the fruit fly Drosophila.6 Sirtuins have roles in CR, but their connection to mitochondria is less clear.7