In a chronically low calorie diet, the body enters a low metabolic state. As we briefly explained here in an article on the calorie restriction diet, a low metabolic state generates less free radicals because their production is proportional to energy requirements. Free radicals are atoms or molecules having an unpaired electron that make them highly reactive with other molecules. Keeping all other variables constant – pollution, radiation, etc – free radical production increases when the metabolic rate increases.

This article explains the science that links our metabolic activity to aging from factors related to oxidative stress, as postulated by the Free Radical Theory of Aging.

Metabolic Energy Systems

All cellular energy depends on the breakdown of adenosine triphosphate (ATP) to release energy. Without ATP, cells will not function. To get to this basic building block of energy source, humans utilize 3 energy systems with multiple metabolic pathways to construct this ATP molecule.

System 1: Creatine PhosphagenThree Metabolic Energy Systems

Relative to a resting state, the body needs a 1,000-fold increase in ATP during bouts of intense exercise. Phosphocreatine provides a buffer stock of ATP, mostly stored in muscle tissue.

The creatine phosphagen system works through 3 reactions: the creatine kinase enzyme converts Phosphocreatine, ADP and H+ to ATP and Creatine; the adenylate kinase enzyme converts ADP to ATP and adenosine monophosphate (AMP); the AMP deaminase enzyme converts AMP and H+ to inosine monophosphate (IMP) and ammonia. The ammonia is subsequently removed from the blood in the liver by conversion to urea.

This energy system does not need oxygen or glucose to release energy, and not much hydrogen is required. The downside is that the system quickly runs out of energy stores. Genetic variations and athletic fitness do give advantage to some people, but fatigue is typically taken over by muscular pain in as little as 10 seconds. Athletes are able to recover their phosphocreatine stores relatively quickly to allow them to repeat the exercise, but this level of metabolic exertion cannot be sustained for longer periods. At some stage, the body has to switch to glycolysis at a decreased power output.

System 2: Glycolysis

After a few seconds of intense exercise, ATP production is increasingly taken over by the glycolytic system. Glycolysis works by catabolizing glucose and glycogen – a store of carbohydrates in muscle and liver cells – to pyruvate. This is otherwise known as the anaerobic respiration, where no oxygen is required.

Through a series of conversions, the pathway of glycolysis goes from glycogen and glucose to glyceraldehyde-3-phosphate (GADP) and subsequently to NAD+, NADH + H+ and ATP. In glycolysis, ATP production rate reaches its maximum after 10 to 15 seconds of exercise and begins to drop off after a few seconds. The system produces lactic acid and phosphate and subsequently ATP.

During glycolysis, the production of lactate works to remove excess pyruvate from the system because the mitochondria does not have the capacity to break down the amount of pyruvate produced during catabolism. Lactate sustains the higher level of performance by reducing the oxidized nicotinamide adenine dinucleotide (NAD+) to NADH. The ability to maintain glycolysis for longer is correlated to the availability of NAD+ in the cytosol. As we age, NAD+ levels diminish and result in a lower level of ATP regeneration in glycolysis.

While Glycolysis allows for a high level of exertion for a longer duration than the creatine phosphagen system, it is eventually replaced by mitochondrial respiration as hydrogen builds up in the muscle. In a 10-second sprint at capacity, the creatine phosphogen system provides 53% and glycolysis provides 44% of energy. In a 30-second sprint, the creatine phosphogen system provides 23% and glycolysis provides 49% of energy. The rest comes from mitochondrial respiration.

System 3: Mitochondrial RespirationMetabolic Energy System Decay Rates

Mitochondrial aerobic respiration requires a sufficient supply of oxygen to break down glycogen, glucose or fatty acids to produce phosphate and subsequently ATP. In aerobic respiration, fatty acids and the pyruvate generated from the glycogen and glucose enter what is known as the Kreb’s Cycle.

The pyruvate, electrons and protons from the glycolytic reduction of NAD+ to NADH enter the mitochondria. Pyruvate is converted to Acetyl CoA, NADH and FADH2 are oxidized to synthesize ATP.

The acyl CoA sythetase converts the fatty acids by adding coenzyme A to fatty acyl-CoA and PPi and AMP. This allows their transport into the mitochondria via the carnitine shuttle, where the carbons are broken down two at a time. The beta-oxidation pathway releases acetyl CoA, NADH and FADH.

Acetyl CoA enters the Kreb’s Cycle to get oxidized and release more energy. The products of carbohydrate and fatty acid oxidation are the same. What is different is what happens before. Carbohydrate oxidation results in a higher NADH to FADH2 ratio, more CO2 and higher ATP generation rate.

The byproducts of metabolizing glucose are carbon dioxide and water. The unwanted byproducts are free radicals that start a vicious cycle of damage to DNA and tissue, accelerating the aging process.

Oxidation and Free Radicals

System 1 does not interact with oxygen. Therefore, there is no oxidation occurring in that pathway. System 2 utilizes carbohydrates in the form of glucose and glycogen, and there is very little oxidation until system 3 kicks in.

With system 3, oxidation occurs at several stages of the Kreb’s Cycle. The process yielding ATP is called oxidative phosphorylation, which transports electrons and protons (H+ ions) across the inner mitochondrial membrane by means of the Electron Transport Chain via a series of oxidation and reduction reactions. The process is not efficient, and it produces several reactive oxygen species (ROS): superoxide radical, nitric oxide, hydrogen peroxide, hydroxyl, hydroperoxyl, and many others.

The process by which cellular damage occurs is a chain reaction where these free radicals take electrons from other molecules they come in contact with, causing the affected molecules to be reactive or changing them entirely in molecules that cannot hold their structure without the missing electron. The chain reaction can produce a wide range of free radicals – some more reactive than others – that attack cells and leave damaged tissue behind.

Free radicals also damage DNA by reacting with molecules in the DNA chain. This can lead to cancer and other dysfunction that exhibits itself in the many effects of aging. Wrinkles, for example, are caused by cross linking between the DNA of fat and protein molecules. Cellular damage further impairs metabolism to create a feedback loop that makes more ROS. As the rate of ROS production increases, so does aging and age-related dysfunction.

Perhaps the most overlooked cause in accumulation of cholesterol in artery walls is the oxidization of LDL molecules. These dysfunctional LDLs damage artery walls and cause inflammation. When attacked by the body’s immune system, the leftover cholesterol remains in the artery walls, and plaque builds up over time as we age.


Afanas’ev, I.B. Biogerontology (2005) 6: 283.

Julien S. Baker, Marie Clare McCormick, and Robert A. Robergs, “Interaction among Skeletal Muscle Metabolic Energy Systems during Intense Exercise,” Journal of Nutrition and Metabolism, vol. 2010, Article ID 905612, 13 pages, 2010. doi:10.1155/2010/905612

Oxidative Medicine and Cellular Longevity Volume 2016 (2016), Article ID 7843685, 10 pages