Let’s face it—your body is always at work. From repairing wounds, breathing, building and moving muscles, and performing all types of processes vital to your existence.
All these actions require energy, and you get this energy from the foods you eat.
But in order for the body to have energy, it must convert the energy from food into a type of energy your body can actually use, namely ATP. This stands for adenosine triphosphate.
To produce ATP, your body’s cells employ a series of oxidation-reduction reactions.
Oxidation involves the loss of electrons and reduction involves the gain of electrons.
The majority of these reactions take place primarily in the mitochondria.
Mitochondria are found in the cells in all mammals, except red blood cells, and the number of mitochondria is between approximately one hundred to over two thousand in liver cells.
The mitochondrial electron transport system consumes approximately 85% of the oxygen utilized by the cells. (1)
So, producing more ATP should result in a longer lifespan, right? There are supplements on the market which make this claim.
So, it makes sense, right? Well, not so fast.
Producing ATP is important to living right now, but many scientists believe it’s the slowing down of ATP production, which can result in a longer lifespan.
How can making cellular energy, work AGAINST a longer lifespan?
One theory involves the leaking of free radicals as a byproduct of ATP production.
One of the oldest and still scientific-supported theories of a major cause of aging is related to the damage due to an imbalance in free radicals.
It’s not surprising that most free radicals, molecules with free electrons and an overproduction of which can lead to oxidative stress, are also produced in the mitochondria.
Mitochondria reduce oxygen to water by adding an electron to oxygen and storing the energy in the ATP.
The first electron addition produces superoxide radical, a second electron addition produces hydrogen peroxide, a third electron produces hydroxyl radical and a fourth electron addition produces water.
While essential to the life of all mammals, this process does not come without a cost… these free radicals ultimately “leak” out of the mitochondria.
Free radicals can lead to oxidative stress, a likely cause of Telomere degradation, DNA damage, DNA Methylation, Mitochondrial Dysfunction, and Inflammaging from Senescent Cells.
Starting at birth there is a 1% electron leakage from mitochondria and in old age, the free radical leakage grows to 2% to 3% because of mitochondrial functional decay.
This massive high energy electron leakage, postulated by Bruce Ames, is enough to account for the aging process itself.
Dr. Ames is a professor of Biochemistry and Molecular Biology Emeritus at the University of California, Berkeley, and a senior scientist at Children’s Hospital Oakland Research Institute.
There are several theories of aging that are centered on mitochondria, from the first theory in 1972 proposed by Denham Harman to the mitochondrial DNA mutation theory of aging first proposed by Miquel et al. in 1980. (3, 4)
In 2009, a more specific theory of aging involving mitochondria was published where the authors concluded that “ the respiratory function decline and increase in the production of the ROS (reactive oxygen species) in mitochondria, accumulation of mitochondrial DNA mutation and oxidative damage, and altered expression of a few clusters of genes…for the major supply of ATP were key contributory factors in the aging process in the human and animals.” (5)
Several experiments have been carried out that demonstrate lowering mitochondrial activity can prolong lifespan. It is well understood that a complete shutdown of mitochondrial activity results in cell and organism death. (6, 7, 8)
However, a mild inhibition of mitochondrial respiration extends the lifespan of many organisms, including yeast, worms, flies, and mice (9, 10, 11, 12, 13, 14, 15) but the underlying mechanism is not clear.
One environmental condition that reduces rates of respiration is hypoxia, low oxygen. Conditions of hypoxia also mean that less free radicals are generated.
Alpha-Ketoglutarate (AKG) is an important biological compound because it’s a vital step in the Krebs energy cycle that helps generate ATP.
Adding AKG to the medium of roundworms, C. elegans, increased their lifespan by inhibiting Complex V of the mitochondrial electron transport chain (the ETC).
Complex V is also called the ATP Synthase and it is the enzyme that converts ADP (adenosine diphosphate) into ATP as the final step in mitochondrial energy production. (16)
The study authors state that “AKG inhibits ATP synthase and inhibition by AKG leads to reduced ATP content, decreased oxygen consumption, and increased autophagy in both C. elegans and mammalian cells.”
Autophagy is the biological process of dissolving and disposing of oxidized proteins and lipids to clear out the cellular machinery in living cells.
The AKG inhibition of ATP synthase decreases ATP in a way that is similar to the effects of dietary restriction and fasting, in a process known as mTOR inhibition.
The inhibition of mTor, is one of the newest mechanisms proposed by scientists, to slow and perhaps reverse the aging process.
The results of these studies are in alignment with the fact that decreasing mitochondrial output increases the lifespan of the diverse other species mentioned.
It once again confirms that metabolism and metabolic rate are directly connected to lifespan.
These results are also in alignment with the free radical theories of aging that essentially state that the generation of free radicals is, in part, responsible for the aging process.
These study results also confirm the mitochondrial free radical theories of aging that also attribute mitochondrial damage directly to free radical production. (17, 18)
References:
1.Ames, BN, Shigenaga, MK, Hagen, TM. Mitochondrial decay in aging. Biochim Biophys Acta.1995 May 24;1271(1):165-70.
2.M K Shigenaga, T M Hagen, B N Ames. Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci U S A. 1994 Nov 8; 91(23): 10771–10778.
3.Harman, D. The biologic clock: the mitochondria? J Am Geriatr Soc. 1972 Apr;20(4):145-7.
4. Miquel, Jaime, Economos, A.C., Fleming, J., and Johnson, J.E. Mitochondrial role in cell aging, Exp Gerontol, 1980, 15: 575-591.
5.Kukat A, Trifunovic A. Somatic mtDNA mutations and aging–facts and fancies. Exp Gerontol. 2009 Jan-Feb;44(1-2):101-5.
6.Isom, GE. Cyanide Neurotoxicity – Necrotic and Apoptotic Cell Death. N.I.H. Res. 2004.Purdue University.
7.Hwang, A, Jeon, D, Lee, SJ. Mitochondria and Organismal Longevity. Curr Genomics. 2012 Nov; 13(7): 519–532.
8.Vendelbo MH, Nair KS. Mitochondrial longevity pathways. Biochim Biophys Acta. 2011;1813(4):634–644.
9.B. Lakowski, S. Hekimi. Determination of life-span in Caenorhabditis elegans by four clock genes. Science, 272 (1996), pp. 1010-1013.
10. B.P. Braeckman, K. Houthoofd, A. De Vreese, J.R. Vanfleteren. Apparent uncoupling of energy production and consumption in long-lived Clkmutants of Caenorhabditis elegans. Curr. Biol., 9 (1999), pp. 493-496.
11.P.A. Kirchman, S. Kim, C.Y. Lai, S.M. Jazwinski. Inter-organelle signaling is a determinant of longevity in Saccharomyces cerevisiae. Genetics, 152 (1999), pp. 179-190.
12. J. Feng, F. Bussière, S. Hekimi. Mitochondrial electron transport is a key determinant of life span in Caenorhabditis elegans. Dev. Cell, 1 (2001), pp. 633-644.
13. Dillin, A.L. Hsu, N. Arantes-Oliveira, J. Lehrer-Graiwer, H. Hsin, A.G. Fraser, R.S. Kamath, J. Ahringer, C. KenyonRates of behavior and aging specified by mitochondrial function during development. Science, 298 (2002), pp. 2398-2401.
14. X. Liu, N. Jiang, B. Hughes, E. Bigras, E. Shoubridge, S. Hekimi. Evolutionary conservation of the clk-1-dependent mechanism of longevity: Loss of mclk1 increases cellular fitness and lifespan in mice. Genes Dev., 19 (2005), pp. 2424-2434.
15. J.M. Copeland, J. Cho, T. Lo Jr., J.H. Hur, S. Bahadorani, T. Arabyan, J. Rabie, J. Soh, D.W. Walker. Extension of Drosophila life span by RNAi of the mitochondrial respiratory chain. Curr. Biol., 19 (2009), pp. 1591-1598.
16.Chin RM, Fu X, Pai MY, et al. The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature. 2014; 510(7505):397–401.
17.Liochev, SL. Reactive oxygen species and the free radical theory of aging. Free Radic Biol Med. 2013 Jul; 60:1-4.
18.Barja, G. The mitochondrial free radical theory of aging. Prog. Mol Biol Trans Sci. 2014;127:1-27.
