Aging is a complex process that, by nearly all educated accounts, appears to involve multiple different interacting processes. Aubrey de Grey has sought to break down the causes of aging into seven categories; others have presented different understandings. One perspective on aging broadly recognized as important, however, is the mitochondrial theory — tying aging to changes in the function of mitochondria, the energy powerhouses of the cell. This article reviews the mitochondrial theory of aging, with an aim of describing enough of the science to give the lay reader a real sense of what the theory is about.
The mitochondrial theory of aging ties in closely with ideas about the role of free radicals in aging. In the mid-1950s, Denham Harman proposed that aging results from accumulated damage inflicted by free radicals – atoms or molecules possessed of a sole unpaired electron in their outer shells. Initially the theory had little support. However, with the discovery of superoxide dismutase (SOD, an enzyme that degrades the superoxide radical) and mitochondrially produced hydrogen peroxide, the theory gained increased acceptance. Further support came from studies demonstrating that administering externally produced antioxidants and heightening antioxidant expression within the body increased some invertebrate lifespans.
Additionally, many long-lived species have lower cellular oxidative damage than short-lived species. However, other studies failed to show increased lifespans (particularly in mammals) after heightened antioxidant exposure. In fact, several long-lived species have higher levels of cellular oxidative damage than short-lived species, weakening support for the free radical theory. In 1972 Harman proposed the Mitochondrial Theory of Aging (MTA), which is considered an extension of the free radical hypothesis. According to this theory, aging is due to the cumulative effects of damage wrought by free radicals on the mitochondrial DNA and function. Here I will briefly review this theory.
To better understand the mitochondrial theory of aging, a little more background on mitochondria may be helpful. Mitochondria are rod-shaped, double-membraned cellular organelles around 0.5-10mM in length. First identified in the 1840s as cellular granules, mitochondria are now known to regulate iron metabolism, heme and steroid synthesis, programmed cell death, and cellular division and differentiation. Mitochondria also produce roughly 90% of the cell’s energy needs, in the form of adenosine triphosphate (ATP). Not surprisingly, cells requiring a lot of energy, such as cardiac muscle, skeletal muscle and neurons have high mitochondria numbers. Although the vast majority of the approximately 3,000 mitochondrial genes are in the nucleus, mitochondria carry their own genome (DNA), encoding twenty-four different RNA types and thirteen polypeptides in humans. Interestingly, phylogenetic (the study of evolutionary links among organisms) analyses of the RNA and protein-encoding mitochondrial genomic regions show a eubacterial origin, indicating a common ancestral symbiont. Additionally, like prokaryotes, mitochondria replicate by dividing in two, have a circular genome, and have an inner membrane composed of a prokaryote-like peptidoglycan cell wall.
Mitochondria-produced oxidants are a major source of oxidative damage in many cell types, particularly those with high-energy demands. Mitochondrial ATP production requires electron flow through the mitochondrial electron transport chain (ETC), eventually terminating with the reduction of O2 and the production of H2O and CO2. Although the ETC is quite efficient, around 0.1-2 percent of the O2 is incompletely oxidized, producing the superoxide radical (.O2–). While superoxide is only weakly reactive and does little cellular damage by itself, within cells it can rapidly convert into several different strongly reactive free radicals (the hydroperoxyl, hydroxyl, and peroxynitrite radicals). These free radicals damage DNA, lipids, and proteins, causing cellular damage ranging from mild to catastrophic depending on their abundance. Interestingly, mild chronic oxidative damage can increase cell growth, division, and mutation promoting carcinogenesis, while higher amounts can cause increase mutations rates, and cause cell death or permanent cellular senescence – all phenomena associated with aging.
Over the past 30 years an enormous amount of experimental data has accumulated supporting the MTA, making it a strong theory of aging;
- Free radicals play a major role in aging and most are mitochondrially produced.
- Mitochondrial DNA lacks the protective DNA-binding protein (called histones), has less efficient DNA repair, and is close to the free radical-producing ETC, resulting in high levels of mitochondrial DNA damage compared to nuclear DNA. One study revealed a tenfold greater mitochondrial oxidative DNA damage compared to nuclear DNA – a difference that increased with age. Similarly, mitochondrial genomic point mutations and deletions increase with age. One analysis of skeletal muscle from a 90-year-old man revealed that only 5% of his mitochondrial DNA was full length, while that of a five-year-old boy was almost completely intact. Other studies of individuals revealed similar results in both point mutations and deletions. Interestingly, the aging-associated the point mutations are often organ-specific.
- Caloric restriction, the only known treatment to increase the mammalian lifespan, reduces mitochondrial free radical production and mitochondrial DNA oxidative damage. Additionally, in many species females live longer than males and the rate of mitochondrial free radical production is lower in females. Interestingly, surgically removing the ovaries increases female rat mitochondrial free radical production while decreasing their lifespans.
- Fibroblasts injected with mitochondria from old rats degenerate more rapidly than fibroblasts injected with mitochondria from young animals.
- The mitochondria of older mammals are often larger and less efficient than those from younger mammals. They also often show markers of increased oxidative damage, such as increased protein and lipid oxidation.
- Targeted increased mitochondrial catalase (an enzymatic anti-oxidant) expression increases the mouse lifespan by around 20%.
- Studies between different species have demonstrated that longer-lived species typically have lower mitochondrial DNA oxidative damage and lower free radical production. In one comparison of eight different mammalian species, mitochondrial oxidative DNA damage levels were inversely related to the mean lifespan.
- Targeted mutation of the mitochondrial DNA polymerase-g, which causes an increased mitochondrial mutation rate with aging, results in a premature aging phenotype. The significance of this data is unknown as the mutation results in age-associated myopathies and sterility, pathologies not associated with normal mammalian aging.
Taken together, data derived from several thousand studies largely supports the MTA. Mitochondrial fee radicals damage the mitochondrial DNA, causing mitochondrial dysfunction with lowered ATP production, cellular energy depletion and death, resulting in aging. Interestingly, free radicals themselves inhibit efficient ETC function and damaged mitochondria often produce increased free radicals, suggesting that mitochondrial dysfunction promotes further dysfunction, resulting in a viscous cycle.
Although the MTA focuses on mitochondria, recent studies have begun to unite the MTA with other aging theories. For example, shortened telomeres are associated with aging, elevated oxidative damage (as seen with mitochondrial dysfunction), and many age-associated diseases. Shortened telomeres induce p53, which in turn suppress two gene products (the PGC-1a and –b genes) whose expression is necessary for mitochondrial function and survival. This results in mitochondrial dysfunction with elevated free radical production, and the appearance of several age-associated diseases. Deletion of p53, or enforced telomerase or PGC-1a expression substantially restores mitochondrial function and lessens the severity of the age-associated diseases, demonstrating a molecular link between telomere loss and mitochondrial function (Nature;470:359).
Although the MTA is generally considered a “strong theory” of aging, there are still many gaps — many aspects of mitochondrial function related to aging remain poorly understood. For example, significant changes have been identified in mitochondrially expressed gene patterns during aging. The significance of most of these changes is largely unknown. Also while events such as increased mitochondrial DNA deletions correlate with aging, these events might result from aging, but not cause it. Last, many gold standard experiments that would test the MTA are technically very challenging. For example, an animal model where mitochondrial free radical production is extremely low, but energy production and other parameters of mitochondrial function are unaltered from the wild-type animal, might be created. If the MTA is correct, animals with low free radical production should have a lengthened lifespan. In the current state of technology, achieving such exact manipulations of mitochondrial activity is difficult. With further research, these difficulties could be overcome and the role of mitochondria in aging and their interrelationship to other age-related molecular events (such as telomere length) be identified. Eventually manipulations (genetic and pharmacologic) could be identified which would increase mitochondrial DNA stability and slow the aging process. We have understood a great deal by now about the role of mitochondria in aging, but there is still a long way to go.