Mitochondrial Theory of Aging

The age-related physiological decline seems to be due to the accumulation of defects in the several metabolic pathways. Looking for potential candidates to progressive accumulation of damage over a lifetime, it seems reasonable to exclude RNA, proteins and other cellular macromolecules with a rapid turned over. For this main reason, studies exploring mechanisms of aging have always been focused on DNA. In mammalian cells, mitochondria and the nucleus are the only organelles possessing DNA. It appears obvious that the physiological integrity of the cell is strongly linked to the integrity of its genome.

Even if mitochondrial DNA comprises only 1%–3% of genetic material in animal cells, its contribution to cellular physiology seems to be much greater than what expected from its size alone. Mitochondrial DNA, in close proximity to the sites of oxygen radical production and unprotected by the histones that are associated with nuclear DNA, is a sensitive target for oxygen radical attack. In fact, it has been estimated that the level of oxydatively oxidized bases in mitochondrial DNA is 10- to 20-fold higher than that in nuclear DNA (Richter et al 1988; Ames 1989). Moreover, mitochondrial DNA encodes polypeptides of the electron transfer chain as well as components required for their synthesis. Therefore, any coding mutations in mitochondrial DNA will affect the entire electron transfer chain, potentially altering both the assembly and function of the products of numerous nuclear genes in electron transfer chain complexes. Finally, defects in the electron transfer chain can have pleiotropic effects because affecting the entire cellular energetics (Alexeyev et al 2004).

It has been demonstrated by the Framingham Longevity Study of Coronary Heart Disease that longevity is more strongly associated with age of maternal death than that of paternal death, suggesting that mitochondrial DNA inheritance might play an important role in determining longevity (Brand et al 1992). Even if the matter is still controversial (Ross et al 2001), several studies demonstrate that longevity is associated with specific mitochondrial DNA polymorphisms (Ivanova et al 1998; Tanaka et al 1998; De Benedictis et al 1999).

The mitochondrial theory of aging is often considered as an extension and refinement of the free radical theory (Harman 1972; Miquel et al 1980). Mitochondrial DNA mutations accumulate progressively during life and are directly responsible for a measurable deficiency in cellular oxydative phosphorylation activity, leading to an enhanced reactive oxygen species production. This latter results in an increased rate of mitochondrial DNA damage and mutagenesis, triggering the onset of a “vicious cycle” of exponentially increasing oxidative damage and dysfunction, which ultimately culminates in death. Supporting the primary importance of mitochondria in the aging process and in determining longevity, it has been documented that several mutagenic chemicals and lipophilic carcinogens (eg, polycyclic aromatic hydrocarbons) tend to preferentially damage mitochondrial DNA (Wunderlich et al 1970; Allen and Coombs 1980; Niranjan et al 1982; Rossi et al 1988). It can then be hypothesized that a life-long exposure to these environmental toxins may lead to a preferential accumulation of mitochondrial DNA damage and accelerate aging.

The superoxide anion radical (or superoxide) and hydrogen peroxide, respectively the products of the univalent and bivalent reduction of oxygen, are produced during normal aerobic metabolism and constitute physiological intracellular metabolites (Cadenas and Davies 2000). Several reactions in biological systems contribute to the steady state concentrations of superoxide and hydrogen peroxyde, although mitochondria seem to be quantitatively the most important source (Cadenas and Davies 2000).

Although mild amounts of oxidative damage such as that experienced during exercise training (Davies et al 1982) may actually be the stimulus for physiological mitochondrial biogenesis, more severe, more extensive, or more prolonged oxidative damage is clearly toxic (Cadenas and Davies 2000).