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The effect of caloric restriction (CR) (40%) on the rates of mitochondrial H2O2 production and oxygen consumption and oxidative damage to nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) was studied for short‐term (6‐wk) and long‐term (1‐year) periods in the heart of young and old rats. Short‐term CR did not change any of the parameters measured. However, long‐term CR significantly decreased the rate of mitochondrial H2O2 generation (by 45%) and significantly lowered oxidative damage to mtDNA (by 30%) without modifying damage to nDNA. The decrease in H2O2 production occurred exclusively at the complex I free radical generator of the respiratory chain. The mechanism allowing that decrease was not a simple decrease in mitochondrial oxygen consumption. Instead, the mitochondria of caloric‐restricted animals released fewer oxygen radicals per unit electron flow in the respiratory chain. This was due to a decrease in the degree of reduction of the complex I generator in caloric‐restricted mitochondria. The results are consistent with the concept that CR decreases the aging rate at least in part by decreasing the rate of mitochondrial oxygen radical generation and then the rate of attack on mtDNA.

The Mitochondrial Free Radical Theory of Aging (MFRTA) proposes that mitochondrial free radicals, produced as by-products during normal metabolism, cause oxidative damage. According to MFRTA, the accumulation of this oxidative damage is the main driving force in the aging process. Although widely accepted, this theory remains unproven, because the evidence supporting it is largely correlative. For example, long-lived animals produce fewer free radicals and have lower oxidative damage levels in their tissues. However, this does not prove that free radical generation determines life span. In fact, the longest-living rodent -Heterocephalus glaber- produces high levels of free radicals and has significant oxidative damage levels in proteins, lipids and DNA. At its most orthodox MFRTA proposes that these free radicals damage mitochondrial DNA (mtDNA) and in turn provoke mutations that alter mitochondrial function (e.g. ATP production). According to this, oxidative damage to mtDNA negatively correlates with maximum life span in mammals. However, in contrast to MFRTA predictions, high levels of oxidative damage in mtDNA do not decrease longevity in mice. Moreover, mice with alterations in polymerase gamma (the mitochondrial DNA polymerase) accumulate 500 times higher levels of point mutations in mtDNA without suffering from accelerated aging. Dietary restriction (DR) is the only non-genetic treatment that clearly increases mean and maximum life span. According to MFRTA caloric restricted animals produce fewer mitochondrial reactive oxygen species (mtROS). However, DR alters more than free radical production (e.g. it decreases insulin signalling) and therefore the increase in longevity cannot be exclusively attributed to a decrease in mtROS generation. Thus, moderate exercise produces similar changes in free radical production and oxidative damage without increasing maximum life span. In summary, available data concerning the role of free radicals in longevity control are contradictory, and do not prove MFRTA. In fact, the only way to test this theory is by specifically decreasing mitochondrial free radical production without altering other physiological parameters (e.g. insulin signalling). If MFRTA is true animals producing fewer mtROS must have the ability to live much longer than their experimental controls.

Caloric restriction (CR) decreases oxidative damage, which contributes to the slowing of aging rate. It is not known if such decreases are due to calories themselves or specific dietary components. In this work, the ingestion of proteins of Wistar rats was decreased by 40% below that of controls. After 7 weeks, the liver of the protein-restricted (PR) animals showed decreases in oxidative protein damage, degree of membrane unsaturation, and mitochondrial complex I content. The results and previous information suggest that the decrease in the rate of aging induced by PR can be due in part to decreases in mitochondrial reactive oxygen species production and DNA and protein oxidative modification, increases in fatty acid components more resistant to oxidative damage, and decreased expression of complex I, analogously to what occurs during CR. Recent studies suggest that those benefits of PR could be caused, in turn, by the lowered methionine intake of that dietary manipulation.

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