The free radical theory of aging proposes that reactive oxygen species (ROS)-induced accumulation of damage to cellular macromolecules is a primary driving force of aging and a major determinant of lifespan. Although this theory is one of the most popular explanations for the cause of aging, several experimental rodent models of antioxidant manipulation have failed to affect lifespan. Moreover, antioxidant supplementation clinical trials have been largely disappointing. The mitochondrial theory of aging specifies more particularly that mitochondria are both the primary sources of ROS and the primary targets of ROS damage. In addition to effects on lifespan and aging, mitochondrial ROS have been shown to play a central role in healthspan of many vital organ systems. In this article we review the evidence supporting the role of mitochondrial oxidative stress, mitochondrial damage and dysfunction in aging and healthspan, including cardiac aging, age-dependent cardiovascular diseases, skeletal muscle aging, neurodegenerative diseases, insulin resistance and diabetes as well as age-related cancers. The crosstalk of mitochondrial ROS, redox, and other cellular signaling is briefly presented. Potential therapeutic strategies to improve mitochondrial function in aging and healthspan are reviewed, with a focus on mitochondrial protective drugs, such as the mitochondrial antioxidants MitoQ, SkQ1, and the mitochondrial protective peptide SS-31.
Alex's notes: As elaborated upon within this free report, substantial evidence supports the central role of mitochondrial oxidative stress in aging and longevity (what the author calls “healthspan”). To summarize, mitochondria generate significant radical oxygen species (ROS) through aerobic respiration that interact with the mitochondria themselves and mutate or damage their DNA. This in turn interferes with cellular functioning and ultimately leads to aging and death. Support comes from several animal models have had their mitochondrial DNA altered in a manner that grants protection and makes it more susceptible to mutations which extend and shorten the lifespans, respectively.
Despite the above, ROS have numerous crucial biological roles in hormesis and the stress response. Indeed, the mitohormesis theory hypothesizes that low levels of oxidative stress induced by either caloric restriction, exercise, or other stimuli may trigger adaptive responses that improve overall stress resistance, probably through increased endogenous antioxidant defense, which may eventually reduce chronic oxidative damage and subsequently achieve lifespan extension. The review goes on to expand the role of mitochondrial ROS within several aspects of longevity including cardiac aging, cardiovascular diseases, skeletal muscle aging, neurodegenerative disease, hearing loss, Alzheimer’s disease, Parkinson’s disease, insulin resistance, diabetes, and cancer. Needless to say, mitochondria are intimately involved with all aspects of our wellbeing.
The review closes with a look at potential therapies to prevent age-related diseases. A main issue with antioxidants is that they have poor distribution to mitochondria. This could be an unexpected flaw, or more likely it is purposely done in order to preserve the hermetic response so crucial for adaptation. Our bodies know best after all. Regardless, several attempts to develop mitochondria-targeted antioxidants have been developed with promising results in animal models that have prompted the move towards clinical trials. One such example is coupling of coenzyme Q10 with the redox agent TPP+ which can potentially result in 100- to 1,000-fold increased accumulation within the mitochondria.