Abstract
Aging is the greatest risk factor for a multitude of diseases including cardiovascular disease, neurodegeneration and cancer. Despite decades of research dedicated to understanding aging, the mechanisms underlying the aging process remain incompletely understood. The widely-accepted free radical theory of aging (FRTA) proposes that the accumulation of oxidative damage caused by reactive oxygen species (ROS) is one of the primary causes of aging. To define the relationship between ROS and aging, there have been two main approaches: comparative studies that measure outcomes related to ROS across species with different lifespans, and experimental studies that modulate ROS levels within a single species using either a genetic or pharmacologic approach. Comparative studies have shown that levels of ROS and oxidative damage are inversely correlated with lifespan. While these studies in general support the FRTA, this type of experiment can only demonstrate correlation, not causation. Experimental studies involving the manipulation of ROS levels in model organisms have generally shown that interventions that increase ROS tend to decrease lifespan, while interventions that decrease ROS tend to increase lifespan. However, there are also multiple examples in which the opposite is observed: increasing ROS levels results in extended longevity, and decreasing ROS levels results in shortened lifespan. While these studies contradict the predictions of the FRTA, these experiments have been performed in a very limited number of species, all of which have a relatively short lifespan. Overall, the data suggest that the relationship between ROS and lifespan is complex, and that ROS can have both beneficial or detrimental effects on longevity depending on the species and conditions. Accordingly, the relationship between ROS and aging is difficult to generalize across the tree of life.
Highlights
Aging can be described as the gradual loss of fitness due to detrimental changes occurring at the cell and molecular level over time
We review comparative studies and studies involving experimental modulation that have investigated the role of reactive oxygen species (ROS) in aging across species
While comparative studies have demonstrated a negative relationship between both ROS levels and oxidative damage, and lifespan, these correlations do not necessarily imply causation, and exceptions to these relationships have been observed
Summary
Aging can be described as the gradual loss of fitness due to detrimental changes occurring at the cell and molecular level over time. A similar study comparing five different species of dipteran flies supported these findings, showing that longer lifespan correlates with relatively low levels of ROS generation (Sohal et al, 1995) In these studies, measurement of superoxide production was carried out in submitochondrial particles by looking at the reduction of cytochrome c due to its interaction with superoxide, while hydrogen peroxide generation was measured fluorometrically by monitoring the oxidation of p-hydroxyphenylacetate (PHPA) coupled to the enzymatic reduction of H2O2 by horseradish peroxidase (Sohal et al, 1989, 1995; Ku et al, 1993).
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