There has been a fair amount of news regarding the SkQ class of mitochondrially targeted antioxidant this past year, most likely because clinical development in Europe is moving ahead. Having one or more for-profit entities involved, even when they are fairly young companies, tends to bring more funding into ongoing research, both directly and indirectly. This type of antioxidant, unlike the antioxidant supplements you can buy in a store, has been shown to modestly slow aging in short-lived laboratory species. It is theorized that additional antioxidants localized to mitochondria soak up some of the oxidants produced by the mitochondria before those molecules can damage mitochondrial DNA. Alternatively, it is possible that the more important mechanism is that a reduction in the flux of oxidants at that point leads to other beneficial changes in cell metabolism, as mitochondrial oxidants are a signaling mechanism as well as a source of damage. Certainly many of the methods shown to slow aging in the laboratory involve altered mitochondrial function, especially insofar as it relates to the rate at which oxidant molecules are generated. The effects of mitochondrially targeted antioxidants on inflammation have proven to be larger and more easily measured, however, which is why present clinical development is focused on inflammatory eye conditions. Still, a steady flow of studies like the following are emerging to show benefits in a range of animal models for various age-related conditions:
Alzheimer's disease (AD) is a progressive, age-dependent neurodegenerative disorder featuring progressive impairments in memory and cognition and ultimately leads to death. According to the most widely accepted theory, the "amyloid cascade" hypothesis, AD arises when amyloid precursor protein (APP) is processed into amyloid-β, which accumulates in plaques. There is growing evidence that mitochondrial damage and oxidative stress lead to activation of the amyloid-β cascade and, accordingly, the mitochondrial dysfunction is a significant contributing factor of the onset and progression of AD. According to the "mitochondrial cascade hypothesis" amyloid-β is a marker of brain aging, and not a singular cause of AD. Many studies have confirmed that mitochondrial dysfunction is likely to be the leading cause of synaptic loss and neuronal death by apoptosis, representing the most likely mechanism underlying cortical shrinkage, especially in brain regions involved in learning and memory, such as the hippocampus. The mitochondrial changes increase amyloid-β production and cause its accumulation, which in turn can directly exert toxic action on mitochondria, thus aggravating the neurodegenerative processes.
Here, using OXYS rats that simulate key characteristics of sporadic AD, we set out to determine the role of mitochondria in the pathophysiology of this disorder. OXYS rats were treated with a mitochondria-targeted antioxidant SkQ1 from age 12 to 18 months, that is, during active progression of AD-like pathology in these animals. Dietary supplementation with SkQ1 caused this compound to accumulate in various brain regions, and it was localized mostly to neuronal mitochondria. Via improvement of structural and functional state of mitochondria, treatment with SkQ1 alleviated the structural neurodegenerative alterations, prevented the neuronal loss and synaptic damage, increased the levels of synaptic proteins, enhanced neurotrophic supply, and decreased amyloid-β protein levels and tau hyperphosphorylation in the hippocampus of OXYS rats, resulting in improvement of the learning ability and memory. Collectively, these data support that mitochondrial dysfunction may play a key role in the pathophysiology of AD and that therapies with target mitochondria are potent to normalize a wide range of cellular signaling processes and therefore slow the progression of AD.