Mitochondrially Targeted Antioxidant SS-31 Improves Cognitive Function in Old Mice

Oxidative damage has long been linked to aging, but the general use of antioxidants does nothing for life span. In fact, the evidence suggests this approach is modestly harmful, possibly due to blocking the oxidative signaling needed for exercise and other, similar mild stresses to produce benefits via hormesis. Antioxidant compounds targeted to the mitochondria are a different story, however, and have been shown to slow aging or partially reverse some aspects of aging in mice and lower animals - as is the case in this open access paper.

Mitochondria are the power plants of the cell, and generate reactive molecules that raise oxidative stress as a side-effect of the processes that produce chemical energy stores. This flow of reactive molecules influences the behavior of the cell in numerous ways; methods of slightly slowing aging have been demonstrated that either lower production, leading to less oxidative damage, or raise it, spurring increased maintenance activities in the cell. In the research here, benefits are derived indirectly: damping down oxidative damage improves the function of blood vessels in the aged brain, which helps to restore some degree of lost cognitive function in old mice. The brain is an energy-hungry organ, and age-related neurodegenerative conditions are characterized by a general decline in the capacity of of the blood supply and mitochondria in cells to supply as much energy as is needed.

Normal functioning of the central nervous system (CNS) requires a continuous, tightly controlled supply of oxygen and nutrients as well as washout of harmful metabolites through uninterrupted cerebral blood flow (CBF). The energetic demands of neurons are very high, yet the brain has very little energetic reserves. During periods of intense neuronal activity, there is a requirement for adjusting oxygen and glucose delivery to local neuronal activity through rapid adaptive increases in CBF. This is ensured by a mechanism known as neurovascular coupling (NVC). The resultant functional hyperemia is a vital mechanism to maintain optimal microenvironment of cerebral tissue and thereby ensuring normal neuronal function.

There is an increasing appreciation that (micro)vascular contributions to cognitive impairment and dementia in elderly patients are critical. Importantly, neurovascular coupling responses are impaired both in elderly patients and aged laboratory animals. Experimental studies support this concept, showing that pharmacologically induced neurovascular uncoupling in mice mimics important aspects of age-related cognitive impairment. On the basis of these findings, we proposed that novel therapeutic interventions should be developed to rescue functional hyperemia in elderly patients to prevent/delay cognitive impairment. Previous studies demonstrate that aging exacerbates generation of reactive oxygen species (ROS) in the cerebromicrovascular endothelial cells, which contribute to age-related neurovascular uncoupling in aged mice by promoting endothelial dysfunction. We hypothesize that pharmacological treatments, which attenuate endothelial oxidative stress, will have the capacity to improve neurovascular coupling in aged individuals.

The mitochondrial free radical theory of aging posits that mitochondria-derived ROS (mtROS) production and related mitochondrial dysfunction are a critical driving force in the aging process. In support of this theory, it was demonstrated that attenuation of mitochondrial oxidative stress (by mitochondria-targeted overexpression of catalase) increases mouse lifespan. There is particularly strong evidence that mitochondrial oxidative stress is implicated in cardiovascular aging processes. Yet, although drugs that improve mitochondrial function have been shown to exert beneficial effects both on the vasomotor function of peripheral arteries, their potential protective effects on the aged cerebral microvasculature has not been investigated.

This study was designed to test the hypothesis that pharmacological attenuation of mtROS can restore cerebromicrovascular endothelial function and thus improve neurovascular coupling in aged mice. To achieve this goal, in aged mice mitochondrial oxidative stress was manipulated by treatment with the mitochondrial-targeted peptide SS-31. We found that neurovascular coupling responses were significantly impaired in aged mice. Treatment with SS-31 significantly improved neurovascular coupling responses by increasing cerebromicrovascular dilation, which was associated with significantly improved spatial working memory, motor skill learning, and gait coordination. These findings are paralleled by the protective effects of SS-31 on mitochondrial production of reactive oxygen species and mitochondrial respiration in cultured cerebromicrovascular endothelial cells derived from aged animals.



Antioxidants do block the benefits of ROS during exercise but the simple solution to that is to avoid taking them before exercise and to wait to take them until 2 to 4 hours after exercise.

Posted by: Nathan at February 9th, 2018 7:31 AM

good paper. i am currently using mitoq

Posted by: scott emptage at February 9th, 2018 7:34 AM

@Nathan, do you have a reference for the 2-4 hour period after exercise? I don't take them before exercise but didn't know about the waiting period. It must take some time for antioxidants to reach the mitochondria from the GI tract so there is already some delay built in by waiting after exercise.

Posted by: Morpheus at February 9th, 2018 1:22 PM

Damn good workouts using 20mg MitoQ pre workout. Never saw any reference for the claims made by Nathan, I Think he is extrapolating from the negative results from Vitamin C and Vitamin E research.

Posted by: arren brandt at February 12th, 2018 5:03 AM

I've experienced 'better' workouts when taking certain supplements but have wondered if they are truly better in terms of garnering the long-term benefits of exercise. Does anyone have any links to review articles or well-researched blog posts than can lay it all out for me?

Posted by: CD at February 12th, 2018 10:29 AM

I don't suppose it's possible to obtain SS-31 at a reasonable cost?

Posted by: bmack500 at February 12th, 2018 12:54 PM

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