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Aging Impairs Mitochondrial ADP Sensitivity

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One of the proposed mechanisms driving the aging process is an increase with age of so-called reactive oxygen species (ROS), also known as free radicals. These chemical species contain unpaired electrons in the outermost orbitals of some of their atoms, which makes them extremely reactive as they attempt to snatch electrons from other atoms to reach a more stable configuration. Atoms that lose electrons to free radicals are said to be oxidized.

While free radicals appear to have also positive roles in the body, as is often the case with most things in biology, their electron-stealing habit is generally bad, because when they succeed, they end up altering the molecules they stole electrons from, thereby damaging them. Among other things, this can, for example, cause mutations in the genes of mitochondria, the energy production facilities of the cell, which also happen to be the main producers of free radicals as a waste product and thus are more prone to oxidative stress, which is essentially the inability of a biological system to make up for free radical damage. This is why mitochondrial ROS emission is thought to be an important piece of the aging puzzle.

An unsolved question

Even though it has been shown time and again that oxidative stress does indeed increase with age, in vitro experiments did not show any increase in mitochondrial ROS. This has led Dr. Holloway of the University of Guelph in Ontario and his team to think that, unless mitochondria were not the culprits responsible for the increase in oxidative stress experienced by aging humans, maybe previous in vitro experiments have misrepresented the actual situation.

Normally, in vitro assessments of ROS amounts in a system are done in the absence of ADP, or adenosine diphosphate. This molecule is a close relative of ATP, or adenosine triphosphate, and is, in fact, turned into the latter (and back) in a number of metabolic processes, including in the mitochondria. ADP metabolization by mitochondria is part of the cellular respiration process and leads to a decrease in ROS levels. Given that ADP is always present in vivo, the researchers decided to try to see what would happen to ROS levels in an in vitro model that included ADP [1].



The experiment

To this end, the researchers took samples of muscle tissue from ten healthy men in their 20s and ten in their early 70s. Upon comparison, what they found out was that cells from the older men were 8 to 10 times less sensitive to ADP, and therefore, even in the presence of the chemical within the system, ROS levels were higher than in the cells of the younger men. This was tried with several different ADP concentrations that are normally found in the human body.

The finding seems to suggest that ADP sensitivity is somehow impaired in the muscle tissue of older men, and this, in turn, results in higher ROS levels that would otherwise be decreased by ADP itself. While it is not clear what impairs ADP sensitivity in the first place, a possibility is oxidative stress itself, hinting that a feedback loop might make the process spiral further down: more ROS cause more oxidative stress causes less ADP sensitivity causes more ROS.

The researcher also wanted to see whether resistance exercise training might help reduce oxidative stress in the elderly subjects. After 12 weeks, ADP sensitivity did improve, although

No significant changes in ROS were recorded. This appears to suggest that aging does indeed come with an increase in mitochondrial ROS emission so that even though reduced ADP sensitivity may be a reason why elderly subjects show higher ROS concentrations, it is not the whole story.



Conclusion

Resistance exercise training might not help in reducing free radical levels, but the researchers found that it did improve other aspects of muscle health—further evidence, if any more was needed, that exercising is good for you, even and especially so in old age. However, further studies on the relationship between ADP metabolism and oxidative stress will be needed.

Literature

[1] Holloway, G. P., Holwerda, A. M., Miotto, P. M., Dirks, M. L., Verdijk, L. B., & van Loon, L. J. (2018). Age-Associated Impairments in Mitochondrial ADP Sensitivity Contribute to Redox Stress in Senescent Human Skeletal Muscle. Cell Reports, 22(11), 2837-2848.

About the author
Nicola Bagalà

Nicola is a bit of a jack of all trades—a holder of an M.Sc. in mathematics; an amateur programmer; a hobbyist at novel writing, piano and art; and, of course, a passionate life extensionist. After his interest in the science of undoing aging arose in 2011, he gradually shifted from quiet supporter to active advocate in 2015, first launching his advocacy blog Rejuvenaction before eventually joining LEAF, where he’s currently fully dedicated to our YouTube show LifeXtenShow. These years in the field sparked an interest in molecular biology, which he actively studies. Other subjects he loves to discuss to no end are cosmology, artificial intelligence, and many others—far too many for a currently normal lifespan, which is one of the reasons he’s into life extension.
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