Mitochondria, the power plants of the cell, suffer a general malaise in older individuals. Their dynamics change and their production of energy store molecules declines. This is distinct and separate from the damage to mitochondrial DNA outlined in the SENS vision for rejuvenation therapies, in that it occurs across all cells rather than in a small but significant number of cells. It is probably a secondary or later consequence of other forms of cell and tissue damage, an inappropriate reaction that makes things worse. This decline in mitochondrial function is implicated in neurodegenerative diseases; the brain requires a great deal of energy to function, and some portion of the changes and symptoms of cognitive decline are due to insufficient energy store production.
Researchers here make some inroads to putting numbers to that portion, at least in mice, but the challenge inherent in the use of animal models of Alzheimer's disease is that they are very artificial. Mice don't normally suffer from Alzheimer's, and their neural biochemistry must be altered significantly in order to produce any of the protein aggregates seen in Alzheimer's disease. The current models only recapture a slice of the full human condition, focusing on amyloid aggregation rather than the full biochemistry of the Alzheimer's. Thus there is always the question for any specific finding as to whether it will also apply to humans, or whether it is a quirk of the model, no matter how plausible the assumptions.
Alzheimer's disease is the most common form of dementia and neurodegeneration worldwide. A major hallmark of the disease is the accumulation of toxic plaques in the brain, formed by the abnormal aggregation of a protein called beta-amyloid inside neurons. Most treatments focus on reducing the formation of amyloid plaques, but these approaches have been inconclusive. As a result, scientists are now searching for alternative treatment strategies, one of which is to consider Alzheimer's as a metabolic disease.
Researchers looked at mitochondria, which are the energy-producing powerhouses of cells, and thus central in metabolism. Using worms and mice as models, they discovered that boosting mitochondria defenses against a particular form of protein stress, enables them to not only protect themselves, but to also reduce the formation of amyloid plaques. During normal aging and age-associated diseases such as Alzheimer's, cells face increasing damage and struggle to protect and replace dysfunctional mitochondria. Since mitochondria provide energy to brain cells, leaving them unprotected in Alzheimer's disease favors brain damage, giving rise to symptoms like memory loss over the years.
The scientists identified two mechanisms that control the quality of mitochondria: First, the "mitochondrial unfolded protein response" (UPRmt), which protects mitochondria from stress stimuli. Second, mitophagy, a process that recycles defective mitochondria. Both these mechanisms are the key to delaying or preventing excessive mitochondrial damage during disease. "These defense and recycle pathways of the mitochondria are essential in organisms, from the worm C. elegans all the way to humans. So we decided to pharmacologically activate them." The team started by testing well-established compounds that can turn on the UPRmt and mitophagy defense systems in a worm model (C. elegans) of Alzheimer's disease. The health, performance and lifespan of worms exposed to the drugs increased remarkably compared with untreated worms. Plaque formation was also significantly reduced in the treated animals.
Most significantly, the scientists observed similar improvements when they turned on the same mitochondrial defense pathways in cultured human neuronal cells, using the same drugs. The encouraging results led the researchers to test in a mouse model of Alzheimer's disease. Just like C. elegans, the mice saw a significant improvement of mitochondrial function and a reduction in the number of amyloid plaques. But most importantly, the scientists observed a striking normalization of the cognitive function in the mice.