Scientists from the Salk Institute for Biological Studies are homing in on exactly how two new experimental Alzheimer’s drugs could be generating the anti-aging effects seen in early animal studies. The discovery of a unique metabolic pathway, associated with both general aging and the onset of dementia, offers researchers novel directions for future anti-aging studies.
Salk researchers have been developing two experimental drugs for several years with a view on improving cognition and slowing the neurodegenerative decline associated with Alzheimer’s disease. Called CMS121 and J147, the drugs were effective in slowing the progression of Alzheimer’s in initial animal tests. However, the compounds also seemed to demonstrate signs of slowing down general markers of brain aging.
As the two drugs move toward human trials, the researchers have been working to uncover exactly what molecular mechanisms are at play to explain how they work. One potential mechanism was uncovered in early 2018 but that was only part of the story. Now, the Salk team has uncovered an exciting new molecular pathway, influenced by the two drugs, that could explain how the compounds slow down brain aging.
The new research administered the two experimental drugs to a strain of mice engineered to age at a faster pace than normal. The drugs were given to the animals at the age of nine months, which is equivalent to between 55 and 65 years old in human beings. Compared to a control group, the treated mice displayed slower rates of age-related cognitive decline as well as showing a number of molecular signs the drugs had protected the brain against age-related degeneration.
The most specific mechanism identified in the new research was an increase in the levels of acetyl-coenzyme A (acetyl-coA), a chemical found to confer neuroprotective effects by preserving mitochondrial homeostasis. Zooming in on this particular molecular pathway in brain cell studies, the researchers discovered age-related molecular changes could be prevented by maintaining acetyl-coA levels.
“There was already some data from human studies that the function of mitochondria is negatively impacted in aging and that it’s worse in the context of Alzheimer’s,” explains Pamela Maher, co-corresponding author on the new study. “This helps solidify that link.”
Both CMS121 and J147 are moving into human trial phases. J147 is the most advanced, with Phase 1 trials commencing earlier in 2019 to test the safety profile of the drug in healthy young and elderly subjects. While the initial target for these compounds is Alzheimer’s disease, the insights into how the drugs influence anti-aging pathways will inform their potential in treating a broad array of age-related degenerative diseases.
There is certainly a long road ahead before these experimental compounds reach the general public but the discovery of these age-related metabolic pathways offer scientists exciting new research directions, not just in treating Alzheimer’s and dementia, but in the broader search for anti-aging medicines.
The new study was published in the journal eLife.
Source: Salk Institute
