There are currently dozens of different molecules and compounds at trial stage, as scientists across the globe search for the knockout anti-aging drug, but most have a common thread: finding a way to keep our old cells firing on all cylinders, while simultaneously making sure they remain savvy microbiological recyclers.
Now, scientists at the Buck Institute for Research on Aging believe they have a strong candidate to do just that, finding success with a natural compound that both extended the lifespan of Caenorhabditis elegans nematodes and improved cellular function in the muscle cells of mice. This bodes well for use in humans.
Dubbed MIC for Micophagy-Inducing Compound, it’s a natural coumarin, which has known anticoagulant, antibacterial, antifungal, antiviral, anticancer and antihyperglycemic properties. It’s also an antioxidant and has neuroprotective benefits. You can find coumarin in plants, but its highest concentration is in certain types of cinnamon.
The scientists found that MIC boosted the activity of transcription factor EB (TFEB), which plays a crucial role in directing cellular autophagy and lysosomal functions. Essentially, it maintains the body’s intracellular recycling system, which is carried out by lysosome organelles. This process, among many others, begins to falter with age.
“Co-author Shankar Chinta started screening natural compounds in neuronal cells and MIC came up as a major hit,” said senior author of the study, Julie Andersen. “Rather than taking MIC immediately into a mouse model we wanted to understand its impact on overall aging and identify its mechanism of action, so we took the work into the worm where we found that MIC is in a different class of molecules that enhance the expression of a key protein, TFEB.”
In C. elegans, which are often used in testing anti-aging therapies, MIC “robustly increased the lifespan” of the worms, and also blocked mitochondrial dysfunction in the mammalian muscle cells of the mice.
As the powerhouses of cells, properly functioning mitochondria are, of course, essential for good health and longevity. Defective mitochondrial function – namely, a specific type of autophagy known as mitophagy – is a large contributor to the development of age-related conditions such as Parkinson’s, Alzheimer’s disease, many cardiovascular diseases and the metabolic diseases of obesity and type 2 diabetes.
It also features heavily in sarcopenia, the loss of muscle mass and strength that contributes to all the complications that come with age-related frailty.
The scientists are confident that MIC might be the first new drug-like molecule to maintain mitochondrial health through efficient mitophagy, setting it up as a potential therapy to slow the aging process.
“Mitophagy is a selective and very significant form of autophagy,” said Buck professor and co-author of the study, Malene Hansen. “The field has recognized TFEB as a player when it comes to quality control in mitochondria. This study provides a possible translational route to induce mitophagy in a TFEB-dependent fashion.”
Underpinning MIC’s efficacy is a brain-gut connection. The gut’s microbiome and the gut-brain axis (GBA) are connected to maintaining cognitive health; microbes in the gut being key regulators of brain function and neurodegeneration.
The scientists found that MIC blocked the activation of the hormone receptor DAF-12 in the worms, which kickstarted effective mitophagy and ultimately extended the animal’s lifespan. The equivalent nuclear hormone receptor in humans is FXR, and age-related microbiome changes in the gut can upset its function, in turn leading to mitochondrial deterioration in neurons especially, because they have a higher number of cell powerhouses.
“The gut microbiome impacts the body’s use of bile acids,” said lead author Manish Chamoli. “Aging impacts our microbiome. If levels of bile acids aren’t correct it hinders mitophagy. That’s how FXR can impact neuronal health. Neurons have a lot of mitochondria which makes mitophagy important in terms of neurodegeneration.”
The team is now looking at neuronal FXR as a potential target for a new Alzheimer’s disease therapeutic.
“This study provides another piece of the puzzle when it comes to understanding the brain/gut connection in terms of health and disease,” said Andersen.
“There’s a bottleneck in efforts to develop potential therapeutics in the field of geroscience, and the bottleneck is that we don’t have enough molecules in the pipeline,” added senior co-author Gordon Lithgow. “MIC is a great candidate to bring forward given its therapeutic effect across multiple models and the fact that it is a naturally occurring molecule.”
The research was published in the journal Nature Aging.
