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A sizable fraction of research aimed at treating aging involves screening natural compounds in search of those that can modestly slow aging in short-lived animal models. This is because the economics of developing such a compound into a drug or supplement are well understood by investors, and because it dovetails well with the scientific goal of increased understanding of how aging progresses at the level of cellular biochemistry, rather than because it is going to make a big difference for patients. If sizable gains in healthy life span were the driving incentive, the field would look very different, and the emphasis would be on different approaches.
Today’s publicity materials are a good example of the way in which unbiased screening works. It tends to find ways to influence the well-known set of mechanisms related to the calorie restriction response, responsible for the plasticity of life span in short-lived species. These include upregulation of autophagy, specific upregulation of mitophagy, the autophagic processes responsible for clearing damaged and worn mitochondria, improvement of mitochondrial function via other means, and so forth. The problem with adopting this approach is that calorie restriction and related alterations in metabolism produce much smaller gains in life expectancy in long-lived species than in the short-lived species used in screening. Thus unbiased screening as a basis for a program is more or less a guarantee of producing marginal therapies. We have to do better than this.
Defective mitophagy is implicated in many age-related diseases. It’s tied to neurodegenerative disorders such as Parkinson’s and Alzheimer’s; it plays a role in cardiovascular diseases including heart failure; it influences metabolic disorders including obesity and type 2 diabetes; it is implicated in muscle wasting and sarcopenia and has a complex relationship with cancer progression. Even though interventions that restore mitophagy and facilitate the elimination of damaged mitochondria hold great promise for addressing these conditions, not one treatment has been approved for human use despite advances in the field.
MIC (Mitophagy-Inducing Compound) is a coumarin, which are naturally bioactive compounds that have anticoagulant, antibacterial, antifungal, antiviral, anticancer, and antihyperglycemic properties (among others) as well as being an antioxidant with neuroprotective effects. Coumarin is found in many plants and is found in high concentrations in certain types of cinnamon, which is one of the most frequent sources for human exposure to the substance. “We started screening natural compounds in neuronal cells and MIC came up as a major hit. 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.”
Researchers found that MIC enhanced the activity of transcription factor TFEB, which is a master regulator of genes involved in autophagy and lysosomal functions. Autophagy is the intracellular recycling process whereby cells clean up damaged proteins; it derives its abilities from the lysosome. Researchers found that MIC robustly increased the lifespan of C. elegans while also preventing mitochondrial dysfunction in mammalian cells.
Mechanistically MIC works upstream of TFEB by inhibiting ligand-induced activation of the nuclear hormone receptor DAF-12 (in worms)/FXR (in humans), which in turn induces mitophagy and extends lifespan. FXR is best known for its ability to act in the liver and gut to maintain lipid homeostasis, where it acts to regulate levels of TFEB as part of a feed-fast cycle, but recently TFEB was shown to also be present in brain neurons. FXR is regulated by bile salts which are formed in the gut microbiome. “The gut microbiome impacts the body’s use of bile acids. 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.”
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