Humans are a tad bit obsessed with our lifespans. In an effort to cheat death (or at least keep it at bay for a while), we search far and wide for all sorts of hacks: toxic fruit, genomes of long-lived animals, and even the blood of the young.
Now, scientists are turning closer to home, focusing on the microscopic powerhouses energizing each and every one of our cells.
In a study published this week in the journal Nature Aging, researchers at Buck Institute in California discovered a natural compound that makes our cellular recycling and waste management system work better. Called mitophagy-inducing coumarin (or MIC for short), this compound extended the lifespan of Caenorhabditis elegans, a worm commonly used as a model organism in scientific studies because of how easy they are to work with and observe. MIC did so by encouraging the worm’s cells to clear out old and damaged mitochondria — a process called mitophagy that naturally tends to decline as we age.
“There’s a bottleneck in efforts to develop potential therapeutics in the field of [the study of aging], and the bottleneck is that we don’t have enough molecules in the pipeline,” Gordon Lithgow, one of the study’s authors and a professor at Buck Institute, said in a press release. “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.”
Releasing the molecular brakes
The crux of longevity research has been finding ways to offset the natural degradation or dysfunction that comes with aging. This has led to an interest in autophagy, the body's innate rejuvenation process whereby all the “junk” we generate on a daily basis, like damaged proteins or worn-out cells, gets thrown out.
Autophagy is super important because without it, all our cellular “junk” will build up, and our bodies will stop working efficiently, much like trying to cook in a dirty kitchen with all the plates piling up in the sink. However, autophagy declining with age is inevitable and responsible for many aging-associated diseases like neurodegeneration or cancer. Studies show that improving autophagy, whether through starvation diets or genetic and pharmacological means, extends the lifespan of several animal models, from fruit flies to non-human primates.
Mitophagy is a type of autophagy specifically involving the mitochondria, a structure within cells that plays a crucial role in energy production, regulating metabolism, and controlling the cell cycle and growth, among many other things. Over time, our mitochondria get damaged or just wear out. In healthy cells, autophagy, including mitophagy, gets switched on by the autophagy-lysosomal pathway (or ALP), which is controlled by a particular set of genes aptly named ALP-related genes. Once activated, there’s a chemical cascade of events that eventually results in our cells eliminating damaged or worn-out mitochondria — a sort of mitochondrial quality control.
For their study, the researchers at the Buck Institute looked at the molecules involved in switching on mitophagy while studying a mouse model of Parkinson’s disease. Shankar Chinta, then a post-doctoral researcher at the Buck Institute, was searching for natural compounds in neuronal cells when he came across MIC as a consistent molecule among so many others that seemed to encourage mitophagy in both worm and mammalian cells in Petri dishes. MIC belongs to a family of chemicals called coumarins found abundantly in various edible plants and vegetables.
“Rather than taking MIC immediately into a mouse model, we wanted to understand its impact on overall aging and identify its mechanism of action,” Julie Andersen, one of the study’s authors and a professor at the Buck Institute, said in the press release.
Turning their sights to Caenorhabditis elegans, the researchers found that MIC influenced other proteins involved in activating mitophagy, in particular, a molecule called DAF-12, which keeps mitophagy on a tight leash and is known for its role in regulating lifespan and energy metabolism in the worm.
When MIC interacted with DAF-12 (its equivalent in humans is FXR), it essentially lifted its foot from the brakes. This, in turn, allowed another protein that manages the ALP-related genes — helix-loop-helix protein 30 (or HLH-30) in worms or transcription factor EB (or TFEB), the equivalent in humans — to turn on the cellular waste management system, allowing that process to work smoothly and without any age-related hiccups. As a result, worms who got MIC enjoyed a couple of extra days, with some living as long as 27 days (the average lifespan for Caenorhabditis elegans is between 18 and 20 days but less at certain temperatures).
New insight needs further research
Before this study, the researchers say no one knew DAF-12/FXR was involved in mitophagy. Not only does this help unravel the molecular mechanisms behind mitophagy, but it could also lend insight into how the gut microbiome is connected to neurodegenerative diseases like Alzheimer’s.
In humans, FXR is responsible for keeping the balance of fats in your body just right. This balance also involves regulating TFEB, which was recently found in brain neurons, the researchers say. FXR is itself controlled by bile salts — chemicals produced by the liver, stored in the gallbladder, and released into the intestines, where they help digest and absorb fats and fat-soluble vitamins — which are heavily regulated by the gut microbiome.
“The gut microbiome impacts the body’s use of bile acids. Aging impacts our microbiome,” Manish Chamoli, the study’s lead author and a research scientist at the Buck Institute, said in the press release. “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.”
There’s one big caveat to all this: Worms are most definitely not humans. While it seems to add days to their lifespan, at least in preliminary studies, we will need further studies to validate these findings before popping a MIC pill to keep your mitochondria — and, by extension, your lifespan — kicking for many more years to come.
