The effects of let-363 mutation on C. elegans — and what that means for human life extension

For the past few weeks, I have spent hours each day with my new best friends. These friends don’t talk (though I often find myself talking to them), preferring to wriggle around and occasionally chase their own tails. Despite being nearly identical, after so much time in their company I’ve become able to tell them apart. And a few days ago, after outlasting their typical lifespan by a shocking fifteen days, my new friends, sadly, began to die.

My companions, during their approximately twenty-five days on this earth, were C. elegans — one millimeter long, transparent nematodes that share a surprising amount of human DNA. These worms had a mutation in the gene let-363, homologous to the human gene mTOR — which has itself been linked to aging and age-related disease in fungi and animals alike, including humans and other mammals. This is because of the key role mTOR plays in autophagy.

Say what now?

Autophagy is a word you may have heard from your favorite fitness influencers in conjunction with “intermittent fasting,” and possibly with “juice cleanse” and “detox” thrown in for fun. Although I cannot guarantee that that influencer’s description contained any scientific backing — or that a given fad diet has any benefit whatsoever — autophagy is a very real biological process, and will likely play a key role in revolutionizing what it means to age.

But how does autophagy actually work?, you ask, curious and cautiously excited. Excellent question. Let’s start with the basics.

Autophagy is consuming your own cells

Self-digestion may not sound like the best health recommendation, but hear me out. When you’re body is low on nutrients, it has a built-in feature that lets it consume itself to power your necessary organs. This means that damaged cells consume the organelles within them that are damaged or problematic, preventing cellular senescence.

Cellular senescence is a phenomenon in which damaged cells, and cells with DNA mutations, fail to commit suicide. They start to occur more and more as we age, and our immune systems become less efficient. These “zombie” cells are inactive but alive, sending out signaling molecules in the hopes of being put out of their misery. Unfortunately, these signal cells inflame the surrounding area and are believed by many to be one of the root causes of aging.

Consuming one’s own senescent cells for energy is exactly the goal of many health trends such as intermittent fasting, which has actually shown some pretty astonishing results, protecting against type 2 diabetes, reducing heart disease, and preventing neurological conditions.

Slightly more in-depth version

Got that? Good. Now let’s take a slightly closer look at what’s actually occurring on the cellular level.

This is mTORC1, the protein coded for by mTOR — remember that one? Its job is actually to prevent autophagy. When you get enough nutrients, mTORC1 is activated and phosphorylates (gifts a phosphate compound to) the aptly named “autophagy-related protein 13” (Atg 13 for short), which in turn prevents Atg 13 from entering what is known as the ULK1 kinase complex, thus halting autophagy. But when you don’t get enough nutrients, and mTORC1 doesn’t get activated, there’s no stopping Atg 13, and autophagy is triggered.

What does this have to do with C. elegans again?

Like most eukaryotes, C. elegans undergo autophagy when they’re low on nutrients. However, the particular C. elegans I have been associating with have a special mutation in the gene let-363, which controls their version of mTORC1 (called let-363, isoform b). This mutation is relatively simple: it makes the associated protein totally inactive. And as you’ll recall, an inactive protein = unlimited autophagy.

You monster!, you shout at me, looking at cute nematode pictures and shopping for your very own C. elegans stuffed animal. Won’t the poor things just… digest themselves?

Precisely. But it’s what happens in the meantime that’s interesting.

The fountain of youth (for roundworms)

The first thing you might find surprising is that the nematodes actually stop aging relatively early. Let’s take a quick look at the life cycle of C. elegans.

They grow up so fast, don’t they? But my C. elegans didn’t. In fact, they didn’t grow up at all. They stopped developing at the L3 stage, which is, if I had to put a number on it, about equivalent to age 12 (or the start of puberty) in humans, although it’s a pretty apples-and-oranges comparison considering we’re five- or six-foot bipedal mammals who frequently live past the age of seventy and they’re literally millimeter-long worms who live for ten days.

Still, the fact that C. elegans start acting like the Lost Boys from Peter Pan just from canceling one gene is pretty insane and might indicate that autophagy plays an even larger role in aging than we had assumed. Still no word on how to get them to age up to twenty-one human years so they can get into bars.

The (fairly unpleasant) drawbacks

Unfortunately for my tiny friends, being permanently in middle school was not the only side effect of the mutation. Their gonads degenerated, and they exhibited severe intestinal atrophy, which interestingly, is not present even in starved C. elegans. This indicates which body parts that were perhaps disproportionately autophagized. Although they ate normally, they did not seem to be able to digest food, opting to consume their own cells instead. Around 25 days — having lived 2.5 times longer than average — they finally starved to death.

So what does this mean for humans?

As of right now, I don’t envy the C. elegans who occupied my home lab (read: repurposed garage) until recently. The bargain they were given isn’t one most people would want to take. However, I believe it is a step in the right direction.

Remember how in these C. elegans, the gene preventing autophagy was totally deactivated? This means that there was no control; they digested themselves willy-nilly. My current research centers around finding the “golden ratio of autophagy” — the level of protein activity where an organism autophagizes just enough to seriously slow aging, without actually starving to death. The closer to this ratio one gets, the longer the lifespan will be. With too little autophagy we age to death, with too much we starve. Perhaps with just the right amount, we won’t die at all.

Would you press the button? What if there was a drug that reset your body to the golden ratio? Respond to this article and let me know!

Quick Recap:

• mTOR plays a key role in mediating aging in a variety of organisms
• C. elegans are one-millimeter nematodes
• let-363 is the C. elegans version of mTOR
• Both mTOR and let-363 control autophagy
• Autophagy is the process in which an organism digests its own organelles
• Autophagy prevents cellular senescence and decreases aging
• C. elegans with uncontrolled autophagy lived 2.5 times longer and stopped aging at the “L3” stage
• They also had severe intestinal atrophy and gonadal degeneration
• If we can find the “golden ratio” of autophagy, it may be possible to live forever

Thank you so much for reading! If you have any questions about my research, shoot me an email at katieannesilverman@gmail.com, or reach out to me on LinkedIn.