The (Cell) Death Cure: Could triggering autophagic cell death with an MTORC-1 inhibitor combat aging and disease?

A quick look at global life expectancies through the years confirms what many of us already know. People are living longer all the time, thanks to advancements in medicine, improvements in quality of life, and decreased infant mortality. It’s easy to assume that your great-great-grandchildren, or great-great-great-grandchildren, will effortlessly live into the triple-digits, far surpassing current possibilities.

However, a closer examination of the graph above will reveal an important caveat: every single graph is concave down. That is, while life expectancy is increasing, the rate of change of life expectancy is slowing. The steep incline of the 19th and 20th centuries no longer applies, particularly in the Americas; but even Africa, the continent with the farthest left to go, has a flattening curve.

In 2019, it was projected that the global life expectancy in 2100 will be 81.69 years. The same calculation, based on past data and the rate at which life expectancy growth slows over time, projected a life expectancy of 73.16 years in 2021. The actual current global life expectancy is 72.81 years — it’s been less than two years, and we’re already falling behind. This means our 81.69 number is optimistic — and even that is an increase of fewer than fifteen years over the entirety of the 21st century.

But more important than lifespan is healthspan — the portion of one’s life spent in good health. Right now, the average healthspan in the United States is 66 years — meaning the average American is healthy for around 84% of their life. Not bad. But if we remained focus on extending the last stretch of our lives with improved management of individual diseases, by the end of the century that 66 years will be only 75% of the average American’s life. An extra decade of sickness, and spending a quarter of your time on Earth struggling with age-related health problems, is not exactly an appealing future.

This necessitates a new and different solution to the issue of health and life expectancy. One that disrupts the process at the root of disease, and rejects the complacency of allowing lifespan to continue to increase gradually until the change is imperceptible.

The root of disease (or rather, most disease) is, of course, aging. But do we know enough about how aging works on a cellular level to devise the ultimate antidote — to aging, disease, and mortality? How far away are we from a death cure — and what would that even look like?

The best cure for insomnia is to get a lot of sleep

The primary difficulty with aging is that it is so ubiquitous and inevitable that it becomes easy to lose sight of the problem. When many people think of slowing or reversing aging, what comes to mind is the wrinkles on their skin, not the folds of proteins within their cells. It is fundamentally a whole-body process, and therefore a singular goal cannot be determined. Still, the same problem-solving process as any other disease can be applied. Let’s practice a few.

Problem: Pain when swallowing

Solution: Gargle with warm water

Problem: Fever

Solution: Put on a cold compress

Problem: Nausea

Solution: Drink some ginger ale

All of these are perfectly valid treatments. However, if we were to take a step back and notice all the problems are symptoms of strep throat, we could actually tackle the problem directly with antibiotics. Aging is similar, on both the macro- and micro-level.

The macro-level would be looking at, say, cardiovascular disease, Alzheimer's, and decreased mobility and realizing they all have a common cause. At this point, that’s kind of old news.

The micro-level, on the other hand, is less well understood. Aging is associated with the shortening of telomeres, the depletion of stem cells and NAD+, cellular senescence, oxidative stress, and other cellular changes you can read about in more depth here.

On the whole, aging can be described in simplest terms as the accumulation of damaged cells over time. From here, the question is: a.) how can we prevent this cellular damage, and b.) how can we repair or remove damaged cells? For the purposes of this article, we’re going to be focusing primarily on the latter. I’m also going to offer up a potential pharmaceutical solution; to learn more about integrative, lifestyle, and holistic approaches to longevity, which will tackle the former through prevention, check out this article.

Macroautophagy (aka, the Healthiest Snack You’ll Never Have)

When our cells are deprived of nutrients, a protein complex called MTORC-1 is inhibited, and fails to phosphorylate a protein creatively titled “Autophagy-related protein 13” (Atg-13 for short). This triggers a process known as macroautophagy (henceforth called autophagy for brevity’s sake), in which autophagosomes enclose old and damaged organelles before merging with lysosomes to digest them. Translation: you digest broken cell machinery. In addition to providing nutrients when you go for extended periods of time without eating, this prevents cellular senescence by eliminating problem organelles.

In addition to this function, it’s also present in what’s called Autophagic Cell Death (ACD), a type of programmed cell death. Although the name would imply that this is when autophagy causes cell death, in reality it’s likely more nuanced than that. While we don't totally understand ACD, we do know that it is a type of cell death that is associated with the large-scale autophagic vacuolization of the cytoplasm. This autophagy could cause the death of the cell, be an attempt at avoiding cell death, or do something else entirely — but what does give us some insight is watching what happens when normal apoptosis is disabled.

In a 2004 study, mouse cells that had been genetically modified to be incapable of apoptosis still died when exposed to DNA damaging agents and other stimuli. This programmed cell death was executed by autophagy regulators ATG5 and BECLIN1, and suppressing these two genes actually prevented cell death altogether.

While triggering cell death may sound bad, this is promising considering that decreased apoptosis associated with aging leads to the accumulation of cancer and senescent cells. This would suggest that autophagic cell death may be a helpful workaround, as inducing autophagy would not only prevent these cell types from forming, but possibly help lead to their destruction.

However, we know both intuitively and from extensive research that too much cell death is bad: in certain cell types, apoptosis increases with age, and causes health complications such as immune system decline, skeletal muscle wasting, loss of heart cells, and neurodegenerative disease. So how do we trigger just the right amount of autophagy, and only in certain cells, while inhibiting apoptosis elsewhere?

Pinocchio Says His Nose Will Grow

When it comes to understanding human aging, it’s safe to assume everything is a paradox. Telomeres exist to cause senescence, which protects against cancer, but the signals sent out by senescent cells cause cancer. Apoptosis decreases with age and causes accumulation of bad cells, but also increases with age to destroy good cells. But luckily for us, this is also true of autophagy.

Autophagy’s paradoxicality is often explored in relation to cellular senescence. Although it is generally recognized that autophagy typically prevents senescence, selective autophagy leading to the consumption of only certain substrates can actually cause senescence, and at a certain point in the process of a cell becoming senescent autophagy actually serves as a catalyst for senescence to accelerate.

Even autophagy’s relationship to cell death is contradictory. Because autophagy is actually . . . wait for it . . . considered to be a protector against cell death.

I know. Why can’t it just make up its mind? It’s hard to say. There are a number of proteins and enzymes heavily involved in both apoptosis and autophagy, such as G9a, Beclin-1, and many of the “Atg”s, so it makes sense that the processes would be heavily intertwined — and considering that apoposis can’t seem to decide whether it’s good for us or not either, perhaps this is a very good thing.

Autophagize More, Live Longer . . . Sort Of

To settle the question once and for all, I dug out my late grandfather’s microscope, got my hands on some C. elegans, and set up a home lab (read: a folding table in the garage). You can read in-depth about my results here (or check out this video), but the TL;DR is:

• They had a mutation in the gene let-363 (homologous to mTOR in humans) that caused them to experience uncontrolled autophagy
• They lived 2.5x longer than worms without the mutation
• They had developmental arrest at larval stage 3 (stopped aging)
• They experienced intestinal atrophy and gonadal degeneration

From this, it is clear that radical autophagy is linked to radical life extension and the total prevention of aging; however, the downsides induced by too much cell death put something of a damper on these positive results. My proposed solution to this is “controlled uncontrolled autophagy” (CUA): a short-term small molecule activator of autophagy that would achieve the same results as genetic mTOR supression on a smaller scale, and without interfering with normal digestion.

NV-6297

2-(4-(3-(1-(2-Cyanophenyl)piperidin-4-ylamino)-2,4,6-trimethylbenzoyl)piperazin-1-yl)pyridine-3-sulfonamide, better known as NV-6297, is a small molecule inhibitor of mTORC1 discovered in 2019 (recall that mTORC1 is the complex that phosphorylated Atg-13 when activated by glucose to prevent autophagy). By inhibiting this complex, it is possible to activate autophagy without caloric restriction.

One of the major challenges of creating a Caloric Restriction Mimetic, or CRM, targeting mTORC1 is that molecules effective against the compound often equally inhibit mTORC2, which can cause negative side effects such as hyperglycemia and insulin resistance not seen with the inhibition of mTORC1 alone.

After several iterations of similar small molecules, NV-6297 was shown to be pharmacokinetic, orally bioavailable, and selectively effective against mTORC1. It has been proven to effectively trigger autophagy both in vitro and in vivo, with a half-life of 2.3 hours (similar to Tylenol) and an impressive 100% oral bioavailability (higher than Tylenol).

The End of Aging?

The discovery of an effective molecular inhibitor of mTORC1 is huge — and if it can be used to induce autophagic cell death in senescent and tumor cells while inhibiting apoptosis elsewhere, that will be a huge advancement.

The combination of NV-6297 with another CRM could be a key component of future longevity treatments; because of the central role of autophagy in aging, it would reduce stem cell senescence (and overall senescence), decrease oxidative damage, and regulate apoptosis and other forms of cell death that become less effective with age. This is an important step on the road to radical health- and lifespan extension, and one that could be feasible in the very near future.

Key Takeaways:

• The decreasing rate of life expectancy increase necessitates targeted innovations to increase health- and lifespan
• Autophagy promotes cell death under some circumstances, and inhibits it under others
• Apoptosis becomes more common with age in certain cell types, and less common in others
• Controlled uncontrolled autophagy would allow temporary, highly effective autophagy to prevent cellular damage and regulate cell death
• NV-6297 is a small molecule inhibitor of mTORC-1 that triggers autophagy in vitro and in vivo
• The combination of NV-6297 with another CRM could create an ideal balance of autophagy for increased health- and lifespan