How Michael Hall’s TOR Discovery Reframed Longevity Science

We trace how a soil-derived drug led to the discovery of mTOR, why growth control sits at the core of aging biology, and where evidence ends for humans. Michael Hall’s quiet breakthroughs explain fasting, autophagy, and rapamycin without the hype.

To read more about this topic and for more science stories, visit our website swisinfo.ch. You can help other people to find our podcast by leaving us a five-star review.

Journalist: Jessica Davis Plüss
Host: Jo Fahy
Audio editor/video journalist: Michele Andina
Distribution and Marketing: Xin Zhang

SWI swissinfo.ch is a public service media company based in Bern, Switzerland.

Chapters

• 0:00 Setting The Longevity Question
• 2:02 Meeting Michael Hall In Basel
• 3:57 Blue Zones And Early Skepticism
• 6:37 From Nuclear Transport To Drug Mysteries
• 9:12 Why Yeast Cracked A Human Problem
• 11:02 The TOR Genes And Controlled Growth
• 14:12 mTOR, Nutrients, And Aging Links
• 16:42 Animal Evidence For Rapamycin
• 18:52 Humans, Hype, And Trial Limits

Transcript

Jo Fahy: 0:33

Hello, I'm Jo Fahy, and this is a Swissinfo podcast. Swissinfo is the multilingual and international public media company of Switzerland. Is there a drug that can prolong our lives? Scientists believe that we're getting close to finding that magic pill. In this episode, we're speaking to a molecular biologist in Basel about how a groundbreaking discovery he made 30 years ago is now fueling one of the biggest health trends of our time: longevity. Have you heard of the drug Rapamycin? I hadn't until we made this episode. It's used to prevent organ transplant rejection or treat certain cancers and many other things. The drug is also known to have some impact on aging. Our healthcare reporter, Jessica Davis Plüss, talked to the American Swiss molecular biologist Michael Hall. He made some of the biggest discoveries about rapamycin. Here's Jessica.

Jessica Davis Plüss: 1:44

Michael Hall is a virtual unknown in today's social media inflated longevity scene. He hasn't published any books on why we age or been featured in any films on the secrets of centenarians. He doesn't have a side business selling supplements or red light therapy or other treatments found in many of today's longevity clinics. Hall's absence from the current longevity craze is all the more incredible given that his research is widely considered to have transformed our understanding of aging and potentially how to slow it down. In the early 1990s, he discovered a gene in yeast that regulates the growth and health of the cell in response to nutrients around it. He named it target of rapamycin, abbreviated to TOR, after the compound Rapamycin, which was discovered from a bacterium. Study after study in animals shows that when you inhibit TOR, which was eventually named MTOR, you extend lifespan. There's now a rapidly growing community of longevity enthusiasts taking Rapamycin. I actually only found out about Hall because he won the Balzan Prize for his work on the biological mechanisms of aging in 2024. I wondered who is this person who seems to have done so much for the aging field, but whom I've never seen at any longevity events. I can't believe you keep all of these things.

Michael Hall: 3:11

This is amazing. Yeah, this was in 2003.

Jessica Davis Plüss: 3:15

I met Michael Hall where he works at the University of Basel. He's now in his early 70s, yet still working past the official retirement age, which here in Switzerland is 65. I quickly learned that Hall encountered the aging field before his groundbreaking discoveries. In fact, it was even before he was a scientist.

Michael Hall: 3:34

My first interaction with science with aging was in the mid-1970s. I had a very um, I would say eccentric uncle, a self-made man, and uh uh later in life one of his ambitions was to live to a hundred.

Jessica Davis Plüss: 3:54

So this eccentric uncle, along with another of Hall's uncles and a friend, both medical doctors, decided they wanted to travel the world in search of what we today call blue zones. Those are regions in the world where it's claimed that people have exceptionally long lives.

Michael Hall: 4:11

The three of them went to Vilkabamba, that's in Ecuador, they went to Georgia and Russia, and they went to uh they're going to all these places, you know, uh on just to study. And then they're gonna go to Okinawa, okay, which is which now recognizes the blue zone. These are all recognized the blue zones now.

Jessica Davis Plüss: 4:30

Hall was still in his early 20s and between studies. He thought it sounded interesting, so asked if he could come along. His uncle said yes.

Michael Hall: 4:38

They brought this whole aging aspect to my attention. In the 1970s, I mean, nobody was talking about aging like today. I mean, it was so typical of my uncles to be so way ahead of the career on this kind of stuff.

Jessica Davis Plüss: 4:48

Do you remember learning anything about aging and I mean the conclusions were that aging is multifactorial.

Michael Hall: 4:54

You know, genes, activity, diet, exactly the things I told you, which people are concluding right now.

Jessica Davis Plüss: 4:59

It also turned out that some people had lied or been misinformed about their age. He still said the trip with his uncles made him appreciate aging as a scientific study. As he started to build his own scientific career, he remembers real scientists studying aging. But he also saw a lot of semi-science that made him skeptical. Was there a reason that you didn't kind of dive as you said, you had just indirect relationship with aging. But was there a reason that you didn't find yourself kind of like a sort of thing?

Michael Hall: 5:29

Well, yeah, yeah. I I I my early uh my early uh experiences with this uh field was that uh there was just too much nonsense there.

Jessica Davis Plüss: 5:39

What was an example of something crazy?

Michael Hall: 5:42

I mean I remember people walking around in robes inside looking like Father Time.

Jessica Davis Plüss: 5:45

Yeah.

Michael Hall: 5:46

People coming in off the street, you know, with this uh uh not even scientists. Uh every every every everybody wanted to make a dollar too, wanted to get some product. I mean there were there were real scientists, but there was also just too much too much noise. Too much noise, and uh and I was working on something else I thought was quite interesting too.

Jessica Davis Plüss: 6:05

Hall did a postdoc in San Francisco where he was investigating how a protein gets transported into the nucleus of a cell. This provides critical insight into how a cell operates. But it wasn't until he moved to Basel when his work really took off. At the time, immunosuppressive drugs like cyclosporin, which is the active ingredient in sandimune, and rapamycin had just been introduced. They were game changers for the medical field. They suppressed the immune system so that it didn't reject donated organs. In other words, they made organ transplants possible.

Michael Hall: 6:37

These drugs were extremely exciting, but nobody knew how sandimune worked, nobody knew how rapamycin worked. The immune system works by recognizing a foreign antigen, a foreign molecule, and it's not normal in your body, and does it by receptors on T cells, uh, and so the antigen binds the receptor and activates the T cell, the T cells amplify, proliferate, and amplify, and mount an immune response. It was known that uh what these drugs did was they blocked uh these uh surface, cell surface, these initial steps, the immune reaction were normal. Antigen, there was a receptor was there, it bound antigen. But everything downstream of that inside the cell, which created the amplification of the T cells, you know, the pathway that signal into the nucleus to activate transcription, to make these functions. Nobody knew what that pathway was, but it was known that the these drugs always block this. So something in the pathway from the cell surface, the receptor, to the nucleus. At that time, not a single signal transduction pathway was was completely known. But what what we knew is that the defect was somewhere in this intermediate step between the cell surface and the nucleus, and that's where, in in very broad brushstrokes, where we were focusing our interest, how how is information transmitted from this place in the cell to this? In our case, the information was a protein.

Jessica Davis Plüss: 8:00

And so Hall went from researching nuclear protein localization to researching how these new drugs worked. And while most researchers did tests on mammal cells, Hall and his team took a different approach, yeast cells.

Michael Hall: 8:15

This is a radical idea because yeast cells are unicellular organisms. Why would you ever give a human drug to a yeast cell? Yeast like you make beer, wine, yeah, bread. And uh it was just physiologically completely irrelevant. But uh it goes back to the fact that in those days you couldn't do genetics with mallian cells, CRISPR didn't exist. Uh but you could do genetics with yeast, and we wanted to do a yeast lab and we wanted to do genetics. Uh and we also knew that rapamycin had been originally isolated from a soil sample collected rapanui, and it had been originally isolated as an antifungal.

Jessica Davis Plüss: 8:55

I should back up here and say a few words about rapamycin. It was discovered in the 1960s from a soil sample collected by Canadian scientists that traveled to Easter Island, which is also called Rapanui, hence the name Rapamyosin. It wasn't actually called that until 1975 when scientists identified it as an antifungal agent. It's because of these antifungal properties that Hall knew it could be studied in yeast. The fact that Hall was in Basel close to Novartis, which at the time was separate companies, C. Bagegi and Sando, also meant he had access to people working on these drugs.

Michael Hall: 9:34

It's just a matter of being in the right place at the right time. Yeah, that's the beauty of Basel. So, you know, this is a town where there's so much science that you bump into these things.

Jessica Davis Plüss: 9:42

Okay. Do you remember the aha moment when you Yeah, I I'm I'm asked this question a lot.

Michael Hall: 9:48

I I I I think this aha moment is uh is a little exaggerated.

Jessica Davis Plüss: 9:53

Uh it's like uh ah, yeah.

Michael Hall: 9:57

I I I I I I say it's a it's a series of mini ahas. I mean, when we uh you know we first saw that rapmycin did something to a yeast cell.

Jessica Davis Plüss: 10:06

Yeah.

Michael Hall: 10:07

Uh huh, maybe our approach is gonna work. When we uh sequence, cloned the genes, and uh and everything made sense. The mutations blocked the body rapmycin to Tor, and all this. Everything fell into a beautiful, very logical, very uh uh irrefutable story. But this is not a specific precise moment where you pick up something, uh-huh.

Jessica Davis Plüss: 10:30

Hall's first major finding was published in 1991 in the medical journal Science. He identified two genes, TOR-1 and TOR-2, that when mutated were resistant to Rapamycin's effects on the cells. His team sequenced the gene to identify the protein encoded by it. Further research found that TOR is a central controller of cell growth, something Hall describes as one of his most gratifying discoveries.

Michael Hall: 10:55

People think our discovery of TOR is our major discovery, but I personally don't think that's our major discovery.

Jessica Davis Plüss: 11:00

Okay.

Michael Hall: 11:00

Our major discovery came later, and that was the fact that cell growth is controlled.

Jessica Davis Plüss: 11:06

That that cell growth can be controlled, and that's probably what influences.

Michael Hall: 11:10

There are three basic things the cell does: divide, grow, and die. People had focused on the division part, cell cycle control, that was well known, increase in cell number, the death part, that was already well figured out. But the growth part was ignored. And the reason that this was completely ignored was the fact that they thought there was no active mechanism controlling cell growth. In other words, it was a passive process where by if you fed nutrients to a cell, you gave them building blocks, and the cell took the building blocks and grew. We had to convince people that growth is controlled and towards the controller. And today, they would think you're crazy if you said cell growth is not controlled. I mean, this it's just it's a it's it's incredibly naive. Looking back, it seemed incredibly naive to think that even question that cell growth is not controlled.

Jessica Davis Plüss: 11:59

Yeah.

Michael Hall: 11:59

It's such a fundamental thing. You know, and now we have all these cell, all these diseases based on advanced cell growth like cancer.

Jessica Davis Plüss: 12:06

Hall started publishing on these findings in 1996. This new knowledge about TOR controlling cell growth revolutionized cancer treatment. Pharmaceutical companies went on to develop a new class of cancer drugs known as m-TOR blockers. But back to aging. Hall also realized something else. TOR responds to nutrients.

Michael Hall: 12:27

Another major discovery we did was to discover that TOR responds to nutrients. That's very simple. It's what senses nutrients and tells the cell to grow. In very simple terms, TOR is what makes us grow and we eat. So we have TOR, it connects nutrients, growth. You know, if you put the dots together, you say Tor could also control aging then.

Jessica Davis Plüss: 12:51

When TOR is suppressed by taking a drug like Rapamycin or by fasting, it shifts the body from a growth mode to a conservation and repair mode. This activates autophagy, which cleans out damaged cells. Without autophagy, damaged cells accumulate, which can lead to age-related conditions such as osteoarthritis and neurodegeneration. This explains why fasting or restricting calories is frequently cited as one of the ways to slow down aging. Rapamycin works in a similar way to eating less calories, and this was only known thanks to Hall's findings. The first real validation of Hall's findings in the aging field came out a few years later. In 2003, a scientist from the University of Fribourg in Switzerland found that blocking tor in worms increased their lifespan by 20 to 30 percent. Numerous studies have been done on other animal species since then.

Michael Hall: 13:49

Then there was shown a couple of years later in flies, you know, worms, yeast, and flies. Then in 2009, there's a big, uh, a huge impact paper shown that Rap amycin extends the lifespan of mice.

Jessica Davis Plüss: 14:02

Mice, okay.

Michael Hall: 14:03

And this was the first pharmacological extension of lifespan in a mammal. This was really this is really explosive.

Jessica Davis Plüss: 14:10

There is now a major trial to see if a low-dose Rapamycin treatment can extend the lifespan of older dogs. Even as more results emerged, Hall never worked on Tor and aging directly. He told me he thought he had bigger fish to fry. Hall's respect for the study of aging has grown. And while it is still filled with hype, Hall said there is much more rigorous science behind it than in the past. Today, Hall's findings are often mentioned in aging conferences, and he's often praised for his discoveries in longevity circles. But it's now 2025, and we still don't really know what Rapamycin does in humans. I asked Hall about this.

Michael Hall: 14:50

Well, you can't do a trial with humans. You can't do an experiment with humans. There are a lot of people. There's a there's a whole online community which is taking Rapamycin.

Jessica Davis Plüss: 15:01

So, but why is it so hard to I mean, we do clinical trials with many, many Because aging is not a disease.

Michael Hall: 15:08

Because aging is not You can't do a clinical trial if something's not a disease.

Jessica Davis Plüss: 15:12

Rapomycin is being tested in low doses in humans against certain age-related diseases like Alzheimer's. Even without the scientific evidence, hundreds of people are said to be taking rapamycin off label for aging reasons, including medical influencers like Peter Atia, who wrote the book Outlive. Some claim to have seen mild benefits ranging from weight loss to pain relief, but some have also reported worrying side effects. Brian Johnson, who is the founder of the Don't Die movement and is known for his documentary on Netflix, decided to stop taking rapamycin after five years of experimentation. He said that the drug had too many side effects, including soft tissue infections and an increased resting heart rate. Still, Rapamycin today is the only drug that has consistently extended the lifespan of different species. Michael Hall, who doesn't take rapamycin, says that while it may not ultimately be the magic pill, any drug to extend our lifespan will inevitably lead back to Tor.

Michael Hall: 16:16

The aging people saying, let's stop treating these individual diseases, you know, creating different, you know, different silos and different budgets. Why don't you just target the aging process? And what fell swoop we will solve all the aging-related diseases, which I think is probably right.

Jessica Davis Plüss: 16:37

I mean, what you're quite hesitant about green.

Michael Hall: 16:40

What you'll be working on is Tor. I mean, Tor is sort of at the center of all this. It's uh it's involved in all these diseases. And uh and this is where the knowledge of Tor is so important, I think.

Jo Fahy: 16:58

Very interesting stuff. Thank you for bringing us that report, Jessica. Just how plausible do you think it is that one day we'll get just one pill that targets a whole range of different problems associated with getting older? Do you think that's something that could happen?

Jessica Davis Plüss: 17:11

I'm not sure if it'll be a single pill, but I do think that there is progress in this area of looking at the root cause of some of these diseases as opposed to tackling each disease individually.

Jo Fahy: 17:24

Okay, thank you very much, Jessica. Over the previous episodes in this season, we talked a lot about technical innovations and new kinds of drugs for old age. But quality of life in old age is also about psychology and perception. We'll talk about this with aging expert and psychologist Dr. Christina Rucke. That's coming up in the next episode of the Swiss Connection Science Podcast. Today's episode was recorded and edited by our science and video journalist Michele Andina. For more content, visit our website swisinfo.ch. I'm Jo Fahy. Thanks for listening.