This three part interview covers the induction of greater numbers of free radicals in tissues as an approach to slow aging. I can't say as I think this is a way to obtain large gains in health and longevity, much greater than those possible through exercise and calorie restriction. Both of those approaches essentially work in a similar way, being beneficial stress responses that include free radical signaling among their mechanisms. Little of the work on recreating these responses via pharmaceutical or genetic means does all that much better in terms of extended healthy life. The background is quite interesting, however.
Over the decades, the scientific understanding of the role that reactive molecules, free radicals, play in aging and metabolism has become much more nuanced. The original formulation of the free radical theory of aging, in which more free radicals are always a bad thing, is clearly not correct and the field has moved on since then. The situation is much more complicated than the presence of free radicals being a straightforward form of damage, reacting with important molecules to break their function. Yes, that breakage happens, constantly, but it is near entirely repaired. Yes, any circumstance that produces very large amounts of free radicals, far more than are produced normally, such as ionizing radiation exposure, is directly harmful (but not all that relevant to what happens during the aging process). Yes, greater amounts of oxidative free radicals and chronic inflammation, which is known to be harmful, go arm in arm.
Nonetheless, it is the case that cells use free radicals as signals in beneficial processes. Mitochondria, the power plants of the cell, are the primary source of free radicals. These free radicals are produced in the progress of producing chemical energy stores to power cellular operations, a necessarily energetic process with a range of byproducts. The benefits of exercise rely upon an increase in free radicals produced by mitochondria. Other forms of mild cellular stress work in a similar way, requiring mitochondrial free radicals in order to instruct the repair systems of the cell to get to work. Numerous methods of modestly slowing aging in short-lived laboratory species involve tinkering with mitochondria to somewhat increase their output of free radicals, and therefore produce a net benefit in cellular maintenance due to increased repair activities.
An adaptation of the original free radical theory of aging, the mitochondrial free radical theory of aging, suggests that mitochondria are both the primary source and the primary important point of damage for reactive molecules. Mitochondrial DNA, distinct from the DNA of the cell nucleus, becomes broken in ways that cause cells to become overtaken by malfunctioning mitochondria. That growing group of faulty cells exports damaged proteins and other molecules to tissues and bloodstream to contribute to degenerative aging. Clearly, given the way in which free radicals can produce benefits, this process of mitochondrial DNA damage has to be somewhat disconnected from the mechanisms of gain through cellular stress - these days some researchers question whether it is free radicals causing the DNA damage, and point instead to replication errors.
The "free radical theory of aging" - where is that theory at now?
It's dead. Well, let's be a bit more precise. The free radical theory of aging dates back to the 1950s, and then there were decades of research on it, which was all very good research scientifically speaking, but it was always in artificial settings with high doses of free radicals that never occur in real life. In real life, in healthy model organisms or humans, free radicals occur in very low doses, and they have very different functions from high doses of free radicals, where they serve as signaling molecules that increase our body's defense mechanisms against external stressors. So in the 1990s, evidence emerged that small doses of free radicals serve as signaling molecules in cells. Around 2006 or 2007 we showed that in C. elegans that we could increase free radical production and that would make the worm live longer.
If normal amounts of free radicals aren't harmful, what's the story with antioxidants?
Well, this was an important issue we looked at a bit later in 2009. It's also well known that exercise produces free radicals, which was already surprising because exercise is probably the most healthy intervention a person can use, and that conundrum lead us to the hypothesis that the increase in free radicals would explain the health-promoting effects of exercise. And we tested this by seeing whether the antioxidant supplementation would kill the effects of exercise in humans, and that was exactly the case - the guys who got the placebo showed the expected effects of exercise on metabolism, and the guys who got the antioxidants had almost none of the effects.
About six or seven years later, another group had even more data available from the public domain, and they found that antioxidants increase all mortality. Meanwhile, experimental groups have shown that antioxidant supplementation in mice increases cancer and metastasis rates. The evidence out there is very straightforward and very bad for the antioxidant industry, but it's widely ignored. Consumption has not decreased for years, but at least it's not increasing.
So we've discussed this effect called hormesis, where substances that are toxic at high doses can actually be helpful in low doses. There's a related word that pops up a lot in your research, "mitohormesis" - what is that?
It's an abbreviation of mitochondrial hormesis, and it essentially translates this hormesis principle, which normally applies to compounds and drugs, to whatever comes out the mitochondria. So mitochondria send out signals that promote health and lifespan at low doses, and at higher doses these signals do the opposite. The most well-established signal from the mitochondria is reactive oxygen species (ROS), but there are also other signals.
Does free radical production become a problem as mitochondria get older and start producing more free radicals?
While older mitochondria do produce more free radicals, it's unclear whether that really accelerates aging. I think it does at very high, artificial doses. For example, one very artificial mouse model showed that mice with a mutation in their mitochondria aged horribly. For human examples, you can look at the hundreds of mitochondrial diseases that cause premature aging and increased cancer and so on, but again, these are very rare. There wasn't much evidence about the effect of mitochondrial ROS production on normal aging until recently. A paper looked at naturally occurring mutations in mice and compared their lifespans, and, contrary to their expectations, they found that the mice producing more ROS lived longer than the mice producing less ROS. And these mice were otherwise genetically identical. So I think that fits in well with the results we've seen with exercise.
You're a big proponent of a particular intervention that plays off of mitohormesis to increase lifespan - glucosamine.
Back in 2007 when we showed that increased ROS extends lifespan in C. elegans, we used a compound that completely blocks glucose metabolism, deoxyglucose. Since the cell can't metabolize glucose anymore, it enters an energy deficit similar to starvation, and responds by switching on its mitochondria. It turned out to be toxic in mice. Then a student in my lab said, "Why don't we use glucosamine?" Glucosamine only slightly inhibits glucose metabolism (glycolysis), and it's known to be completely harmless to humans. It's like the cell being on a diet: it still activates its mitochondria, still produces a bit more ROS, but not to the excessive level that it would with deoxyglucose. We took two year old mice, which is equivalent to something like 55 or 60 in humans, and gave them glucosamine, which caused both males and females to live longer. The effect was stronger in females, but it was independently detectable in both sexes.
Do you think there will be a trial for glucosamine akin to the TAME trial for metformin?
There should be. I think it's long overdue. It's an ideal supplement because it's cheap, there's no intellectual property attached to it, and it could improve healthspan significantly at almost no cost. The return on investment for both insurers and individuals would be significant. The evidence for glucosamine in C. elegans and mice is about the same as for metformin.
Are there compounds besides glucosamine that you find promising as geroprotectors?
Both my lab and others have been working on lithium, which is found in drinking water, and we've both seen it extend lifespan in C. elegans. Then we did a study with some Japanese colleagues who had data on lithium concentrations in drinking water all over Japan, and they worked out that areas with more lithium in the drinking water lived longer on average, so there was a positive correlation between lithium concentration and lifespan. And then another study from Texas came out a month or two ago saying the same thing, so there's several lines of very independent evidence that all points in the same direction. So that could have a pretty direct impact on supplementation. Low-dose lithium is something people could start to think about incorporating.
And can you tell us what motivates your research?
Well, first of all, I always like to question established concepts. That's probably the most driving source, especially when it's evident that something is wrong and no one is discussing it - like the common wisdom around reactive oxygen species, for instance. So that's one side of things. The other is that I'd ideally like to work on something that impacts quality of life for humans. That's quite distant from questioning fundamental concepts, but on certain occasions they come together - for instance, questioning antioxidants, or finding safe, easily available compounds like glucosamine that could make a huge difference. Of course, there's also increasingly good evidence that preventing age-related diseases while people are still healthy is so much smarter than treating existing diseases later on, and that's a very unique win/win situation. It's one of the rare cases where tremendous increases in individual quality of life and decreases in socioeconomic costs coincide, because normally it's either one or the other. And so I think it's almost mandatory to work on something like that.
What are the biggest challenges you see ahead?
In Western medicine nowadays, you only start taking care of health once it's gone, and I think that approach is totally wrong. That perception will have to change. Instead we need to prevent diseases from occurring in the first place, and people can do that by eating healthily, and exercising, and so on. And individuals are willing to take care of that - but only to a limited extent. We could make the success rate much higher if we came up with a drug or combination that mimicked certain aspects of healthy lifestyle, rather than requesting that everyone follow all of these rules their whole lives. Because the majority of us are simply not willing or capable of following them at all times, and I think that's just human nature. I'm not endorsing it, but I think it's a matter of fact.