#470 The New Science Linking Your Body Clock to Longevity - Greg Potter PhD

Greg Potter (0:00)

Many of the anti-aging interventions that people are very interested in are targeting the circadian clock. Access to food is clearly a really big drive out at the appropriate circadian time of day.

Siim Land (0:12)

Greg, welcome back to the podcast.

Greg Potter (0:15)

Thanks, Siim. Nice to see you.

Siim Land (0:17)

Yeah, and I'm happy to have you on the show because you gave me this insight that I haven't heard before, which is that the circadian clock dysfunction is probably going to be called a new hallmark of aging in the near future. And when I did some research as well, then I discovered a few papers on the topic as well of linking this circadian clock dysfunction with aging. Now, it's something that a lot of people might have intuitively known already before, but it hasn't been worded in that sense so far. So, I'm happy to have you as a circadian rhythm expert on the podcast and discuss what is this circadian clock dysfunction that happens with age and what can we do to prevent that. And maybe we can start with, so many people might have an understanding of what are the circadian rhythms and what do they do, but how do they actually relate to aging and what could possibly go wrong during aging that it would actually contribute or it could be characterized as a hallmark of aging?

Greg Potter (1:29)

I think we should probably take a step back first and think about the hallmarks of aging and how those were developed, what they are, and whether we should be thinking through the lens of the hallmarks of aging. So, do you mind if I just backtrack and briefly touch on those?

Siim Land (1:50)

Yeah, sure. Yeah, we can do that.

Greg Potter (1:53)

I think many listeners will be familiar with what they are, but they were put forward about 15 years ago, nearly now. And I think a lot of that was inspired by this hallmarks of cancer paper that came out in 2000 And the idea behind them is that these are drivers of aging. And so if that's the case, then if you amplify them, you should be able to accelerate aging. If you dial them down, you should be able to retard aging. And also one of the ideas is that they're conserved across different organisms. So they might accelerate aging in mice and humans, and brown worms and fruit flies and various different model organisms that are used to assess human aging, recognizing that it's hard to actually work out what's driving aging in people, because we live such a long time. So the way that they were first developed was basically just by way of a narrative review. It was a group of scientists with particular interests, and the hallmarks that were proposed largely mapped to the interests of those scientists. And you can kind of trace the hallmarks to the individuals that contributed to the paper. And they were a good first approximation, but we need to bear in mind they weren't identified by any sort of systematic, unbiased process. They've been added to over time, so a few years ago, they were updated, and there were three more that were added. Others have put forward some other hallmarks, such as changes in the extracellular matrix, changes in RNA splicing.

And I mentioned all of this just because people nowadays are so focused on the hallmarks of aging. And I think many scientists feel that if they're going to get a grant proposal funded, then they have to frame things in the light of the hallmarks of aging. But really the actual foundations that those are based on are somewhat shaky. So let's just bear that in mind and also consider that these are biological processes that I think do contribute to aging. And I think the evidence behind some of them is much stronger than others. So the body of evidence supporting the idea that chronic inflammation or genomic instability are drivers of aging is very strong. But for some of the others, I think it's less strong and some of them are impressively vague too. So one of them being altered into cellular communication, which can span massive time scales. And we could be speaking about communication between cells locally, so paracrine mechanisms, or systemically over longer periods, so that might include hormones. And therefore, I don't actually think that they're all that helpful when it comes to trying to improve aging. And also they have network-like properties. So for the most part, if you address one node in the network, other things will respond to that. Some other things that we should be considering, I think, include the fact that there are some age-related phenotypic changes that we're all interested in. Some of those are very obvious to the eye. Skin wrinkling, loss of hair, hair graying, that type of thing. And some of the model organisms that are used to assess whether interventions influence these hallmarks of ageing use models that don't actually recapitulate these types of age-related changes. And trying to translate research from, say, mice to people often doesn't work very well. If you look at mice, for instance, and people will hold up something like the Interventions Testing Program, or some sort of goal-standard way of identifying whether a nutraceutical or a drug affects ageing by looking at lifespan of mice, when it comes to mice, about 70% of their deaths are due to cancer. But in people, if you look at the top five causes of mortality, then cancer isn't one of them. So there's that limitation too. So let's not over-interpret the hallmarks of ageing, just as a general starting point.