Drug research chemist Derek Lowe:
Caloric restriction increases healthy lifespan. That’s true in a range of organisms, and probably in humans. But it’s never going to be popular – and what’s more, it’s not going to be feasible, either, given how clearly people like to eat. So the search has been on for just how it exerts its effects, with a number of interesting clues turning up.
And now there’s another one. There’s a longevity gene in fruit flies known as INDY (short for, I fear, “I’m Not Dead Yet”, and if you don’t get that reference, you should probably turn in your geek license. This would be a good time to note, as required by law, that the fruit fly people are a longstanding and apparently endless fountain of weird nomenclature). Reducing INDY expression definitely lengthens lifespan in flies and in the nematode C. elegan.
A recent paper in Cell Metabolism, from a large-multicontinent team involving the Shulman group at Yale and many others, explores the effects of the mammalian homolog, mINDY, in mice. The knockout mice are smaller, although they take in the same number of calories. They are much leaner, though, with remarkable less fat. Their metabolism seems to be ramped up, as you might figure from that situation, and they’re especially good at fat oxidation in the liver. Very interestingly, they maintain this phenotype as they age, while normal mice tend to put on more fat. They have lower basal glucose and insulin levels, and are better at clearing glucose, apparently through better uptake in skeletal muscle. They also seem resistant to the bad effects of a high-fat-chow diet, show a much reduced tendency to putting on weight and developing insulin resistance. All in all, this is what you’d call a desirable metabolic phenotype, and it fits in very well with what has been worked out in the fruit flies.
So what does this gene code for? Turns out that it’s a citrate transporter, which might not be the most obvious thing at first, but it makes sense. Citrate is converted to acetylCoA, which is the building block for fatty acid synthesis. Cutting down its availability basically starves the liver tissue, which depends on fatty acids for a good part of its energy needs, and causes it to efficiently burn off whatever fatty acids it can acquire. And this effect might just be one of the things that produce the benefits of caloric restriction – in other words, you might not have to deprive your whole body of calories, just the key parts of it. To show that I’m not overinterpreting here, I’ll let the authors say it:
These data suggest that mIndy may be a key mediator of the beneﬁcial effects of dietary energy restriction. Since prolonged caloric restriction is very difﬁcult to achieve in humans, our observations raise the tantalizing possibility that modulating the levels or function of mIndy could lead to some of the health-promoting effects of calorie restriction, without requiring severe caloric restriction.
And as they go on to suggest, this makes for a very interesting target for obesity, diabetes, and fatty liver disease. What about extending lifespan? Well, I’ve dug through the paper several time, and can find no mention of mice older than 8 months, and no numbers on their longevity. I assume that this will be the subject of another paper as the rodents get older – it’s too big an issue to ignore, and this paper seems determined not to say a word about it.