SENSible Question: Wouldn’t Worms Be Faster?

And on the other hand, when scientists treat mice that have already reached the mouse equivalent of 60 years of (human) aging with monoclonal antibodies that block IGF-1 from transmitting its signal to cells, it fails to increase lifespan at all in males. In fact, it’s worse than that: surprisingly, the animals instead die with an even heavier burden of tumors at death than untreated animals do. The same antibodies do initially reduce deaths in older females — but without moving the needle on maximum longevity, and at the cost of worsening their age-related muscle loss. And some mutations that extend lifespan in these animals are not just ineffective in humans: they’re pathological. For example, mutations in the genes for some mitochondrial components increase the production of mitochondrial free radicals and lengthen the lives of C. elegans. But in humans, those same mutations instead cause terrible mitochondrial congenital diseases such as Leigh syndrome, Friedreich’s Ataxia, Sengers syndrome, and progressive external ophthalmoplegia. Because some metabolic pathways play similar roles in driving aging damage across the animal kingdom, one might expect that some of the traditional “messing-with-metabolism”-type longevity therapeutics that work in these simpler organisms would also work in mammals like mice (and us). That’s true in some cases (the standout example in laboratory rodents is rapamycin), but the track record shows that drugs that slow aging in C. elegans and Drosophila often don’t work out in mice. In a recent study, researchers went through lifespan studies that had shown lifespan-extending effects of particular drugs and supplements in roundworms and flies and then looked to see if the same molecules had also lengthened life in mice. First, they looked at all such studies that had ever been curated in our colleague João Pedro de Magalhães’ DrugAge database. They identified 37 drugs and supplements that had been tested in one, the other, or both of the lower species, and had also been tested in mice. But only 56% of agents that had worked in the worms wound up working in mice. The chances were better in Drosophila, though still not a slam dunk: about two-thirds were successful. But the bar in this initial analysis was pretty low for all three organisms because the researchers included all the studies they could find without regard to their quality or reproducibility. And as we’ve discussed before, there are a lot of garbage lifespan studies in the published scientific literature. So they followed up with a second analysis where they only considered C. elegans and mouse studies that were part of two structurally high-quality lifespan study programs for these organisms: the National Institute on Aging (NIA) ’s Interventions Testing Program (ITP) in mice and the Caenorhabditis Interventions Testing Program (CITP) in worms. We’ve talked about the ITP program before: see the section “Failing the Gold Standard” in a previous post about its test of the diabetes drug metformin for lifespan. It’s an effort to test different drug-type longevity therapeutics using a systematic design that ensures that the results are as reliable as possible from the very first report. The CITP is an attempt to apply the same rigorous design to lifespan studies in the roundworm, with the additional advantage that — since testing in C. elegans is so cheap — they can effectively run multiple separate “colonies” of worms through the same study in each of the three independent labs. Since there is no “ITP for flies,” the researchers carefully combed through the Drosophila lifespan studies to make sure they met quality benchmarks. Then they made apples-to-apples comparisons between the results of these more rigorous fly lifespan studies with worm and mouse studies conducted with the same drugs and supplements by the CITP and ITP (respectively). But the results came back more or less the same as the first analysis: only half of the drugs and supplements that extended the lives of CITP worms did so in mice, and only three-quarters of those that passed the bar in quality Drosophila studies worked out in ITP mouse studies. And that probably overstates how well a study first conducted in C. elegans can predict success in mice, because many of the drugs that the CITP tested were included for testing precisely because they had already worked for mice in the ITP. So it’s a mistake to count such studies as evidence that testing longevity therapeutics in short-lived worms first would save time by highlighting promising candidates for mice when it actually happened the other way around. By contrast, one of the key reasons to favor “damage-repair” strategies is that they undo existing aging damage and don’t depend on manipulating developmental or any other metabolic process. Conceptually, that gives SENS rejuvenation biotechnology much more power than conventional “messing-with-metabolism” longevity therapeutics to postpone age-related illness and death when your first chance to take advantage of them happens when you’re already in or past what is currently “middle age.” (That’s the same reason why effectiveness later in life is a key principle of the Robust Mouse Rejuvenation (RMR) goalpost). Plus, some of the worm results were worse than just not translatable to mice. For instance, N-acetylcysteine (NAC) and glutathione accelerate aging in C. elegans, but it either has no effect on (females) or slightly increases life expectancy in (male) mice. (Before you rush down to the supplement aisle, note that there’s a bit of a wrench in this result: about two weeks into the experiment, the mice fed NAC-fortified chow suddenly started losing weight — and while the females stabilized at a new, lower weight, the males just kept dropping grams. You might think that a combination life extension and weight loss drug is like getting some chocolate with your peanut butter. But actually, the weight loss suggests that NAC may have caused the animals to eat less, in which case the apparent life extension in males might simply be the result of unintended Calorie restriction. That would be consistent with the fact that NAC only “worked” (if it did) in males. Whatever the case, we can say at least that NAC did not put the mice’s aging process on fast-forward as it did for the worms).