Coverage of the Caenorhabditis Intervention Testing Program

As you may be aware, a faction at the National Institute on Aging has for some years run the Interventions Testing Program (ITP). The objective is to pick out methods shown in the past to extend life span in mice, and rigorously rerun those studies in order to obtain gold standard data that definitively proves or disproves effects on aging. Unfortunately the budget extends no further than a couple of interventions each year, and the focus is on paths that can do no more than modestly slow aging at best. It should really be considered an adjunct effort to the primary goal of mapping metabolism, not an effort to make meaningful inroads into producing treatments for aging as a medical condition.

Motivations to one side, the need for such a gold standard program in aging studies is evident from the fact that so many claims of slowed aging in mice put forward in past decades cannot be reproduced. A common culprit is calorie restriction; in a way it is a pity that calorie restriction has such a large effect on health and aging. It means that many, many studies have been poisoned over the years, the data made useless because the authors failed to control for calorie intake in the animals involved. Even mild inadvertent calorie restriction produces effects that outweigh many others, and have caused researchers to draw entirely incorrect conclusions, misdirecting further research.

Still, to be honest, this doesn't matter much when it comes to the production of therapies at the end of the day. Rejuvenation treatments worth pursuing are highly unlikely to emerge from this part of the field, that concerned with calorie restriction mimetics, marginal slowing of aging via neutraceuticals, and the like. That could all vanish tomorrow and little of value would be lost; rejuvenation will emerge instead from the SENS repair-based approach, an entirely different area of research and development. However, these efforts to modestly slow aging in mice do matter for the researchers who are attempting to map the progression of aging at the detail level, a vast project proceeding hand in hand with efforts to map all of cellular metabolism. Methods of slowing aging are an important tool from that perspective, a way to identify areas of cellular biochemistry for further investigation. Given that this work is very slow and very expensive, false starts and mistaken directions have a large cost.

The problem of inadequate reproducibility is universal in the life science community, not just in mice and not just in aging research, but for today let us consider that in particular it is a challenge when running studies of aging in the nematode worm Caenorhabditis elegans. A great many such studies take place in comparison to the much more expensive undertaking of a mouse study of aging. Most investigations of the biochemistry of aging start in yeast and nematodes precisely because it is so much cheaper and faster than working with even short-lived mammals. The economics make sense, even accounting for the fact that a fair portion of the findings fail to prove relevant to mammals. Wasting time is wasting time, however, and so it also makes sense to create a Caenorhabditis Intervention Testing Program, analogous to the NIA Interventions Testing Program in mice.

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The study promised to be a big step toward cracking the code of aging: In 2000, scientists reported that giving roundworms a compound that blunted the effects of oxygen on their cells could boost their lifespans by 44 percent. After publishing their paper, team leader Gordon Lithgow recalls, "We felt our work had moved the field on into seriously thinking about chemical slowing of aging." But soon after, they started getting phone calls from another lab. Researchers led by David Gems couldn't get the same results, no matter what they tried. And in 2003, they published a paper saying so. That dashing of hopes was "exceedingly disappointing."

But the story has a happy ending, one that illustrates the way science works best. The experience jolted Lithgow to join with researchers around the United States to standardize testing of potential anti-aging compounds in roundworms. That project, known as the Caenorhabditis Intervention Testing Program (CITP), has led to its first results published this week: that, in carefully controlled side-by-side testing, most "fountain-of-youth" chemicals gave mixed results at best, but one drug did in fact extend the worms' lifespan. The impetus to form the CITP was the realization that Lithgow wasn't alone. Once, it was antidepressants that researchers said could extend lifespan. Not according to follow-up studies by other labs, though. The same thing happened with compounds known as sirtuins. So what was going on? One possible answer was that "nothing works in Europe," Lithgow told a laughing audience at a Buck Institute conference in August. "The other possible conclusion … is that we don't really know what we're doing here."

So Lithgow's lab catalyzed the beginnings of the CITP, joining forces with others to test 21,000 worms from 22 strains, just to see whether their lifespans - untreated - were consistent. They weren't. The lifespans of roundworms turn out to vary greatly, even within labs. In fact, the largest variation was when the same researchers repeated experiments. Suddenly, it made sense that testing the same compound on what seemed like the same worms would lead to a different result: The worms weren't identical after all. Armed with that information, Lithgow and his colleagues started doing things differently.

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"The goal of the CITP is to identify pro-longevity chemicals that are effective across diverse genetic distances making them excellent candidates for trials in more complex animals, including mammals," said Gordon Lithgow, PhD, a professor at the Buck Institute for Research on Aging and a senior author of the paper. Lithgow runs the Buck lab that in 2011 showed that Thioflavin T extended lifespan in healthy nematode worms by more than 50 percent and slowed the disease process in worms engineered to mimic aspects of Alzheimer's disease. "Running experiments in three discrete laboratories allowed us to demonstrate the reproducibility of our study with Thioflavin T. But it's important to note that some of our other compounds did not pass this stringent test - getting feedback on the 'fails' also furthers the larger effort."

Researchers characterized the lifespans of 22 Caenorhabditis strains spanning three species. Thioflavin T was found to be the most robust pro-longevity chemical, as it extended the lifespan of all strains tested. In addition, researchers found that six out of the ten pro-longevity chemicals significantly extended lifespan in at least one strain of Caenorhabditis. Three dietary restriction mimetics were mainly effective across strains of C. elegans but showed more variable responses in other species. "Nearly 100,000 worms were individually monitored during this initial project. We hope that the scope and focus of this project will give confidence that our consortium can identify promising compounds for further testing on aging. The genetic differences between the three species of Caenorhabditis utilized by the CITP were vast - they were comparable to the differences between mice and humans. Aging is a variable process. Identifying compounds that promote longevity across all of those species increases the odds that we are hitting pathways common to many animals, including humans. These are the ones that warrant further exploration."

"Reproducibility has been a sticking point in aging research. Compounds that significantly extend lifespan in simple organisms make a big splash in a journal, only to come under question when results can't be duplicated in other labs. I look back at earlier studies and I think many different labs were working in different strains of worms and using different methods. While mouse studies are an essential part of pre-clinical research, they are also expensive to do. Our hope is that the CITP will yield robust and reproducible candidates that will help fuel success in higher organisms, including humans, where these compounds might be candidates for drugs to combat chronic diseases."


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