When things get controversial: The scientific process in action

A recent article in the journal Nature calls into question previous findings about the scientific basis of lifespan extension. The authors of that article argue that the scientists who first reported lifespan extension in model organisms compared their “long-lived” organisms to improper control organisms, rendering their experimental findings invalid [1-3].

In order to understand this controversy, let’s first consider how science works. The excitement of science stems from its novelty: exploring new territory, asking new questions, and gradually accumulating new knowledge to better understand the world in which we live. Delving into the unknown requires scientists to design experiments that manipulate and test specific variables, while doing their best to keep other variables constant so that the impact of their main variable of interest can be evaluated. However, even the best-designed experiment can be confounded by a variable that the scientists haven’t thought about carefully. (See the Understanding Science website for more information).

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For example, in genetics, researchers use organisms that have been highly inbred to create a common genetic background – the overall genetic makeup of an organism – against which they can assess the effects of specific genetic changes. These specific genetic changes are the variables in this sort of experiment. Keeping genetic background the same is crucial for genetic experiments, as it is the only way to ensure that the genetic changes of interest are responsible for any observed differences between the mutant organism and the controls.

So how does this apply to the lifespan extension story? As reported in a recent issue of the Flash, in the 1990s scientists found they could extend lifespan in yeast and roundworms through caloric restriction, providing the bare minimum set of nutrients necessary for survival [4]. Other groups extended these findings to other organisms (including fruit flies and mice), mimicked the effects of caloric restriction with a small molecule called resveratrol, and found that this molecule not only extended lifespan, but also prevented obesity-related disease [5]. Scientists believed that caloric restriction and resveratrol treatment both acted through molecular machines called sirtuins. However, this finding has recently come under scrutiny [1-3].

The controversy

The first reports on the subject of lifespan extension were based on model organisms, like fruit flies and roundworms, which were genetically manipulated to produce excess sirtuins. These reports concluded that organisms with higher levels of sirtuins lived approximately 15-50% longer than organisms with normal sirtuin levels. Scientists were able to make such a conclusion because, presumably, the only difference between the experimental and control organisms was the over-production of sirtuins. However, the group of researchers in London who published the recent Nature article, mentioned at the beginning, reported that other genetic differences between these organisms may be the true cause of their different lifespans [2]. When the UK group repeated the original experiments with the proper controls (i.e. organisms with the same genetic background), they found no sirtuin-related lifespan extension.

The authors of the original study responded in the same issue of Nature and agreed that their previous experiments were flawed [6]. However, these scientists also repeated their previous experiment with proper controls and found that over-production of sirtuins did make roundworms live longer, albeit not by as much as originally claimed (only 10-14%).

These contradictory findings were troubling enough that Nature chose to publish a paper essentially based on negative results — experimental results that disprove rather than prove a hypothesis. This is a rare occurrence for a high-profile scientific journal known for publishing significant scientific advances. It should be noted, though, that it is common for a journal to publish two potentially contrary studies side-by-side, or in rapid succession with added expert commentary to illuminate the debate. That is science at work!

Years of research, and even entire companies seeking to develop anti-aging drugs, have been based on the idea of sirtuin-related lifespan extension. The use of small molecules and caloric restriction to extend lifespan is still valid even if those effects depend on some undiscovered molecular machine and not, in fact, on sirtuins. Furthermore, the authors of the new study explicitly state, “Our findings do not rule out a role for sirtuins in determination of metazoan [animal] lifespan, but they do cast doubt on the robustness of the previously reported effects of sirtuins on lifespan in C. elegans [roundworms] and Drosophila [fruit flies].”

Science at work

This case illustrates the value of continuously challenging hypotheses and the need to remain critical and objective when reading and using the scientific literature. It also highlights the fact that the scientific process works, and gives a rare peek into what happens behind-the-scenes: scientific peer review. Peer review is a mechanism by which new research findings are evaluated by independent experts prior to acceptance for publication [7].

What’s important about peer review is that research is approved for publication on the basis of its scientific merit and internal consistency – not because it conforms to existing scientific understanding. This gives room for exactly the kind of controversy that is playing out in the longevity field. And that’s a good thing! The foundations of science rest upon the reproducibility of results. One or two studies are never enough to conclusively support – or refute – a scientific theory. Only when overwhelming evidence has been amassed by independent research groups studying the same phenomena would new knowledge be accepted by the field.

Until that time, science is rife with controversy. This is, in fact, a healthy and necessary part of research, as long as the scientists themselves don’t become too adversarial. For high-profile topics like longevity, controversy is sometimes depicted as a step backward. In fact, controversy and debate go on throughout all fields of science at all times, on large and small scales, and they are what fuel science and drive progress. What makes science uniquely powerful as a way to learn about the world around us is its openness to being proven wrong, via continuous critical analysis of all findings, old and new alike.

Laura Strittmatter is a PhD student in the Harvard Chemical Biology program.

References:

[1] “Longevity Gene Debate Opens Trans-Atlantic Rift” (Nicholas Wade, New York Times) <http://www.nytimes.com/2011/09/22/science/22longevity.html?ref=resveratrol>

[2] “Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila” (Camilla Burnett et. al., Nature 2011) <http://www.nature.com/nature/journal/v477/n7365/full/nature10296.html>

[3] “Longevity genes challenged: Do sirtuins really lengthen lifespan?” (Heidi Ledford, Nature 2011) <http://www.nature.com/news/2011/110921/full/news.2011.549.html>

[4] “Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans” (Heidi A. Tissenbaum and Leonard Guarente, Nature 2001) <http://www.nature.com/nature/journal/v410/n6825/full/410227a0.html>

[5] “Longer Lives for Obese Mice, With Hope for Humans of All Sizes” (Nicholas Wade, New York Times) <http://www.nytimes.com/2011/08/19/science/19fat.html?scp=2&sq=resveratrol&st=cse>

[6] “Regulation of Caenorhabditis elegans lifespan by sir-2.1 transgenes” (Mohan Viswanathan and Leonard Guarente, Nature 2011) <http://www.nature.com/nature/journal/v477/n7365/full/nature10440.html>

[7] “I Don’t Know What to Believe: Making Sense of Science Stories.” (Sense About Science) <http://www.senseaboutscience.org/data/files/resources/16/IDontKnowWhatToBelievereprint2008.pdf>

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