Of flies and worms: is the science behind the benefits of resveratrol in peril? - Pittsburgh Medical Technology | Examiner.com

A research study published a week ago in Nature will shake the credibility of the research that supports the notion that sirtuin-2 is an anti-aging gene and also challenge the view that resveratrol extends the lifespan. Today's study published in Nature was spearheaded by Dr. David Gems from the Institute of Heatly Ageing and Department of Genetics, Evolution and Environment, University College London. Contrary to popular belief, his group proved that sirtuin-2 gene does not expand the lifespan in both worms and flies. This is a very bold claim that goes against a huge wave of scientific research that consistently showed that modulating the levels of sirtuin-2 can reverse the aging process in different animal models.

In 2003, a study also published in Nature showed that increasing the number of copies (1- 3) of sirtuin-2 robustly and significantly increased the lifespan of worms. The story caught the attention of the news media and it revolutionized the field of aging research. Hence, many other research groups started looking at different natural compounds that regulated the activity of sirtuin-2 and suddenly reseveratrol, a component of red wind, was discovered to increase sirtuin activity and extend lifespan. Resveratrol was regarded as the new "fountain of youth" ever since and many natural supplement companies and investors capitalized to spend millions to develop and sell a product that is currently available at the market.

However, Dr. Gem's group claimed the initial observation that sirtuin-2 extends the lifespan in C. elegans (worm model) was flawed since the worm containing the extra copies of sirtuin-2 was compared to a parental wild-type worm that does not have the same genetic background. In other words, the worms containing the sirtuin 2 gene were not backcrossed five generations in order to obtain wild-type worms of the same genetic background. Hence, the right comparisons were never made. The authors of the study also showed that flies that overexpressed sirtuin-2, used in a previously published study, also lived longer compared to the parental wild-type fly strain but did not live longer compared to a fly strain of the same genetic background. These results were independently and blindly repeated by a different research group.

So what caused the worms to live longer in the first study? Interestingly, Dr. Gem's group found that another gene, called "neuronal dye filling defect", but not Sirt-2 was actually the gene responsible for extending lifespan in worms in the 2003 Nature study (go figure). Adding more insult to injury, Dr. Gem's group showed biochemically that resveratrol does not activate sirtuin-2. Interestingly, Dr. Gem's group did not refute the observation that simply increasing the number of sirtuin 2 genes to three copies in worms did efficiently extended the lifespan of worms just expressing one copy of the gene. This observation seems to hold water at least in my view.

Is the science behind sirtuin-2 in peril?

Yes and no. Aging is a very complicated biological process that cannot be explained by a single gene in either worms or flies, let alone in humans. Although today's Nature study damages the view that sirtuin-2 alone can extend lifespan, many other studies in mice and worms have shown that sirtuin-2 can extend the lifespan when interacting with other genes (Daf) and other studies have shown that sirtuin can efficiently regulate insulin growth factor metabolism. Sirtuin-2 may not be a drug target. Moreover, many other studies have shown that resveratrol can be a neuroprotective aging in models of Alzheimer's disease and has been extremely well characterized as an antioxidant. In other words, people will still buy resveratrol based on this other research showing the medical benefits of resveratrol.

Take home message

It is interesting to know that the paper that refutes the work of others which was originally published in Nature gets to be published in the same journal which it is in itself a stunning revelation. So what happened here? It is on the scientist's responsibility to design good hypothesis driven experiments which can lead to publishing false results. However, the reviewers in this case bear the most responsibility for not demanding the appropriate experimental controls from the authors. Ironically, this new study may have revealed another anti-aging gene to pursue: the "dye filling defect"

The controversy will sure go on for many more years...

Although this Examiner article thoroughly reviewed many C. elegans and Drosophila anti-aging studies and makes a scientific argument for both sides of the debate, you can read a sample article published in the media today that somewhat exaggerates the impact of this Nature study.

References:

1.Burnett et al., 2011 Absence of the effects of increasing the expression of Sirt-2 on lifespan of C. elegans and Drosophila. Nature.

2. Tissenbaum, H. A. & Guarente, L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410, 227–230 (2001).

3. Viswanathan, M., Kim, S. K., Berdichevsky, A. & Guarente, L. A role for SIR-2.1 regulation ofERstress response genes in determining C. elegans life span.Dev. Cell 9, 605–615 (2005

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