Resolving the controversy over anti-aging sirtuins

They hold the promise of not only treating manifold diseases, from Type 2 diabetes, to neurodegenerative, cardiovascular and inflammatory disease, but also of extending life and improving general health.

They’re called sirtuins, a class proteins that appear to trigger our ‘longevity genes’ - the most famous sirtuin being resveratrol, found in red wine - and they’re currently at the centre of a maelstrom of controversy, with their efficacy called into question.

Professor David Sinclair, the Australian-born researcher based at the Harvard Medical School, who rose to fame with his 2003 paper outlining the beneficial effects of resveratrol on extending the lifespan of yeast, has now reentered the fray, claiming he has discovered a key protein that will settle the ongoing dispute between pharma giants GlaxoSmithKline, Pfizer and Amgen.

The kerfuffle started in December last year when researchers from Amgen published a paper claiming that the activation of the key SIRT1 gene by sirtuins was an artefact of the experimental method used by Sirtris.

Another paper in January of this year published by Pfizer researchers backed up Amgen’s claim and also failed to replicate the beneficial effects of another sirtuin, SRT1720, in diabetic mice.

GlaxoSmithKline, which bought Sitris for US$720 million in 2008, also released a paper confirming that the sirtuins don’t appear to directly activate SIRT1, but do so indirectly along with the fluorescent peptide found in the substrate.

However, GSK continues to assert the beneficial effects that sirtuins have, citing other in vivo studies in yeast, mice and other organisms.

Things were looking somewhat grim for the bold claims made by Sirtris. However, now Sinclair claims he has uncovered the reason why certain sirtuins appear to only work in certain conditions.

“We’ve found a missing piece to the puzzle that will make sense of all the data they’re arguing about,” said Sinclair. “A piece people haven’t realised was missing.

“In the test tube, the reaction works under some conditions and not under others, and people don’t understand why,” said Sinclair. “Pfizer says that because it doesn’t work under every condition, then it’s an artefact. Yet GSK says the reason it doesn’t work under every condition is the system is complicated and we don’t understand everything.

“We agree with the latter, and it turns out there’s a protein partner that is part of the mechanism and, until now, people haven’t realised it needs to be in the reaction to mimic what happens in the body.”

According to Sinclair, sirtuins work in vivo in the presence of this natural enzyme, which is absent in in vitro studies, and this is what is giving the inconsistent results reported by GSK, Pfizer and Amgen.

Sinclair is yet to reveal the details of this protein-binding partner, but he will be giving more information about it in a talk at the Australian Health & Medical Research Congress in Melbourne on Wednesday, November 17.