Sinclair and Brenner disagree on why SIRT1-activator drug programs were discontinued

Sinclair and Brenner disagree on why SIRT1-activator drug programs were discontinued

On September 10, a study on the compound SRT1720 was published: it was tested on rat kidney cells and on rats with sepsis. On September 11, biologist David Sinclair connected this experiment to the older story of SIRT1 activators, a protein involved in cellular metabolism. On September 12, biochemist Charles Brenner offered a different account of why those earlier programs were shut down.

In the paper on sepsis-induced kidney injury, the authors tested how SRT1720 affects kidney damage and mitochondrial function (mitochondria are cellular structures that produce energy). The compound was first tested on rat kidney cells, then in an animal model of sepsis. The animal experiment used 16 male rats divided into four groups. SRT1720 was associated with lower markers of kidney injury, creatinine, and blood urea nitrogen; EX-527, an inhibitor of SIRT1, produced the opposite pattern on several of these measures.

On September 11, Sinclair wrote in his thread:

"Life-extending drugs could have been available to the world around 2015, had flawed work by a major pharmaceutical company not knocked the field off course and halted trials."

He cited the SRT1720 experiment as another example of the biological effects of such compounds.

Brenner responded with a series of six posts. In his account, GlaxoSmithKline had been running Phase I and Phase II studies across several therapeutic areas, and the programs were discontinued because of a combination of safety concerns, questions about clinical efficacy, and doubts about target engagement, meaning whether the compounds actually acted on the protein they were designed to hit. In his thread he cited a publication on SRT501 and his own review on sirtuins.

The SRT1720 study addresses a question about cell and rat models of sepsis. The history of the clinical program requires answers about target engagement, safety, and efficacy in humans. Sinclair and Brenner disagree on how much connection can be drawn between these two sets of questions when explaining the discontinuation of the earlier programs and the prospects for longevity therapeutics.

In his last post, Brenner connected this debate to early trials of partial reprogramming in humans. He had previously discussed cancer risk in that area with Yuri Deigin in a spring exchange about the Life Biosciences single-eye protocol.