From Yeast to Humans: Sirtuins and Aging Decoded

June 28, 2025

June 28, 2025

Sirtuins are a frequently mentioned term in longevity research. This text explains where the concept comes from, what we know today, and why early enthusiasm has given way to a more cautious assessment.

If you are interested in longevity, you will certainly have heard about sirtuins, one of the buzzwords that has stirred hope, headlines, and hefty investments. But what’s the fuss about it? Why did a gene from yeast make global news, and what has happened since? The story of sirtuins is one of scientific curiosity, media hype, and hard-earned lessons about how complex the biology of aging really is.

Silent Origins: What’s in a Name?

When MIT professor Leonard Guarente began researching aging with yeast cells in the early 1990s, he was initially met with a great deal of skepticism. To many, the idea of using a single-cell model to study human ageing seemed absurd. But together with his students Brian Kennedy and Nicanor Austriaco, he took the plunge. The three discovered that a gene called Sir2 influences the lifespan of yeast cells. More Sir2 prolonged the life of the cells, less Sir2 shortened it. This was the first time they showed that individual genes can directly influence cell ageing.

Sirtuins are named after the Sir2 gene, short for “Silent Information Regulator 2”. Initially, it was known for silencing regions of DNA, especially near telomeres. But researchers soon realized it did more than genetic housekeeping. It appeared to influence how many times a yeast cell could divide before becoming inactive. This sparked immense excitement. If one gene could slow down aging in yeast, might it work in more complex organisms too?

It turned out that Sir2 had equivalents in worms, flies, and humans. These homologs, now known as SIRT1 through SIRT7, form a family of proteins that regulate cellular processes like metabolism, stress resistance, and DNA repair. They depend on NAD, a molecule central to energy metabolism, which declines with age. That dependency helped tie sirtuins to calorie restriction, an intervention known to extend lifespan in many species.

A Fast Rise: Hope, Wine, and Biotech Billions

In the early 2000s, MIT scientist Leonard Guarente and his postdoc David Sinclair began to explore sirtuins in mammals. They focused on SIRT1 and found it could be activated by resveratrol, a compound found in red wine. The media latched onto the idea. A red wine molecule that mimics caloric restriction and slows aging?

It sounded too good to be true. Turns out it was.

⇥ Read more: The myth of resveratrol

Sinclair helped launch Sirtris Pharmaceuticals to commercialize sirtuin activators, and GlaxoSmithKline bought the company in 2008 for 720 million dollars. But follow-up studies cast doubt on the original claims. Some showed that resveratrol’s effects were experimental artifacts. Others failed to replicate lifespan extension in animals. Eventually, GSK shut down Sirtris, and the field entered a phase of deep skepticism.

What the Science Says Now

Today, sirtuins are still of interest, but with much more cautious expectations. Their primary role is as deacetylases, enzymes that modify other proteins to influence gene expression. Some, like SIRT6, are essential for DNA repair and metabolic stability. Mice lacking SIRT6 die young, while those overexpressing it may live longer.

"Correct. The truth about resveratrol and sirtuins has been clear since 2005 for anyone who wanted to see it. It's really not very confusing".
Matt Kaeberlein, Ph.D. (16. Feb. 2022)

However, the broader connection between sirtuins and aging is far less clear than once hoped. Initial claims that sirtuins mediate the effects of caloric restriction have been questioned. Some studies show that caloric restriction extends lifespan even without Sir2, suggesting that other pathways are at play. The sirtuin story, once a symbol of optimism, is now a case study in the need for rigorous validation.

A Realignment in Longevity Science

While sirtuins sparked widespread excitement, they are no longer the focal point of longevity research. Much of the field has shifted toward pathways with more consistent and reproducible effects, such as IGF-1 and TOR. Caloric restriction, for example, appears to act through multiple, interconnected pathways, not just one. TOR, a nutrient-sensing pathway, has become especially central. The drug rapamycin, which inhibits TOR, extends lifespan in multiple species and protects against age-related diseases in mice.

By contrast, boosting sirtuins pharmacologically has not yet produced comparable effects. The field has moved from single-gene fascination toward systems biology, focusing on how networks of genes, proteins, and metabolites interact to influence aging.

Shifting Focus: From Sirtuins to TOR

The field has evolved. Even pioneers like Brian Kennedy and Matt Kaeberlein have stepped away from sirtuins, redirecting their attention toward more promising pathways, especially TOR. This pathway, inhibited by the drug rapamycin, has shown consistent effects on lifespan and age-related disease resistance in animal models. Unlike sirtuins, the TOR pathway offers clearer mechanistic insight and more reproducible results. The pivot reflects a broader maturation in longevity research, a move from charismatic but uncertain targets toward interventions grounded in robust, cross-species evidence. Sirtuins sparked curiosity, but TOR and rapamycin now lead the way.

From Buzzword to Cautionary Tale

The journey of sirtuins underscores the excitement and pitfalls of longevity science. It began with a yeast gene, grew into a biotech gold rush, and ended, at least for now, with sobering data and redirected attention. While sirtuins may still play a role in the complex symphony of aging, they are no longer seen as soloists.

In the end, the story is not about failure but about refinement. Science moves forward by testing claims, discarding what does not hold up, and following the data, even if it leads away from the hype.