Sirtuins (SIRT1-7): Longevity Genes

Sirtuins are known as longevity genes because they regulate lifespan.  These NAD dependent molecules facilitate cellular function, gene expression, and DNA repair.  The fact that sirtuins require NAD to regulate lifespan in turn links energy metabolism to aging and aging-related disorders.  

Functionally, Sirtuins are known to be activated by reduced caloric intake, commonly referred to as Calorie Restriction.  Although scientists have known for over 50 years that calorie restriction extends lifespan, it wasn’t until the sirtuin connection was made that they understood why.

You see, Sirtuins regulate various metabolic processes that allow the cell to adapt to nutrient stress.  Sirtuins through these stress signaling pathways promote hormesis where cells move from active growth and proliferation to a state of maintenance and repair.  In fact, “the hormesis theory states that low levels or intensity of stress leads to “priming” in which cells can then withstand other stresses that would normally prove terminal”.    

The hormesis hypothesis states that low levels or intensity of stress leads to “priming” in which cells/tissues/organs can then withstand other stresses that would normally prove terminal

As you can imagine, there is plenty of interest in the development of sirtuin activating compounds that activate the same metabolic and stress response pathways induced by longevity interventions without actually restricting caloric intake.  Related benefits include weight loss, promoting fat mobilization, and DNA repair. In the meantime, we have naturally occuring molecules that activate sirtuins:  Resveratrol, Fisetin, Pterostilbene, and Catechins.   

As discussed, modulation of sirtuins activity has great promise for the development of therapies against a number of metabolic and age-related disorders. Although almost all sirtuin activators have been described only for SIRT1, in mammals there are seven sirtuins (SIRT1-7), of the natural sirtuin activators listed above, Resveratrol has shown the most promise in it’s ability to boost longevity genes.  More specifically Resveratrol has been shown to boost SIRT1, SIRT3, and SIRT5; Fisetin and Pterostilbene SIRT1; and Catechins SIRT6.

To piggyback our digital biology post, it’s exciting that researchers have identified longevity genes and the molecules that activate them. Even more exciting is the fact that these molecules are readily available in polyphenols that we get in certain plant based foods.

Additionally, because Sirtuins are also nutrient sensors, they are believed to promote feeding behavior. This is important for a couple reasons: 1) SIRT1 promotes fat as energy (ketosis) and 2) SIRT1 promotes feeding control by improving hormone sensing. We’ve already covered Calorie Restriction Mimetics but the implications for obesity, diabetes, and longevity can not be understated.

SIRT1 in peripheral tissues promotes the use of fat as energy (ketosis), and SIRT1 in the central nervous system (CNS) promotes homoeostatic feeding control by improving hormone sensing10,11. Therefore, we hypothesized that CNS SIRT1 might regulate macronutrient intake by shifting the macronutrient preference to match the metabolic need in peripheral tissues (i.e. supply the appropriate substrate for use).