Sirtuins: Linking the Circadian Clock to Your Metabolism

Have you noticed your metabolism slow over time? Are you wondering how you can boost your metabolism to ensure optimal results from your health and fitness routine? Then you may be interested in reading about sirtuins. These longevity genes are the key mediator between your circadian clock and your metabolism and are essential to keep your metabolism in ….

What is circadian rhythm?

The circadian rhythm is our internal clock, it operates on a 24-hour period to regulate and maintain balance within our cell. It tells us when to wake up, when to sleep and tells our organs when they need to perform certain activities and when they can recover. This is relevant as any alterations to the circadian clock can be damaging to our metabolism and can stimulate aging pathways.

The circadian clock is present to maintain homeostasis within our bodies. Homeostasis is the bodies way of keeping balance within the cells. To do this every cell has lots of sensors to detect even small changes in its environment. This is because all the reactions which occur in our cells work best in certain conditions. Therefore, cells ensure that everything remains consistent; any fluctuations are detected, and normality is restored.

The circadian clock is no exception and is, therefore, under a high level of control. It responds to changes in our environment such as light and food consumption, which are detected by sensors within our cells.

The Circadian Clock Regulates NAD+ Production

The circadian clock regulates itself via a feedback loop, the enzymes which it produces accumulate during the day and at high levels they inhibit their own production. This process takes around 24 hours and then it begins again, as the clock is reset.

The two main proteins involved in this process are CLOCK and BMAL1. They bind to each other and increase expression of its target genes. This is of importance due to its impact on NAMPT because NAMPT is the key enzyme in NAD+ production. Levels of NAMPT directly control how much NAD+ is made by the salvage pathway – the primary mechanism youthful cells use for NAD+ production. This in turn regulates sirtuin levels as they are dependent on NAD+ for their activation. Therefore, they only work when NAMPT levels are high and NAD+ production is also high.

During the day levels of NAMPT increase supporting NAD+ production but when the NAMPT expression decreases so does NAD+ production. Therefore, sirtuin activation is also a rhythmic process increasing and decreasing throughout the day in accordance with the fluctuations in NAD+ levels.

Sirtuins Link Metabolism to the Circadian Clock

The circadian clock directly regulates sirtuin levels and it does this through NAD+ production. Because sirtuins are involved in various cellular functions including metabolism, this impacts the body’s rate of metabolism. For example, during a fasted state (when you have not consumed any food in a while) your NAD+ levels increase and this increases sirtuin activation. This increase in sirtuin activation goes on to boost your metabolism.

So, what impact do sirtuins have on our metabolism? Well to appreciate that we must first acknowledge how our metabolism usually functions. Glucose (blood sugar) is the main source of energy for our cells. Glucose is obtained by the food we eat and is broken down to fuel our bodies. Therefore, when sirtuins detect that glucose levels are low because you haven’t eaten in a while it changes the genes expressed in the liver, muscle and fat cells.

This is important as it stimulates a change in your metabolism so rather than breaking down carbohydrates (glucose) for energy your cells break down fat tissue (fatty acids) as the main energy source. This process works best when your NAD+ and sirtuin levels are high and therefore when your circadian clock is working at its best.

The Circadian Clock Declines with Age

In younger cells the circadian clock works efficiently to maintain our NAD+ and sirtuin levels but as we age it does not work as well contributing to the decrease in NAD+ levels and slowing of our metabolism.

As we get older the circadian clock is rewired leading to a buildup of cellular damage. Although this may sound alarming recent studies have shown that the core components of the circadian clock remain unchanged and activities such as calorie restriction and exercise can help to ‘fix’ the damaged clock so that it works more effectively, just like when we were young.

As we age our metabolism can slow down which impacts our levels of NAD+ and sirtuin activation. This decline can be the cause of many signs of aging within our bodies. Therefore, to ensure that our circadian clocks and metabolism are working at their best it is vital to maintain levels of NAD+ within the cell.

References

• Chang, H. C., & Guarente, L. (2014). SIRT1 and other sirtuins in metabolism. Trends in endocrinology and metabolism: TEM, 25;138–145.

• Eckel-Mahan, K., & Sassone-Corsi, P. (2013). Metabolism and the circadian clock converge. Physiological reviews, 93; 107-135.

• Ohkubo, R., Chen, D. (2017). Aging: rewiring the circadian clock. Nat Struct Mol Biol. 24; 687–688.

• Reinke, H., Asher, G. (2019). Crosstalk between metabolism and circadian clocks. Nat Rev Mol Cell Biol 20; 227–241.