Sleep 10: Genes, sleep, and age-related disorders

(Thanks to LDK in STL for sending me this article)

I rolled back into my hotel room this evening at about 8:30, and by 9:00 my body simply demanded, "SLEEP!"

It's to be expected. After getting just 3 hours of sleep the night before, 5 hours the night before that, and 2 hours the night before that, it was bound to happen. So I set my alarm for a few hours, got up just after midnight, refreshed enough to once again start typing.

I don't adhere to those patterns every day, but my sleep routine is bizarre enough that the concept of Sleep itself is one I continue to find fascinating.

This article from the Record at Washington University in St Louis (a school known for producing brilliant astronomer/educators in the early-mid 90s) discusses research that identifies the mechanism linking the circadian rhythm to age-related disorders such as diabetes.

"Our study establishes a detailed scheme linking metabolism and aging to the circadian rhythm," said one of the lead authors, Shin-ichiro Imai, M.D., Ph.D., associate professor of medicine and of developmental biology. "This opens the door to new avenues for treating age-related disorders and ways to restore a healthy daily circadian rhythm. It also could yield new interventions to alleviate metabolic disorders such as obesity and diabetes."


It's an interesting idea. But now I face my scientific article conundrum. I have some problems with the article. It appears to make some assumptions that it doesn't justify. Perhaps the actually scientific study addresses these concerns, and the article writers simply drop them for the sake of brevity and simplicity. Unfortunately, those shortfalls lead me to question the credibility of the data, even though it may be sound.

Of course, bloggers drop further details as we comment on articles about scientific papers, leading to further bastardization of the material.

This phenomenon leads to a lot of bad science writing for mass consumption, and that can drown out the good science writing. Unfortunately, bad writing about science encourages people to question what may actually be sound scientific principles and studies.

Speculating even further (and contributing more to the problem myself) I wonder how much of the controversy surrounding human-made global climate change can be attributed to simply bad interpretation of actual scientific study. But that's a topic for another post.

In the meantime, I'm just going to go ahead and exacerbate the problem myself. It's much easier than providing an actual solution.

The article leads off by saying:

All animals, including humans, have an internal 24-hour clock or circadian rhythm that creates a daily oscillation of body temperature, brain activity, hormone production and metabolism.


I may be nitpicking here, but that's not quite true. While there is a definite circadian rhythm that governs the body's wake/sleep cycle, it's not a 24-hour rhythm. It fluctuates and we routinely force it into a 24-hour cycle (through alarm clock, prime time TV schedules, and the general mechanisms of modern life).

Other studies have shown that the actual rhythm runs about 25-hours. Studies in Germany in the late 60/early 70s isolated people in underground bunkers, removing all artificial time cues (such as clocks) and natural time cues (such as the sun).

Over the course of the experiment, almost all of the people settled into a 25-hour cycle, gradually falling out of sync with above-ground dwellers on a standard 24-hour cycle. Interestingly, a small percentage of them developed a cycle that was closer to 48-hours, often staying awake and active for very long stretches of time. However, their body temperatures still fluctuated on cycle that was close to 25 hours.


When left to my own devices, I seem to drift onto a 36 hour wake/sleep cycle, but that's just me.

The article that kicked off this post deals with the gene SIRT1:

SIRT1 influences glucose breakdown and production, cholesterol metabolism, fat burning, and insulin sensitivity. Increasing the activity of proteins related to SIRT1 extends the life span of yeast, worms and flies. SIRT1 is activated when calories are restricted below normal, which has been shown to extend the life spans of some laboratory animals until food becomes more readily available.


In order for SIRT1 to work, it relies on a chemical called NAD.

In mice, the researchers found a daily oscillation of the metabolite NAD (nicotinamide adenine dinucleotide), an important compound that is the body's way of exchanging energy and moving it where it's needed. Previously, scientists believed the amount of NAD in cells stayed fairly constant.


While the chemical is a natural one produced by the human body, the name makes me wonder how smoking/tobacco consumption influences this process.

Regardless, the research in this article found that the body does not produce a consistent amount of NAD. Instead, the production is tied directly to the clock genes, and therefore subject to the wake/sleep cycle. At different points in the circadian cycle, the body produces more or less of it.

The researchers found that this NAD rhythm was linked to the daily rise and fall of the activity of "clock" genes, those that serve as the gears that run the body's internal clock. They discovered that the clock genes directly interact with a biochemical process that produces NAD.

NAD is required for SIRT1 to function, suggesting that SIRT1 activity increased and decreased along with NAD oscillation in the mice. Since SIRT1 is known to inhibit the clock genes, the cycle of its activity feeds back into the clock mechanism.


In other words, the sleep cycle influences NAD production, which impacts the functioning of the SIRT1 genes, which in turn influences glucose and insulin production and cholesterol breakdown. It impacts things like aging, obesity, and diabetes.

And tying it all back to the beginning of the cycle, SIRT1 activity also impacts the clock genes and the circadian rhythm, which in turn impacts NAD production, and we are once again, off to the races.

So that's my contribution to bad science writing and likely my misinterpretation of data. Since this research was mainly about the mechanism involved, it may not provide actionable information. Follow-on research will be needed for that.

My speculation would be that this would be relevant to other studies which have demonstrated a link between obesity and lack of adequate sleep. It may provide further insight to the nature of the link and exactly what the cause/effect relationship is.

And perhaps it could lead to a deeper unstanding of or treatment for diabetes. Or perhaps even aging itself.

But for now, it's time to go to bed.


Sharkbytes (TM) said...

I easily fall into 25 + hour cycles, and sleep about 6 hours to wake refreshed. Often do several shorter hours in a row like you though. But the nights that are shorter often require extra food to stay awake. I think that's one reason little sleep contributes to overweight. So far, I'm skinny enough.

LDK in STL said...

Wow, I'm famous!

The full citation for the original journal article about which The Record article was based is:

Ramsey, K., Yoshino, J., Takahashi, J., Imai, S., Bass, J., Brace, C., Abrassart, D., Kobayashi, Y., Marcheva, B., Hong, H., Chong, J., Buhr, E., & Lee, C. (2009). Circadian Clock Feedback Cycle Through NAMPT-Mediated NAD+ Biosynthesis. Science, 324(5927), 651-654.

Another related article in the same issue of Science is:
Nakahata, Y., Sahar, S., Astarita, G., Kaluzova, M., & Sassone-Corsi, P. (2009). Circadian Control of the NAD+ Salvage Pathway by CLOCK-SIRT1. Science, 324(5927), 654-657.

Perspectives on the above two articles are also offered in this issue:
Wijnen, H. (2009). A Circadian Loop as SIRTs Itself. Science, 324(5927), 598-599.

And for more fun with science, or Science as it were, the table of contents for this entire issue is here:

Cromely said...

@Sharkbytes: The food aspect of it is interesting. Staying awake would seem to require more energy/calories than sleeping, and yet lack of sleep is often associated with obesity. What's interesting is the interplay, then, of sleep and insulin productions I suppose. Or sleep still burn plenty of calories in other activities.

@LDK: And deservedly so.