SERcadian Rhythms
The amino acid L-serine may be the next melatonin. A new study showed administration of 3 grams ~30 minutes before bedtime advanced melatonin onset dramatically, almost instantly. It didn't increase the concentration of melatonin, just onset (Yasuo et al., 2017). For a higher concentration, you'd need AM sunlight and PM blue blockers or actual mel supps (preferably the former) (eg, Burke et al., 2013).

Important and interesting caveat in the L-serine story: it only worked if the participants received bright light in the morning.

In the figure below, "day 1" is no AM light and "day 2" is yes AM light. In both the L-serine and placebo groups, there is a phase advance on day 2 because of the AM light treatment. The advance is markedly greater when the participants received 3 grams of L-serine:

Using rodent models (which mimicked the human effect almost exactly), GABA-A receptors were implicated.

Interesting for a couple reasons.

GABAnergic agents like benzo's and alcohol don't really put you to sleep; they knock you out, which isn't proper sleep. This suggests a non-circadian effect of L-serine; however: 1) GABA-A prevents light-induced SCN activation; and 2) serine advanced melatonin onset (specifically only when combined with light in the morning).

Potentially important caveat: L-serine converts to D-serine via serine racemase. D-serine and serine racemase are increased in Alzheimer's (Madeira et al., 2015). That's not how L-serine worked in this study, because D-serine acts via NMDA and an NMDA antagonist had no effect on the phase advance. And I suspect the conversion of L- to D- serine is highly regulated and not substrate-driven because L-serine administration didn't increase D-serine levels. This might be a great example of "correlation =/= causation."

Why L-serine? I don't know, but they tested many other amino acids in their rodent model and serine was the only one that worked. And they didn't need much of it (in humans): 3 grams. That's about as much as is found in a regular diet.

Two important blog posts which may hint at how this happened: LIGHT timing for circadian entrainment and Melatonin sensitizes the system.

Ask any basic biochemistry student about serine and they'll tell you it's purpose in proteins is more functional than structural (also methyl-metabolism, anaplerosis, and a few others). "Post-translational modification." For example, serine can be phosphorylated to increase or decrease enzyme activity without changing enzyme level. That's important because enzymes aren't cheap. It's much easier and less energy-intensive to stick on or remove a phosphate group than degrade an enzyme and build it again (both of which require cellular energy).

Serine is also kinda famous in the history of circadian biology due to it's role in Familial Advanced Sleep Phase Syndrome (FASPS). In FASPS, one of the serines in the circadian protein Per2 is switched to a glycine and people with this polymorphism fall asleep and wake up a few hours earlier than everyone else. Scientists have also knockout the normal copy of Per2 in mice and replaced it with the FASPS version: same thing.

However, I don't think that has anything to do with the light-induced serine-mediated advance of melatonin onset - which seems to be more like a dark-mimetic. That is, L-serine acts via GABA-A and GABA-A blocks light-induced SCN activation. And when we have darkness, we get melatonin. That's exactly what happened in this study.

There's another phenomenon, in plants, wherein serine (but not other amino acids) accumulates and when it reaches a critical threshold, triggers expression of the light-induced photorespiration apparatus. This could be mimicked by applying L-serine directly. This might be similar to what happened in the Yasuo study. Ie, an interaction between light and serine. Pretty cool, in any case.

Anyone gonna try L-serine?

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