ADRB1 Mutation Grants a Lesser Need for Sleep, and thus a Longer Subjective Life

We lose a third of our life to sleep. If we didn't need to sleep at all, then we would have the experience of living 50% longer, considered subjectively. We would accomplish much more, experience much more. There are, unfortunately, few useful ways to safely reduce the amount of time spent asleep, without reductions in the quality of life while awake. Here, researchers report on a rare human genetic variant that manifests itself in a family whose members with the mutation need comparatively little sleep to be fully rested, and who appear to be otherwise unaffected by this genetic difference.

This discovery may well prove to be the basis for enhancement treatments to reduce required sleep time in the years ahead. We should consider the caveats, however: sleep appears to be important in clearance of some aggregates from the brain, and it could be the case that individuals who sleep less have raised rates of neurodegenerative disease in late life, but these possible risks and associations have not yet been evaluated.

An understanding of the regulatory mechanism for sleep lays at the foundation for healthy living and aging. Sleep behavior has long been thought to be regulated by the interactions of circadian clock and sleep homeostasis pathways. In humans, variations of genetically inherited sleep features in the population have been recognized for a long time. Importantly, human sleep has unique features that are different from that of animal models. For example, human sleep is usually consolidated, whereas mice sleep throughout the 24 hour day. Drosophila sleep-like behavior is consolidated into one long period, but the level of similarity between the Drosophila and human molecular regulatory mechanisms remains unclear.

Previously, we identified a series of genetic variations that influence the timing of sleep in humans, and mouse models of these mutations mostly recapitulate the phenotypes. Timing of sleep is heavily influenced by the circadian clock, which has been intensely studied, and we now have a large and growing body of knowledge on how the clock is regulated at the molecular level. On the other hand, our understanding of sleep homeostasis regulation for human lags behind. We reported a mutation in the human DEC2 gene that causes mutation carriers to sleep 6 hours nightly for their entire lives without apparent negative effects. Another mutation in DEC2 was later reported in a single individual who is a short sleeper and resistant to sleep deprivation. Identification of additional genes participating in modulation of human sleep duration provides a unique way to expand our knowledge of genes and pathways critical for human sleep homeostasis regulation.

Noradrenergic signaling in the central nervous system (CNS) has long been known to regulate sleep. The network involving the noradrenergic neurons has been extensively studied, and most of the receptor subtypes have been genetically defined. In contrast to α1 and α2 adrenergic receptors (ARs), relatively little is known about the function of β receptors in the CNS. βARs within the brain were previously suggested to mediate the effect of norepinephrine (NE) for alert waking and rapid eye movement (REM) sleep. Clinically, β-blockers are widely used and can be associated with difficulty falling asleep and staying asleep, possibly due to reduced production and release of melatonin.

We report here a rare mutation in the β1AR gene (ADRB1) found in humans with natural short sleep. Engineering the human mutation into mice resulted in a sleep phenotype similar to that seen in familial natural short sleepers. We show that β1AR is expressed at high levels in the dorsal pons (DP). Neuronal activity measured by calcium imaging in this region demonstrated that ADRB1+ neurons in DP are wake and REM sleep active. Manipulating the activity of these ADRB1+ neurons changes sleep/wake patterns. Also, the activity of these neurons was altered in mice harboring the mutation. Together, these results not only support the causative role of this ADRB1 mutation in the human subjects but also provide a mechanism for investigating noradrenaline and β1AR in sleep regulation at the circuit level.



Two points about this: 1) I get a very good show most nights. I wonder if these people get less? 2) It is the span of novel activities, advancement, and achievement that I measure life in. If you offered me only 10 awake hours a day, but that I got to live 50% longer, I'd definitely take the deal.

Posted by: Tom Schaefer at September 23rd, 2019 7:02 AM

The mutation appears to produce a less stable beta-1AR protein. The result, as described in the paper, is that less externalization of the receptor occurs at the cell membrane-- i.e., fewer of these receptors are exposed.

The paper goes on to note that the activity of the receptor in the wake-promoting neurons that express it does not appear to depend on the extent of exernalization. Meanwhile, the wake-inhibiting neurons expressing it do appear impaired somewhat in their response thereto by the smaller number of receptors present.

With that in mind-- would a sufficiently long-acting selective beta-1AR antagonist produce a similar effect pharmacologically...? Several beta blockers have been noted to potentially cause insomnia as a side effect.

Something like betaxolol might be most suitable-- it is selective for beta-1AR, is sufficiently lipid-soluble to have CNS effects in clinical observation, and has a half-life of 14-22 hours.

Given this is an aging website-- does anyone here have experience with it, or with similar compounds? Does it reduce the number of hours slept per night, on average, without causing excessive fatigue, difficulty concentrating, or other indications of acute sleep deprivation?

Posted by: TH at March 21st, 2020 1:34 AM

I don't know which mutation I have, but have been averaging about 4 hours sleep my entire life and really have not had a tired day throughout. I wore a fitbit for more than a year, it averaged 4h20m over that time (rarely with an alarm clock, just for things like flights), it listed that my time falling asleep was mostly 0 minutes and sometimes 1 minute. I went 20+ years at a company, only missing 19 days sick total (with 14 of those being in a row for food poisoning, though there were a decent number of injury days off additionally in there). As for dreams? Usually don't have them (at least no memory), unless I stay in bed and go back to sleep, in which case I wake up tired! So that effectively makes me get up at 4 hours.

It is wonderful having 1/4 more life than everyone else, though you spend much of it alone! And about the comment above for longevity, I seem to be aging slower than everyone around me since I NEVER get too little sleep!

Posted by: Robin M at March 6th, 2021 7:15 PM

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