7/28/2019 La luce artificiale influisce negativamente sul sonno.

1/3S 1 0 | N A T U R E | V O L 4 9 7 | 2 3 M A Y 2 0 1 3

B Y M I C H A E L E I S E N S T E I N

By the time Elizabeth Klerman boards thetrain to go to her office at Brigham &Womens Hospital in Boston, Massachu-

setts, the conductor has been awake for hours,rising in the dead of night for his first trainat four oclock. This schedule is not merelydemanding, but contrary to most peoples circa-dian rhythms, the pattern of physiological andmetabolic activity that is roughly in synchronywith the rising and setting of the Sun.

Some people are trying to live and workwith an abnormal relationship between theircircadian rhythm and the clock, says Kler-man, who studies human sleep patterns. Mostof us have experienced this mismatch in the

form of jetlag. For shift-workers and oth-ers with unnatural routines, however, thisdesynchronization occurs every day and canresult in chronic sleep deficits. Researchers arenow trying to understand the prevalence andseverity of the problem, and to devise strat-egies that can help reset these clocks.

THE TIME MACHINE

Many body tissues have their own timetables,organized by cyclic oscillations in the expres-sion of a network of numerous clock genes.The entire body is a clock, says Derk-Jan Dijk,director of the Surrey Sleep Research Centre

in Guildford, UK. Its a house with clocks in

every room and every corner, yet in one way oranother they work in an organized way. Thetiming of all these various peripheral oscilla-tors can profoundly affect metabolic activity,immune cell proliferation, and numerous othercritical functions. But there is a central pace-maker that gives the body a sense of the timeof day: the suprachiasmatic nucleus (SCN), agroup of neurons in the hypothalamus (seeThe anatomy of sleep, page S2).

When melanopsin photoreceptors in the eyedetect light, the SCN is activated and respondsby initiating a host of rhythm-establishingphysiological responses, including suppress-ing production of the hormone melatonin bythe pineal gland (see The light switch). Theperipheral oscillators can be shifted by physi-

cal activity or by altering meal times, but mostresearch suggests that light exposure is by farthe most important determinant of rhythmsdriven by the SCN. If you look at the data forhumans, every time they suggested that exer-cise or food may shift the clock, they also sug-gest that light may have been involved, saysDebra Skene, who studies chronobiology at theUniversity of Surrey, UK.

Light is the dominant influence on circadianrhythms, but other factors can come into play.A small subset of completely blind people wholack melanopsin photoreceptors, for example,can still achieve some circadian entrainment

through external cues and lifestyle1. This

timetable can be shattered by a trip across afew time zones, however, requiring long peri-ods of readjustment without the assistanceof light to signal the time of day. Many othertotally blind individuals fail to entrain at all,with profound effects. They sleep at nightbecause thats when theyre told to sleep, sothey have very short sleep of poor quality, andat lunchtime their circadian system starts say-ing they should go to sleep, says Skene. So wesee them extremely tired they nap and theydont perform well.

BASIC INSTINCTS

Humans are diurnal animals and so tend to beactive by day and rest at night. But personalpreferences for when to sleep can differ consid-

erably among individuals, and even at differentstages in the same persons life the differencebetween being early birds or night owls.

Researchers are still grappling with the bestapproach to measure the innate timing ofsomeones internal clock. As an indicator ofbiological night, levels of melatonin in variousbody fluids can give researchers a way to moni-tor the SCN cycle directly in an individual. But

this requires repeatedbody fluid sampling overextended periods, and istherefore impractical forpopulation-scale stud-

ies. Instead, most sleep

C H R O N O B I O L O G Y

Stepping out of timeHow can people better adapt to an unnatural world of artificial lighting and alarm clocks?

NATURE.COM

Scientists tinker

with our circadian

clocks:

go.nature.com/dqg4hl

SLEEPOUTLOOK

2013 Macmillan Publishers Limited. All rights reserved

7/28/2019 La luce artificiale influisce negativamente sul sonno.

2/32 3 M A Y 2 0 1 3 | V O L 4 9 7 | N A T U R E | S 1 1

researchers rely onsurveys in which peo-ple self-report theirsleeping habits.

One of the big-gest surveys of sleep-ing habits, with more

than 150,000 respondents from around theworld, is the Munich Chronotype Question-naire (MCTQ), run by Till Roenneberg at theLudwig Maximilians University in Munich,Germany. His team devised an online surveythat asks people to describe the timing of theirsleep behaviour on a day-to-day basis, both onnormal working or school days and at week-ends or holidays. By characterizing individualsleep patterns what Roenneberg calls achronotype it is possible to quantify habitspreviously observed only at an anecdotal level,such as the tendencies of children to wake earlyand of teenagers to sleep late. We were able toshow how drastically the clock gets later fromchildhood through adolescence, reaching peaklateness in women at 19-and-a-half and in menat 21, and after those ages people get earlieragain until they die, says Roenneberg.

ALARM CLOCK SHOCK

The MCTQ data have also provided insightsinto how our biology is altered by living andworking in the artificially illuminated, indus-trialized world2. By assessing both rural andurban populations, Roenneberg and othershave shown how modern life scatters peoplessleep patterns even further around the clock.If we were all farmers, working outside allday, chronotypes would vary only by three tofour hours, says Roenneberg. But since mostof us work predominantly indoors and use arti-ficial light after sunset, our clocks dont receive

strong synchronizing signals anymore, and

chronotypes nowadays span up to 12 hours.Circadian desynchrony is most acute in peo-

ple whose work schedules make them live noc-turnal lives. They are exposed to a very complexlightdark cycle, where there is artificial lightat night but still some natural light that youmay see during the commute home or to work,says Dijk. In the majority of those types of shiftworkers, their central clock does not adapt.

Roennebergs team has found that circadiandesynchrony may be far more pervasive, how-ever. Many modern workers effectively liveon two different timetables one enforcedby their weekday alarm clock, and the otheraligned to their weekend socializing and sleep-ing in resulting in disruption that he hasdubbed social jetlag3. In most people, it looksas if they were travelling from Europe to theUnited States on a Friday evening and back ona Monday morning, because their displace-ment is so large, says Roenneberg. This dis-connect begins at adolescence, when our bodyclocks reach their latest preferred wake time,and continues all the way to retirement age.

People who operate on schedules notaligned to their internal rhythms, either due

to shift work or social jetlag, often exhibit signsof chronic sleep restriction or disruption thatcan impair both job performance and overallwellbeing. During wakefulness, you will haveproblems maintaining sustained attention,says Dijk. You will be sleepier and experiencedisruption in working memory you will seethe effects across all cognitive domains.

In the long term, such desynchrony can exac-erbate the risk of cardiovascular disease, obe-sity and other health problems3,4 (see Heavysleepers, page S8). In our animal models ofclock gene mutations, were seeing diabetesand a propensity for obesity and metabolic

disorders, says Joseph Takahashi, who studies

circadian rhythms at the University of TexasSouthwestern Medical Center in Dallas. Sev-eral studies have found a similar connectionin shift workers and other individuals operat-ing on schedules not aligned to their internalrhythms3,4. These findings dont necessarilymean that there are immediate health conse-quences, says Dijk, but we can see the impactof being asleep or being awake at the wrongphase of your circadian cycle immediately.

BLUE IS THE COLOUR

At night, artificial lighting continues to acti-vate the SCN and disrupt the natural release ofmelatonin, which normally heralds the onsetof biological night (see Casting light on sleepdeficiency, page S13). But not all light stimu-lates the SCN equally. Skene and others haveshown that specific wavelengths are especiallyimportant waking signals. We observed peaklight sensitivity at a wavelength of around 460to 480 nanometres a nice, deep blue, shesays. Red light, by contrast, has only a weakimpact on melanopsin receptors and is lessprone to stimulate wakefulness. So adjustingthe relative levels of blue and red light that peo-

ple are exposed to throughout the day couldpreserve normal circadian timing even duringprolonged exposure to artificial light.

Klerman is collaborating with her colleagueSteven Lockley at Brigham & Womens Hospitaland with George Brainard of Thomas JeffersonUniversity in Philadelphia, Pennsylvania, to testthis approach in an extreme situation: the Inter-national Space Station. Long-term isolation incramped quarters poses many problems forastronauts, and they also experience disorient-ing lightdark cycles resulting from the stationsorbital time of 90 minutes. This is too shortfor our circadian system to synchronize, says

Lockley. The body clock starts to free run on

N A S

A

E A R T H

O B S E R V A T O R Y / N O A A

N G D C

Exposure to light

after sunset tricks the

body into thinking

its still daytime,

delaying the onset of

biological night.

OUTLOOKSLEEP

2013 Macmillan Publishers Limited. All rights reserved

7/28/2019 La luce artificiale influisce negativamente sul sonno.

3/3S 1 2 | N A T U R E | V O L 4 9 7 | 2 3 M A Y 2 0 1 3

its own time, just like for blind people. This isfurther confounded by the need to interact withpeople operating on various Earth schedules,such as mission control in the United States orcrews arriving from Russia.

Lockley and colleagues previously showedthat blue light could help to synchronize Earth-based crews with the Martian day as part of the

Phoenix Mars Lander mission5

. The researchersare now exploring programmable LED (light-emitting diode) systems that dynamically shiftfrom blue-enriched to red-enriched white lighton a 24-hour cycle. Were working on shiftingpeoples rhythms more quickly and maintainingtheir alertness at a better level, says Lockley.

This technology may be most valuable inextreme places such as spacecraft, submarinesor Antarctic research facilities, but the broaderpotential is obvious. The electronics companyPhilips, based in Amsterdam, the Nether-lands, is one of several developing controllable,dynamic lighting systems for homes, schools

and offices that boost blue wavelengths early inthe day and in the post-lunch slump, and shiftto redder wavelengths later in the afternoon.

A DOSE OF RHYTHM

It is not yet known whether these lighting sys-tems will be effective in groups composed ofpeople with widely varying chronotypes, butdrugs that tinker with circadian rhythms couldprovide a more personalized approach. The hor-mone melatonin may not be sufficient by itselfto send someone to sleep, but it neverthelesshelps the body to prepare for sleep, and thereis evidence it can affect the timing of sleep.The general consensus is that melatonin canphase-shift circadian rhythms when properlyapplied, says Klerman. Indeed, a growing bodyof work suggests that the combination of prop-erly timed melatonin dosing and managed lightexposure can counter the circadian problemsassociated with both jetlag and shift work6.

Melatonin requires a prescription in Europebut is available over the counter at health-foodstores in the United States. However, the USFood and Drug Administration has limitedoversight over the quality and content of suchnatural supplements, so it is difficult for USconsumers to achieve correct dosing. As a morereliable alternative, several drug companies

are developing synthetic agents that mimic theeffects of melatonin, such as tasimelteon, devel-oped by Vanda Pharmaceuticals in Washing-ton, DC. Klerman and colleagues have shownthat tasimelteon can improve sleep quality intime-shifted human subjects7, and it is now in aphase III clinical trial for use in blind individu-als who lack melanopsin receptors. Such peoplehave recurrent jetlag, says Klerman, so theyare an ideal population that you would want totry to entrain with melatonin agonists.

Several other potential circadian modula-tors have been discovered in the past two years.Pharmacology researcher Thomas Burris and

colleagues at the Scripps Research Institute in

Jupiter, Florida, identified two compounds, forexample, that alter circadian rhythms by actingon a key regulator of clock gene activity. Thesecompounds, known as SR9009 and SR9011,also affect weight gain and metabolism in

mice

8

. Small molecules that can reset the clockmight help in recovering from jetlag more rap-idly, says Takahashi,who collaborated withthe Burris team andhas launched a circa-dian drug-discoverycompany, Reset Thera-peutics, based in Burl-ingame, California. Headds that circadian

drugs could potentially treat metabolic prob-lems associated with off-kilter body clocks, andcounter the disturbed sleep that commonlyafflicts elderly people.

It is less clear whether these drugs would bean appropriate solution for chronic, lifestyle-associated jetlag, however. Medication shouldbe used if people are sick, says Roenneberg.Im not comfortable with using medicationto align people to what society wants. As analternative, he recommends designing workschedules to suit individual employees and theirparticular chronotype, which can be determinedby questionnaires such as the MCTQ.

SMART SCHEDULES

Several industries are already using smarterschedules and training methodologies that

maximize the health, performance and effi-ciency of their workers. Major corporationssuch as Procter & Gamble and Goldman Sachsare using sleep hygiene programmes basedon circadian research to keep their personnelsharp for example, coaching staff to optimizetheir individual sleep schedules, and to switchoff laptops and e-readers in advance of bedtime.The need for such efforts is especially keen inindustries with round-the-clock operations particularly those where working while tiredcould prove fatal, such as mining or manu-facturing. In aviation, the US Federal Avia-tion Administration has recently put in place

fatigue risk management systems that aim to

improve the safety of air travel by using care-fully regulated work schedules and mandatedrest time to minimize flight-crew fatigue.

However, Lockley questions the wisdom ofretraining the public to adapt to schedules that

are contrary to their biological needs. Wherewe have to have 24/7 society in health andsafety services, for example we should do it,he says. But we should critically review whetherwe need 24-hour supermarkets or TV.

To help people make the most of their sleepwhile also leading happy and productive lives,we need a better sense of what natural humansleep patterns really are, and how our lifestylesreshape them. But this requires more data. Sev-eral research groups are now working with pre-industrial communities in the Amazon to get abetter understanding of how the natural humanclock runs in a non-electric world. Meanwhile,Roenneberg hopes to build on the success ofthe MCTQ with a much broader Human SleepProject that will bring together leading sleepresearchers to characterize circadian rhythmsand sleep patterns at the population scale.

Waking up early to start work at four oclockin the morning may never be entirely natural forpeople such as Klermans train conductor, butbetter insights into sleep management couldmake such schedules more comfortable and thetransition from weekend to the working weekless jarring. We need huge databases wherethousands to millions of people have contrib-uted data from their daily life, says Roenneberg.Once we understand that, we can change our

society and technology so that people can sleepin their proper, individual sleep windows.

Michael Eisenstein is a science writer based inPhiladelphia, Pennsylvania.

1. Czeisler, C. A. et al.N. Engl. J. Med.332, 611 (1995).2. Roenneberg, T., Wirz-Justice, A. & Merrow, M.J. Biol.

Rhythms18, 8090 (2003).3. Roenneberg, T. et al.Curr. Biol.22, 939943 (2012).4. Buxton, O. M. et al.Sci. Transl. Med.4,129ra43

(2012).5. Barger, L. K. et al.Sleep35, 14231435 (2012).6. Revell, V. L. & Eastman, C. I.J. Biol. Rhythms20,

353365 (2005).7. Rajaratnam, S. M. W.et al.Lancet373, 482491

(2009).

8. Solt, L. A. et al.Nature485, 6268 (2012).

Im notcomfortablewith usingmedication toalign people towhat societywants.

Light

T H E L I G H T S W I T C HLight controls the body clock by activating

the suprachiasmatic nucleus (SCN).

T H E L I G H T S W I T C HLight controls the body clock by activating

the suprachiasmatic nucleus (SCN).

1. Melanopsin receptorsin the eye respond tothe presence of light bytransmitting signals tothe SCN

3. Lightdark entrainment of theSCN synchronizes 'peripheraloscillators' throughout the body,although these cansubsequently be shifted byfactors such as eating, exerciseand body temperature

SCN Pineal gland

2. Light-inducedactivation of the SCNprevents the pineal gland

from producingmelatonin, a hormonethat otherwise signals'biological night'

SLEEPOUTLOOK

2013 Macmillan Publishers Limited. All rights reserved