>> A PIONEER IN TRANSLATIONAL
AND CLINICAL SLEEP AND CIRCADIAN
MEDICINE RESEARCH.
DR. ZEE HOLDS MULTIPLE POSITIONS
AT NORTHWESTERN'S UNIVERSITY'S
FINEBERG'S SCHOOL OF MEDICINE.
NOTABLY SHE CREATED AND IS
CURRENTLY THE DIRECTOR OF THE
CENTER FOR CIRCADIAN SLEEP
MEDICINE AND SHE IS ALSO A
PROFESSOR OF NEUROLOGY AND
NEUROBIOLOGY.
I EMBASSY IN HER SPARE TIME, YOU
ARE ALSO DIRECTOR AND CHIEF OF
SLEEP MEDICINE AND THE SLEEP
DISORDERS CENTER AT NORTHWESTERN
MEMORIAL HOSPITAL.
DR. ZEE'S RESEARCH AND STUDIED
HOW SLEEP CIRCADIAN RHYTHM AND
DEVELOPMENT MEET THE EXPRESSION
OF NEUROLOGICAL AND CARDIO
METABOLIC DISORDERS.
SHE ALSO DEVELOPED SLEEP AND
CIRCADIAN BASED INTERVENTIONED,
AIMED AT IMPROVING COGNITIVE AND
CARDIO METRICS TAB O LOAMIC
HEALTH POPULATIONS IN HEALTH AT
RISK.
TODAY'S LECTURE WILL EXPLORE
THIS DYNAMIC INTERPLAY OF
CIRCADIAN RHYTHMS AND SLEEP ON
HEALTH.
BEFORE CALLS
DR. ZECERTAINLY--CERTAINLY TO
THE PODIUM LET ME DO 2
HOUSEKEEPING THINGS WHICH ARE
VERY IMPORTANT.
FIRST FOR IN OF YOU CME CODE FOR
WEDNESDAY APRIL 3rd : 50119.
OKAY, I THINK I DID THAT RIGHT
AND SECOND FOR THOSE WHEN OF YOU
WHO BRAVED THE ELEMENTS, THERE
IS A SMALL RECEPTION OUTSIDE
FOLLOWING THE LECTURE AND YOU
GET THE DELICIOUS COOKIES THAT
ARE MADE AVAILABLE FOR THESE
PURPOSES.
WITH THAT MY GREAT PLEASURE TO
INTRODUCE DR. ZEE.
[ APPLAUSE ]
>> WELL, THANK YOU VERY MUCH FOR
THIS IMMENSE HONOR AND I'M
REALLY DELIGHTED TO BE HERE
ALTHOUGH IT IS ON A FAIRLY RAINY
DAY AND ALL THE PLOSES --BLOSSOE
FALLEN ALREADY.
I MISS THEM ALL THE TIME.
I WANT TO ESPECIALLY THANK
DR. NEAL SHORE FOR INVITING ME.
I GOT A BOWFUL E-MAIL SEVERAL
MONTHS AGO, DR. DAN CHI FOR
HOSTING AND FOR THE AAN PH I FOR
HOSTING ME, THE OFFICE OF
WOMEN'S HEALTH RESEARCH AND ALSO
HAD A LOVELY MEETING WITH THE
WOMEN OF COLOR INTEREST GROUP
HERE AT THE NIH, THIS MORNING.
WHAT I THINK I'M ANYTHING TO DO
IS GIVE YOU A LITTLE BIT OF AN
OVERVIEW, BUT ALSO SOME SPECIFIC
EXAMPLES OF HOW SLEEP AND
CIRCADIAN HIGHT
IMPEDIMENTS--IGHT HIMS ARE
INTEGRATED.
FIRST I HAVE A COUPLE CONFLICTS
OF INTEREST YOU MAY WANT TO TAKE
A LOOK AT.
I DON'T THINK ANY OF THESE
DIRECTLY AFFECT ANYTHING I'M
SPEAKING ABOUT BUT AS MENTIONED
I DO SEEM TO BE DOING A LITTLE
TOO MUCH.
SO HERE'S THE OUTLINE, I FIRST I
WILL DESCRIBE VERY BRIEFLY HOW
CIRCADIAN RHYTHMS AND SLEEP
HOMEOSTATIC MECHANISMS ARE
INTEGRATED AT VARIOUS LEVELS OF
ORGANIZATION EMPLOY THEN WHAT IS
THE MOST IMPLICATION OF THIS
INTERACTION, NOT SO MUCH ABOUT
OR THE OTHER BUT THEIR
INTERACTION ON THE 2 COMMON
DISEASES THAT WE WORK ON, SOME
OF THE NEUROLOGICAL DECS LIKE
NEURODEGENERATION, AND CARDIO
METABOLIC DISORDERS.
AND FINALLY, WHAT IS THAT
FUTURE, WHAT IS THE PROMISE,
POTENTIALLY HARNESSING THIS
SYNCHRONIZED INTERPLAY, SLEEP
AND CIRCADIAN RHYTHMS, BOTH ARE
FUNDAMENTAL BIOLOGICAL
PROCESSES, BOTH AT THE BRAIN
LEVEL, BUT ALSO THROUGHOUT YOUR
ENTIRE BODY AND MOST OF YOUR
TISSUES AND HOW WE CAN MOVE THAT
FORWARD IN CLINICAL RESEARCH,
AND MEDICINE TO ENHANCE THE
HEALTH SPAN OF COURSE, HOPEFULLY
THE LIFE SPAN AS WELL.
SO MY VIEW, IS THAT SLEEP AND
CIRCADIAN RHYTHMS ARE KIND OF
MIRROR IMAGES, THEY SHOULD NOT
BE SPOKEN ABOUT NECESSARILY
SEPARATELY.
IT SHOULD BE SLEEP AND CIRCADIAN
BECAUSE YOU WILL SEE HOW WELL
INTEGRATED THEY ARE AND WHEN WE
LOOK AT THE DISEASE, SOME OF THE
CONSEQUENCES, IT USUALLY IS THE
CONSEQUENCES OF THE INTERPLAY
BETWEEN THESE 2 SYSTEMS, RATHER
THAN HOW WE TEND TO THINK ABOUT
IT WHEN WE DO OUR RESEARCH, WHEN
WE--EVEN IN THE CLINIC THAT
THEY'RE ACTUALLY SEPARATE AREAS.
SO, FROM THE VERY BEGINNING OF
THE EARTH'S ROTATION ON ITS
AXIS, WE KNEW THAT THESE SYSTEMS
WERE INTEGRATED.
THERE WAS LIGHT.
THERE WAS DAY.
CIRCADIAN RHYTHMS HAD TO DEVELOP
IN SOME WAY TO COORDINATE THE
BIOLOGICAL CYCLES WITH THAT OF
THIS REVELATION OF THE EARTH AND
THESE PROMINENT PHYSICAL
NIGHT-DAY CYCLES AND HENCE LATER
ON WE DEVELOPED THESE
REST/ACTIVITY CYCLES AND WHAT WE
WOULD CALL AWAKE AND SLEEP IN
ANIMALS AND HUMANS.
AND PERHAPS THE BASIS OF THIS IS
THE SIRCHG RONNIZATION OR
ALIGNMENT OF BIOENERGETICS,
METABOLIC ACTIVITY WHERE THERE'S
A SINGLE CELL OR COMPLEX
ORGANISM WITH THAT OF THE
LIGHT-DARK CYCLE AND THUS IS NOT
SURPRISING THAT OUR ACTIVITIES,
WE ARE ACTIVE DURING THE DAY AND
ACTIVE EXCEPT NOCT URNAL 1S AND
WE ALSO TEND TO SLEEP WHEN
THERE'S DARKNESS AND AS MOST OF
YOU KNOW OUR MODERN SOCIETY'S
HAVE CHANGED A LOT OF THAT
BECAUSE WE CAN MANIPULATE OUR
LIGHT-DARK CYCLES AND SO FORTH.
SO IF YOU LOOK AT, THIS IS AN
OLD OF COURSE, PICTURE BUT IT'S
HOPEFULLY EXPRESSED HOW
INTEGRATED THESE 2 SYSTEMS ARE,
SO IF YOU LOOK AT CIRCADIAN, THE
WORD CIRCA DIAMEANS ABOUT 24
HOUR.
SO WE'RE LOOKING AT THIS AND
WE'RE SAYING, WELL ALL THIS
PHYSIOLOGY BEHAVIOR, WHETHER
WE'RE LOOKING AT THE RISE IN
CORTISOL AND THAT BEGINS WHETHER
YOU STAND UP OR GET UP IN
PREPARATION FOR GETTING UP,
METATONIN SECRETION STOPS,
PROTHOM BOTTIC FACTORS,
PLATELETS ARE MORE ACTIVE IN THE
EARLY MORNING HOURS, PERHAPS
THAT'S 1 OF THE REASONS,
CERTAINLY NOT THE ONLY REASON
WHY WE TEND TO HAVE MORE
THROMBOTIC STROKES FOR EXAMPLE,
DURING THAT PERIOD AS WELL AS
OTHER TYPES OF COAGULOPATHYS.
ALERTNESS IF YOU LOOK AT
BEHAVIORS, THEY ALSO CHANGE
ACROSS THE ENTIRE DAY, THEY'RE
BETTER TIMES FOR EVERYTHING, SO
THE--THE EXERCISE OFFICIALIAN
ADOSSA WELLs AS PROFESSIONAL
TEAMS, THEY'RE VERY INTERESTED
IN THIS, SO WHEN CAN THEY GET
THE BIGGEST ADVANTAGE BECAUSE
THEY CAN BE VERY SMALL
ADVANTAGES AS WELL.
OF COURSE, THE 1 WE'RE MOST
AWARE OF IS THAT OF OUR SLEEP
AND WAKE CYCLE AND INDEED SLEEP
HAS A VERY SPECIAL PLACE IN THIS
KIND OF RHYTHMIC BEHAVIOR ACROSS
THE ENTIRE DAY.
SLEEP NOT ONLY IS A
PHYSIOLOGICAL MARKER BUT WITHIN
SLEEP WE HAVE DIFFERENT TYPES OF
STAGES WHERE WE CALL IT STATES
OF SLEEP WHICH WE WILL CALL
NONREM, REM SLEEP, RAPID EYE
MOVEMENT, AND BEHAVIORIALLY AND
PHYSIOLOGICALLY THEY'RE ALL
DIFFERENTITATES ALTHOUGH THEY
ALL COALESCE WITHINIT SLEEP
PERIOD AND AUTOQUITE DIFFERENT
BETWEEN THESE 2 STATES.
AND WITHIN SLEEP ITSELF WE KNOW
THERE ARE PHYSIOLOGICAL THINGS
THAT HAPPEN.
BLOOD PRESSURE DIPS, THERE'S
INCREASE IN HEARTERATE
DURABILITY, I'LL TALK A LITTLE
BIT ABOUT FILIC FLOW, ALL THESE
THINGS BUT AT THE SAME TIME WE
NOW KNOW THAT CLOCKS, THE
CIRCADIAN RYTH HIMS ALSO
REGULATE MANY OF THE SAME
PARAMETERS, SO AGAIN, THESE ARE
EPITHELIAL GREATED, THEY STARTED
TOGETHER AND NATURALLY, AND
THEY'RE STILL INDGREATED, SO
JUST A LITTLE DRAWBACK TOWARD
HISTORY OF WHY, PERHAPS UNTIL
MAYBE THE LAST 15-20 YEARS THAT
WE TENDED TO SEE THESE FEELS AS
SEPARATE, SO LET'S FESTER TAKE A
LOOK AT THE SLEEP FIELD AND WHAT
YOU SEE HERE THIS IS JUST VERY,
VERY SELECTED EMPLOY FIRST KIND
OF SLEEP CYCLES, RECORDED REM
SLEEP WHICH WAS COVERED IN THE
1950S, REM SLEEP A BIT LATER,
AND THEN WE HAD THE GENETIC
EVOLUTION, REVOLUTION, OF OF
LOOKING AT YEENS FOR NARCOLEPSY
FOR EXAMPLE, DISCOVER MANY OF
THESE SLEEP DISORDERS, SUCH AS
REM BEHAVIOR DISORDER, BEING
DRIEBED, SLEEP APNEA BEING
DRIEBED DURING THIS WHOLE
PERIOD, THE DORPHY IN THE 19,
ALMOST 2000 OF THE AREXIN
SYSTEM, ALSO THIS IS THE WAKE
PROMOTING SYSTEM OF THE BRAIN,
BUT ALSO THE VENTRAL LATERAL
PREOPTIC NUCLEUS WHICH IS A
SLEEP INDUCING PERIOD, 1999 BY
DR. SAPERs GROUP AND THEN ONCE
WE MOVE ON, THE FIELD AND FOCUS
ON WHAT SLEEP LOST IT.
IF YOU HAD SLEEP DEFICIENCY AND
THIS DISORDER AND ASHING IMMUNE
SYSTEM, CARDIOVASCULAR,
COGNITION, ON AND ON, RIGHT IN
NOW LET'S LOOK WHAT HAPPENED TO
THE CIRCADIAN FIELD, SO AROUND
THE SAME TIMELINE, IF YOU LOOK
AT CIRCADIAN RHYTHMS IN HUMANS,
IT WAS SHOWN THAT THESE CLOCKS
ARE ENDOGENOUS, SO PUT A HUMAN
HERE IN THE BUNKER STUDIES, IN
GERMANY, THESE RHYTHMS WITHOUT
ANY LIGHT-DARK CYCLES, CONTINUE
TO TICK AT THIS NEAR 24 HOUR
RHYTHM, HAND CIRCA RHYTHMS
ATTRIBUTED HERE TO ASCHOFF, WE
CAN ALSO SEE THE WORK THAT
THEY'RE GENETICALLY REGULATED
FROM WORK BY DROSOPHILA AND THAT
THERE WAS A CLOCK IN THE BRAIN
CALLED THE SUPER CHIASMATIC
LESION IN THE.
BECAUSE IF YOU STUDY THESE
BEHAVIORS,A BEINGIVITY BEI
REALLY HAS, THE REST OF THE
OTHER BEHAVIORS WERE ABOLISHED
AND THEN GENETICS SIMILARLY
ACROSS THE SLEEP TIMELINE,
CLONING OF THE PER CLOCK GENE,
ET CETERA AND ALSO IN
NORTHWESTERN, THE CLONING OF THE
HOUSE GENE BY JOE TAKAASSHES HI,
AND MARTHA AND FRED, AT THAT
TIME.
DISP THEN WE GO ON TO MORE
GENETICS AND REALLY AG
CELLERATED IN THE GENETICS AREA,
AND WITH--REGARDS TO CIRCADIAN
RHYTHMS AND IN 2017, THE KIND OF
CULMINATION OF MUCH OF THIS FOR
THE NOBEL PRIZE WAS GIVEN TO
YEFERSON--JEFFERSON HALL
[INDISCERNIBLE] AND MICHAEL
YOUNG FOR THE DISCOVERY OF THE
MOLECULAR MECHANISMS UNDERLYING
CIRCADIAN RHYTHMS AND WHY THAT
MIGHT BE, IS BECAUSE WE BEGIN TO
REALIZE THAT IT HAS TREMENDOUS
AFFECTS ACROSS ALL TISSUE YOU
BUT ALSO PERHAPS IN DISEASE
PREVENTION, MODIFICATION, AND
PERHAPS EVEN A DISEASE
DEVELOPMENT.
SO 2 OF THE MAJOR THINGS I THINK
WAS REALLY IMPORTANT WAS THAT WE
THINK OF THESE AS BEING
SEPARATELY, YOU KNOW THESE 2
FIELDS KIND OF EVOLVE
SEPARATELY.
AT LEAST SCIENTIFICALLY, AND
CERTAINLY CLINICALLY, WE'RE WAY
BEHIND.
BUT IN 1938, WE THINK OF
KLEITMAN WE THINK OF HIM BEING
THE FATHER OF SLEEP.
AND HIS FIRST EXPERIMENTS WERE
EXPERIMENTS IN THE MAP OGHT
CAVES IN KENTUCKY WHICH WAS LIKE
A BUNKY STUDIES, IN GERMANY
WHERE HE WANTED TO LOOK AT WHAT
WOULD HAPPEN TO SLEEP, THESE
RHYTHMS AND METABOLIC ACTIVITY,
DURING TIME ISOLATION, SO FROM
THE VERY BEGINNING, YOU KNOW,
FROM THE ROTATION OF THE EARTH
AND REALLY EVEN FOR THE
BEGINNING OF THIS HISTORICAL
PERSPECTIVE, SLEEP AND RHYTHM
WERE TOGETHER, THEY GOT A BIT
SEPARATED.
A COUPLE THINGS THAT HAPPENED
HERE IN THE 1980S, IT WAS
PROPOSED THAT SLEEP AND
CIRCADIAN RHYTHMS AT LEAST WERE
REGULATED IN THIS 2 PROCESS
MODEL AND I'LL SHOW YOU A LITTLE
BIT ABOUT THAT AND I THINK IT
WAS A GAME CHANGER AND THEN MUCH
LATER IN THE GENERIC ERA,
MOLECULAR ERA, THAT WAS A CLOCK,
A CIRCADIAN CLOCK MUTATION THAT
SHOULD ONLY AFFECT TIMING,
RIGHT, PRETTY MUCH, ACTUALLY
ALSO AFFECTED SLEEP HOMEOSTASIS.
IT WAS HARD TO IMAGINE THEA THE
TIME.
SO THESE WERE IN SOME WAYS GAME
CHANGERS.
AND THEN OF COURSE WE'RE IN THIS
REALLY HOT PERIOD IS WHERE THE
NIH, AND THE NATIONAL CENTER FOR
SLEEP DISORDERS RESEARCH WAS
MANDATED BY CONGRESS AND
ESTABLISHED HERE AT NIH BUT
UNDER NHLBI.
SO WE CAN LOOK FORWARD TO THAT,
LET'S GIVE YOU SOME EXAMPLES.
HERE'S A PROPROCESS MODEL,
CONCEPTUALLY THAT THERE ARE 2
PROCESSES, 1 IS THE SLEEP
HOMEOSTASIS, THAT'S REGULARLY
HOMEOSTATICLY, THE MORE, THE
MORE TIME YOU'RE AWAKE, THE
BUILD UP OF THIS PROCESS, IT
COULD BE AT A MOLECULAR LEVEL,
IT COULD BE AT THAT TIME, WE DID
NOT KNOW, ADEN O SEEN WOULD BE 1
OF THESE POTENTIAL
NEUROMODDULATORS THAT BUILD UP
DRINK-WAKE, DURING SLEEP IT'S A
MORE LINEAR PROCESS BUT WE KNOW
THAT'S NOT EXACTLY WHAT IT LOOKS
LIKE IN REAL LIFE AND THEN
THEREFORE THEY PROPOSE THERE'S A
CIRCADIAN PROCESS, C-PROCESS
OVER HERE THAT THEN REGULATINGS
NOT JUST THE TIMING OF SLEEP AND
WAKE BUT ALSO THE PROPENSITY
ACROSS THE 24 HOURS FOR SLEEP
AND WAKE AND IT IS THE
INTERACTION, THE INTEGRATION OF
THESE 2 SYSTEMS, THAT THEN
DETERMINES, HOW MUCH SLEEP, WHEN
YOU SLEEP, AND PROBABLY HOW GO
YOUR QUALITY OF YOUR SLEEP IS.
SO IT WAS REALLY THIS MODEL IS
NOT PERFECT BY ANY STRETCH OF
THE IMAGINE, TODAY, BUT IT WAS
REALLY A GAME CHANGER AND
CONCEPTUALLY, 1 CAN APPLY IN
RESEARCH AT ALL LEVELS, NEARLY
ALL LEVELS OF INTEGRATION XI
WILL SHOW YOU THAT FROM CELLS,
TO REALLY TISSUES, AND
PHYSIOLOGY AND ALSO OVER THE
YEARS, YOU CAN ADAPT IT TO THE
INFLUENCES OF EXTERNAL, VIERMAL
LIKE LIGHT AND CERTAIN TYPES OF
BEHAVIORS AND HOW THEY CAN
MODIFY THIS SYNCHRONY BETWEEN
THESE CIRCADIAN AND SLEEP
PROCESSES.
THERE'S MANY, MANY CITATIONS AND
AS AN OLD, OLD STUDY, YOU CAN
SEE THE NUMBER OF PUBLICATIONS,
NUMBER OF CITED PUBLICATIONS ARE
INCREASING BECAUSE I DO THINK
THIS IS WHERE WE'RE BEGIN TO NOW
RECOGNIZE, THAT THESE 2
PROCESSES ARE VERY, VERY TIGHTLY
INTEGRATE JUST TO GIVE YOU A BIT
OF AN EXAMPLE.
THIS IS A TODAY DONE BY THE
HARVARD GROUP, CHUCK
[INDISCERNIBLE]'S GROUP, THEY
TOOK HUMANS, THERE'S
30-SOMETHING DAYS IN HERE.
THEY TOOK VERY HEALTHY HUMAN
ANDS THEY PUT THEM UNDER THESE
CYCLES WHERE IT WAS LONGER THAN
24 HOURS, MUCH LONGER THIS, IS
ALMOST 28 HOURS, SO THE
CIRCADIAN SYSTEM WHICH HAS A
MOLECULAR CLOCK OF ABOUT
24-POINT WOP 7 HOURS COOPERATE
TRAIN TO THIS SO THEY BEGIN TO
FREE RUN, RIGHT, FROM THIS.
AND FROM THIS TYPE CALLED FORCE
OF SYNCHRONY, WE CAN THEN
DISASSOCIATE THE SLEEP VERSUS
THE CIRCADIAN PROCESSES AND WHAT
THEY FOUND THAT WAS SLOW WAVE
SLEEP WAS PRIMARILY UNDER THE
S-CONTROL, THE HOMEOSTATIC
CONTROL.
REM SLEEP WAS HOMEOSTATIC
CONTROL BUT MUCH MORE UNDER
CIRCADIAN CONTROL, THE TIMING,
THIS IS WHY WE DON'T GET REM
SLEEP DURING THE DAY.
ONLY NARCOLEPSY PATIENTS GET
SLEEP DURING THE DAY, OKAY IN
AND EVEN THOSE NOW THAT WE'RE
RECOGNIZING A SLEEP AND SLEEP
SPINDLES WHICH ARE VERY
IMPORTANT FOR MEMORY
CONSOLIDATION, THEY ARE ALSO
CIRCADIAN AND SLEEP GATED SO YOU
CAN SEE THE COMBINATION OF THE
2.
SO WHAT ABOUT CIRCADIAN RHYTHMS.
I THOUGHT FOR THE AUDIENCE, I
GISTLED AN INTRODUCTION OF THIS,
THIS IS COURTESY OF JOE
TAKAHASH, AND CIRCADIAN RHYTHMS
ARE GENETICALLY GENERATED BUT
THEY'RE ALSO REGULATED BY A
SUPER CLOCK IN THE BRAIN .
WHEN I WAS GROWING UP, THIS IS
ALL I KNEW, IT WAS ALL ABOUT THE
BRAIN, A SEBTERALLY GENERATED
HIGHT IMPEDIMENTS AND ALL THESE
OSCILLATORS WERE SLAVE
OSCILLATORS MEANING THEY WERE
RHYTHMIC BECAUSE OF THE BRAIN
AREA, YOU CAN SEE THE NEURONS
ARE RHYTHMIC, THEY HAVE NIGHT,
THEY ARE RHYTHMIC AND HAVE NEAR
24 HOUR FOGZ, AND WITH THAT OF
COURSE IS THE MOLECULAR LEVEL
AND THIS IS REALLY IMPORTANT
DISCOVERIES.
I THINK WHAT'S REALLY IN MY
OPINION CHANGED SOME OF THE WAY
WE THINK ABOUT THIS IS THAT NOW
WE KNOW THAT THE CIRCADIAN
RHYTHM ANDS PERHAPS EACH SLEEP,
DEPENDING HOW YOU DEFINE SLEEP,
AS ENERGY CYCLES, BUT NOT
ASENTIOUS EG OF COURSE MAY EXIST
AT THE CELLULAR MOLECULAR LEVEL
AND ALL TISSUES AS WELL AS A
METABOLIC SIGNAL AND ALSO THAT
NEARLY 50% OF OUR GENOME IS
ACTUALLY RHYTHMIC, AND THIS IS
THE CORE CIRCADIAN MACHINERY.
SO YOU HAVE B-MAIL--OOPS, SORRY.
YOU HAVE B-MAIL AND CLOCK AND
THEY DIMERIZE IN THE NUCLEUS AND
THEY BEGIN TRANSCRIPTION AND
TRANSLATION OF PERIOD AND CRY,
PERIOD IS 1 OF THE GENES THAT
WAS ACTUALLY DISCOVERED BUT ALSO
UNDERSTOOD BY THE NOBEL TEAM.
AND THEN THEY EXIT, THE PROTEINS
THEY EXIT INTO THE CYTOPLASM AND
THEY GET PHOSPHORYLATED BY THESE
LITTLE PINK THING ANDS THEY THEN
THEN DIMERIZE AGAIN AND THEY
REENTRY INTO THE NUCLEUS, AND AS
YOU WILL SEE, VERY, VERY SHORTLY
DEPENDING HOW MUCH IS BUILD UP
INTO THAT NUCLEUS, IT THEN SITS
BACK ON THIS EBOX AND SHUTS ITS
OWN PRODUCTION DOWN.
SO IT'S R-O REGULATORY FORWARD
NEGATIVE FEEDBACK LOOP, HOW
QUICKLY ALL THIS OCCURS, KIND OF
DETERMINES THAT CYCLE WHETHER
24, 25 HOURS, 23 OR SHORTENED TO
24 HOURS.
NOW, AS I SAID EARLIER, ALL
THESE CLOCKS ARE NEARLY ALL
TISSUES OF THE BODY, WHERE
THEY'RE LOOKING AT THE SEN OR
WHETHER YOU'RE LOOKING HERE
PERIPHERALLY, A LIVER OR LUNG,
THEY ARE SUSTAINED EVEN IN
TISSUE CULTURES, AT LEAST FOR A
LITTLE BIT.
BUT NOT ONLY THAT, ARE A
RHYTHMIC IN ALL TISSUES BUT IF
YOU LOOK AT THIS DROSOPHILA
PICTURE HERE, EACH OF THESE DOTS
ARE THE MODULES OF GENES THAT
ARE BEING EXPRESSED AND IF YOU
LOOK AT THE BEHAVIOR, THESE
YEENS ARE BEING EXPRESSED VERY
DIFFERENTLY, DIFFERENT TIMES OF
THE DAY, WHETHER IT'S DURING THE
LIGHT PHASE OR DURING THE DARK
PHASE, SO IT'S RHYTHMIC ACROSS
THE DAY AND NOT ALL OF THEM, ARE
DIFFERENTIALLY RHYTHMIC
DEPENDING ON THE SYSTEM THAT IS
INVOLVED.
SO I SAID EARLIER 1 OF THE GAME
CHANGERS WAS THE DORPHY OF THE
MAIL-IN CIRCADIAN CLOCK MUTATION
AT NORTHWESTERN.
DR. [INDISCERNIBLE] DISCOVERED
THE PHENOTYPE UP THERE, THE
WILD-TYPE WHEREAS THE MUTANT
ACTUALLY ALMOST WAS VERY, VERY
LONG CIRCADIAN PERIOD, SO EVERY
DAY, IS HOPPING ON THE WHEEL,
THIS ANIMAL LATER AND LATER
THIS, HAS NEVER BEEN--THIS WAS
NOT SEEN IN THE TYPICAL
WILD-TYPE WHICH HAS A CLOCK
FORWARD OF LITERALLY LESS THAN
24 HOURS.
TO MAKE A VERY LONG STORY SHORT,
IS THAT THIS MUTATION ACTUALLY
RESULTED IN THE SINGLE BASE PAIR
SUBTITUTION AND THAT CREATED
THAT MUTATION, 1 OF THE EARLY
FIRST DISCOVERIES THAT A SINGLE,
SIMPLE CHANGE LIKE THIS COULD
AFFECT BEHAVIOR IN SUCH A
DRAMATIC WAY.
MORE, SO TO THE POINT OF THIS
LECTURE IS THAT, THIS CLOCK,
CIRCADIAN CLOCK MUTATION,
REMEMBER THAT'S THE CLOCK GENE
THAT'S IN THE NUCLEUS, THAT ALSO
AVENGHTED SLEEP HOMEOSTASIS,
IT'S 1 OF THE FIRST
DEMONITRATIONS THAT IT PROMOTED
MORE WAKEFULNESS, A LITTLE LESS
NONREMETABOLISM SLEEP AND ALSO
ALTERED THIS REM TO SLEEP RATIO.
AND ALSO IN THE SAME THING THAL
CLOCK MUTATION NOT ONLY AFFECTED
SLEEP BUT IT AFFECTED THE BODY
MASS.
THESE WERE MORE OBESE, THEY WERE
HEAVIER, SO THIS IS A
DEMONSTRATION THAT A SINGLE CLO
CLOCK GENE COULD AFFECT
PHYSIOLOGY IN MANY OTHER
BROADWAYS.
SO THIS IS THAT INTEGRATION
AGAIN BETWEEN SLEEP AND RHYTHM
ANDS METABOLISM EMPLOY BUT YOU
CAN GO THE OTHER WAY AROUND, YOU
CAN SAY WHAT IF I SLEEP DEPRIVE
HUMANS, SO JUMPING FROM ORGAN
SYSTEM TO POINTS THIS IS IN
HEALTHY HUMANS, WHAT THEY DID
HERE, THIS IS GEORGE YOUNG'S
GOWP, THEY SLEEP DEPRIVED
INDIVIDUALS, THEY GAVE THEM
EITHER, YOU KNOW THEIR 7-8 HOURS
TIME IN BED OR RESTRICTED THEIR
SLEEP, TO MAYBE 6 HOURS IN BED,
AS I REMEMBER, AND SO THEY WERE
GETTING LESS SLEEP THAN A
NORMALLY WOULD.
WELL, WE SAW AND AS YOU WOULD
EXEC, THERE WERE SOME DOWN
REGULATION AND SOME UPREGULATION
UNDER THESE SLEEP DEPRIVED
CONDITIONS MAINLY IN THE
METABOLIC INFLAMMATORY IMMUNE
CELL GENERATION PATHWAYS.
BUT NOT ONLY DID THE SLEEP
DEPRIVATION ALTER THE EXPRESSION
OF THESE GENES BUT ALSO SLEEP
DEPRIVATION ALTERED THE NUMBER
OF GENES WITH CIRCADIAN
ALTERATION BY HALF.
THAT'S WHAT IT BASICALLY SHOWS
AND SLEEP DEPRIVATION WITHOUT
CHANGING TIMING NOW, ALSO
CHANGED THE PHASE OF WHEN THESE
SIR YAIDIAN GENES ARE BEING
EXPRESSED SO THAT IT'S BIMODAL,
YOU CAN SEE SLEEP RESTRICTION,
NOW YEENS NOW ARE IN THE RED ARE
EXPRESSED HERE AT THE NIGHT TIME
AND THE WRONG TIME OF THE DAY.
SO A BI-DIRECTIONAL LOOK, YOU
CAN DO BOTH WAYS, YOU ULTRA
CLOCK, YOU ULTRA SLEEP, YOU
ULTRA SLEEP, YOU CAN ALSO ALTER
CLOCK FUNCTION.
SO THEY'RE INTEGRATED, THE
PROPROCESS MODEL AS BEEN APPLIED
BOTH AT MOLECULAR AND CELLULAR
LEVELS, AND JUST SHOW YOU, NOT
SO MUCH, THE DATA ON THIS, BUT
THERE'S--THERE'S MANY NOW
STUDIES AND BEAUTIFUL, BEAUTIFUL
SCIENCE STUDY SHOWING THE YEENS
IN SLEEP HOMEOSTASIS AND I WILL
TALK A LITTLE BIT ABOUT THIS
NEURON WHICH IS RECENT DATA FROM
THE GROUP, AND ALSO THAT CLOCK
CHANGE CHANGES IN PERHIVERAL
TISSUE, ALL THESE PERIPHERAL
CLOCKS EVERYWHERE AS WELL,
RIGHT, CAN ALTER SLEEP, SO IT'S
MUCH FURTHER AWAY NOW FROM THE
BRAIN AND I WILL SHOW YOU SOME
DATA ON THAT.
THIS IS JUST 1 EXAMPLE FROM
DR. SEGAL'S GROUP WHERE THEY'RE
LOOKING AT THE SLEEP PRESSURE
NEURONS WHICHY --WHICH WE WILL
CALL SLEEP NEURONS.
YOU DEPRIVE SLEEP, SEE THE SLEEP
BUILDING UP, THE FIRING OF THE
NEURONS BUT THEN THERE ARE
NEURONS, ABOUT 75 ON EACH SIDE,
CLOCK NEURONS OR CIRCADIAN
NEURONS IN THE DNY REASON REGION
IS WHAT THE GROUP FOUND WAS THAT
HERE THEY ARE, THEY CALLED THEM
HUGGING NEURONS, THESE NEURONS
ACTUALLY RELAYED INFORMATION
FROM THE CLOCK NEURONS, THE
SLEEP PRESSURE NEURONS AND VICE
VERSA.
SO, NOW YOU CAN SEE, THAT THIS 2
PROCESS, AND IN SOME WAYS
INTEGRATEDDA THE CELLULAR AND
MOLEC LA LEVEL, SO HERE'S THE
COOL STUFF, DR. PAUL SHOWED
SEVERAL YEARS AGO, THAT IF YOU
KNOCK OUT B-MALL, IN THE BRAIN
IT DOESN'T DO MUCH FOR SLEEP,
BUT IF YOU KNOCK OUT BMAL IN THE
SKELETAL MUSCLE, IT INCREASES
SLEEP.
INTERESTING, AND BDNF ON 1 OF
THE MODULATORS HERE AND YOU SEE
THEN WHEN HE OVEREXPRESSES THIS
MORE RECENT WORK, I THINK IT'S
HASN'T BEEN PUBLISHED YET, BUT
WHEN HE OVEREXPRESSES THE BMALL,
THE CLOGGED GENE, YOU CAN SEE
BDNF IS HIGHER IN THE MUSCLE,
AND HE'S SLEEP DEPRIVED OR HIS
GROUP SLEEP DEPRIVED THESE
ANIMALS 5 DAYS FOR CHRONIC SLEEP
LOSS AND IN THIS OVEREXPRESSED
SKELETAL MUSCLE, BMALL
OVEREXPRESSION, THERE WAS NO
SLEEP REBOUND.
SO WHEN YOU SLEEP DEPRIVE, THE
HOMEOSTATIC SLEEP PROCESS KICKS
IN, RIGHT TO RECOVER IT, AND IT
DIDN'T LOOK ANY DIFFERENT.
SO THESE SLEEP REGULATORY
PROCESSES ARE SOON TO BE
EXCLUSIVE TO THE BRAIN, THAT'S
WHAT WE THOUGHT, BUT BY THESE
EXPERIMENTS LIKE XOKING OUT COL
YEENS AND MUSCLE, IT AFFECTED
THE AMOUNT OF SLEEP AND
OVEREXPRESSION REDUCES RECOVERY
RESPONSE TO SLEEP LOSS.
SO, WE CAN CONCLUDE THAT MUSCLE,
AND MAYBE OTHER PERIPHERAL
TISSUES, CLOCKS REGULATE BRAIN
SLEEP HOMEOSTASIS.
NOW YOU'RE LOOKING AT THIS, AT
THE MOLECULAR LEVEL.
SO COMING BACK TO HUMANS AND
COMING BACK TO THE NORMAL KIND
OF PHYSIOLOGY LIFE, YOU CAN SEE
THAT WHAT HAPPENS IS THAT THESE
CLOCKS ARE RUNNING AT A NEAR 24
HOURS, BECAUSE THEY'RE NEVER
EXACTLY 24 HOURS, TO BE EXACTLY
24 HOURS, YOU HAVE TO GET THEN
GET INPUT OR TIME GIVERS, LIGHT
IS THE STRONGEST AT THESE TIME
GIVERS AND HERE'S THE SEN, IT'S
NOT THAT BIG BUT HERE IT IS.
AND IT'S RECEIVING LIGHT
INFORMATION THROUGH THE RETINAL
HYPOTHALAMIC TRACT AND THEN THIS
INFORMATION GETS RELAYED TO
OTHER BRAIN REGIONS AND ALMOST
ALL OTHER BRAIN REGIONS AND
TRANSMITTED TO THE PERIPHERAL
TISSUES, IN OF IT, AT LEAST 1
PATHWAY THROUGH THE AUTONOMIC
NERVOUS SYSTEM.
BUT OF COURSE WE DO KNOW NOT
ONLY IS THAT, BUT WE KNOW THE
MELA TONIN SECRETED BY THE
GLAND, THAT CAN AFFECT SLEEP AND
WAKE CYCLES, SLEEP ITSELF IS
BI-DIRECTIONAL NOW, SLEEP ITSELF
ALSO WHAT YOU SEAT, --EAT, I WIL
SHOW YOU ABOUT THAT, YOUR
MICROBIOME, I WILL NOT TALK
ABOUT THAT BUT CLEARLY THEY ARE
IN THE HORIZON THAT PEOPLE ARE
LOOKING AT BUT 1 THINK THIS WE
DO MESS UP A LOT IS WHERE EATING
OR DOING THESE BEHAVIORS AT THE
WRONG TIME, OUT OF SYNCH WITH
THE MASTER CIRCADIAN CLOCK, WELL
I CALL IT CENTRAL CLOCK, WE
DON'T CALL IT MASTERS ANYMORE,
CENTRAL CLOCK AND ALSO WHEN WE
EXPOSE OURSELVES TO THE LIGHT
DARK CYCLES, LATE AT NIGHT
AND/OR LIVE IN THESE LARGE
CITIES, WE ARE PROVIDING THE
WRONG LIGHTING INFORMATION TO
THE CLOCK AND LIGHT IS THE MOST
POWERFUL MOST OF THESE TIME
GIVERS FOR [INDISCERNIBLE] OF
THE LIGHT CLOCK.
SO IF YOU CHANGE SOCIAL WORK,
WALL CLOCKS AND CYCLE, BEHAVIORS
SUCH AS EATING, EXERCISE OR
SLEEP TIMING, IT'S GOING TO
AFFECT THE SYNCHRONIZATION
BETWEEN THE ENVIRONMENT
BEHAVIORS WITH YOUR INTERNAL
BIOLOGICAL CLOCKS AND THIS OF
COURSE AS I SAID IS IN ALL THIS.
AND MISALIGNMENT CAN CREATE BOTH
CIRCADIAN AND SLEEP DISRUPTION
AND MISALIGNMENT CAN ALSO THEN
INCLUDE NOT JUST BETWEEN THE
INSIDE WORLD AND THE OUTSIDE
WORLD BUT ALSO WOULD THIN THE
INSIDE CLOCKS THEMSELVES OR
PERIPHERAL CLOCKS THEMSELVES AND
THAT HAS BEEN SHOWN IN MULTIPLE
STUDIES NOW TO SHOW THAT IT HAS
BROAD IMPLICATIONS AS RISK FOR
NEUROLOGIC, PSYCHIATRIC,
CARDIOVASCULAR, WHATEVER
INSTITUTE YOU'RE IN, IT SHOULD
AFFECT THAT, OKAY, IT SHOULD
AFFECT THAT WE'RE DOING SOME
WORK, MATERNAL FETAL DATA AS
WELL, SO IT'S REALLY EVERYTHING,
MOST THINGS THAT PEOPLE HAVE
LOOKED AT, YOU REALLY SEE THAT,
BUT AS A CLINICIAN, I WOULD SAY,
IF YOU HAVE THESE DISORDERS, YOU
CAN ALSO AFFECT THE CIRCADIAN
SYSTEM, YOU CAN ALSO AFFECT
SLEEP, SO IN MANY WAYS AGAIN
IT'S BI-DIRECTIONAL OR
MULTIDIRECTIONAL PROCESS, SO TO
SUMMARIZE THAT WE HAVE THESE 2
PROCESSES CONCEPTUALLY, THE
SLEEP HOMEOSTATIC DRIVE WHICH IS
VERY SIMPLY GETS MORE AND MORE,
BUILDS UP AND YOU DISSIPATE
DURING SLEEP, ALMOST ON A LINEAR
WAY, AND THIS IS DISSIPATED
DURING SLEEP PERIOD, AND THEN
HERE'S A CIRCADIAN SYSTEM.
ONE OF THE ROLES OF THE SCN IS
TO SEND THE SIGNAL TO SECRETE
MELATONIN FROM THE PINEALL
GLAND.
THE OTHER ROLE IS THAT IT
PROTIEWSS THIS COUNTER ALERTING
SIGNAL, THESE NEURONS WHEN
THEY'RE FIRING DURING THE DAY,
DURING THE LIGHT PERIOD, THEY'RE
PROY DUCING LEARNING SIGNALS TO
COUNTERACT THIS INCREASING DRIVE
FOR HOMEOSTATIC SLEEP. THIS IS
WHY WE CAN STAY AWAKE DURING THE
DAY AND RIGHT NOW, DIPPING RIGHT
HERE AND YOU SEE THAT, I FORGIVE
YOU IF YOU FALL ASLEEP, EXCEPT
FOR THOSE WHO ARE REMOTE AND YOU
CAN SEE THAT.
AND THEN REALLY, IT PICKS UP
THIS ALERTING SIGNAL RIGHT
BEFORE YOU GO TO SLEEP, MAYBE
IMPLICATING INSOMNIA DISORDERS,
MEL AN TONEIN GETS SECRETED,
SIGNALS GO DOWN, PERFECT TIME
FOR YOU TO RECOVER THE
HOMEOSTATIC DEBT HERE AS WELL AS
PERFECKLY ALIGNED TO GET YOUR
7-8 HOURS OF SLEEP.
AND OF COURSE, ALL OF THIS CAN
CHANGE WITH AGE, THERE ARE SEX
DIFFERENCES AND ALL THIS LIFE
TILE DISEASE CAN ALL AFFECT THE
INTERACTION BETWEEN THESE 2
MAJOR PROCESSES.
ALL RIGHT, WHAT ABOUT SLEEP
CLOCKS AND BRAIN HEALTH AREAS
THAT WE'VE BEEN INTERESTED IN?
SO THERE'S REIS Z ACTIVITY,
SMLITUDE, WITH ANY ORGANISM,
WHETHER WE'RE LOOKING HERE AT
THE MOUSE, YOUNG MOUSE,
BEAUTIFUL RHYTHM, 24 HOUR
RHYTHMS, OLD MOUSE, LITTLE
FRAGMENTED ALREADY, IF WE LOOK
HUMANS IN THE RUNNING WHEEL
WHICH WE DON'T DO BUT WE DO
HERE, WE SEE SIMILAR PATTERNS.
YOUNG HEALTHY PERSON, STRONG
RHYTHMS HERE, THIS IS SLEEP IN
THE WHITE PERIOD AND THIS IS THE
ACTIVITY LEVELS.
MITTED AGE WE SEE ALREADY SOME
FRAGMENTATION OF THE SLEEP HERE
ACROSS SEVERAL DAYS, THIS IS 7
DAYS OF RECORDING FROM THE WATCH
AND HERE'S A--BITS OLDER ADULT
WITH DEMENTIA, IT'S HARD TO EVEN
SO WHERE THE RHYTHM IS AT, THAT
SLEEP-WAKE RHYTHM AND AT AND
INDEED THIS TYPE OF SLEEP
FRAGMENTATION HAS BEEN SHOWN
EARLY ON, THIS IS A CLASSICAL
STUDY BY ADAPTED RUE LIMPs
GROUP SHOWING THE AMOUNT OF
FRAGMENTATION OF THE SLEEP-WAKE
CYCLE PREDICTS INCIDENT
ALZHEIMER'S DEDISEASE AND
COGNITIVE DECLINES AND 6 YEARS
LATER AND THERE'S MANY STUDIES
SINCE THEN THAT CONSISTENTLY
SHOW THIS PATTERN, HOWEVER, THIS
WAS 1 OF THE FIRST 1S.
MORE RECENT STUDY LOOKING AT A
MORE HYPER COMMON DEGENERATION
IN PARKINSON'S DISEASE, HERE'S A
HEALTHIER PERSON SPECIAL HERE'S
THOSE WITH PARKINSON'S DISEASE
AND WHAT WE SEE IS THIS CHANGE
IN THE AMPPLITUDE.
LOTS MORE VARIABILITY BUT
OVERALL LOWER AMPLITUDE AND WHEN
LENG YING'S GROUP DID ANALYSIS,
AND THEY SAW A DECREASE--I CAN'T
REMEMBER HOW MANY THOUSANDS OF
PEOPLE THIS CAME FROM, THAT THE
AMP LIAISON FEUD CAN OTHER
MEASURES OF CIRCADIAN ROBUSTNESS
WERE FAVORED, THE DEVELOPMENT OF
INCIDENT PARKINSON'S DISEASE, SO
THERE'S SOMETHING ABOUT THAT, SO
IT'S VERY SIMILAR, ALL THESE
NEURODEGENERATIVE DISORDERS, AND
HE'S AT MASS GENERAL, PART OF
THE K23, WORK WITH ME.
AND AGAIN, IN PARKINSON'S DEC,
YOU SEE ALREADY, THIS
FRAGMENTATION BUT HE DREW BLOOD
FROM THESE INDIVIDUALS EVERY
HOUR OR EVERY 2 HOURS, BRING
THEM INTO THE CLINICAL RESEARCH
UNIT FOR MELATONIN AND YOU CAN
SEE THE PARKINSON PATIENT WAS
NOT ONLY ACTIVITY BEHAVIOR, LOW
AMPLITUDE BUT ALSO THEIR
MELATONIN RHYTHM AND IN
PARTICULAR WITH THOSE
INDIVIDUALS WERE THE SLEEPIEST
OF THE PARKINSON'S PATIENTS, AT
THE LOWEST SUGGUESTING THAT
MAYBE THE LACK OF ALERTNESS IN
THE INDIVIDUALS MAY BE A
CIRCADIAN, PARTIALLY A CIRCADIAN
PROCESS.
THIS IS A REVIEW WHICH IS A
REALLY NICE REVIEW FROM USEC,
AND [INDISCERNIBLE] AND
[INDISCERNIBLE] GROUP.
HOW TO INTEGRATE CLOCKS AND
SLEEP, RIGHT?
THEY'RE BI-DIRECTIONAL AS I
SHOWED YOU ALREADY, THIS IS SEN
AFFECTS SLEEP AND OF COURSE THE
CLOCKS AND ALSO THESE PERIPHERAL
METABOLIC AND/OR INFLAMMATORY,
ET CETERA, TISSUES WHICH THEN
CAN AFFECT THE PERIPHERAL,
METABOLISM, HOME VASCULAR
REGULATION AND ALSO AT THIS
LEVEL, BRAIN HOMEOSTASIS FROM
ALL THESE DIFFERENT ANGLES.
SO I'M SURE ALL OF YOU HAVE
HEARD ABOUT THE LYMPHATIC
SYSTEM, RIGHT?
ABOUT HOW THE BRAIN DOESN'T HAVE
A GREAT LYMPHATIC SYSTEM AND
THESE TOXIC MOLECULES OR
PROTEINS GET FLUSHED OUT LIKE
ABETTA AMYLOID OR TAU THROUGH
THE LYMPHATIC PROCESS.
WELL DURING SLEEP, CLASSIC
STUDIES SCIENCE, DURING SLEEP,
THERE WAS HIGHER FLOW RIGHT
THROUGH THE INTERSTITIAL FLUID
AND WHEN YOU'RE AWAKE, THERE WAS
NOT, SO IT APPEARS TO BE 1 OF
THE METHODS, THIS BRAIN
ORGANIZED FLOW AND DYNAMICS WAS
1 OF THE WAYS TO FLUSH OUT THIS
MATERIAL, THIS IS THE--THIS IS
THE MRI HERE IS FROM LAURA
LEWIS' GROUP AND THEY SHOWED
WITH THE EEG, THEY WERE ABLE TO
SEE THIS FLUID FLUXES THAT EACH
OF THESE, MANY OF THOSE WERE
PROCEEDED BY SLEEP AND IN
PARTICULAR THIS DEEP SLEEP WHICH
IS ABOUT 1 HERTZ--LESS THAN HALF
TO MAYBE 2 OR 3-HERTZ PER
SECOND, SO IT WAS SAWL SLEEP
REGULATED AND THAT'S WHAT WE ALL
THOUGHT.
WELL, THIS IS A REVIEW ARTICLE,
BECAUSE I'M NOT GOING TO GO
THROUGH ALL THE DATA.
THERE'S REALLY BUILDING DATA
BOTH FROM AN ASTRO SIGHT LEVEL
OR NOT, BUT THAT THE BLOOD BRAIN
BARRIER IS CIRCADIAN CLOCK
REGULATED AS WELL BECAUSE
THERE'S DIFFERENT WAYS YOU CAN
KNOCK OUT CLOCK GENES AND SO
FORTH AND YOU BEGIN TO SEE A
BREAK DOWN OF THE BLOOD BRAIN
BARRIER AS WELL AND THAT ITSELF
COULD BE PROMISE.
AGAIN IT'S NOT JUST ABOUT SLEEP
BUT ALSO THEY HAVE TO BE
INTERNATIONAL CLASSIFICATION
GRADED.
[INDISCERNIBLE] BROWN SAID TO
ME, I'M A NEUROLOGIST, TELL ME
HOW DOES THIS REALLY WORK, HE
SAYS, WELL, CLOCKS ARE LIKE, HE
SAYS, IT TELLS YOU WHEN TO MAKE
SOMETHING, LET'S SAY THESE
MOLECULES OR THESE PROTEINS,
SLEEP TELLS YOU HOW MUCH.
SO WE CAN TURNOVERLY ENHANCE
RYTH--CERTAINLY ENHANCE RHYTHMS
WITH ALL THE THINGS, I'M TRYING
TO SEE THE CLOCK, IT SAYS 2
MINUTES DOES IT MEAN I ONLY HAVE
2 MORE MINUTES?
>> [INDISCERNIBLE].
>> GREAT.
ENHANCING SLEEP SO I THINK WE
HAVE NOW THE POTENTIAL WITH THIS
TYPE OF UNDERSTANDING TO USE
CIRCADIAN SLEEP-BASED PRINCIPLES
TO PERHAPS ENLANCE SLEEP.
NOW LET'S TALK ABOUT ANOTHER
AREA THAT I'VE BEEN ACTUALLY
WORKING ON OR OUR GROUP AND
OTHERS, IS ABOUT CIRCADIAN
INTEGRATION FEETING AND
METABOLISM.
WE KNOW THAT--YEAH, IT'S MY
PHONE.
SORRY.
SO ANOTHER AREA WOULD BE HOW IT
AFFECTS METABOLISM WHERE WE TOLD
YOU THAT EVEN A CIRCADIAN CLOCK
MUTATION CAN RESULT IN WEIGHT
GAIN OR OBESITY IN THE CLOCK
VIEWED MOUSE.
SO WE HAVE LIGHT, BRAIN, SCN,
THE SAME THING WE TALKED ABOUT
AT THE CLOCK OSULAR LEVEL AND
REMEMBER ALL THESE PERIPHERAL
TISSUES, MUSCLE, LIVER, THEY ALL
HAVE THE SAME MOLECULAR
MACHINERY OF THE CLOCK.
AND THEN WE HAVE FOOD, AND
LIGHT, SOMETIMES THEY'RE NOT
SYNCHRONIZED WITH EACH OTHER.
WE'RE EATING AT THE WRONG TIME
AND THAT'S VERY LIKELY NOT TO
OHM AFFECT THE OUTPUTS OF THE
CLOCK BUT ALSO REALLY THE STATE
OF WHICH THE TISSUES ARE GOING
TO BE ABLE TO BE MORE RESISTANT,
METABOLICALLY MORE CHALLENGED,
SO OOPS I DON'T KNOW WHERE THAT
MEANT, SO HERE'S 1 OF THE HERE'S
ANOTHER STUDY WHERE BY THIS IS A
STUDY BY FRANK SHEER, A CLASSIC
EARLY STUDY WE TOOK HEALTHY
HUMAN ANDS YOUNG RELATIVELY
HEALTHY AND YOUNG AND HE CALLED
CIRCADIAN MISALIGNMENT YOU
SHOULD THE PROTOCOL I TALKED TO
YOU WHERE YOU CAN PUT PEOPLE IN
THESE FORCED SIRCHG RONNIE
PROTOCOLS AND TRY TO,A LIEN OR
MISALIGN THEIR RHYTHM WITH SLEEP
AND AWAKE.
SO IF YOU LOOK AT THE GREEN,
THIS IS L LINE, YOU CAN SEE THE
TOP LEVELS, LEPTIN LEVELS UNDER
CIRCADIAN MISALIGNMENT WAS LOWER
WHICH MEANS THESE INDIVIDUALS
WERE LIKELY TO BE HUNGRIER, IT'S
A SATIETY PROBLEM.
LOOK AT THE CORTISOL, IT'S
ALMOST FLIPPED OVER.
SO CIRCADIAN RHYTHMS WERE
CONNECKED TO APPETITE AND
HORMONE AND TBLUICOSE METABOLISM
DISREGULATION, AND LATER SLEEP
TIMING ARE RELATED TO POOR
DIETARY HABIT ANDS BMI, SO
THERE'S A WHOLE HOST OF STUDIES
THAT SHOW THE LATE TIME EATING
RELATIVE TO THAT TIME, MAYBE A
STATE OF MISALIGNMENT AND THAT
INCREASE OF RISK BOTH FROM
EPIDEMIOLOGIC STUDIESAs WELL
AS VERY CONTROLLED EXPERIMENTAL
STUDIES OF RISK FOR METABOLIC
DYSFUNCTION.
THIS IS A FIELD STUDY WHERE
CHRIS AND CANNED
CANNED--[INDISCERNIBLE] AT
NORTHWESTERN SHE JUST LOOKED AT
A MEAL CATEGORY WHERE PEOPLE
CONSUME 25, 50, AND 75% OF THE
TOTAL CALORIE INTAKE FOR THE
DAY.
AND LOOKING AT THE MATSUDA
INDEX, YOU CAN SEE CLEARLY,
EARLIER THEY CONSUMED THEIR
CALORIES OR 50%, THEY HAD BETTER
INDID YOU LYNN SENSITIVITY AND
THIS WAS THE CASE WHERE YOU LOOK
AT A PROPORTION OF THE ENERGY
INTAKE IN THE MORNING AS WELL AS
LATE IN THE EVENTING AS WELL.
SO THE EARLIER YOU STARTED
EATING AND THE MOST OF YOUR
FOOD, THE BETTER INSULIN
RESISTANCE BUT IT DOESN'T TELL
US MUCH ABOUT WHY OR HOW, SO
IT'S NOT REALLY HOW MUCH WE EAT
OR SLEEP BUT I THINK THE MESSAGE
IS IT HAS TO BE COMBINED AND
INTEGRATED WITH WHEN YOU SLEEP,
AND EAT AND OF COURSE GET LIGHT.
THESE ARE OUR LIGHT HILLS ACROSS
THE UNITED STATES, YOU CAN SEE
WHERE YOU MAY BE LIVING, I CAN'T
SEE BUT LOOK AT ALL THESE, THIS
IS AT NIGHT, RIGHT?
THIS IS--THERE'S NO REAL GOOD
NIGHT, DARKNESS ON EARTH.
IF YOU'RE STAYING UP LATE, YOU
GOT LIGHT LATE, YOU ARE ALSO
EATING LATE, SO ALL THESE
BEHAVIORS ARE MOVING TOGETHER,
JUST A LITTLE BIT ABOUT LIGHT.
THIS IS A STUDY DONE BY
[INDISCERNIBLE] LOOKING AT
HEALTHY ADULTS IN CHICAGO WITH A
STUDY FUNDING BY THE NIH.
AND IF LOOK AT ANY LIGHT, ANY
LIGHT AT ALL WAS ASSOCIATE WIDE
INCREASED RISK FOR OBESITY,
CHANGE IN BIN, I OF MORE THAN
10%, DIABETES, AS WELL AS
HYPERTENSION, I'M NOT SAYING THE
LIGHT IS DOING THAT, BUT LIGHT
MAY BE CAUSING THIS MISALIGNMENT
BECAUSE THOSE PEOPLE MAY BE
EATING LATER.
WE DON'T HAVE THAT DATA, WE ONLY
HAVE THE OTHER DATA BUT IF
SOMETHING IS FOOD BASICALLY FOR
THOUGHT, SHE DID THE SAME STUDY
HERE IN THE NICHD AND NHLBI
FUNDED STUDY CALLED
[INDISCERNIBLE] TO BE, AND IN
HEALTHY PREGNANT WOMEN,
RELATIVELY HEALTHY PREGNANT
WOMEN, SHE LOOKED AT ACTIGER
DATABASEROPHY, AND REST WITH
LIGHT ACTIVITY AND NO DIFFERENCE
BETWEEN THOSE WITH GUESTATIONAL
DIABETES AND THOSE WHO DID NOT
WITH THE AMOUNT OF PHYSICAL
ACTIVITY OR THE TIMES OF
PHYSICAL ACTIVITY ACROSS THE
ENTIRE 24 HOURS.
BUT IF YOU LOOK AT THE LIGHT
INFORMATION LOOK AT THE RED LINE
HERE, THOSE WITH GUESTATIONAL
DIABETES WERE ALSO THOSE MORE
LIKELY TO HAVE EXPOSURE TO LIGHT
WITHIN 3 HOURS OF AT BED TIME.
SO THAT LIGHT IS CAUSING SOME
KIND OF DISREGULATION OR
MISALIGNMENT AND THIS IS A
REFLECTION OF THIS, THAT IF YOU
ELECTRIC AT THOSE WHO HAD THE
HIGHEST LIGHT, BEFORE BED TIME,
YOU CAN SEE THAT IT'S
PRETTY--IT'S--YOU KNOW WE HAVE
THESE, EVEN ADJUSTED UNAJUSTED
ODDS RATIO OF LIKE 3 OR 4 SO
IT'S REALLY A LARGE AFFECT SIZE.
SO WE WENT OVER THIS KIND OF
REGULATORY SYSTEM FROM SYSTEM TO
PERIPHERAL AND HOW THEY'RE
INTEGRATE WIDE THE BEHAVIORS OF
THE EXTERNAL LIGHT DARK CYCLE,
SLEEP, WAKE, AND FEEDING
BEHOUSTON AND RICE FOOTBALLS.
SO WE CAN CLEARLY NOW SAY, WELL
WHAT CAN WE DO ABOUT THAT,
RIGHT, WE DID DO A LIGHT, WE
TALKED ABOUT WE CAN ACTUALLY DO
LIGHT THERAPY, THERE ARE MANY
STUDIES LOOKING AT THAT IN
NEURODEGENERATION, MAYBE LESS IN
METABOLIC SYNDROMES, WE CAN GIVE
MELATONIN, CAN I TAKE MELATONIN,
SURE, WE HAD THE PERIPHERAL
CLOCKS, WE CAN DO ACTIVITY, ALL
OF THESE WE HAVE DONE IN THE
PAST AND MANY OTHERS IN THE
FIELD ARE WORKING ON VERY, VERY
IMPORTANT TYPES OF THINGS MUCH
WE CAN IMPROVE SLEEP, REMEMBER
SLEEP IS THIS KIND OF GEAR,
BI-DIRECTIONAL GEAR,
MULTIDIRECTIONAL GEAR FOR ALL OF
THESE THINGS BUT I WANT TO FOCUS
ALL THESE THINGS ON THE SLEEP
CYCLE.
THIS IS WORK WE'RE DOING
RECENTLY.
WHAT IS TIME RESTRICTED FEEDING,
THERE'S A SUBSTANTIAL AMOUNT OF
NICE, REALLY IMPORTANT DATA IN
ANIMAL STUDIES, YOU CAN SEE IN
REALLY, REALLY NICE ARTICLES,
TIME RESTRICTED FEEDING.
BASED ON A CIRCADIAN PRINCIPLE
CAN IMPROVE METABOLIC FUNCTION
AND WE ALSO KNOW THAT LATE
ISOCALORIC EATING DECREASES
HUNGER, ENERGY EXPENDITURE AND
WE DID STUDIES IN OTHERS, FRANK
SCHEER'S GROUP AND MANY OF THESE
STUDIES SHOWING THE FASTING THAT
THEY'RE REALLY RELATED TO EACH
OTHER AND TIME RESTRICTED
FEEDINGS DURING CERTAIN WINDOWS
OF THE DAY MAY HAVE BENEFICIAL
EFFECTS.
SO THIS IS A STUDY THAT WE ENDED
UP DOING, THIS IS FUNDED BY AN
RO-1 FROM NHLBI AS FAR AS PART
OF THE PEEL 1 BY NIA WHERE WE
LOOK AT MIDDLE AGE AS WELL AS
OLDER ADULTS WE THOUGHT, WELL
WHAT WE IF JUST ENHANCE THE
CIRCADIAN SIGNAL BY USING THE
FEED FAST CYCLE AS A PERIPHERAL
KIND OF METABOLIC SIGNAL, RIGHT?
BEING WE THEN IMPROVE THIS CROSS
TALK BETWEEN THE CENTRAL CLOCK,
PERIPHERAL CLOCKS, SLEEP AND
RHYTHMS AND COULD WE THROUGH
THOSE MECHANISMS, IMPROVE CARDIO
METABOLIC FUNCTION IN THESE
ACULTS WHO WERE NOT DIABETIC,
THEY WERE OVERWEIGHT IN GENERAL
AND THEY MAY HAVE CONTROL, THEY
WERE HYPERTENSION BUT THEY WERE
FAIRLY WELL CONTROLLED AND WE
JUST LOOKED AT THE FEEDING
DURATION.
THE INTERVENTION WAS THAT THEY
HAD TO DIM ALL THE LIGHTS OUT,
EVERYBODY IN THE CONTROL GROUP
OR EXPERIMENTAL GROUP 3 HOURS
BEFORE BED TIME BECAUSE WE
DIDN'T WANT LIGHT TO AFFECT
THEM.
WE HAD DATA FROM BEFORE THAT
HAVING BRIGHT LIGHT WHEN EATING
ASHINGS YOUR METABOLISM AND IT
DIFFERS BETWEEN THE MORNING AND
AFTERNOON.
SOPHISTICATEDY WE WANT TO
CONTROL FOR THAT AND THEN WE
EXTENDED THEIR OVERNIGHT FAST
FROM 3-12 HOURS, 12-16 DEPENDING
ON THE INDIVIDUAL AND WE ASKED
THEM TO STOP EATING 3 HOURS
BEFORE BED TIME THIS, IS THE
INTERVENTION GROUP, THE OTHER
GROUP JUST DIMMED THEIR LIGHTS
OUT 3 HOURS BEFORE BED TIME AND
PARTICIPANTS WERE ALLOWED TO
CHOOSE WHETHER TO STOP EATING
EARLIER TO MAKE THAT LONGER
FASTING FORWARD, WITH THE
OVERNIGHT FAST OR START EATING
LATER AFTER AWAKENING AND THIS
IS THE GROUP OF TALENTED WOMEN
WHO ALSO WERE CO INVESTIGATORS
IN THIS STUDY, CATHY REID,
DANIELA AND [INDISCERNIBLE]
ABBOT, AND CHRISTEN KNUTSON.
SO THIS IS 1 DURING THE
PANDEMIC, THIS WAS REALLY HARD.
WE DID A SCREENING PERIOD, THEY
CAME INTO THE CLINIC SO WE CAN
DRAW BLOOD AND DO SLEEP
RECORDINGS FOR THROW DAYS.
WE ADMITTED THEM AND THEN WE GOT
THE FIRST BASE LINE INFORMATION
FROM THEM EMPLOY AND THEN WE
RANDOMIZED THEM, AND THE
HABITUAL AND THEN WE FOLLOW THEM
FOR, IT WAS A 6 WEEK
INTERVENTION AND THEN AFTER THE
6 WEEKS THEY CAME BACK INTO THE
CLINICAL RESEARCH UNIT AND WE
DRAW ALL THEIR BLOODS AGAIN FOR
3 DAYS AND THEIR SLEEP AND
PERFOR THE PURPOSANCE MEASURES,
THERE'S REALLY QUITE A FEW
MEASURES THAT WE DID.
WHILE THEY'RE IN THE FIELD
DURING THE 6 WEEKS THEY GOT
CONTINUOUS ACTIGER DATABASERAPHY
AND SLEEP AND FOOD LOGS AND
CGMS, AND LOOK AT GLUCOSE
MONITORING ON A CONTINUOUS LEVEL
FOR SEVERAL DAYS AND A HEART
RATE.
SO THIS IS THE ACTIVERAPHY
RECORDING IN THE INDIVIDUAL, AND
IN THE BLUE HERE IS THEIR SLEEP
PERIOD AND IN THE DASH LINES
WILL BE THEIR FEEDING INTERVAL,
SO HERE'S AT BASE LINE.
THEY WERE ALL FAIRLY NORMAL
SLEEPERS.
WE DIDN'T WANT ANYBODY WHO WAS A
SLEEP DEPRIVED OR SHORT SLEEPERS
OR THEY HAD A CIRCADIAN EXTREME
CROHN O TYPES.
SO THIS WAS THE INTERVENTION, WE
INCREASE THE DURATION OF THEIR
FAST, AND THEY MAINTAIN THAT
THROUGHOUT THOSE 6 WEEKS.
WE CALLED THEM EVERY OTHER DAY
TO MAKE SURE THEY WERE DOING
THAT AND IT CAME BACK TO THE
CLINICAL RESEARCH UNIT, AFTER
THE INTERVENTION HERE, TO SEE
WHAT AFFECT THIS HAD.
THEY KEPT THESE FOOD DIARIES
EVERY DAY AND WE WERE ABLE TO
LOOK AT MACRONUTRIENTS, WE WERE
ABLE TO LOOK AT TIMING, TIME
STAMPS AND LOOKING AT WHEN THEY
WERE BUILDING IT AND THIS IS 1
EXAMPLE PLUS WHERE WE CAN LOOK
AT THE RELATIONSHIP BETWEEN
MODAL THINGS SO IN THIS LITTLE
PART IS THE--IF YOU LOOK AT THE
FASTING INTERVAL HERE, CAN YOU
SEE THAT DURING THE INTERVENTION
THE FEEDING--THE FASTING
INTERVAL DID INCREASE, RIGHT?
BUT THIS IS ACTIGRAPHY DATA HERE
SO WE SEE THE SLEEP-WAKE TIMING,
ALL THE PEAKS WERE RELATIVE
ACROSS THE 24 HOURS AS WELL AS
LOOKING AT OTHER PARAMETERS, WE
COULD LOOK AT ACTIVITY, HEART
RATE VALID AND RELIABLABILITYS,
WE CAN PLOT THESE IN THE
CIRCULAR PLOT TO LOOK AT THESE
RELATIONSHIP BETWEEN MULTIPLE
PHYSIOLOGICAL AND BEHAVIORIAL
ACTIVITIES, WITH EACH OTHER AND
WHETHER THAT IS THAT
SYNCHRONIZATION ALIGNMENT WOULD
IN ANY WAY BE--WE'RE STILL NOT
THERE YET, WE NEED SOME REALLY
COMPUTATIONAL POWER TO DO THAT.
SO JUST A LITTLE BIT THIS, IS
SOME PRELIMINARY DATA WE JUST
FINISHED ANALYZING SOME OF THIS,
WE CLOSED THE STUDY, AND WHAT
YOU CAN SEE, THIS IS FROM
THE--OUR PRIMARY OUTCOME WAS THE
ORAL DPLU COSTOLERANCE TEST IN
THE MORNING AS A METABOLIC
PARAMETER.
AND HERE'S THE DPLUICOSE BETWEEN
VISIT 3, BLUE IS BASE LINE,
ORANGE IS POST INTERVENTION.
THERE WAS NOT MUCH DIFFERENCE IN
DPLUICOSE.
YOU MAY SEE, MAYBE BUT THERE WAS
NOT MUCH DIFFERENCE IN GLUCOSE,
AT LEAST NOT SIGNIFICANT.
BUT THERE WAS A SIGNIFICANT
DECREASE IN THE AMOUNT OF
INSULIN THAT WAS SECRETED AND
ESPECIALLY WHEN YOU LOOK AT THE
2-HOUR GLUCOSE PERIOD HERE, 120
MINUTES.
AND IT LOOKED LIKE, IT TOOK THEM
A LITTLE BIT--LITTLE BIT SHORTER
TO GET TO BASE LINE IN THE ORAL
DPLUICOSE TOLERANCE TASK AND
HERE'S THE INSULIN AS WELL.
THIS IS THE NON--THIS IS THE
CONTROL GROUP.
WHAT WAS REALLY INTERESTING,
SURPRISING WAS THE FREE FATTY
ACIDS, SO THE OGT OF COURSE AT
0-POINT HERE AND SO BEFORE THIS
IS FASTING, RIGHT?
MINUS 15 IS FASTING, THERE'S
DECREASE IN THE PRE3 FATTY ACIDS
WHEREAS YOU DON'T SEE THIS IN
THE NONEXTENDED OVERNIGHT FAST
GROUP.
HOOK AT PLASMA CORTISOL, WE CREW
BLOOD FROM THEM LIKE EVERY 2
HOURS, SO ACROSS THE 24 HOURS
THIS IS THE CORTISOL PLASMA, AND
THE EXTENDED OVERNIGHT FAST
GROUP, BASE LINE, VERSUS END OF
THE INTERVENTION, YOU CAN SEE
DURING THE SLEEP, THIS FIRST
LEAP PERIOD, THERE IS A
SIGNIFICANT DECREASE IN CORTISOL
COMPARED TO HERE IN THE NONOOF
CONDITION, AND IN THE PEER
GROUP, THE SLEEP PERIOD AT THE
END OF THE STUDY ARE
SIGNIFICANTLY LOWER ABOUT A 33%
REDUCTION IN THE SLEEP TOWARD,
SO THAT'S VERY INTERESTING.
WE ALSO LOOKEDDA THE CARD QUO
VASCULAR FUNCTION AND SLEEP.
WE LOOK AT HEART RATE AND ALSO
PLP, HEART RATE AT THE TOP,
BLOOD PRESSURE AT THE BOTTOM AND
THE DARK BAR HERE INDICATES THE
SLEEP AND/OR AT LEAST THE TIME
OF LIGHTS OUT.
AND MOST OF THESE INDIVIDUALS
FELL ASLEEP FAIRLY QUICKLY, THEY
DID NOT HAVE INSOMNIA ISSUES.
AND YOU CAN SEE THE DIPPING OF
THE BLOOD PRESSURE, MORE
PROMINENTLY HERE IN THE OOF
GROUP AND NOT SO MUCH NO REAL
CHANGE HERE IN THE CONTROL GROUP
AND THE SAME THING HERE WITH
HEART RATE?
SO IT TURNS OUT THAT IT'S ABOUT
3% REDUCTION IN HEART RATE
DURING THE SLEEP PERIOD.
AND ABOUT A 6% REDUCTION IN
DIASTOLIC BLOOD PRESSURE.
WE DID NOT SEE CHANGES IN SIS
TOLL-LIKE RECEPTORIC BLOOD
PRESSURE.
MORE OVER WHEN WE LOOKED AT THE
CHANGES IN THE PLP DIPPING IT
WAS CORRELATED WITH THE
CONTINUOUS SLEEP SO THE TIME OF
WAKE AFTER SLEEP ONSET OF
FRAGMENTATION OF SLEEP, THE
IMPROVEMENT IN THAT WAS
ASSOCIATED WITH IMPROVEMENT IN
THE--IN SOME OF THESE
CARDIOVASCULAR POINTS.
SO I'M GOING TO KIND OF ALMOST
END BY SAYING THAT IT IS PERHAPS
TIME NOW TO BE TARGETING
CIRCADIAN AND SLEEP INTERACTIONS
TOGETHER BETWEEN AND ALSO
BETWEEN CENTRAL AND PERIPHERAL
MECHANISMS WHETHER IT'S CLOCK OR
SLEEP MECH NICHES, THERE ARE
MULTIPLE THINGS WE CAN DO AS WE
TALKED ABOUT EARLIER AND I THINK
IT'S REALLY RECIPROCAL BETWEEN
CENTRAL CLOCKS, PERIPHERAL
CLOCKS AND SLEEP WAKE TIMING,
HOW CAN WE USE THIS TYPE OF
INFORMATION THAT WE ALREADY HAVE
TODAY TO LOOK AT INTERVENTIONS.
THIS IS WHAT IS MISSING DURING
THIS TIME, WE HAVE HONE THAT
MAYBE IT IS EFFECTIVE FOR CARDIO
METABOLIC DISEASE RISK BUT WE
DON'T KNOW ABOUT NEURODEN
GENERATION BUT THAT IS QUITE
POSSIBLE, SO AGAIN, CIRCADIAN
AND SLEEP MEDICINE COULD BE PART
OF WHAT I WOULD HOPE IS PART OF
MY FUTURE HERE.
THEY'RE REALLY INTEGRATED.
WE NEED BIOMARKERS, WEARABLES,
CLINIC DATA, TIMING OF DIAGNOSIS
COULD BE IMPROVED, WE COULD
CONTINUE TO USE TYPICAL METHODS
LIKE LIGHT, MELATONIN, EXERCISE,
TIME RESTRICTED EATING AND
PERHAPS WITH THE MOLECULAR
MECHANISMS TO DRUG THE CLOCK AS
WELL TO CHANGE THE PERIOD OF
CLOCK, TO CHANGE THE FACE OF THE
CLOCK WITH MEDICATIONS.
AND AS MENTIONED EARLIER, WE DO
AT NORTHWESTERN HAVE THE FIRST
CIRCADIAN MEDICINE CLINIC.
IT TOOK ME THE LONGEST TIME,
TOOK YEARS TO CHANGE THE PLAQUE.
IT WAS JUST CALLED THE SLEEP
CENTER.
AND NOW YOU CAN SEE SLEEP
CLINIC, CIRCADIAN CLINIC AND
SLEEP LABORATORY AND THE NAME AS
CHANGED TO CIRCADIAN AND SLEEP
DISORDERS CENTER WHERE ALL THE
PATIENTS CAN SEE, SO I SAID THE
FUTURE WILL BE IN CROHNAL
DIAGNOSTICS BIOLOGICAL TIME
INNING IN THE CLINIC, USING
SENSORS MULTIPLE SENSORS, USING
DIFFERENT MODELS, ALGORITHMS TO
LOOK AT TEMPORAL PROFILE AND SO
FOR EXAMPLE, WE HAVE DIFFERENT
OMICs TO DETERMINE WITH 1 OR 2
BLOOD SAMPLES WHAT PHASES IT IN
YOUR BODY, RIGHT?
BECAUSE WE CAPTAIN BE DOING 24
HOUR BLOOD DRAWS FROM PEOPLE
EVERY 2 HOURS, THAT'S GREAT, BUT
THAT IS NOT GOING TO BE SCALABLE
TO TO THE CLINIC.
SO THIS IS SOMETHING THAT'S
MOVING INTO THE FUTURE AS WELL.
THIS IS JUST--I THOUGHT I WOULD
SHOW THIS, A DARPA STUDY THAT
WAS GIVEN TO JONATHAN
[INDISCERNIBLE], FRED CANNED
CANNED--FRED [INDISCERNIBLE] AND
MARTHA [INDISCERNIBLE],
COLLABORATORS ON THIS.
THIS IS CRAZY, THIS IS FROM THE
FUTURE.
HOW WILL WE DETECT CENTRAL AND
PERIPHERAL CLOCK AND ACLE
CELLERATE ARK DATA
PROTECTIONATION?
THIS IS JUST 1 POSSIBILITY, WE
CAN ESTIMATE PHASE, OOPS IN THE
CLOSED LOOP SYSTEM, DETERMINE
DOSE AND TIMING OF ANYTHING,
CREATE THIS FACE RESPONSE GROUP
SO IN A CLOSED GROUP SYSTEM, WE
CAN SAY, WE CAN ESTIMATE, WE CAN
DETECT THE TIME AND WE CAN ALSO
AFFECT A TREATMENT BASED ON A
SPECIFIC TIME AND THIS IS AN
IMPLANTABLE DEVICE RIGHT NOW.
SO I WANT TO END BY SAYING THAT
WE HAVE MANY WAYS IN WHICH WE
CAN USE SLEEP AND CIRCADIAN
PRINCIPLES AND APPROACHES TO
AFFECT MULTIPLE OUTCOMES WHERE
THEY WERE LOOKING AT
NEUROLOGICAL CARDIOVASCULAR,
POPULATION HEALTH, SURGICAL
CRITICAL CARE, STUDIES ARE
ONGOING AND ALMOST ALL OF THESE
AREAS, SO THIS FIELD IS REALLY
GROWING BEYOND, INCLUDING BUT
BEYOND JUST SLEEP AND WAKE
REGULATION.
AND WAWHAT REALLY EXCITES ME A
LOT IS THAT WE CAN AMRI THE
CIRCADIAN AND SLEEP SCIENCE TO
PUBLIC HEALTH, NOT JUST TO MY
CLINIC BUT ALSO TO PUBLIC HEALTH
AND MEDICINE TO ADDRESS HEALTH
DISPARITIES.
I JUST WANT TO SHOW YOU THIS.
THIS IS FROM THE CDC THIS, IS A
PUBLICATION WE DID A FEW--LAST
YEAR IN LANCET PUBLIC HEALTH.
THIS IS INSUFFICIENT SLEEP, THIS
IS THE AREAS IN OUR COUNTRY OF
INSUFFICIENT SLEEP, SAME LOOK OF
POOR GENERAL HEALTH, POOR MENTAL
HEALTH, POOR BRAIN HEALTH,
OBESITY AND HYPERTENSION.
SO I THINK THIS IS AN
OPPORTUNITY ALSO TO THINK ABOUT
REGIONS WHERE THERE IS BOTH
HEALTH DISPARITY AND HOW CAN WE
USE SLEEP AS SLEEP INSUFFICIENCY
AS 1 OF THESE HEALTH
DISPARITIES, SO I WANT TO THANK
THOSE OF YOU WHO ARE HERE AND
THOSE OF YOU ONLINE FOR
LISTENING TO ME AND ALSO THANK
YOU, THE NIH, FOR MANYIERS OF
FUNDING AND CONTINUOUS FUNDING
FOR THE WORK THAT WE AND MANY
OTHERS IN OUR FIELD DO AS WELL
AS TO THOSE WHO I--WHOSE WORK I
ACTUALLY MENTIONED HERE, YOU SEE
THEIR PICTURES AND REALLY A
GREAT TEAM OF COLLABORATORS
ACROSS NORTHWESTERN AND ALSO
ACROSS THE COUNTRY.
SO THANK YOU AGAIN.
>> I WOULD LIKE TO GET IN A
COUPLE QUESTIONS.
IS THERE ANYTHING, ANYBODY HERE,
PLEASE USE THE MICs, I CAN
HAVE 1 TO GET STARTED.
WHY IS THE CIRCADIAN CYCLE 24.2
HOURS, WHEN THE DAY IS 24 HOURS?
ALSO, HOW DOES THE CYCLE APPLY
TO HUMAN WHO IS HAVE LIVED FOR
THOUSANDS OF YEARS IN ARCTIC
REGIONS WHERE THE DAY-NIGHT
CYCLE VARIES RADICALLY?
>> IT'S NOT ALWAYS, I MEAN
HUMANS, YOU KNOW WE THINK IT'S
ABOUT 24.17 HOURS BUT IN ANIMALS
IT CAN BE SHORTER, THEY CAN BE A
LITTLE BIT LONGER, OFTEN BUT
THEN ALSO VERY CLOSE, ALWAYS TO
24 HOURS AND I THINK IT'S
ADAPTATION, RIGHT?
AND THIS IS WHY YOU WANT--THAT'S
WHY YOU NEED THE TIME GIVERS,
YOU NEED THE LIGHT, THE DARK,
THE FEED, ALL THESE THAT TRAIN
YOU TO BE IN SYNCHRONY WITH THE
24 HOUR.
AND WE CAN MESS THIS UP SO
EASILY RIGHT BY EATING AT THE
WRONG TIME, BY HAVING OUR SOCIAL
ACTIVITY, GETTING LIGHT AT
NIGHT, RIGHT?
AND ALL OF THESE THINGS ARE
DECREASING THEIR ABILITY FOR
THAT MOLECULAR SO I THINK FOR
ADAPTATION PURPOSES AND FROM AN
EVOLUTIONARY STANDPOINT.
NAND THE SECOND PART,
DETRIMENTAL EFFECTS LIVING SOME
DAYS IN COMPLETE DARKNESS, THE
ARCTIC REFERENCE ?
>> WELL, EVEN THERE THEY TRY TO
USE VERY SPARINGLY THEIR LIGHTS
BUT THEY DO TRY TO GET THESE
LIGHT-DARK CYCLES EMPLOY YOU
DON'T HAVE TO HAVE LIGHT IN THE
ENTIRE DAY FOR 8 HOURS, YOU
COULD ACTUALLY JUST HAVE IT AT
THE ENDS BECAUSE I DIDN'T HAVE
TIME TO TALK ABOUT HOW THE
CIRCADIAN CLOCKS SYSTEM RESPONDS
TO LIGHT, RIGHT, AT CERTAIN
TIMES OF THE DAY, IT WILL DELAY
THE RHYTHM AND OTHER TIMES OF
THE DAY WHERE IT WILL ADVANCE
ITG IMPEDIMENTS SO THIS IS HOW
WE THINK THE SYNCHRONIZATIONS
ARE OCCURRING IS THAT LIGHT IN
THE MORNING AND ALSO AT DUSK,
LIGHT EMPLOY SO THEY DO BUT IT
IS A PROBLEM, ABSOLUTELY.
IT IS A PROBLEM.
MOOD DISORDERS, I MEAN YOU LOOK
AT THE NORTHERN CLIMATES, RIGHT?
>> THANK YOU VERY MUCH.
COOL TALK.
MY QUESTION IS ABOUT--I HAD A
FEW--I WAS WONDERING ABOUT
PLASTICITY OF THESE TRAITS SO
LIKE WHEN YOU PUT--SOMEONE WHO
GETS--WHO HAS LESS SLEEP THAN I
WOULD LIKE, AS YOU--WHEN
SOMEONE'S CIRCADIAN CLOCK HAS
BEEN PERTURBED BECAUSE OF THEIR
BEHAVIOR, HOW EASY IS IT, IF THE
CENTRAL CLOCKS AND PERIPHERAL
CLOCKS ARE OUT OF WHACK HOW EASY
IS IT TO KIND OF PERTURB THEM
BACK IN SYNCH OR DOES YOUR BODY
ADAPT SPECIAL HOW DOES IT CHANGE
IF YOU AGE?
LIKE IF YOU HAVE HAD YEARS OF--
>> YEAH, FOR MOST PEOPLE IF
THERE'S NOTHING UNDERLYING THAT
THEIR GENETIC CLOCK MAY NOT BE
SO LONG.
I HAVE PATIENT'S WHO CLOCK MAY
BE RUNNING AT 28, OR 26 HOURS
THEY BECOME NON24 HOURS SO THEY
CAN'T EVEN DRAIN TO THE
LIGHT-DARK CYCLE ALTHOUGH
VISUALLY INTACT, THEY'RE NOT
BLIND, RIGHT IN SO IT WILL
DEPEND BUT FOR A USUAL PERSON, I
THINK YOU CAN.
WE DON'T KNOW THAT MANY, MANY
YEARS OF THIS, I DON'T KNOW WHAT
THAT WOULD AFFECT BUT IN GENERAL
WE CAN USE LIGHT, MELATONIN,
TIMING OF MEALS AND EXERCISE.
ALL THESE CAN BE TIME GIVERS FOR
THE CLOCK AND IT'S VERY
IMPORTANT, THE TIMING OF IT, IF
YOU GET THESE THINGS AT THE
WRONG TIME, YOU ACTUALLY CAN DO
THE OPPOSITE OF WHAT YOU REALLY
WANTED TO DO SO MELATONIN CAN
SHIFT YOUR RHYTHM, EITHER MORE
IN THE FORWARD DIRECTION WHEREAS
LIGHT CAN ACTUALLY DO BOTH, SO
TIMING OF THAT IS VERY
ESSENTIAL.
SO CERTAINLY WE CAN MANIPULATE
THE CLOCK >> OKAY, WELL, I HOPE
THIS IS THE RIGHT TIME, JUST
REMINDING EVERYBODY THAT THERE
ARE LIGHT REFRESH AMS OUTSIDE
AND PLEASE JOIN ME IN THANKING
DR. ZEE.
>> THANK YOU.
THANK YOU.
KD--SALLY ARK PLAWZ
[ APPLAUSE ]