Age-related changes in circadian factors and light interventions in healthy and pathological human ageing
Debra J. SKENE
Chronobiology University of Surrey, Guildford, UK
[email protected] Metabolomics
• better understanding of circadian and sleep/wake regulation of metabolism
• Powerful tool to elucidate mechanisms linking sleep restriction, circadian misalignment and metabolic disturbances - peripheral clock phase/function during circadian misalignment - biomarkers to track sleep and circadian disruption; and monitor recovery Age-related changes in circadian factors and light interventions in healthy and pathological human ageing
Debra J. SKENE
Chronobiology University of Surrey, Guildford, UK
[email protected] 2 process model
Borbély, A. A.Hum.Neurobiol., 1982 Daan, S., Beersma, D. G. M. and Borbély, A.A. Am. J.Physiol., 1984 Human circadian timing system
Human circadian timing system Circadian rhythms Effect of ageing
Treatment strategies - melatonin, light - in ageing Challenges Circadian rhythms and ageing research?
Only measure clock outputs (eg melatonin, rest/activity) Confounded – field studies
Cross-sectional, rarely longitudinal Older people - medication/mobility issues Participant numbers 7 care homes in south-east England
Total number of residents = 256
Suitable = 131 Not suitable = 125 (51%) (49%)
No = 51 Yes = 80 (39%) (61%)
Wearing AWL = 73 In analysis = 48 (91%) (66%)
Hopkins, S. et al. Current Alz. Res 2017 Not a homogenous group n = 80 Mobility Fully mobile 20% Walking stick 11% Walking frame 16% Wheelchair 53%
MMSE score 27 – 30, no impairment 13% 21 – 26, mild 26% 11 – 20, moderate 53% 0 – 10, severe 8%
8 registered blind (2NLP; 6 LP) Hopkins, S. et al. Current Alz. Res 2017 24h activity profiles (7 days) (A) (B)
(C) (D)
(E)
Hourly activity counts mean ± SEM A + C = fully mobile B + D = wheelchair E = walking frame
Hopkins, S. et al. Current Alz. Res 2017 Challenges Circadian rhythms and ageing research?
Only measure clock outputs (eg melatonin, rest/activity) Confounded – field studies The suprachiasmatic nuclei (SCN) of the hypothalamus
Site of circadian oscillator
Courtesy of Dr Michael Hastings The Clock in the Brain
Hz A5
2
0 B7b
4
0 D1
3
0 G3b
4
0 24 48 72 Time (hours) Welsh, Logothetis, Meister & Reppert, Nature 1995
Courtesy of Till Roenneberg Retina-SCN-PVN-SCG-pineal pathway
Stehle, J.H., et al. 2011
SCN rhythmicity drives melatonin rhythm Entrained to 24 h by light/dark via the retina-RHT pathway (Retina)-SCN-PVN-HPA axis
Courtesy of Andries Kalsbeek (Retina)-SCN-PVN-ANS
Courtesy of Andries Kalsbeek SCN-driven melatonin and cortisol rhythms in constant routine conditions
males n = 14
Gunn et al., 2016 Confounders • Light/dark cycle • Sleep/wake cycle • Activity/exercise • Drugs • Food • Posture • Stress • Menstrual cycle? Challenges in measurement
Diurnal versus circadian rhythms
Diurnal – exogenous and endogenous Rhythms may be influenced, or even driven, by environmental cycles
Circadian – endogenous Rhythms driven by endogenous timing mechanisms (“clocks”) persist in constant conditions Early “Clock” Experiments
DAYTIME NIGHT TIME Leaves are open Leaves are closed
Mimosa pudica
de Marian, 1729 Diurnal versus circadian rhythms the constant routine protocol
• Designed to remove/minimise effects of external environment and behaviour (e.g. sleep)
• No knowledge of clock time • Constant dim light • Semi-recumbent posture • Minimal social interaction • Regular (e.g. hourly) small isocaloric snacks Human circadian rhythms - endogenously generated persist in constant conditions
• Melatonin • Cortisol • Rectal temperature • Activity • Sleep • Mood • Performance Circadian rhythms melatonin
core body temp
subjective alertness
task performance
triacylglycerol
Rajaratnam &Arendt 2001 Constant routine protocol versus entrained diurnal sleep/wake
Czeisler & Klerman 1999 Recent Prog Horm Res 54:97-132 Melatonin as a reliable marker of circadian phase
• unaffected by: meals, stress, bathing, sleep
• dim light conditions (< 8 lux) • exclude drugs • control posture, exercise Markers of the melatonin rhythm used to characterise the timing of the circadian clock
80 duration
70 ) l m / 60 g
p acrophase (calculated peak time) (
* 50 n i n o t 40 a l e
m 30 mid-range crossing a * * m 20 s
a 25% rise/fall l p 10 * * onset/offset * * 0 1500 1700 1900 2100 2300 100 300 500 700 900 1100 1300 1500 1700 clock time (h)
‘biological night’
Arendt & Skene, Sleep Medicine Reviews (2005) 9:25-39 Benloucif et al., 2007 SCN extra-SCN brain oscillators peripheral clocks
• synchrony between different internal rhythms • synchrony between internal rhythms and external cycles e.g. for diurnal animals: sleep at night, visual function and metabolic responses optimal in the day Diagnosis Measures used to assess - human circadian timing system
- SCN-driven rhythms (melatonin, cortisol)
- Markers of peripheral clocks? Human peripheral clocks
• Buccal tissue (Cajochen et al., 2006) • Blood cells (Archer et al., 2008; O’Neill and Reddy, 2011; Ackermann et al., 2013) • Skin fibroblasts (Brown et al., 2005; 2008) • Hair follicles (Akashi et al., 2010) • Adipose tissue (Otway et al., 2011) • Skeletal muscle (van Moorsel et al., 2016) SCN extra-SCN brain oscillators peripheral clocks
Markers of human peripheral clocks? Plasma metabolome Blood cells, buccal tissue, skin fibroblasts, hair follicles, adipose tissue, muscle Skene et al., PNAS, 2018 Effects of Prior Simulated Shift Work on Metabolite Rhythms (Examples)
Sphingolipid SM C20:2
24/27 (89%) had significantly shifted (reversed) rhythms
Skene et al., PNAS, 2018 Conclusions
• Rhythms in most metabolites dissociated from the SCN pacemaker rhythm
• Vast majority aligning with the preceding sleep/wake and feeding/fasting cycles
• Metabolic profiling (metabolomics) in plasma may provide a window onto peripheral clocks and the biobehavioral factors orchestrating them
Skene et al., PNAS, 2018 Pathways of peripheral clock entrainment
From Mohawk et al. Annu. Rev. Neurosci. 2012 Human circadian timing system
Human circadian timing system Circadian rhythms Effect of ageing Possible causes of age-related changes in circadian system Possible causes of age-related changes in circadian system
Output pathway
RHT Pineal SCN PVN SCG Gland Input pathway cortisol
temperature sleep/wake melatonin ? ? ? ? Output pathway
RHT Pineal SCN PVN SCG Gland Input pathway cortisol
temperature sleep/wake melatonin Possible causes of age-related changes in circadian system 1. Clock disturbance
2. Entrainment abnormalities
3. Insufficient zeitgebers (time cues) Biological rhythms
Period Phase
Amplitude
Circadian Terminology T 21 ) l m /
g 18 p ( s l 15 e v e L 12 Amplitude n i n o t 9 a
l Mean e
M Mesor 6 y r phase angle a v i l 3 bedtime a S 0 12 16 20 24 4 8 12 16 20 24 4 8 12 Clock Hour Courtesy Ken Wright Age-related changes
1. Amplitude 2. Period 3. Phase 4. Phase angle of entrainment 5. Response to light
Phase angle of entrainment = phase relationship between a circadian rhythm and the environmental signal entraining the rhythm (e.g. light-dark cycle; sleep onset) Duffy et al., Sleep Med. Clin. , 2016 Possible causes of age-related changes in circadian system 1. Clock disturbance Output pathway
RHT Pineal SCN PVN SCG Gland Input pathway cortisol
temperature sleep/wake melatonin
Reduced amplitude 1. Clock disturbance
Human SCN - reduced number of vasopressin neurons - reduced amplitude of rhythm
- alterations in the neural and temporal organization of the SCN
Hofman and Swaab, 1988; review 2006 Hofman and Swaab, 1988; review 2006 Age-related changes in melatonin
- reduced melatonin amplitude Plasma melatonin
Waldhauser et al., 1988 Urinary 6-sulphatoxymelatonin (aMT6s)
Bojkowski and Arendt, 1990 Pre- and postmenopausal women (n=160)
Skene et al., 1990 Pineal melatonin - human postmortem tissue
Skene et al., 1990 Melatonin in CSF
Liu et al., 1999 Possible causes of age-related changes in circadian system
Output pathway
RHT Pineal SCN PVN SCG Gland Input pathway cortisol
temperature sleep/wake melatonin
Concretions, reduced sympathetic innervation, -receptor changes, reduced NAT Age-related changes in melatonin
- reduced melatonin production/amplitude most studies (diurnal, entrained) Constant routine study
65+ Elderly- disease and drug free Dim light, semi-recumbent, sleep deprived, isocaloric meals
Zeitzer et al., 1999 Possible causes of age-related changes in circadian system 1. Clock disturbance
2. Entrainment abnormalities Output pathway
RHT Pineal SCN PVN SCG Gland Input pathway cortisol
temperature sleep/wake melatonin
Reduced amplitude Phase advance of circadian rhythms Age-related change in circadian period?
Explain phase advance of circadian rhythms i.e shorter period as age? Human circadian period () Forced desynchrony n = 11 young Sighted n = 13 old
= 24.18 0.02 h
Czeisler et al., Science, 1999 aMT6s Period and Age
Totally blind 25 24.9 Real life 24.8 24.7 24.6 aMT6s 24.5 tau (h) 24.4 24.3 24.2 24.1 r = -0.02 24 n = 23 23.9 0 10 20 30 40 50 60 70 80 Age (yrs) Skene et al., unpublished Age-related changes in melatonin
1. decreased melatonin production - decline in amplitude
2. phase advance of melatonin rhythm
Earlier aMT6s peak time with ageing 7 D
S 6
n a
e 5 m e s 4 a h p o r 3 c a s 6
T 2 M a 1
0 16-20 21-30 31-40 41-50 51-60 61-70 71-81 16-81 years
18 83 18 13 4 136 n English et al., unpublished Older compared to young adults
Earlier wrt clock time
Later wrt to biological time i.e. sleep/darkness
solid line - older group Duffy et al., Sleep Med. Clin. , 2016 Possible causes of age-related changes in circadian system 1. Clock disturbance
2. Entrainment abnormalities Output pathway
RHT Pineal SCN PVN SCG Gland Input pathway cortisol
temperature sleep/wake melatonin
Age-related changes in the eye Age-related changes in the eye
pupil size S-cones melanopsin RCGs
lens transmission
Adapted from Weale, 1988 Age-related changes in the eye increased lens density reduced transmission of light
25 years 47 years 60 years
70 years 82 years 91 years
Lerman, 1980 Age-related changes in the lens reduce transmittance of short wavelength blue light
2.5 20 yrs 60 yrs y t i 80 yrs s 1.5 n e D
l a c i t
p 0.5 O
-0.5 380 420 460 500 540 580 620 660 Wavelength (nm)
Average spectral density of the lens (adapted from Pokorny et al., 1987) Spectral sensitivity?
Arendt, 1995 Spectral sensitivity of light-induced melatonin suppression
Suppression by short wavelength light
2 140 o 424 nm 16 W/cm n n ) l n m 120 n 2 /
g O 472 nm 36 W/cm O p O n O ( o o 100 O
n o o i
n O n n
o 80 t n Oo
a no Oo l
e o 60 m o a O O m 40 s a l
P 20
0 23:00 23:30 0:00 0:30 1:00 1:30 2:00 Clock time (hours)
Thapan, Arendt & Skene, J Physiol, 535, 261-67, 2001 Melatonin suppression as a function of wavelength and irradiance
70 t t £ t l
) £
% 60 uu ( n £ n t u o nl i 50
s l u£ l s n 424 nm e r 40 l 456 nm p p n l 472 nm u l
s u
30 496 nm
n i £ £ 520 nm n n o 20 t t l 548 nm a u l l t
e t 10 n M £ £ l £ 0 1E+11 1E+12 1E+13 1E+14 1E+15 5E+15 Photons/cm2/sec Thapan, Arendt & Skene, J Physiol, 535, 261-267, 2001 Age-related changes in the eye
Effect on non-visual light responses? Light-induced melatonin suppression
max 456 nm max 548 nm Hypotheses 1. A significantly reduced response to the short wavelength light (456 nm) in the older group
2. No difference between age groups in response to medium wavelength light (548 nm)
2.5 20 yrs 60 yrs y
t 80 yrs i s n
e 1.5 D
l a c i t
p 0.5 O
- 0.5 380 420 460 500 540 580 620 660 Wavelength (nm)
Average spectral density of the lens (adapted from Pokorny et al., 1987) Age-related changes in short wavelength blue light sensitivity
Reduced responsiveness in the elderly
Exp Gerontol 40, 237-242, 2005 Increased alertness in young during and after blue (456 nm) light
more 5 young ) s e
alert s n 4 (n = 11) i e l e n t s 3 r a e b l 2 a o
t
e
d 1 v i e t s i c l 0 e a j m b older more r -1 u o S sleep n (n = 15) ( -2 y 0 1 2 3 4 5 6 7 Time from start of light (h)
Time: F = 4.68, p < 0.0001 Sletten et al., J. Biol. Rhythms, 2009 Age: F = 35.76, p < 0.0001 No effect of age on alertness during and after green (548 nm) light
young (n = 11) more 5 ) older (n = 10) s e
alert s n 4 i e l e n t s 3 r a e b l 2 a o
t
e d
v 1 e i t s i c l 0 a e j m b more r -1 u o S sleep n y ( -2 0 1 2 3 4 5 6 7 Time from start of light (h)
Sletten et al., J. Biol. Rhythms, 2009 Time: F = 4.84, p < 0.0001 Conclusions AGEING • Acute responses to blue light are impaired - melatonin suppression, alerting effect
• Phase advancing effects of blue light retained
• Acute and phase shifting responses: Differentially affected by age? - Different photopigment contribution? - Different melanopsin RGCs (M1 and M2)?
Herljevic et al., 2005; Ackermann et al., 2009; Jud et al., 2009; Sletten et al., 2009
Age-related changes
1. Amplitude reduced 2. Period shorter (faster)? No 3. Phase earlier clock time 4. Phase angle of sleep at earlier biological entrainment time 5. Response to light reduced acute effects phase shifting effects?
Duffy et al., Sleep Med. Clin. , 2016 Possible causes of age-related changes in circadian system 1. Clock disturbance
2. Entrainment abnormalities
3. Insufficient zeitgebers ocular light, ↓ melatonin signalling Output pathway
RHT Pineal SCN PVN SCG Gland Input pathway cortisol
temperature sleep/wake melatonin
LIGHT MELATONIN Chronotherapy to hasten adaptation LIGHT MELATONIN
Phase shift circadian rhythms Light Melatonin
• shifts circadian rhythms sleep timing melatonin temperature cortisol Management/Treatment of Circadian Rhythm Sleep-wake Disorders Light Melatonin supplementation Increase zeitgeber strength
Increase circadian amplitude Why light supplementation
for older people? Age-related ocular changes Reduced sensitivity to blue light** Reduced environmental light exposure - reduced mobility - homes poorly lit
Older people require 3-5 times more light
**Herljevic et al., 2005; Jud et al., 2009; Sletten et al., 2009 Optimisation of lighting for the elderly
increase blue light content
increase longer wavelengths - enhance any M- and L-cone input - melanopsin photoreversal
Revell and Skene, 2009 Why light supplementation
for older people? Light treatment shown some benefits - older demented patients Van Someren et al., 1997; Fetveit et al., 2003; Riemersma-van der Lek et al., 2008
Blue-enriched 17000 K lights - office workers; living environments Francis et al., 2008; Viola et al., 2008; van Hoof et al., 2008; Vetter et al., 2011 Spectral composition Blue-enriched white light Control white light high colour temperature low colour temperature 17000 K 4000 K
300 n l
a o 200 i r t t 17000 K lights u c b e i p r t s 4000 K lights
s 100 i e d v i r t e a l w e
o 0 R
p 400 450 500 550 600 650 700
-100 Wavelength (nm) Field studies
Effect of blue-enriched and control white light on sleep quality and daytime alertness in older people?
- in the community
- in care homes
EU FP6 Marie Curie RTN ESRC New Dynamics of Ageing/Philips Lighting Community study - skeleton photoperiods
Baseline week 1
week 2 Light exposure week A or B 3 week 4
week Washout period 5 week 6
week 7 Light exposure week 8 A or B week 9
week Washout period 10 week 11
light exposure A or B Field studies
Effect of blue-enriched and control white light on sleep quality and daytime alertness in older people?
- in the community
- in care homes
EU FP6 Marie Curie RTN ESRC New Dynamics of Ageing/Philips Lighting Care home study - protocol 12-week study, randomised, crossover design September - April in 2008/2009 and 2009/2010 Weeks
1 2 3 4 5 6 7 8 9 10 11 12
Weeks
1 2 3 4 5 6 7 8 9 10 11 12
wash out base line 4000 K light period care home 17000 K light ~ 200 care home lights ~ 900 lux lux lights ~ 60 lux ~ 60 lux Aims • To increase light levels and light exposure in older people
• To test if increasing light levels will affect sleep, activity, alertness and mood
Hypothesis high intensity blue-enriched (17000 K, 900 lux) > control (4000 K, 200 lux) Care room original light conditions
Dimly lit, not uniform 59 ± 52 lux (mean ± SD, n = 20 rooms)
Indoor lighting measured weekly (lux meter), after sunset In direction of gaze (vertical plane) Supplementing light in care homes
Care home #1, 4000 K lights Care home #8, 17000 K light More uniform, higher light levels
4000 K 195 ± 31 lux17000 K894 ± 129 lux Care home 59 ± 52 lux Hopkins, S. et al. Current Alz. Res 2017 24 hour light profiles
17000 K vs washout 1500 1700017k K WO
l Washout e 1000 n v a e l e
x M u l 500
0 0 4 8 12 16 20 24 Time (Hours)
4000 K vs washout 1500 WO 40004K K l
e 1000 Washout n v a e l e
x M u l 500
0 0 4 8 12 16 20 24 Time (Hours) Conclusions Blue-enriched light supplementation - well tolerated - positive effects reduced anxiety increased daytime activity advanced activity rhythm - negative effects increased night-time activity reduced sleep efficiency reduced sleep quality
Hopkins, S. et al. Current Alz. Res 2017 Using Light: Challenges Controlled laboratory studies practical real life situations?
Need more large, randomised, placebo controlled studies for light optimisation
Adapt to specific subjects groups e.g. older people (shiftworkers etc)
Caution with high intensity “activating” blue-enriched light Melatonin • shifts circadian rhythms sleep timing melatonin temperature • acute effects lowers temperature lowers alertness, transient sleepiness improves sleep (mood, performance) Acute effects of 5mg melatonin Core body temperature 37.2
37 Rectal Temperature 36.8 ( C) 36.6
36.4 Alertness 10010036.2
80 Placebo Subjective Melatonin Alertness 60 (%) 40
20 17:00 19:00 21:00 23:00 01:00 Meal Time (h) Deacon et al., 1994 Melatonin as a “sleep aid” • Not a classical sedative hypnotic Reduces sleep latency Increases total sleep time? Reduces night awakenings?
• Older adults with sleep problems • (Children with neurodevelopmental disorders autism, ADHD) reducing sleep onset latency in primary insomnia (p = 0.002) in delayed sleep phase syndrome (p < 0.0001) regulating the sleep-wake patterns in blind patients compared with placebo.
Auld et al., Sleep Med Rev. 2017 Melatonin receptor agonists
Valdoxan ® Takeda
Servier Sleep-onset insomnia Major depressive disorder TASIMELTEON – HETLIOZ® Selective MT1/MT2 agonist FDA approved for non-24 h S/W disorder
melatonin Vanda Pharmaceuticals Acknowledgements
LIGHT Benita Middleton Kavita Thapan Lloyd Morgan Victoria Revell Samantha Hopkins Mirela Herljevic Daniel Barrett Tracey Sletten Katrin Ackermann Helen Thorne Katharina Lederle Shelagh Hampton MELATONIN FOOD Steven Lockley Sophie Wehrens Lisa Hack Cheryl Isherwood Josephine Arendt Skevoulla Christou Simon Archer Michelle Gibbs Jonathan Johnston Acknowledgements Current and recent funding EU Marie Curie RTN EU FP6 IP
ESRC New Dynamics of Ageing
STOCKGRAND LTD STOCKGRAND LTD
Past funding BHF, EU Biomed, EU FP5, MRC, Pfizer, Servier R & D, Wellcome Trust
k you Than [email protected]
@debrajskene References - Reviews References - Reviews References - Reviews