Lecture 8- Ageing in the Circadian Clocks

Question 1

Healthspan

Answer 1

Time spent as disease and medication free (chronic)

Question 2

Clock MT mice health problems

Answer 2

obesity, hyperglycaemia and hypoinsulinemia

Question 3

Per2 MT mice health problems

Answer 3

More cancer prone, more susceptible to irradiation, advanced hair greying

Question 4

Bmal1 KO mice health problems

Answer 4

Premature aging, reduced hair growth, decreased subcutaneous fat, reductions in bone mass, sarcopenia, cataracts, shorter lifespan and massively increased mortality rate

Question 5

Chronotype

Answer 5

How early/late you are naturally active

Question 6

Factors affecting chronotype

Answer 6

Age, sex (and disease status)

Question 7

First biomarker of the end of adolescence?

Answer 7

Advance in chronotype

Question 8

Dominance of sleep stages in infants compared to adults and the elderly?

Answer 8

infants: awake>REM~non-REM
adults: awake>non-REM>REM
old: awake>non-REM>REM

NB elderly are awake more intermittently

Question 9

Consequences of sleep pattern changes in the elderly

Answer 9

Advances sleep onset, frequent napping and night awakening, lower quality sleep, daytime sleepiness and fatigue

Question 10

Which 2 processes regulate sleep?

Answer 10

Accumulation and dissipation of sleep debt

Question 11

What closes sleep gate at night?

Answer 11

Homeostasis

Question 12

What regulates the phase of sleep?

Answer 12

The circadian clock (does not regulate duration of sleep)

Question 13

Circadian rhythms in the elderly

Answer 13

Advanced sleep onset, frequent napping and interrupted sleep, core body temp cycles are advanced by ~2 hours and decreased in amplitude, advanced phase of melatonin rhythm, compromised adaptation

Question 14

Biology of ageing:

Answer 14

DNA damage, oxidative stress, cell senescence, epigenetic changes (sirtuins), telomere attrition, genomic instability, metabolic dysfunction, loss of proteostasis, decreased nutrient sensing, stem cell exhaustion, altered IC communication

Question 15

Hayflick’s limit

Answer 15

Number of times a normal (human) cell can divide before division ceases

Question 16

Only lifestyle change proven to slow ageing?

Answer 16

Caloric restriction
Rhesus study showed CR reduces age related diseases by 30%
Okinawa people eat 40% less than americans, have highest % of centenarians and have lower rates of age related disease

Question 17

SIRT1

Answer 17

NAD+ dependent histone deacetylase (HDAC)

epigenetic regulator

Question 18

How is SIRT1 activated?

Answer 18

Caloric restriction, increasing expression of SIRT1 mimics the effects thereof

Question 19

SIRT1 wrt clock transcription

Answer 19

Rhythmic histone acetylation key to clock transcription

Question 20

SIRT1 binds directly to BMAL1…

Answer 20

…to activate transcription, SIRT1 and clock machinery decline rapidly in ageing mice but the effects of this can be slowed with overexpression of SIRT1

Question 21

Animals with high SIRT1…

Answer 21

… increased physiological activity and response to jet lag

Question 22

Animals with low SIRT1

Answer 22

…decreased physiological activity and response to jet lag

Question 23

CLOCK

Answer 23

is a histone acetyltransferase (HAT) which is regulated by SIRT1 (Per2 acetylation) in a feedback loop (CLOCK also regulates SIRT)

clock mediated chromatin remodelling !!!

Question 24

Chrondocytes

Answer 24

Balance catabolic proteolysis and autophagy with synthesis of joint matrix

Question 25

Perturbation of ageing on chrondocytes

Answer 25

Mechanical stress of ageing can shift normal function in favour of catabolism, producing MMPs, Adamts IL1β, TNFα

Question 26

Ageing… (disease risk)

Answer 26

…is the single biggest risk factor for a spectrum of diseases including OA

Question 27

OA (osteoarthritis)

Answer 27

Prevalent, debilitating and painful joint disorder, involving progressive loss of articular cartilage

Question 28

Symptoms of OA show…

Answer 28

daytime variation (manual anxiety, pain, stiffness and swelling)

Question 29

Environmental disruption of clocks in mice…

Answer 29

…can predispose them to OA like changes in the knee joint

Question 30

Chronic jet lag in mice leads to….

Answer 30

…loss of proteoglycan and surface integrity of chrondocytes, depleted immune system

Question 31

Mouse longbone-Per2:luc

Answer 31

as long as tissue is living, chrondocyte clocks are oscillating

Question 32

Bioluminescence of Per2:luc in SCN (over time)…

Answer 32

decreases, but seems to undergo periodic reboots in xiphoid c cartilage

Question 33

Cartilage entrainment

Answer 33

Temperature

Question 34

Rate limiting enzyme of SIRT1

Answer 34

Nampt (circadian clock feedback by Nampt mediated NAD+ synthesis)

Question 35

What percentage of the cartilage transcriptome is under circadian control?

Answer 35

4%

Question 36

Altered clock expression at early stages of OA suggest…

Answer 36

…potential involvement in disease initiation

Question 37

CLOCK and BMAL1 wrt DBP and chromatin

Answer 37

Rhythmic Bmal1 and Clock function drive circadian Dbp transitions and chromatin remodelling