lecture 9 Flashcards
(11 cards)
Describe how calorie reduction extends life
Rat fed with a diet containing lower calories, but same level of essential nutrients live longer
Chronic high calorie intake is a risk factor in CVD, cancers, type-2 diabetes and stroke
Importantly, calorie restriction also improves health in old age:
Less cancer, neurodegeneration, arthritis etc. AND of course less obesity linked disease
It has been known for a while that calorie reduction increases lifespan. 10% calorie restriction increases a rat’s lifespan by 20%, and this can be increased significantly by further calorie restriction.This calorie restriction is not to the point of malnutrition, which also reduces life - need to find the balance between not eating enough and eating too much. The problem is not what we eat, it’s the fact that we are always eating…
Describe how Fasting and Energy Restriction Regulates Many Metabolite -controlled longevity pathways
Reduced energy consumption increased resilience, metabolic homeostasis, tissue repair and organismal function
Improvements in these areas can act as direct modifiers of the four domains of the ageing phenotype:
Body composition
Balance between energy availability and energy demand
Signaling networks that maintain homeostasis
neurodegeneration
What are circadian rhythms?
Intrinsic circadian clock driven mechanisms can turn physiological behavioral responses on/off before tissue need.
Controlled by the suprachiasmatic nucleus
What are biological clocks?
The suprachiasmatic nucleus in the hypothalamus serves as the brain’s “master clock”
SCN Synchronizes physiological processes with the day-night cycle by photo-entrainment.
Light can reset the biological clock/SCN. Light is a Zeitgeber
The SAN is in the hypothalamus of the brain and is controlled by light, and so light can reset the biological clock. Light controls the SAN, which controls the central pacemaker, which in turn controls the endocrine and peripheral nervous systems, which then gives rise to rest-active cycles and regulates body temperature. This all then in turn then regulates the peripheral tissues.
What regulates the SCN?
Light is strongest regulator Sleep occurs with circadian (circa daily) periodicity, which persists under constant conditions When light is removed (i.e. in a cave), the sleep/wake cycles are still present but not controlled by day and night. When light is returned, this circadian rhythm resyncs.
What is the circadian rhythm’s molecular clock?
A Transcription-Translation feedback loop
Clock/Bmal1 induce transcription of Per (period) and Cry (cryptochrome) genes via E-box elements.
Per and Cry proteins are translated, associate and diffuse back into nucleus inhibiting Clock/Bmal1 to prevent their own transcription. During the night Per and Cry proteins are degraded, allowing Clock/Bmal1 to transcribe again.
Two genes associated with each other, Clock and Bmal1, can regulate the transcription of other genes - cause transcription of Period and Cryptochrome. Per and Cry then dimerise and during the day return to the nucleus to inhibit the binding of Clock and Bmal1. During the night, this means that Per and Cry are degraded, and so Clock and Bmal1 to transcribe them again.
A feedback loop where there is Cry and Per transcription during the night but this transcription causes Cry and Per to then inhibit their own transcription in the day - this gives circadian rhythms.
What is circadian metabolism?
Activity of different enzymes peaks at different times of day/night
Insulin secretion peaks during day time; enzymes, e.g. trypsin, peak during night time
Jejunal motility peaks during day time
The pancreas secretes insulin during the day and trypsin at night. At around 6pm, the pancreas stops secreting insulin - this is why you shouldn’t eat late into the night, as insulin is not being secreted and excess calories are converted into fat. Similarly, the liver breaks down all the food during the day and again has reduced activity in the evening. Gastric emptying occurs in the morning, but the bowels aren’t active at night.
Explain how There is synchronization between the circadian rhythm and feeding
Essentially there is a link between the circadian clock and food (though light is a stronger regulator)
Feed-fasting programmes show strong respiratory circadian patterns
Another regulator of circadian rhythms (Bmal1 and Clock) is fasting and feeding - when you are hungry and eat something, NADPH is converted into NADP+ which causes a change from anabolic to catabolic processes which activates Sirt1 etc.Don’t really need to know the details of this, just know that there is a link between the circadian rhythm and food, although light is a stronger regulator.Ad libitum = can eat whatever you want.Calorie reduction leads to acute increases in metabolic rate when there is calorie restriction according to the day and night cycles - i.e. only eating during the day. Eating during the night as well as the day removes the efficiency of respiration, and those who are more efficient at respiration live longer.
RER= Respiratory Exchange RatioIf you undergo starvation, then AMPK is activated by a high AMP to ATP ratio, which in turn phosphorylates and inhibits mTOR. mTOR is the inhibitor of autophagy, and so if you inhibit mTOR then autophagy increases.During the night, we shift from anabolism to catabolism, and so ideally we see an increase in autophagy…
Describe how TFEB regulates Autophagy Gene Expression in a food-dependent Rhythmical manner
In peripheral tissues, starvation induces TFEB (and TFE3) to translocate to the nucleus
Transcription of autophagy genes
Also transcription of REV-ERB[alpha]
REV-ERB[alpha] represses autophagy gene expression. A feedback loop
Ad libitum eating represses circadian rhythms and reduces autophagy efficiency. Reduces longevity and promotes ageing.
TFEB regulates lysosome and autophagy gene transcription is also controlled by feeding, with a food-dependent circadian rhythm. Under starvation, TFEB is no longer phosphorylated and goes to the nucleus to make more lysosomal and autophagy proteins. It also transcribes REV-ERB-alpha, which in turn binds to the same regions required for transcription by TFEB to inhibit its activity.Therefore when there is an induction of autophagy, REV-ERB-alpha is transcribed and can go on to reduce autophagy - cyclic circadian rhythm with autophagy in a food-dependent manner.Constant eating represses the circadian rhythms, causing a flatline of autophagy - reduction in autophagy efficiency means you don’t have cellular clearance and rejuvenation, decreasing longevity.Note: TFE3 is another transcription factor which does very similar things as TFEB.
Explain how The Hepatic Clock is Regulated by the Gut-Microbiome
The gut can contain up to 2kg of bacteria
Recent studies have shown that gut bacteria can be considered as an ‘organ’ signaling to the brain
Gut bacteria have been linked to depression, insomnia and obesity
Bacteria diversity (from a varied/high fibre diet) is being promoted as key to longevity
The Hepatic clock and metabolism is regulated by diet-dependent gut-microbiome and light-dependent SCN.
There are 2kg of bacteria in our intestines, and recent studies have suggested that these bacteria can be considered an organ which signals to the brain. A highly complex level of bacteria in the gut is meant to be beneficial for health.All the bacteria in the gut produce small metabolites which can signal to the brain. This can deregulate the circadian rhythm.
Gut microbiota exhibit diurnal oscillations in composition and metabolite production that are driven by diet and are associated with the host circadian rhythm
Diurnal variations in gut microbes are driven by dietary and host cues
High fat diets disrupt gut microbe patterns
Microbial metabolite oscillations link to host circadian rhythms and metabolism
Distubances of host-microbe circadian networks may promote diet-induced obesity
If you take a rodent and remove its gut microbes, you can then feed this animal both a low fat or high fat diet as no bacteria will signal to the brain and the circadian rhythm and autophagic response is normal - the rodent is lean.In normal rodents, if you feed them a low fat diet then microbial oscillations and normal microbial signals will mean the circadian rhythm and autophagic response is normal - the rodent is lean.In normal rodents, if you feed them a high fat diet then the diversity of the microbiome is shifted and reduced. This means they have limited production of metabolites and reduced microbial oscillations. This leads to disruption of the circadian rhythm, meaning the acute response to food and increase in autophagy at night is lost, more ROSs etc. This leads to obese mice.Based on this it is not what you eat, its when you eat.
