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David Rollo

nd February 2 , 2012 One question per courseware reading; longer ones will have 2 questions per reading. Framework for physiology synthesis: The first framework was body size (virtually all physiology scales with body size). A lot of synthetic power with the science of allometry. Not a common framework but a powerful one There are fundamental regulatory systems (mechanisms of heterodimers, oxidative modification of cysteine residues, various kinds of transcriptional controls, etc). What we’re doing now is putting those mechanisms into another large framework which will give us a perspective that many people do not have. This will be the main model for regulatory organization particularly in eukaryotes. There are 3 different temporal windows or phases across the 24 hour day. There is an internal clock that is fairly accurate. Your body inherently knows what time it is. That is a fundamental underpinning of what your body is doing. Niche interfacing is another task that your body has (ecology). A lot of physio reflects the problems the organism has in its environment. In later sleep, the preparedness systems that anticipate a huge surge in blood P, free radicals and heartbeat and exercise (early in the day) associated with oxidative stress. Your antioxidants are all charged up, and your detoxification systems are all charged up. I.e. if you’re eating plants with toxins, you would need your detox systems. Many DNA repair systems have specific windows of activity (e.g. excision repair) to ensure that DNA is not exposed to oxidation. These processes are usually done in reducing conditions. Typically when we look at rats and mice, most of the DNA repair systems happen in their late sleep phase. This is the most reduced phase of their daily physiology. The circadian rhythm of DNA repair. There is a transition to black (because mice are sleeping in the blue part. The repair system comes up right to the end of their sleep period). The other DNA repair systems in rats look very similar. Circadian Oscillation (Kang T et al) Some of the genes mentioned on the axis of this slide are clock genes. The liver is an important system for sleeping; makes mostly glucose (gluconeogenesis). This is made by the liver and has circadian rhythms; it is upregulated as part of the preparedness systems in the late sleep phase. Some of these sugars in various species can be protective. If you look at the physiology of other types of animals and plants, you see the production of trehalose (blood sugar disaccharide used by insects). Because it is a disaccharide, it has less osmotic pressure on insect blood, and they can pack a lot of E into their hemolith without upsetting their water balance. However, it is also a great antioxidant. Many other organisms manufacture trehalose as a stress sugar or a defensive mechanism. These circadian patterns are metabolic cycles and real progress is being made with yeast. In yeast, you can synchronize the cell culture and measure the dissolved O in 2he cell culture which means the yeast are respiring more when there is less O . 2Shows a picture of metabalome data). Dissolved oxygen shows a really nice cycle. Because of the redox aspect of these cycles, there are a bunch of redox pairs. There are a bunch of redox pairs that are good bioindicators of where the system is in terms of redox. The glutathione system produces reduced glutathione which is the main cellular antioxidant, but another one is the NADPH redox couple, which is fundamental to these redox systems. It turns out to be very tightly linked to the regulation of the clock. These NADPH systems are part of the regulatory systems for clocks. On the far left side we have the NADPH labeled; we can see by the green measurements associated with the blue which is the oxygen, we can see the tight correlation and linkage between the oxidative metabalome redox indicators and the redox cycles in the yeast. We can see the same thing in the circadian rhythm of a vertebrate mammal. There is a tight linkage of the redox states (respiration states) to oxygen consumption and ATP production and oxidative redox troubles. The growth hormone signaling axis is using an NADPH oxidase to run its signaling pathway; needs to generate free radicals using that system. Oxidizing NADPH using the oxidase The fact that the AA are highly correlated with TOR (target of rapamcyin) activity is not a surprise. TOR is the intracellular mediator of the growth hormone axis signalling. It is involved in the protein translation, production, cell cycle growth process in the body. The fact that the AA is highly correlated with TOR activity should not be a surprise. TOR activity is very highly associated with early sleep - It is happening at a very narrow time window which puts it into an interesting context. Just to decide on the target of rapamycin. Rapamycin is an anti-fungal agent produced by bacteria; it is an anti-immune material that inhibits TOR (target of rapamycin). It is used to prevent tissue rejection. You can use rapamycin to suppress TOR, which extends the longevity of mice at old age by 10% (2009). Rollo’s group found an 11% increase in longevity with mice using a diet supplement. Some Redox Couples: How these things are linked together: The NADPH couple is central to almost everything else. The NADP is used for signaling to the sirtuins, FOXO and caloric restriction responses. The FOXO expression looks like it’s in late sleep (reducing conditions); it is a TF that translocates into the nucleus under reducing conditions, and activates the stress responses (basically the same thing as the longevity assurance system). It is looking like stress responses are basically anti aging responses. It is trigged by NADPH. The sirtuin is a deacetylase that closes up certain kinds of DNA. It is closely associated with the dietary restriction response as well. Red wine contains flavonoids. If you drink enough red wine, you can turn on these dietary restriction responses which would allow you to eat 40% less calories than you do presently. These things are linked to NADPH oxidases. The mitochondrial free radical production and ATP production are linked into this circuit. Sometimes, we just use acronyms because the names are too long (e.g. TOR and FOXO). If you have a lot of oxidative damage, this thing can actually eat up the equivalent of NADP and the cell can go into dysregulation, partly because of this overconsumption of the acute redox system.* These systems are also intimately involved in production of neurotransmitters (e.g. dopamine, tryptophan). The dopamine system in humans is very complex. It is simpler in insects where the dopamine system is their main activating neurotransmitter. It is very strongly associated with controlling system. Another linkage to sleeping & the clock through redox cycles. There are interlinkages that we may not expect. If we want to go on and understand regulation, we are going to talk about the systems that are fundamental to the major endocrine hormones within a circadian framework. Fundamentally, we want to think about: How do these things evolve, how are they controlled, are they interregulated? We will not be looking at a homeostatic framework. We will look at a bigger framework involving multiple control systems. The clock is a fundamental component of how vertebrates work. Just above the pituitary, we have a small microprocessor (that divvies up all the time and resources). ) called the hypothalamus (integrates all the signals that come in from the periphery). Once you’re pregnant, the fetus runs the show. Interesting example of regulation. That’s why in mice an
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