May 24 2012
The Aging Brain
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Nice article. Ultimately the operation of the brain is based on physiology and any degradation of the brain is based on that physiology not keeping everything in good repair.
Neurodegeneration happens to be a major focus of my nitric oxide research. The physiological systems that maintain the brain are controlled to do so, and a major signaling molecule that regulates that control is nitric oxide.
My hypothesis is that neurodegeneration comes from ischemic preconditioning that has gone on for too long. Ischemic preconditioning is a valuable protective mechanism, that protects tissue compartments, including the brain, from insufficient ATP due to reduced blood flow, hypoxia, hypoglycemia, and other things. The brain has such limited reserves (a few seconds), that it needs mechanisms to prevent loss of function if reduced ATP availability goes on longer (a few minutes).
Maintaining the brain in a conscious and active state is always a matter of life and death. If an organism is running from a predator, to lose consciousness is certain death. The brain needs to be able to continue to function at high fidelity, even if its ATP supply is compromised. But if there isn’t enough ATP to do everything, something has to be turned off. My hypothesis is that in the brain, long term maintenance has a lower ATP priority than does ongoing high fidelity function. It is ok to lose a few million brain cells while running from a predator, it is not ok to lose consciousness.
The idea that physiology maintains itself through homeostasis is wrong. Physiology maintains itself by controlling the things that need to be controlled, but because there is no teleology, physiology can only use chemical signaling to determine what needs to be done. Screw up the signaling and physiology will do things that may be not good. I am pretty sure that is where neurodegeneration comes from.
My hypothesis is that the brain enters a state of ischemic preconditioning and never leaves it. There are all different degrees of ischemic preconditioning, some are easier to measure than others. In all of them there is the diversion of ATP from long term maintenance to short term consumption to maintain function. The brain triages ATP resources and prioritizes maintaining consciousness over maintaining DNA and repair systems. The damage to DNA is cumulative, there are DNA repair enzymes, but they have limits and use ATP. There is no way to fix it if it gets too bad.
I think the alcohol effect is real, and the mechanism is that it amounts to a transient stress that physiology has to cope with and which then goes away. I think the same is true of exercise. It isn’t the depletion and overloading of muscles that extends lifespan, it is the activation of repair afterwards. I think that is why caffeine helps too. It isn’t that constant anything helps, rather it is intermittent use of something that exercises the control pathways that keep everything “in sync”.
I thought that the moderate alcohol benefit was from raising your HDL, and decreasing the clotting factor of blood which should lower the incidence of stroke. Also, I have noticed that after a couple of drinks,that my blood pressure gets significantly lower.
tmac, I suspect the effects of alcohol are more complicated than that. The mechanism of intoxication is still not understood. It is very similar to the mechanism of inhalation anesthetics (which is also not understood). I suspect that they relate to interactions of nitric oxide with lipid membranes, where the inhalation anesthetic is soluble in the lipid membranes and that modifies the NO interactions of proteins partially embedded in those membranes (such as neurotransmitter receptors).
Conditions that raise NO levels (starvation, donating blood) make one more susceptible to alcohol.
I suspect that the balancing of NO generation outside of neurons with NO destruction inside due to superoxide produced by mitochondria is a delicate balance that needs to be maintained. I suspect that the re-adjustment of that balance is what causes a hangover. High alcohol simulates a high NO level, so the brain responds by generating more superoxide to balance it, but the time constant for lowering the superoxide level after the alcohol goes away is longer than the alcohol metabolism time constant.
There are systemic effects that raise local NO levels which (might possibly) cause neuropathy through a rebound effect, for example vibration induced neuropathy. Vibration does increase local NO levels (shear activates eNOS) and does cause things like Raynaud’s which are clearly due to deranged regulation of NO status. Peripheral diabetic neuropathy is likely (I think) due to low peripheral NO due to high superoxide from high glucose and RAGE products.
Whatever the mechanism(s), it is likely something at the single cell level because cells are subject to neurodegeneration one at a time and due to processes mediated by that cell. ATP regulation is done internal to each cell, as is mitochondria regulation.
“My hypothesis is that the brain enters a state of ischemic preconditioning and never leaves it.”
This makes sense to me if there repeated ischemic insults over time (as one would expect from some of those risk factors Steve mentions), but I’m not sure why you say “never” leaves it. It seems that there would be sufficient damage that would result from repeated episodic episodes of transient ischemia. Also, in addition to the damage from ischemia there is also some damage that can result from reperfusion (oxidative stress), which I assume would also occur with transient insults that are subclinical at the time in which they occur.
A question–
If genetics play a factor, then couldn’t the techniques developed by Catterall (and his staff) be useful in determining which genes are responsible for longevity of brain function?
“Ineluctable”– a new word for me.
Cool…
CC, Ischemic preconditioning occurs to many different degrees. It is a stress response where the tissue uses less ATP than “normal” (what ever “normal” is). What is “normal”? That depends on what the brain is trying to do.
In all of the neurodegenerative disorders, there is a reduction in basal brain metabolism and blood flow. Is that reduction “normal”, or is that a “new normal” corresponding to a degree of ischemic preconditioning that has not been turned off?
There are at least hundreds of thousands of pathways that consume ATP in the brain. How many have to be turned off or turned down to make up the ~25% reduction in glucose consumption that is observed in neurodegenerative disorders? If it was only a few, they would have been found by now. ATP production and consumption is controlled by each cell independently (but there is communication so they work together “in sync”). The reduction in ATP production and consumption is global over the whole brain, and blood flow is reduced to match it. That doesn’t look like bad regulation to me, but rather good regulation around a bad setpoint. Nitric oxide is what regulates ATP levels, blood flow and is what is measured in fMRI (the change in blood flow due to changes in NO levels). A reduction in the basal level of NO would skew the ATP level low and would lead to this cascade of events.
A major ATP sink that can be easily turned off for short periods is axonal transport. In the brain, all the axons are supplied by stuff made in the cell body and transported out the axons to the tippy end. Mitochondria are made in the cell body and carried out axons to the tippy end. For motor neurons this can be a meter away. It takes a long time to move stuff a meter in an axon because stuff moves slowly. Anything that takes longer than the length of the ATP crisis can safely be turned off during that ATP crisis because that pathway wouldn’t produce what ever it was that it was doing before the crisis is over anyway.
Axonal transport consumes about half the ATP that the brain produces. In all neurodegenerative disorders, there is what is called “white matter hyperintensities”, where the white matter (axons) show up as hyperintense on MRI because there is reduced water diffusion in the white matter. What MRI measures isn’t so much “diffusion” as it is “movement”. MRI can’t distinguish between passive diffusion and active movement by ATP powered motors (except the latter stop when ATP is depleted).
The precise cause of white matter hyperintensities is not understood. There is no apparent lesion that is visible on autopsy, and brain that is hyperintense before death stays hyper intense to a degree after death (relative to the surrounding tissues), so it can’t be just ATP mediated movement (that all stops at death). There can be “jamming” of cargo in axons if cargo stops in regions without enough ATP. There are also regions of hypermobile water around some proteins (heat shock proteins and chaperon proteins for example).
Sonic, at some level everything is genetic, but if the incidence of neurodegenerative disorders is affected by environmental factors, so to that extent it isn’t genetic. The incidence is so high now, and essentially everyone gets it if they get old enough, it is very likely that a “normal” genome can support the development of neurodegenerative disorders.
It isn’t exactly true that “there is no apparent lesion that is visible on autopsy” when speaking about white matter hyperintensities – a variety of lesions can be seen. See this recent reference:
http://www.ncbi.nlm.nih.gov/pubmed/20935330
White matter hyperintensities are often associated with vascular abnormalities, both histologically as outlined in that reference, and also clinically with the various risk factors Steve outlined in his post. More vascular risk factors correlate with increased white matter hyperintensity burden on brain imaging. When that burden of white matter hyperintensity is severe, there are predictable changes in cognitive performance, likely related to disruption of the connectivity between different cortical brain regions. CADASIL would be the prototypical example of “pure” vascular dementia, unrelated to the most common cause of dementia, Alzheimer’s disease. You do not invariably see white matter hyperintensities with Alzheimer’s disease.
Of interest, one other condition associated with increased white matter hyperintensities is migraine, which makes sense in that migraine pathophysiology is felt to be driven by an interplay of cerebral vascular and neuronal factors.
“A recent study sheds some light on the brain changes that correlate with cognitive decline in the elderly.”
I only have access to the abstract, but I don’t see anything in it about brain changes that correlate with cognitive decline in the elderly.
sonic,
““Ineluctable”– a new word for me.”
How old are you anyway!!!
On the other hand, I came across a word yesterday on this blog that I had to look up but I can’t quite remember what that word was.
When I said there was no apparent “lesion” associated with WMH, what I meant was that the WMH doesn’t correspond 1:1 with lesioned tissue where the lesion seems to be causing the WMH.
There can be lesions that occur over time, but in terms of what is “causing” WMH. Increased lesions seem to be caused by what ever is causing WMH, not the other way around. Some WMH are reversible and go away over time. The lesions that are found on autopsy don’t go away. In experimental animals, vessel occlusion reliably causes WMH in a few minutes.
The association with migraine is all consistent with it being ischemic preconditioning. There is no apparent lesion with migraine either. Migraine is triggered by nitroglycerine, which also triggers ischemic preconditioning. Sildenafil also triggers migraine.
Migraine is thought to be an example of spreading depression. To me, spreading depression sounds a lot like a transition from a normal state to an ischemic preconditioned state that is triggered by an acute ATP shortage (due to potassium overload for example) that is propagated from the initially triggered cells to adjacent cells.
I very strongly suspect that the propagation of spreading depression and migraine is due to a local reduction in nitric oxide (which is why Sildenafil and nitroglycerine trigger migraines, they both lower the NO level through a rebound effect). Lowering NO level is one way that ischemic preconditioning can be triggered.
Since we essentially are our brains…
Met any disembodied brains lately?
Woody, I sent you the poster I presented at SfN 2011 which lays out some of the background for where I am coming from. Maintaining consciousness has to be a lot more difficult than maintaining metabolic capacity. Why deficits are so difficult to detect in the early stages of neurodegeneration tells me that consciousness is prioritized over maintenance. The degeneration happens after not enough repair for a long time. One thing that turns off repair is ischemic preconditioning.
Dr. Novella, I have a question. i know that you would prefer to leave the discussion of mind/brain behind at his point. but I’ve been wondering:
If we’re only aware of our brain’s processing, and do not cause it (I agree that there’s no way for something supernatural to affect the physical world) as when the brain is active several seconds before a decision is made, and a person is only conscious of that decision after the brain has made it, then how can we learn what information is being processed to make that decision? We can locate and describe the brain activity, but how can we learn what specific information is being considered by the brain in its decision-making process if the person who’s making the decision can’t report on that consideration?
thanks
Ack, don’t want to follow this too far, but: why do we study how people make conscious decisions if those people are really just telling us a story their brain told them about what it did in secrecy? What does it matter if we know how they think they made their decisions if it’s really the brain that made the decision and not the mind?
Mlema, there is a lot of randomness in the brain, the brain and all of physiology operates using what is called stochastic resonance.
https://en.wikipedia.org/wiki/Stochastic_resonance
So what is happening is that physiology is adjusting the tendency for a neuron to fire, and then a blip of noise causes the activation threshold to be reached and the neuron fires. There is no information content in the specific blip of noise that caused the neuron to fire, the “information content” is in the rest of the neural network that is primed to respond to that neuron firing.
Depending on the status of the rest of the neural network, that blip of noise coming a few microseconds earlier or later could have large effects or no effects.
I have only observations, certainly not research related. Many years ago when my grandmother was 82, she happily listened to the radio, kept up the yard, supported herself with crocheted items, and cooked and cleaned for herself. A well meaning person bought her a television set. When she started spending a lot of her time watching TV, she started deteriorating mentally and physically. Is this a use it or lose it kind of thing or does the TV somehow hypnotize.
I am now 72. I have taken a lesson from my grandmother. I use the TV as entertainment, I don’t make it a lifestyle. I read alot, garden, write stories, paint with oils, and enjoy the fresh air. Many of my friends and neighbors are tired, depressed and have glazed over eyes from constant TV fare. As I said, just an observation.
thanks daedalus2u,
that’s interesting.
I’ll try to rephrase the question:
Dr. Novella has explained that our awareness is simply a result of our conscious functioning. that is, that most functioning of consciousness is executed at a level that our awareness doesn’t notice (which is obvious, because we know we don’t have to think about all the things that consciousness achieves in order for them to be achieved) He also indicates that the “mind”, that is, our awareness, is simply a result of the brain’s functioning. And that the mind doesn’t create brain states, but is, again, caused by them. One evidence of this is that before a person is aware of making a decision, the brain is operating. (I’m not sure how we can know that whatever the brain is doing several seconds before a decision is made is actually determining that decision, but, anyway…) All we ever know of the content of a person’s thoughts (which are determined by brain activity/state) is what they report to us. We don’t have a way to study the brain to know what they’re thinking, and even if we did, we can’t know what is causing a person to think that way because we don’t know what information is actually being processed when we study the pre-awareness brain activity.
So, what i’m wondering is: on what basis do scientists believe that we will be able to know the nature of a particular person’s conscious experience, if most of what comprises it is unavailable for reporting by the very person experiencing it?
If Stephen Hawking were unable to “report” (reporting is one of the basics of consciousness) then how could we ever access his brain directly to learn what his thoughts were? Especially since many of his thoughts are thoughts that no one’s ever had before, so we couldn’t compare his brain states to other people’s brain states. Thanks to modern technology we will hopefully not lose communication with Hawking while he’s alive, since we’re already able to implant electrodes directly in the brain to allow communication. And it seems we’ll continue to improve our technology to allow reporting/communication.
It’s easy to confuse “reporting” with the ability to actually know another person’s thoughts directly from studying their brain, since we are studying a person’s brain when they tell us what they’re thinking. Studying a person’s brain directly means: examining the brain through whatever technology appropriate. But, either way, since not even Stephen Hawking knows how his brain comes up with the thoughts he has, but can only report what knowledge he has that contributes to his thoughts, how does Dr. Novella believe we can ever learn the content of conscious thought by studying the physical brain? What sort of technology could make this possible? What are the leading research scientists saying about this aspect of consciousness?
Brain causes mind, mind causes brain, who cares? It’s not important to science, only philosophy. But I would like to know what those studying the brain’s physiological means of consciousness are saying about this aspect.