An Interview on Mitochondrial Decline in Aging and Neurodegeneration

In this interview, a researcher focused on mitochondrial biochemistry discusses the role of these important cellular structures in aging and neurodegeneration, particularly Parkinson's disease. There are really two ways of looking at mitochondria in aging. The first, the view incorporated into the SENS program, looks at damage to mitochondrial DNA and its consequences. A small but significant number of cells fall into a dysfunctional state because some forms of randomly occurring mitochondrial DNA damage can replicate rapidly within the cell, leading to cells that pollute their surroundings with reactive, harmful molecules. This might be addressed by providing backup copies of mitochondrial genes, a methodology known as allotopic expression.

The second view looks at mitochondrial dynamics and morphology, both of which change considerably in response to differences in the environment between old cells and young cells, old tissues and young tissues. This is a much more complex problem to consider, as no-one has yet mapped the chains of cause and effect that stretch from the fundamental forms of damage at the root of aging to this downstream manifestation of aging. Nor is it entirely clear how to best go about reversing these changes - not to mention whether or not some are adaptive to the damaged environment, protective rather than the cause of even more harm.

How many mitochondria are there within each dopamine producing neuron and how frequently are they created?

The dopaminergic neurons in the pars compacta of the substantia nigra, the ones most related to Parkinson's disease, have enormous axons. If you add up all the branches, it is estimated that you would have several meters of axon coming from each cell. If you take the density of mitochondria in a segment of axon, you can then calculate what the total would be. The number is roughly two million mitochondria in each neuron. That's two million mitochondria frantically consuming oxygen and making ATP, all to keep that one cell alive.

On top of that, the proteins in the mitochondria are not going to stay stable for the 80 to 100 years that we live for. The proteins start to fall apart because of heat and the environment they are in. It turns out the mitochondria are a particularly dangerous place for a protein to be, because the mitochondria, in the process of its respiration, generate reactive oxygen species (ROS) which collide with proteins and chemically alter and damage them. Proteins everywhere in the cell have to be constantly degraded and replaced; in a mitochondrion that is even more true because the proteins get damaged even faster.

So we did a back of the napkin calculation, and asked how many mitochondria that cell would have to create every day in order to keep its two million mitochondria healthy and happy? The answer is something like thirty thousand mitochondria created every day. Most of the cells in our body don't have this problem, skin cells and liver cells are tiny and don't need nearly as many mitochondria. That could be part of the reason why, when something is wrong with our mitochondria, it is our neurons that suffer first, particularly the biggest neurons.

Does all that explain why, in Parkinson's disease, these neurons die and not other neurons?

Well, we don't know for sure yet what makes one cell more sensitive than another, but I think that is an excellent guess. The fact that those nerve cells fire at a very high rate, and that every time they fire it opens up a particular type of calcium channel that lets a lot of calcium in, means that you are going to need a lot of ATP to pump that calcium back out of the cell, as well as pumping sodium and other things. That puts a very strong demand on the cell. Then the fact that it has so many branches and so many synapses on the end of it also means that you are going to need a lot of energy to power those synapses. It is indeed a very energy hungry type of nerve cell, and nerve cells are the most energy hungry type of cell in the body. So it has this dual problem of supplying enough mitochondria and then putting strain on the mitochondria to travel through the axons and pump out enough ATP.

Which therapies that target mitochondrial health are you most hopeful for?

I think there are four ways to try to approach it. If you can figure out what is damaging the mitochondria and stop the damage that would be a great thing. In some cases antioxidants might do that. In cases where there are environmental toxins, like paraquat or rotenone, getting those out of the environment is definitely going to help. But in the case where there is a genetic mutation, you can increase the rate at which damaged mitochondria are removed and hope that the cell compensates by increasing the rate of production of healthy ones. There are also genes that control how mitochondria replicate and how they get new proteins added to them, if we can figure out how the cell controls the number of mitochondria and increase that number, that could improve the health of the cell.

Finally, the one that I am most interested in is the transportation problem. It is one thing to try and get proteins into the mitochondria in the cell body, but that cell body is just a tiny fraction of the volume of the neuron, way less that 1% of the cell. The cell has to somehow get mitochondria all the way out to the periphery of the cell and through all of its many axons. Improving the delivery of mitochondria into the remote regions of the cell should also improve the health of the cell.



Hi ! Just a 2 cent.

''The number is roughly two million mitochondria in each neuron. That's two million mitochondria frantically consuming oxygen and making ATP, all to keep that one cell alive. ''

''how many mitochondria that cell would have to create every day in order to keep its two million mitochondria healthy and happy? The answer is something like thirty thousand mitochondria created every day. Most of the cells in our body don't have this problem, skin cells and liver cells are tiny and don't need nearly as many mitochondria. That could be part of the reason why, when something is wrong with our mitochondria, it is our neurons that suffer first, particularly the biggest neurons. ''

2 Million mitochondrias per neuron, that tells you how Underestimated mitochondrial theory of aging is.
5000 mitochondrias per cardiomyocyte cell in heart
200 mitochondrias per skeletal muscle myocyte.

Wow.I don't know about you, but neuron are major -M-ajor consumer of ATP, the brain is ATP sucking and producing organ. So many mitos per brain cell, it's cRAzY This tells you how LTP is so important for longevity, as was demonstrated in epigenetic studies on long lived people; the longest lived ones maintained LTP (Long Term Potentiation/neuron function preservation over long term), and not surprisingly, they had the youngest DNA methyl clock in brain. Likewise, centenarians that were the most cognitively capable (memory test, speed of reaction/thought, etc...), had the strongest LTP and also were more likely to survive the next 5 years; while the senile/debilated/mentally degenerated were starting to show stronger brain pruning, amyloid accumulation/protein aggregation and neuron death - and will die in the next 5 years.

What's more is NRG (neuregulin-1) is equal to mammal MLSP, higher NRG higher MLSP, thus this demonstrates how Crucial mitochondrial aging is about the intrinsic aging, since the brain's neurons carry 2 millions mitos each one and we have so many neurons, this mega-amount of mitos means VERY high ROS production in brain in all these mitos, demonstrating that neurons are VERY vulnerable to the excess ROS from this mitomass and why the brain neurons need the Redox to protect them from ROS/lipid peroxidation chains more than all organs; also neurons are present elsewhere like in the intestine (I doubt they consume as much ATP and have as many mitos there; but they sure must have because they communicate in concert with the brain for digestion, food passage and bile into intestine).

This is also corroborâtes with mitochondrial DNA lesions count equalling mammal MLSP. Once more showing that cell ATP/energy loss is major driver of intrinsic aging (and also epigenetic aging which methylation showed concordance with) by ROS-auto-destructing mitos.

Just a 2 cent.

Posted by: CANanonymity at March 30th, 2018 12:29 PM

The millions of mitochondria in the neurons are protected against ROS by the uncoupling protein UCP2. When the neurons get over-heated and give off ROS species, this activates the UCP2 gene which uncouples and releases the excess heat, thereby protective damage to the mitochondrial membranes. The main SNP involved is rs6600339 with the TT alleles being the most protective. I have the TC heterozygous SNP condition. Those with the CC alleles have shorter Lymphocyte telomeres as well.

Posted by: Biotechy at March 30th, 2018 2:33 PM

PS: The UCP3 SNP rs660039 that is homozygous for the T allele is a longevity SNP.

Posted by: Biotechy at March 30th, 2018 4:43 PM

Hi Biotechy ! Thanks for that. Just a 2 cent.

Very true, I think UCPs are very important and underestimated too. I think there are part of the equation because mouse that have UCP activation live longer lifespans but still, evidently, do not reach the age of a human; as such UCPs are mostly fail safe mechanism for mitochondrial membrane potential ROS production modulating; but it does not stop minute ROS production enough, and thus that ends up, Still, damaging IMM inner mitochondrial membrane and OMM outer mitochondrial membrane. This, in turn, ends up as lipid peroxidation chains that reach/damaget the nearby mitochondrial DNA. Redox is mostly responsably, above UCPs, to control this; such as SOD, CAT, ASC, and especially, GSH, GPx and GST. It is the thiols that work in tandem with the thioredoxins and glutaredoxins system, such TRX-1, GRX-1. They, together, are capable of quenching H2O2, iron-fenton reaction hydroxyl radical and superoxide anion production (the ROS basis) at Complex I in ETC. But it is the lipid Peroxides that reach and damage the mtDNA that make for accelerated aging; through peroxidation of long chain PUFAs in mitomembrane phospholipids.

There is a good study about this, that demonstrates that UCPs, HSPs thermogenesis and mito
heat-dissipating (like a radiator) through ATPase proton pump/proton gradient uncoupling is good 'temporary' mechanism to reduce ROS slightly and make a slight reduction of ATP production but at the reward of less ROS chain damage; Overt UCPs is bad as was shown in studies with ATP loss, only modest uncoupling is beneficial. I think it equals to roughly exercise or CR in terms of effect, just like UCP BAT WAT activation (in adipose tissue adipocyte burning) that increases lifespan but making muscles/insulin better capapble of evacuating glucose in the muscles once the white/Brown adipose tissue is burnt. It's why thérapies that improve skeletal fitness can improve insulin resistance T2D, the minute you lose/burn the visceral fat and the adipose tissue it triggers PGC1-a cascade, faster metabolism, peroxisomal fat burning, ketosis and improves skeletal muscle mitochondrial function. This essentially means if you burn fat fast and abdominals show with slighter higher body temperature, it's a good sign because your metabolism is faster than slowed metabolism piling waist visceral fat. CR makes you lose weight but it actually slows metabolism and reduces body temperature; albeit, it may depend on the length of the CR, which at the start may increase metabolism and ketosis; later, it will slow down metabolism and body temperature will lower. My guess, is that this is a compensation for lack of nutrient (since you are starved/fasting), as such it will not burn anymore calorie since there is no more energy/nutrient coming in (and thus, energy will become sparse/falling/which compromises the body and DNA/protein synthesis capacity (i.e. restriction is good up to a point only)). It will be 'conserving' energy by slowed metabolism from longer CR. It is the exact same thing when you go to sleep, your body's metabolism slows down and its temperature drops during your sleep. HAving fever/high body temperature/being stressed out before ttrying to sleep will make it much harder to fall asleep. It'S why they recommend dropping temperature of room before sleep, your feet will become colder and they are a good 'detector' of temperature and will signal brain to produce more melatonin/enter sleep (along with darkness/absence of light registered by your skin fibroblasts activating melatonin 'night-genetic program' circadian clock). If you are warmer and temperature too high, your brain is more 'alert' and has more difficulty falling asleep (since slowed metabolism by colder temperature will reduce your cognitive activity to 'enter sleep' cycle).

For me, if a mouse has strong UCP activaation and lives no more than a dwarf mouse, than it means UCPs are just safe control mechanism but not the major controller; that is the redox that alters the mitochondrial ROS emission depending on the thiol milieu being reduced or oxidized.

Just a 2 cent.

Uncoupled and surviving: individual mice with high metabolism have greater mitochondrial uncoupling and live longer

Uncoupling to survive? The role of mitochondrial inefficiency in ageing.

Further Support to the Uncoupling-to-Survive Theory: The Genetic Variation of Human UCP Genes Is Associated with Longevity

Posted by: CANanonymity at March 30th, 2018 5:48 PM

PS: this corroborates what you said about a specific TT allele :

''We found that carriers of the TT genotype (rs15763), and carriers of the -55 T allele (rs180084) were significantly over-represented among long-lived subjects. The rs15763 is located in the 3′UTR of the gene and has no clear functional role so far; on the contrary, the -55 T allele has been associated with a significantly increased gene expression and has been shown to positively modulate the resting metabolic rate of skeletal muscle [81], [82]. In addition, the over-expression of UCP3 in muscle cells has been shown to be associated with decreased production of ROS as well as with facilitating fatty acid oxidation [17], [83]. The physiological status of the muscle mass reflects a complex equilibrium between nutrition, metabolism and the response to stress. Aging muscle is characterized by a progressive loss of mass and a gradual increase of weakness leading to sarcopenia, a condition associated with physical disability, and with an increased risk of developing disorders such as atherosclerosis, type II diabetes and hypertension [84]. Sarcopenia is closely linked to a decrease in resting metabolic rate as well as to mitochondrial dysfunction and oxidative stress [85]. Therefore, in the context of the proposed functions of UCP3, the physiological consequence of an increased UCP3 activity in skeletal muscle might be to slow down the age related decline of muscle performance as a result of decreased ROS production, an increased protection of mitochondria from lipid peroxidation, and better metabolic efficiency [28], [83]. Accordingly, it has been found that mild uncoupling has an impact on cellular aging in human muscles in vivo [86]. This is in keeping with our previous work, where we have shown that the hand grip strength, the most effective death predictor in the elderly, was higher in the carriers of rs1800849-T allele than in the remaining the population [42].''

Posted by: CANanonymity at March 30th, 2018 6:18 PM

Here we describe some clues toward decoding the mitochondria circuit through not just basal ganglia, but entire nervous system and body. Basically one can explainmany details based on the need to perform mtDNA repair in (quiescent) neurons where overlapping repair machinery is reduced. Mito flux into and out of these circuits compensates for repair and other metabolicinefficiencies brought about by the need to restricted gene expression profiles econdary to differentiated cell types. Funny cause its true, no more need for allotopomania, thanks boys, you go get it Reason, Josh, SENSmen.

Posted by: john hewitt at April 3rd, 2018 1:52 PM

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