Health Note - REST Protein, Your Pumps, Sodium & Potassium

 Beloved, 

I wish above all things that thou mayest ...be in health,...

3 John 1:2

"So far, research has suggested that severely limiting calorie intake

can have a beneficial effect, as can manipulating certain genes in laboratory animals. 

 

But recently in Nature, Bruce Yankner, a professor of genetics and neurology at Harvard Medical School, and his colleagues reported on a previously overlooked controller of life span: the activity level of neurons in the brain. In a series of experiments on roundworms, mice and human brain tissue, they found that a protein called REST, which controls the expression of many genes related to neural firing, also controls life span. 

They also showed that boosting the levels of the equivalent of REST in worms lengthens their lives by making their neurons fire more quietly and with more control. How exactly overexcitation of neurons might shorten life span remains to be seen, but the effect is real and its discovery suggests new avenues for understanding the aging process. 

 

A key early finding was that the inactivation of a gene called daf-2 was fundamental to extending the life span of the worms. “daf-2 mutants were the most amazing things I had ever seen. They were active and healthy and they lived more than twice as long as

normal,” Kenyon wrote in a reflection on these experiments. “It seemed magical but also a little creepy: they should have been dead, but there they were, moving around.” This gene and a second one called daf-16 are both involved in producing these effects in worms. 

By 1997, researchers had discovered that in worms daf-2 is part of a family of receptors that send signals triggered by insulin, the hormone that controls blood sugar, and the structurally similar hormone IGF-1, insulin-like growth factor 1; daf-16 was farther down that same chain. Tracing the equivalent pathway in mammals, scientists found that it led to a protein called FoxO, which binds to the DNA in the nucleus, turning a shadowy army of genes on and off. 

 

 Some years later, they realized that many of the changes they’d seen were caused by a protein called REST.  

--REST, which turns genes off, was mainly known for its role in the development of the fetal brain: It represses neuronal genes until the young brain is ready for them to be expressed.

But that’s not the only time it’s active. “We discovered in 2014 that [the REST gene] is actually reactivated in the aging brain,” Yankner said. 

 

To understand how the REST protein does its job, imagine that the network of neurons in the brain is engaged in something like the party game Telephone. 

--Each neuron is covered with proteins and molecular channels that enable it to fire and pass messages. 

--When one neuron fires, it releases a flood of neurotransmitters that excite or inhibit the firing of the next neuron down the line. 

--REST inhibits the production of some of the proteins and channels involved in this process, reining in the excitation.

 

In their study, published in October 2019, Yankner and his colleagues report that the brains of long-lived humans have unusually low levels of proteins involved in excitation, at least in comparison with the brains of people who died much younger. This finding suggests that the exceptionally old people probably had less neural firing. To investigate this association in more detail, Yankner’s team turned to C. elegans. They compared neural activity in the splendidly long-lived daf-2 mutants with that of normal worms and saw that firing levels in the daf-2 animals were indeed very different. 

 

“They were almost silent. They had very low neural activity compared to normal worms,” Yankner said, noting that neural activity usually increases with age in worms. “This was very interesting, and sort of parallels the gene expression pattern we saw in the extremely old humans.”

 

When the researchers gave normal roundworms drugs that suppressed excitation, it extended their life spans. Genetic manipulation that suppressed inhibition — the process that keeps neurons from firing — did the reverse.

Yankner and his colleagues found that in worms the life extension effect depended on a very familiar bit of DNA: daf-16. This meant that REST’s trail had led the researchers back to that highly important aging pathway, as well as the insulin/IGF-1 system. 

 “It is intriguing that something as transient as the activity state of a neural circuit could have such a major physiological influence on something as protean as life span,” Yankner said." QuantaMagazine 

 

"During the resting membrane potential there are:

• more sodium ions (Na$^+$start superscript, plus, end superscript) outside than inside the neuron
• more potassium ions (K$^+$start superscript, plus, end superscript) inside than outside the neuron

The concentration of ions isn’t static though! Ions are flowing in and out of the neuron constantly as the ions try to equalize their concentrations. The cell however maintains a fairly consistent negative concentration gradient (between -40 to -90 millivolts). How?

• The neuron cell membrane is super permeable to potassium ions,
  
  and so lots of potassium leaks out of the neuron through potassium leakage channels (holes in the cell wall).
• The neuron cell membrane is partially permeable to sodium ions, so sodium atoms slowly leak into the neuron through sodium leakage channels.
• The cell wants to maintain a negative resting membrane potential, so it has a pump that pumps potassium back into the cell and pumps sodium out of the cell at the same time.

During the resting state (before an action potential occurs) all of the gated sodium and potassium channels are closed. These gated channels are different from the leakage channels, and only open once an action potential has been triggered. We say these channels are “voltage-gated” because they are open and closed depends on the voltage difference across the cell membrane. Voltage-gated sodium channels have two gates (gate m and gate h), while the potassium channel only has one (gate n).

• Gate m (the activation gate) is normally closed, and opens when the cell starts to get more positive.
• Gate h (the deactivation gate) is normally open, and swings shut when the cells gets too positive.
• Gate n is normally closed, but slowly opens when the cell is depolarized (very positive).

Voltage-gated sodium channels exist in one of three states:

1. Deactivated (closed) - at rest, channels are deactivated. The m gate is closed, and does not let sodium ions through.
2. Activated (open) - when a current passes through and changes the voltage difference across a membrane, the channel will activate and the m gate will open.
3. Inactivated (closed) - as the neuron depolarizes, the h gate swings shut and blocks sodium ions from entering the cell.

Voltage-gated potassium channels are either open or closed." Khan

 

"We might roughly expect energy used by the brain to scale in proportion both to the spiking rate of neurons and to volume. This is because the energy required for every neuron to experience a spike scales up in proportion to the surface area of the neurons involved, which we expect to be roughly proportional to volume.

So we can calculate:

energy(cortex) = volume(cortex) * spike_rate(cortex) * c

energy(brain) = volume(brain) * spike_rate(brain) * c

For c a constant.

Thus,

energy(cortex)/energy(brain) = volume(cortex) * spike_rate(cortex)/volume(brain) * spike_rate(brain)

From figures given above then, we can estimate:

0.44 = 0.8 * 0.16/spike_rate(brain)

spike_rate(brain) = 0.8 * 0.16 /0.44 = 0.29

Or for a high estimate:

0.44 = 0.8 * 1/spike_rate(brain)

spike_rate(brain) = 0.8 * 1 /0.44 = 1.82

So based on this rough extrapolation from neocortical firing rates, we expect average firing rates across the brain to be around 0.29 per second, and probably less than 1.82 per second." A1