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.
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.
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.”
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 (Nastart superscript, plus, end superscript) outside than inside the neuron
- more potassium ions (Kstart 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:
- Deactivated (closed) - at rest, channels are deactivated. The m gate is closed, and does not let sodium ions through.
- 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.
- 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