A Demonstration of Reduced Cerebrospinal Fluid Flow through the Cribriform Plate in Aged Mice

Neurodegenerative conditions are characterized by increasing amounts of molecular waste in the brain, such as amyloid-β, α-synuclein, tau, and a few others. In the case of Alzheimer's disease, evidence suggests that the condition starts because the drainage of cerebrospinal fluid (CSF) out of the brain through the cribriform plate declines with age. The plate becomes ossified and less porous as the inflammatory, altered biochemistry of aging changes cell behavior for the worse. This loss of drainage allows many varied forms of molecular waste to build up to harmful levels in at least some parts of the brain.

The cribriform plate isn't the only path by which CSF drains from the brain, but it is the one that drains the area of the brain, the olfactory bulb, where Alzheimer's pathology and amyloid-β aggregation first develops. The biotech startup Leucadia Theraputics was founded to develop assays and therapies based on this view of the origin of Alzheimer's disease. The staff there have demonstrated - in ferrets rather than mice, because mice don't normally exhibit any of the biochemistry of Alzheimer's disease - that artificially blocking drainage through the cribriform plate causes an accelerated buildup of molecular waste and cognitive impairment.

Today's open access materials, from another team, provide good supporting evidence for the CSF drainage view of Alzheimer's disease. The researchers show that the ossification of the cribriform plate with age in mice clearly reduces CSF drainage. We'd expect to see much the same in other mammalian species. Given a model like this, it would be interesting to see whether or not cognitive decline in normal aged mice correlates in any way with CSF flow through the cribriform plate. Given the lack of naturally occurring Alzheimer's mechanisms in mice, and the presence of other drainage pathways that are less impacted by age, that could go either way.

Cerebrospinal fluid drainage kinetics across the cribriform plate are reduced with aging

Continuous circulation and drainage of cerebrospinal fluid (CSF) are essential for the elimination of CSF-borne metabolic products and neuronal function. While multiple CSF drainage pathways have been identified, the significance of each to normal drainage and whether there are differential changes at CSF outflow regions in the aging brain are unclear.

Here, dynamic in vivo imaging of near infrared fluorescently-labeled albumin was used to simultaneously visualize the flow of CSF at outflow regions on the dorsal side (transcranial and -spinal) of the central nervous system. This was followed by kinetic analysis, which included the elimination rate constants for these regions. In addition, tracer distribution in ex vivo tissues were assessed, including the nasal/cribriform region, dorsal and ventral surfaces of the brain, spinal cord, cranial dura, skull base, optic and trigeminal nerves and cervical lymph nodes.

Based on the in vivo data, there was evidence of CSF elimination, as determined by the rate of clearance, from the nasal route across the cribriform plate and spinal subarachnoid space, but not from the dorsal dural regions. Using ex vivo tissue samples, the presence of tracer was confirmed in the cribriform area and olfactory regions, around pial blood vessels, spinal subarachnoid space, spinal cord and cervical lymph nodes, but not for the dorsal dura, skull base, or the other cranial nerves. Also, ex vivo tissues showed retention of tracer along brain fissures and regions associated with cisterns on the brain surfaces, but not in the brain parenchyma. Aging reduced CSF elimination across the cribriform plate but not that from the spinal SAS nor retention on the brain surfaces.

Collectively, these data show that the main CSF outflow sites were the nasal region across the cribriform plate and from the spinal regions in mice. In young adult mice, the contribution of the nasal and cribriform route to outflow was much higher than from the spinal regions. In older mice, the contribution of the nasal route to CSF outflow was reduced significantly but not for the spinal routes. This kinetic approach may have significance in determining early changes in CSF drainage in neurological disorder, age-related cognitive decline, and brain diseases.


Hi there! This probably my longest message ever but I think it will clear this (though still ambiguity) TL DR: it's too long. I have pinned down telomeres now/aging..and think it is what happens and we have to stop our telomeres shortening rate (on this study here CSF is important with age, and leaks...but I am talking another topic, telomeres my fav 1).
Ok so here it goes, I now know pretty well what happens Per phase/slice/diff. ages of a life; it is a downhill slope (y, means years; kbp means kilo-basepairs, bp basepairs (telomeric DNA TTAGGG base pairs)):

newborn (0y): 9-13kbp (11kbp avg.)
child (5y): 8-10kbp (9kbp avg.)
old teen/young adult (18-25y): 7-9kbp (8kbp avg.)
midlifer (50y): 7kbp
senior (65-80y): 5.5-6.5kbp (6kbp avg.)
elder (90-100y): 4.0-5.0kbp (4.5kbp avg.)
(super)centenarian (100-120y): 3.0-4.25kbp (3.5kbp avg.)

Fluctuations in Telomere Shortening Rate/Speed per Age Range Bracket in Humans:

(3kbp/3000bp) telomere size lost, 0-20y: 150bp/y Shortening Speed
(3kbp/3000bp) telomere size lost, 20-80y: 50bp/y Shortening Speed
(2kbp/2000bp) telomere size lost, 80-100y: 75bp/y Shortening Speed
(1kbp/1000bp) telomere size lost, 100-120y: 50bp/y Shortening Speed

80bp/y avg. linear loss (over entire lifespan)

But from this, it shows it is Not linear/constant same speed loss in a lifespan; there
are key moments in life where telomere attrition rate is accelerated;
namely at birth/childhood (when becoming young teenager/entering puberty)
and in late life (elder age, where most people die in their 80-90s; and
do not reach 100 years old); it makes sense, puberty and early childhood/newborn
are moments of immense growth; taller telomeres and faster shortening
rates of telomeres (despite taller telomeres), while in very elder age
you are nearly at the end of life; as such there could be a 'acceleration'
that 'finish off' the person and that is what happens. Being that old means
that now there is actually an acceleration at this last point.
Now, I see it as more like 'dysfunction', and this can suddenly end the
life of the person; because if they still had 'more' telomere left...
they could continue to (super)centenarian age; since this last phase
is slowing down aging once more for a 'final push' until 'the maximum'
is reached.

One studies showed that women in their 20s and in their 50s-early60s, specifically
these 2 slices of lifespan are affected more, because they are the menopause/parity/menarch
periods; the 20s is the reproduction phase and pregnancy is high cost (diversion
of somatic tissue maintenance/DNA repair resources towards sexual reproduction resources; it was shown
that women have more kids have more lesions on DNA, because all their resources were for the reproduction/none left
for their own body going 'through it'/pregnancy) and at 50s, there is a reduction in oestrogen levels;
thus less telomerase (because estrogenic receptors activate telomerase; estrogen triggers estrogenic receptors),
menopause causes heat flashes and can in severe cases cause cardiac arrest; that is to show you, once you lose
hormonal-dependent telomerase protection you are not protected anymore; same thing for men, andropause accompanies
reduction of telomerase because become infertile (sexually senescent) and loss of testosterone/androgens means
reductionof telomerase too; for, androgens are converte to estrogen by aromataze enzyme (in men, and women too), so
then loss of endocrinal telomerase in males too. Studies showed that women had a slower telomere shortening rate
(40bp/y), while men it was higher (50bp/y), that is due mostly to estrogen/telomerase and double-XX chromosomes
protecting them better (than male Xy chromosome arrangement - compromised y/lack genetic material;
X confers more genomic stability than y, double XX is (double) more robust DNA/genome). This means
a slower telomere shortenign rate in women. Albeit, it was not always 'statistically' significant...but still significant;
10bp/y is Still 10bp/y less speed. Thus, from this we can infer women age 20% or so slower in telomere speed shortening rate
(in general), some women are aging Faster than men though; but in general most 'young/youthly' women age slower by a slower
telomere shortening rate (about 20% slower). And it kind of fits the fact that 9 out 10 centenarians are women, not men.
That only 1 man would become a centenarian (is sad for us men..) is a stark contrast. That 20% slower aging is needed
to become one of those 9 centenarian women out 10 centenarians ones.

The most perplexing and paradoxical, but makes senses (in a twisted 'inverted way'), is that Taller telomeres shortern at a Faster rate.
You would think that short telomeres...shorten faster..right?...Nope, it's the inverse...a Total Catch 22.

Now Why? Because evolution decided that we can't outwit it...if we have Taller Telomeres, then they will shrinken
faster...so to Offset the increase...thus, our cells are 'compensating' on 'small' telomeres...they know these small
telomeres will soon enough be 'emptied' (because are short) and then genome will be compromise; short telomeres = replicative senescence.
So...evolution would select the smallest telomeres - for protection...not the tall ones. By protecting the smallest
ones First, it would ensure survival (and this was demonstrated with mice, mice that accumulate Highest Total Number of *short* telomeres
are the first to die; so the number of short telomeres is critical and means genomic 'instabilit/telomere dysfunction/DDR (DNA Damage Response) signal at telomeres'
and this causes senescence.

But..the thing?.....of tall telomeres being TALLER and FASTER shrinking than small ones, ???! ambiguous much...that's one hell of 2-faced thing/a catch 22, indeed,
short sized telomeres shrink LESS fast/in terms of shortening speed...because the body puts all the resources at the 'weakest link' - the shortest telomeres; 'compensating our weak points', short telomeres are the final destination
before senescence; so it makes sense that the cell would 'work on the smallest telomeres to preserve them while still 'hanging''. And thus,
Tall telomeres are just 'cannon fodder'...not really protected and only used 'to post-pone' aging..since after all, tall telomere shrink faster...but if you have MORE TALL telomeres
then..you effectively have more 'shield/cannon fodder' to blast on, 'quantitatively/in total number of tall telomeres'....but it's 'Light' fodder, in terms of its 'quality/composition'...short telomeres are Stronger/and shorten slower...while tall telomeres
is 'fluff' in its content...they shorten so quickly (they would Not shorten so quickly if they were more sturdy)..-Despite being tall/having more size.
So, this means 'solidification' of the weakest links and 'Fortification' of the smallest telomeres/places that need 'fixing/reinforcing'; namely, short telomeres.
And, in doing so, short telomeres become hardened and thus, slow to shrink/slow to shorten in size. They shorten slower than tall telomeres.
I believe this is also related to 'cell replication/cycling/mitosis' dynamics - that tall telomeres allow fast cell replication but this means accelerated growth; and we know that
growth is related to fastened telomere loss (such as when entering puberty/growth for sexual reproductive maturity); so cell division is a double-edged sword; the faster it runds
the faster telomeres will shrink. As we saw, human cells can take hours long to cycle 1 cycle; while very faster cells from other animals or bacterias, cycle in a few minutes...and they live barely long.
Thus, cell cycling/division dynamics and kinetics/speeds and cell turnover/replacement rates are partly related to telomere length (especially in Stem Cells). And, also indirectly, to telomere shortening rate/speed..because telomere length Dictates telomeres shortening speed.

It is intriguing because when you look at the later elder age (90 years or so), there seems an acceleration of aging
in that before-centenarian age phase....where most people end life...but the telomeres are SHORTER...so I mean
they should shrink SLOWER...but that's not what happens, in that period, there is acceleration of telomere shortening
DESPITE them having shorter telomeres. It means, that in certain periods of life, you ahve 'added layers' of shortening
rate/like say, DNA damage/genomic dysfunction (and rising ROS levels) taht would Compound the 'regular basal shortening rate'...so, even if the shortenign rate was slower
and the telomere were smaller size...the 'aging process' would accelerate in that last phase - and Cause Telomere Shortening
Rate to Accelerate - despite having shorter telomeres. As such, it means, 'added speed layers' of telomere shrinking (on top of the shortening base speed);
the telomere size dictating shortening speed,.. in that case, becomes moot/near null.

One study in zebra fish was able to pinpoint important key tissues that dictage aging/longevity...they found
that gut (mucosa)/intestinal (mucosa) and muscles are Very important to longevity...almost just as much as the
heart or brain; because they were able to induce sarcopenia (a feature of late aging)/fat waisting...to make them
become 'skeleton-like' (when you are nearly dying, you can lose nearly 50-100 lbs...I lived that, atherosclerosis
causes sarcopenia), when theze zebrafish became nearly dead, they saw that gut mucosa and muscle sarcopenia were
very hit hard, and there was drastic telomere loss in these specific tissues (there are telomere loss in All tissues;
but these ones seems hit harder), it makes sense, we eat, our digestive system is 'beaten' to a pulp...by the toxic
crap we eat...and thus why, Calorie Restriction helps a lot..it relieves the digestive system from those bad calories
and the whole digestive process (we Overdo it), we're not supposed to eat whoppers, bacon, fat donought and big macs, our digestive system
can't take it over long run; it Will show telomere attrition, faster. Same thing for intestine, our colon digests
lots of shit (litterally..because taht is what comes out), our poor colon gets the rough end, and the instestines are HUGE size...Long....
so that is a Lot of tissue to damage; very consequential. They foudn that the intestine's stem cells were depleted and the mucosa 'thinned'
with age (loss of collagen/loss ECM scaffold), same thing for stomach mucosa/stem cells...if we lose our stem cells/the telomeres
in these niche stem cells were shortened...as such that means less replacement of cells to make new tissue (as the stem cells die). And this manifests as thinning
and ulcers/damage to walls of these organs. If these organs stop working = death. While in muscles, they saw 'thinning' of muscle fibers...
they became sarcopenic, frail and decrepit skeleton, the myocells (muscle cells) had reduction in telomere length.
Muscles are important they have direct contribution to blood glucose homeostasis; and loss of muscle 'grip' is a predictor of death.
It is why exercise is crucial to preserve your muscle mass and repush as far the sarcopenia of verty old age or in a disease (like I had, with atherosclerosis).
Just packing more lean muscle immediately affects insulin/glycemia, promotes insulin sensitivity and stops insulin resistance; pushes away diabetes and hypertension.
It also affects BAT/WAT (brown adipose tissue/white adipose tissue) and makes UCPs/HSPs more efficient (Uncoupling Proteins and Heat Shock Proteins)
so that means better autophagy/mitophagy/cell waste disposal. Slight uncoupling in the mitochondria was able to reduce ROS levels and create 'heat'
from the mitos; this in turn activates HSPs; which they are autophagic chaperones/protein folding/protein quality control chaperones.

To finish, the most curious point, is why is it that when we do overcome the telomere loss we STILL lose telomere and still die on time;
when you look at it; an increase in telomeres means a Increased Proportial Loss of telomeres by a faster shortening rate:

10,000bp size - 100-150bp/y speed loss
5,000bp size - 50pb/y speed loss

So, in effect we are 'nullifying' the lenghtening of the telomeres; because the tall telomeres shrink faster - despite being taller.
So, that is 'null' gain...no gain/not net gain. I mean a 10kbp telomere size is losing 100-150bp per year...almost DOUBLE OR TRIPLE
the speed of a short telomere of 5kbp size...(half the size), so it is 'inversely proportional' between 'tallness' vs 'speed'.
So, if we use telomerase/hTERT/hTERC we gain telomeres size; but from studies using TA-65 astragalus; in one year they gained 200-800bp; avg. 500bp
let me repeat it, they Gained 500bp on their telomeres; now we know that humans'cells REDUCE at a rate of roughly 80bp/y (some say lower like 20-30bp..I'm using a higher metric),
some periods of life they srhink at 50bp..some periods of life they shrink at 150bp....but for nearly 60 years period..they shorten at 50bp/y or so.
That is the largest 'chunk' of life between 20 and 80 yaers old; it's called 'the plateau-ing' as our body slows down in metabolism and we age the Slowest in that adult/midlife/latelife...of telomere shortening rate; for 60 years.
As such, 50bp/y seems about right; but that is excluding the other periods of life where it is accelerated; as such, the AVG is 80bp/y 'if linearly averaged' for TOTAL LIFE.

But to come back to the TA-65 example, they gained FAR MORE than they loss; I mean you lose 20-150bp RANGE per year...they gained 500bp...that NULLIFIES the loss of 150bp (at worst),
they thus gained 350bp (at the very worst...); and at the best they gained 400-600bps...

So that is what stlil irches...me, wht studies in mouse show only 13% extension of lifespan after hTERT in mouse, maybe these telomere lenghtenening are not enough to matter;
maybe Only Few cells get that lenghtening (select (sub) cells); while other cells 'continue their course' unabated...
for example, in mouse they telomeres of mouse went up from 45kbp to 52kbp...that is 7kbp INCREASE in telomere lenght....
I mean not even humans get that kind of telomer eextension...of course mouse are different their telomeres are Huge/Tall (50kbp)...and theystill die in 2 years or so;
and that is due to their Telomere Shortening Rate being 100x times fasster than humans (50bp/y in human vs 7000bp/y in mouse); so they lose it Reallly fast.
It does not matter that they 'gained' 7000bp...tehy lost 7000 in the last year.

NOT SO...in humans, we lose 20-150bp/y in nearly all cells...and TA-65 is able to Overcome this loss/negate the loss to make 'net gain' - because we net gained over 400bps in 1 year.
IN 1 YEAR. We have 120 years to live, mouse have 2 years to live (because losing 7000bp/y), thus it means that telomerase is Far More Effective and Useful/as in 'has a use' in long lived animals
because tehy Do gain something...they gain more than they lose. ..Not in mouse. Telomere/hTERT cannot overcome the immense loss in mouse; but in humans we are ALREADY very low speed loss...
so, in that case, we Would Gain something if we Did increase telomere lenght.

It's still ambiguous, but if Each Year...you gain 500bps...then you are Effectively reversing aging; and Yes, Taller Telomeres SHRINK FASTER - but NOT FAST ENOUGH to OVERCOME THE 500BP NET GAIN;
remember we lose 150bp at FASTEST POSSIBLE RATE..so in that TALLEST OF TALLEST telomeres...but you Gained 500...indeed you have negated the Fast Loss of Tall Telomeres; despite that your teloemrse are being Taller.

That is what I am still wondering, but if it's so, then...it is the same as ultra long lived animals; like quahogs, greenland sharks or even more, Bristle cone pines, they have active telomerase in cyclical bouts;
bristlecone pines can live 5000 years. Same thing with jellyfish hexactinelida, they are technically *mmortal because they have permanent telomerase in their stem cells/germ cell lines; they can revert to prepubescent state after reproduction
(because of telomerase/telomere lengthening in them). They all Lose telomere shortening...but they Overcome it by Adding More than losing it (the shortening rate is overcomed).
Shortening rate might be 6000bp/y...it does not matter anymore..if you gained 12,000bp in that last year..you effecitively 'canceled' that loss. 'you froze/halted' the loss. In effect, that is 'maintenance' of the telomere size - no loss - no gain.
With that said, it can't be no loss no gain, forever...at a certain point you do end up losing..so you must actually ADD more than losing, more so than just 'enough to cancel loss'; it needs to be a positive gain above the 'maintenance -no loss no gain'.

I'm still perplexed about it; telomere shortening rate is dictated by its lenght/size..but the causal element to it is by the mitochondrial ROS/oxidation of normal respiration process;
and other 'layers' on top such DNA damage/y-H2AX foci that appears on telomers (telomeric damage that activates DDR) and causes DNA frags SSBs/DSBs in nucleus.
It is why humans can live 120 years healthy or live HGPS (hutchinson gilford progeria) 15 years; 120y = 80bp/y, 15y = 500bp/y. Same thing with dogs, they lose 500bp/y, an live in general 15 years (like HGPS people).
If we can gain more than we lose, then indeed lifespan would be increased, possibly forever (that is if we stop mutations or residue accumulation, and epigenetic age signature to change);
One study in an artic iceland clam of 192 years old (A. Islandica) showed that its mantle foot and heart...lost telomeres with age; but during the 30s age mid life phase..it stabilitzed the telomere loss and Then there was a GAIN continuous gain up to 10kbp...so it maintained tall telomeres
for over 200-250 years...and then around the 200s...there was sudden drop of teloemres once again (this means 'late life' damage of old taking its toll/possibly residues and mutations would cause that). So it HAD TO GAIN telomeres ALL THIS TIME to reach 2 cenutires...gain more than lose;
otehrwise it would not have reach 2 centuries.

Just a 2 cents.

Posted by: CANanonymity at December 12th, 2020 4:32 PM
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