What is the Contribution of Demyelination to Cognitive Decline in Aging?

Myelin is an insulator that sheaths the axons forming nervous system connections. It is essential to the correct electrochemical function of the nervous system. Severe conditions such as multiple sclerosis result when myelin is lost, degrading nervous system function to the point of disability and death. In normal aging, myelin is also lost, though to a lesser degree. It is reasonable to think that this contributes to neurodegeneration and cognitive decline, but the only straightforward way to determine the relative importance of demyelination versus the many other mechanisms at work in the aging brain is to fix the problem in isolation and observe the results.

Like all structures in the body, myelin must be constantly maintained by a dedicated hierarchy of specialized cells. In this case, this means oligodendrocytes and their precursors. Significant disruption of this population results in demyelination. There is a good deal of evidence to suggest that oligodendrocytes are negatively affected by mechanisms of aging, such as the growing chronic inflammation provoked by the secretions of senescent cells. The population diminishes in size and undergoes changes in behavior. Thus strategies focused on restoration of oligodendrocyte populations via cell therapy, or at least the restoration of their youthful behavior via suitable delivery of signals, may be a good approach to restoring lost myelin and evaluating contribution of demyelination to cognitive aging.

Replenishing the Aged Brains: Targeting Oligodendrocytes and Myelination?

Age-related neurofunctional decline may negatively impact the daily life for the elderly, and no effective strategies are available so far in the clinic. This present review mainly focuses on myelin degeneration, decreased myelinogenesis during aging and the possible mechanisms. Admittedly, a lot of questions remain unanswered. For instance, are there spatial or temporal differences in the degeneration process in the central nervous system (CNS)? What is the deciding point for one oligodendrocyte (OL) or one myelin segment to initiate degeneration and could we inhibit this bad process through modulating one key factor? Is the newly generated myelin more stable compared to preexisting myelin in the aged brain? If this is the case, we may find some clues about repressing myelin degeneration in the aged. The decreased myelinogenesis during aging is likely a result of arrested differentiation of oligodendroglia precursor cells (OPCs), thus it is plausible that promoting adult OPCs maturation may be a feasible and realistic approach to improve age-related neuronal function decline for the elderly. Meanwhile, rejuvenating subventricular zone (SVZ) stem cells may also help with myelinogenesis ability in the aged. More efforts are needed to further confirm those effects in human.

Moreover, oligodendroglial lineage cells display more behaviors than differentiation and forming new myelin sheaths. For example, OPCs may form synaptic connections with neighboring neurons, and that regulates neuronal signals in the CNS. In addition, the expression of connexin channel proteins in oligodendroglial lineage cells is an intriguing feature and the connexins could function either as hemichannels or gap junctions. The gap junction enables OLs to be connected as a glial network with astrocytes, allowing transportation of small molecules such as calcium and energy metabolites, which may be important for homeostasis of the CNS. Recent studies even showed that OPCs could exert immunomodulatory functions, which are particularly relevant in the context of neurodegeneration and demyelinating diseases. Besides, OLs are found to be heterogenetic in the mouse juvenile and adult CNS, the response of different subtypes to aging remains unknown. It is not clear whether the functions mentioned above and their correspondent molecules are altered during aging. Future works are needed to give us a more comprehensive understanding of the role oligodendroglial lineage cells played in aged brains, which could shed light on the clinical therapeutic strategies considering age-related neuronal functional diseases.


Merry Christmas to you Reason. Thanks for all that you do.

Posted by: Matt Pease at December 23rd, 2021 3:15 PM

Likewise/seconding, Merry Christmas Reason, Matt and every one else coming to fightaging.org and caring about defeating aging or improving health for all...Thank you very much.
And a Happy New Year 2022...! Let's hope for the best.
To your continued great health (and long longevity/life)...

PS: -Rejuvenation advancements, progresses, to happen. One more year...and to think that SENS and other endeavors were all started over 15-20 years ago (that mirage thing again - grasping at ghosts/(des)illusions); let's hope the pace (and funds) accelerate.....instead of dry/slow (with the pandemic being both bad and good at the same time on biogerontology/ biorejuvenation domain; the pandemic showed that the bureaucratic red tape can be reduced and things can accelerate - because of imperativity of the aging process and people dying of it (or in the pandemic case, the covid/virus requiring attention now); it's not to say we wish to skip the process (that is needed so that things are secure and not dangerous experimentation with 0 safety/spin the roulette and hope nothing goes wrong taking the therapy (risks/2ndary side-effects)); but we wish to speedy it up and have more clinical data/trial, faster, because too long; in the end, it most likely will be 'a big experiment'...and you will have to take your chances. It's why I said earlier, that we have to calculate the risks to interventions to reverse aging; and, put that in consideration, to the speed at which new stuff will happen (like therapies of the future). Because, it's a safety/regulation vs speed/time/money/concretization thing....just a 2c.

Posted by: CANanonymity at December 23rd, 2021 5:55 PM

AGEing is the biggest pandemic there is and ever was. But World Health Organization recognizes only new diseases as pandemic. And Old Age is a very Old Disease. It is endemic in the population. Therefore there is NO SENSE of urgency for most researchers, officials, to cure it, except for SENS organization. Every one of us (humans) is one more year older compared to last year in December. One more year closer to the grave (appointment with grim reaper). But none of us was rejuvenated by one year.
Real progress in Longevity / Rejuvenation will be when every passing year humans will be rejuvenated by one year and one year is added to our LIFE SPAN.

Now , about the subject of this article : neurodegeneration and cognitive decline in Old Age. Those who experience it - can not be wise. Old Age does not bring wisdom - it brings a lot of stupidity, foolishness , and mental disability. Wisdom - if anyone has it, is in middle age, some one who was practicing life long learning, before any cognitive decline and neurodegeneration. Someone who ages slowly may avoid cognitive decline in his / hers eighties. But usually / generally Old age means physical and mental decline and associated suffering - and urgent need for cure.

So why is there no sense of urgency to end the Pandemic of Aging?
Because to cure Aging will be too expensive. Oldsters are easily replaced by new generation of young people. It is much cheaper to replace Old Humans with Young humans - from society's and governmental point of view. But from your personal , individual point of view - you don't want to be replaced, die so the young can continue to live. Your individual instinct of self-preservation screams : " I want to live for ever, and let society's values be damned"
Humans are treated like Old Cars or any other Old machine / equipment- when old car is so old that repairing it will cost much more than scrapping it and buying a new car. Usually , the old car is replaced by a new one ( the old one goes to scrap yard to be recycled).[grave yard for old dead humans]
In rare cases, some wealthy person may decide to restore, repair , renovate the old car - even if it costs much more than buying a new one. So by analogy, if there ever will be real rejuvenation/renovation of humans - it will be done in rare cases to wealthy individuals.

Posted by: Nicholas D. at December 26th, 2021 12:41 PM

@Nicholas D

For many centuries it was not simply too expensive it was impossible and it still is. There were charlatans and delusional healers. At the end, it was proven time and time again that it is a fool's errand to try to fight aging. Therefore, the rational and smart approach is to make peace with it and don't waste the precious little time left on chasing the philosopher's stone.

What is interesting, for a medical technology to be perfected it has to be used on massive scale. For sure, a billionaire can pay for a custom lab to do genetic modification and grow organs. However, if it is one-off it will always be too risky and expensive. Would the richest person in the world want to be a guinea pig ? A couple of billionares might want to be. Yet, most of the effort is R&D with some lab equipment and technician time . Once such an effort is done , the second time it could be done much cheaper.

But let's imagine a nice movie plot. A billionaire (apparently not Musk, who doesn't believe it , but say Bill Gates or Bezos ) hires the best minds in biology and medicine to buy him 30 more years. Unless it involves killing a fully adult clone (there's a nice movie "The Island", which was funny to watch. However, the plot allowed for memory transfer by the somatic cells. Nobody payed attention that this is a kind of personal immortality) , all the researchers will try to replicate the results for themselves. And they will do it at much lower cost. So the "second-hand" treatments that were stolen or leaked from the lab will be affordable now to the regular millionaires (say net worth > $10M ). The third wave will bring the cost down to be within the reach of the upper middle class. From that point on , it is a question of bringing the costs down to the average joe/jane.

What is ironic, that for a medical treatment to be safe it has to be widely used . To have a large patient base which will experience all the weird corner cases and side effects.

There will always be some expensive procedures, but the bulk of the costs are R&D and regulatory approval. All the once-expensive procedures become more affordable over the time. At the end there will be tens of therapies each one costing like the top trim lasik, say 3-10K. Quite pricey for the whole set but still much cheaper than paying for keeping a 90years old on constant life support with a nurse on standby and several visits a year to the emergency. Eventually all of those procedures will be done as preventive treatment to everybody where there's a meaningful medical system(poorer countries will use the cheapest materials and treatments, of course). And there's a rule of thumb that by doubling the user base/production you reduce the costs by 15%. going from a single person to 4B people is 32 doublings (the 4GB Ram limit for the 32-bit machines has the same nature) will bring the cost from 100 to 1000 times down. And this is for the treatment alone, which is dwarfed by the R&D expenses.

I am surprised that there's so little investment in the area. After all, Uber managed to get so many billions when it was clear that they are just burning the cash. There are so many examples of huge money being invested on patently stupid things. Yet the whole longevity field is probably less than a billion. Anybody with the first generation human treatment will be able to fleece the millionaires and they would be happy. Then after a few years make the treatments mass-produced and make even more money. Probably the venture capital is too skeptical or doesn't see an immediate path tho the monetization yet.

Anyway, what we most likely will see is some partial repair in more narrow areas. Like removal of the atherosclerosis plaque (waiting for news from Repair Bio), senolytic treatments, stem cell therapies, organ printings, anti-cancer vaccines and such. Nobody will walk out 30 years younger even if combining all the treatments but the people will be healthier and be able to live longer.

Posted by: Cuberat at December 26th, 2021 5:24 PM
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