December 18, 2006
Aged Neural Stem Cells Divide Less
In the hippocampus of aged rats the neural stem cells spend less of their time dividing to create new neurons.
The common assumption had been that the brain drain was due to a decreasing supply of neural stem cells in the aging hippocampus, said lead study investigator Bharathi Hattiangady, Ph.D., research associate in neurosurgery. Neural stem cells are immature cells that have the ability to give rise to all types of nerve cells in the brain.
In the current study, however, the researchers found that the stem cells in aging brains are not reduced in number, but instead they divide less frequently, resulting in dramatic reductions in the addition of new neurons in the hippocampus.
To conduct their census, the researchers attached easy-to-spot fluorescent tags to the neuronal stem cells in the hippocampus in young, middle-aged and old rats.
Parenthetically, the hippocampal stem cells are not the only stem cells in brains. But the hippocampal stem cells are important because of the hippocampus's role in formation of new memories.
The rat hippocampus has only 50,000 stem cells and the number does not diminish with age.
They found that in young rats, the hippocampus contained 50,000 stem cells -- and, significantly, this number did not diminish with aging. This finding, the researchers said, suggested that the decreased production of new neurons in the aged brain was not due to a lack of starting material.
The researchers then used another fluorescent molecule to tag all stem cells that were undergoing division in the process of staying "fresh" in case they were recruited to become mature nerve cells.
While the number of hippocampal stem cells does not change the percentage engaged in cell division (during which new neurons are formed) does diminish with age.
They found that in young rats, approximately 25 percent of the neural stem cells were actively dividing, but only 8 percent of the cells in middle-aged rats and 4 percent in old rats were dividing. This decreased division of stem cells is what causes the decreased neurogenesis, or birth of nerve cells, seen with aging, the scientists said.
The reported difference in the percentage of neural stem cells dividing may even understate the difference in the rate of generation of new neurons. If the old stem cells divide more slowly then the difference in the rate generation of new stem cells may be even greater than the multiple of 6.25 (25 divided by 4) we might expect as the difference in rate of new neuron generation.
Replacement of aged stem cells by younger stem cells will some day be a core component of rejuvenation therapies. So how many neural stem cells will we need to replace in our hippocampuses? Some human brains weigh 1400 grams as compared to 2 grams for a rat.. The difference is approximately a factor of 700 (though human and rat brain sizes vary considerably). So if we could create 700 times 50,000 or about 35 million human neural stem cells and inject them into a human brain's hippocampus we should be able to make our aging brains act younger again.
Think about that. We know one of the causes of lower brain performance as we age: A very small portion of all brain cells gradually lose their ability to divide. That portion of brain aging is a problem that seems solvable within a couple of decades at most.
A human brain contains about 100 billion neurons. All the neurons age. We need to find ways to rejuvenate all those 100 billion neurons. That's probably the toughest challenge in human rejuvenation because we have to fix all those cells rather than replace them. But the very small fraction of that 100 billion that are the hippocampal neural stem cells play an outsize role and they are are obvious candidates for replacement.
Now, one issue arises: Suppose we can find a way to deliver new neural stem cells. How to get rid of the old stem cells ones that are already there? Likely the neural stem cells have a mechanism for regulating their total number. So delivery of new younger stem cells might cause some of the older ones to commit cellular suicide (known as apoptosis). But it might be necessary to do several rounds of replacement stem cell therapy to gradually weed out the older stem cells.
What I want to know: If we had a way to create young hippocampal stem cells could needles deliver the cells safely into the hippocampus without causing brain damage in the process? Or could surgeons guide a flexible tube up arteries to the hippocampus to deliver the stem cells that way? Or how else could the stem cells get delivered?
What else I'd like to know: Do people who have better memories have more neural stem cells in their hippocampuses? Or do their neural stem cells get triggered more easily to divide? The potential exists to use replacement neural stem cell therapy as a way to bring in stem cells that are genetically engineered to form memories more rapidly.
This research finding is something I suspected for over 10 years.
Obviously something happens to the molecular machinery in these stem cells that reduces their ability to self-replicate. This process is likely to be one or more of the four that Aubry de Grey discusses in the context of his SENS idea (MtDNA mutations, cellular junk accumulation within and between the cells, Glycation of proteins). These processes slowly damage and render the stem cells less and less capable of replication. If this is true, Aubry is right in saying that stem cell regenerative therapy is unlikely to result in healthy lifespan increase. Indeed, it is likely that stem cell replacement therapy will turn out not to be the most optimal method for regenerative medicine either. Rather, methods that remediate and repair the damage within these stem cells will restore their regenerative capacity which, in turn, will result in regeneration/rejuvination of the rest of the body.
In a way, its kind of an "elementry my watson" finding.
OT : A question on Ethanol,
I read the most recent 3-4 articles you have here on Ethanol. Assuming that corn ethanol is just a preliminary exercise and that switchgrass/other cellulose ethanol technology becomes cost-competitive by 2012, is there not a high chance that the US could replace most of the 140 billion gallons of gasoline we use a year?
I know that Ethanol only produces 2/3 the energy per gallon as gasoline.
So, what do you think are the chances that the US can produce 200 billion gallons of Ethanol per year, available to end users for $2/gallon, by 2015? If not, how about just 50 billion gallons?
I doubt that accumulation of junk messes up stem cells. Their divisions tend to dilute the junk. I would expect most junk accumulates in post-mitotic (no longer dividing) cells. Neurons that are decades old certainly have that problem.
Whether the problem is mitochondrial DNA mutations or nuclear mutations my guess is that mutational damage plays a big role reducing the stem cell division. Also, telomere shortening might be a limiting factor.
Biomass can't scale. There's not enough land. Even if we could scale it I would be opposed because the amount of land used would be enormous. Go back thru my Energy Biomass archive and read my posts and read the comments. In some of the comments threads I hash out various scenarios on how much land would be needed. If you post on those threads I'll see your comments. I get notifications on all new comments made.
Nuclear and solar are my preferred energy sources for the future.
I suspect the reduction in division is due to a 'aging hormone' that generally damps down cell proliferation. This hormone would have been an adaptation to delay the onset of cancer. Young cells would respond to this hormone just as much as older cells, but you couldn't get rid of it without causing the disease it was inhibiting.
I heard a news story in 2004 about a Harvard team researching ways to deliver cell therepies into the brain through a pill in which neurons are stimulated. They were optimistic it could work by 2015 or so, although the news clip didn't provide details.
Yes, there is evidence for the idea that some chemical(s) circulating in the blood as we get older dampen down stem cell vigour. See my post Young Mice Blood Turns On Regenerative Ability Of Old Mice Muscle. That's really bad news for hopes to do stem cell therapies.
This means it is much harder to do small incremental rejuvenation steps. We've got to replace all the cells that send out those signals. But that is hard. Plus, then we'll need therapies to kill off or repair all the stem cells and other cells that are on the verge of going cancerous.
Or we've got to program injected stem cells to ignore those signals for some length of time (say a couple of decades). That's an approach that is more promising to me. But it then becomes yet another problem we have to solve to create rejuvenating stem cell therapies.
That is also a result that makes sense evolutionarily. It makes sense for the body to send out stem cell suppression signals as we get old because the stem cells become greater risks as sources of cancer.
Still, having said all that I still expect youthful stem cells to confer some benefit even in bodies which contain higher levels of chemicals that suppress stem cell division. The suppression signals are probably not the only reason stem cells become less vigorous. Plus, the stem cell therapies will reduce our risk of cancer.
The same mechanism that leads to slower proliferation also leads to slower maintenance-and-repair, which involves autophagy to break down junk, and then re-synthesis. So there might well be accumulation of junk in these cells. Lab animals get fed rubbish food, and age just like we do on our rubbish diet. Iron accumulates, produces free radicals, and is not balanced by sufficient manganese to prevent mitochondrial damage. Zinc is not balanced by sufficient copper. Calcium is not balanced by sufficient magnesium. You can't make protein or ATP without enough magnesium, and your mitochondria will not work without copper.
The first question I would ask about any agent that increases neurogenesis is whether it does so by causing damage elsewhere. In other words, increased neurogenesis could be caused by increased signals indicating inflammation or damage. Not saying that is true for any of the agents you cite. Just keep it in mind.
Second, do antidepressants cause increased neurogenesis in non-depressed people?
Third, do agents that increase neurogenesis do this in the aged? If so, to what extent? In the case of these rats we'd need to increase neurogenesis by a full factor of 6 to achieve juvenile levels of neurogenesis.
Fourth do these factors work additively?
Dr Jane Karlsson said "Iron accumulates, produces free radicals, and is not balanced by sufficient manganese to prevent mitochondrial damage. Zinc is not balanced by sufficient copper."
Dear Dr Karlsson, Roughly what ratio of manganese is needed to balance iron and How much copper is needed to balance zinc? What forms of these elements should be ingested? Do the effects depend on the valance of the metal?
Reports on Cu have been mixed. Some (in the Proc. Nat. Acad. Sci)indicating it causes Alzheimer's in mice and others indicating that it is neuroprotective. Does anyone understand this conflict? What is going on?
Too bad that the current U.S. regime is unlikely to fund research which would answer them.
My guess is that each approach would benefit some of us and harm others.
Stress hormones, e.g., cortisol, probably play a major role in reducing neurogenesis in both aging and depression,
so the anti-anxiety effect seems to play a central role.
Here are some references possibly relevant to some of your questions:
"Inflammation is detrimental for neurogenesis in adult brain" at
"Neuroplasticity in old age: Sustained fivefold induction of hippocampal neurogenesis by long-term environmental enrichment" at http://www3.interscience.wiley.com/cgi-bin/abstract/93521304/ABSTRACT
(too bad it's not 'sixfold')
Lower neurogenesis in those who are younger and depressed is probably not due to some aging process. So I'd expect, say, antidepressants to raise neurogenesis in them.
Environmental enrichment in rodents is done by comparing controlled environments. I'm guessing for most smarter people environmental enrichment isn't needed. I'm not expecting to need to enrich my environment when I get older. I already have far too many things to do that are intellectually interesting and stimulating. I suspect this is true for many others.
As for stress and aging: As we age the expression of inflammation-related genes goes up. Aside from calorie restriction I wonder what else might reduce that. Certainly, if one does bad things like smoking or eating junk food one can stop doing those things. But for someone who eats a good diet and gets some exercise and who is not depressed I have my doubts that any of these above mentioned interventions would help.
Hi Jim Rose,
Thanks for your question. The only way to get the right ratio of these pairs of metals is to eat a whole-food diet. The best way to get the wrong ratio is to eat a lot of meat, which is high in highly-available iron and zinc, and a lot of refined carbohydrate, which has had most of the metals removed. White flour has added iron and calcium, which makes things worse.
Look up 'martha morris copper' on Google Scholar and look at Table 1. The paper implies that copper is bad for the brain, but Table 1 astonishingly shows exactly the opposite. People with the highest intake of copper had a global cognitive score SIX TIMES HIGHER than people with the lowest intake. The authors appear to have made a major error analysing their data.