January 28, 2006
Immune System Rejuvenation May Partially Rejuvenate Brain

The brain is going to be the the hardest organ in the body to rejuvenate. We will not be able to replace the brain since it contains our individual identity. So we'll need to repair it in place. By contrast, some day we'll be able to grow replacements for other organs in the body such as the liver, kidneys, heart, or pancreas. Since the brain is the hardest rejuvenation therapy target I'm always heartened by any research that suggests promising avenues for development of brain rejuvenation techniques. A team of researchers in Israel have made discoveries that suggest rejuvenation of the immune system might some day partially slow or partially reverse the aging of brains.

REHOVOT, ISRAEL -- January 16, 2006 -- A team of scientists at the Weizmann Institute of Science, led by Prof. Michal Schwartz of the Neurobiology Department, has come up with new findings that may have implications in delaying and slowing down cognitive deterioration in old age. The basis for these developments is Schwartz's team's observations, published today in the February issue of Nature Neuroscience, that immune cells contribute to maintaining the brain’s ability to maintain cognitive ability and cell renewal throughout life.

Until quite recently, it was generally believed that each individual is born with a fixed number of nerve cells in the brain, and that these cells gradually degenerate and die during the person's lifetime and cannot be replaced. This theory was disproved when researchers discovered that certain regions of the adult brain do in fact retain their ability to support and promote cell renewal (neurogenesis) throughout life, especially under conditions of mental stimuli and physical activity. One such brain region is the hippocampus, which subserves certain memory functions. But how the body delivers the message instructing the brain to step up its formation of new cells is yet unknown.

Schwartz's group believes immune system T cells enter the brain to carry out functions beneficial to the brain. Schwartz already found evidence that immune cells carry away toxins. She now presents evidence that immune T cells stimulate brain stem cells to produce new nerve cells (neurogenesis).

The central nervous system (CNS), comprising the brain and spinal cord, has been considered for a long time as "a forbidden city", in which the immune system is denied entry as its activity is perceived as a possible threat to the complex and dynamic nerve cell networks. Furthermore, immune cells that recognize the brain's own components ("autoimmune" cells) are viewed as a real danger as they can induce autoimmune diseases. Thus, although autoimmune cells are often detected in the healthy individual, their presence there was perceived as an outcome of the body's failure to eliminate them. But Schwartz’s group showed that these autoimmune cells have the potential ability if their levels are controlled to fight off debilitating degenerative conditions that can afflict the CNS, such as Alzheimer’s and Parkinson's diseases, glaucoma, amyotrophic lateral sclerosis (ALS), and the nerve degeneration that results from trauma or stroke.

In their earlier research, Schwartz and her team provided evidence to suggest that T cells directed against CNS components do not attack the brain but instead, recruit the help of the brain's own resident immune cells to safely fight off any outflow of toxic substances from damaged nerve tissues.

In the present study, the scientists showed that the same immune cells may also be key players in the body's maintenance of the normal healthy brain. Their findings led them to suspect that the primary role of the immune system's T cells (which recognize brain proteins) is to enable the "neurogenic" brain regions (such as the hippocampus) to form new nerve cells, and maintaining the individual's cognitive capacity. The research team led by Prof. Schwartz, included graduate students Yaniv Ziv, Noga Ron and Oleg Butovsky, and in collaboration with former graduate student Dr. Jonathan Kipnis and with Dr. Hagit Cohen of the Ben-Gurion University of the Negev, Beer Sheva.

Mice lacking T cells generate fewer new neurons in response to a mentally stimulating environment.

It was reported before that rats kept in an environment rich with mental stimulations and opportunities for physical activity exhibit increased formation of new nerve cells in the hippocampus. In the present work, the scientists showed for the first time that formation of these new nerve cells following environmental enrichment is linked to local immune activity. To find out whether T cells play a role in this process they repeated the experiment using mice with severe combined immune deficiency (scid mice), which lack T cells and other important immune cells. Significantly fewer new cells were formed in those mice. On repeating the same experiment, this time with mice possessing all of the important immune cells except for T cells, they again found impairment of brain-cell renewal, confirming that the missing T cells were an essential requirement for neurogenesis. They observed that the specific T cells that are helping the formation of new neurons are the ones recognizing CNS proteins.

To substantiate their observations, the scientists injected T cells into immune-deficient mice with the objective of replenishing their immune systems. The results: cell renewal in the injected mice was partially restored finding that supported their theory.

In another set of experiments, they found that mice possessing the relevant CNS-specific T cells performed better in some memory tasks than mice lacking CNS-specific T cells. Based on these findings, the scientists suggest that the presence of CNS-specific T cells in mice plays a role in maintaining learning and memory abilities in adulthood.

The use of the immune system to carry away toxic substances could potentially include removal of intracellular and extracellular junk. The removal of such junk is one of the major SENS (Strategies for Engineered Negligible Senescence) categories for the development of rejuvenation therapies. The use of the immune system to stimulate the production of new cells is also another SENS category.

Rejuvenation of the immune system would bring other advantages aside from encouraging neurogenesis. People would become less susceptible to death from infections in old age. Infections would not last as long and one would become less susceptible of getting sick in the first place. Also, a sufficiently sophisticated immune system rejuvenation would cure many auto-immune diseases.

This result illustrates a more general point about rejuvenation therapies: Rejuvenation of some subsystems of the body will cause other subsystems to work better. An aged subsystem will work better if other subsystems become young again. We do not have to make every part of the body younger to make the entire body function more youthfully overall.

Share |      Randall Parker, 2006 January 28 07:53 PM  Aging Studies

Lou Pagnucco said at January 28, 2006 10:23 PM:

Perhaps the following observations are relevant-

SSRIs (and other anti-depressants) lead to neurogenesis in the hippocampus.
The following reference indicates that the immune system may be involved:

"Popular Antidepressants May Also Affect Human Immune System"

The aging male brain loses mass faster than the female brain.
Possibly, steroid effects on the immune system are responsible.
For example, refer to:

"Aromatase inhibitors regenerate the thymus in aging male rats"

"Immunosenescence: potential causes and strategies for reversal"
A couple of excerpts:

"Treatment with interleukin 7 leads to a reversal of thymic atrophy with increased thymopoiesis"

"Analysis of the effect of testosterone also revealed an intricate involvement with thymic
cellularity. Surgical or chemical castration of old rats was shown to lead to the
reappearance of a histologically normal thymus, in contrast with sham-operated animals
[52,53], and the regeneration of the thymus in castrated animals was inhibited by
testosterone implants."

Randall Parker said at January 29, 2006 2:49 PM:


What I've always wondered about thymus aging is why? What causes it to shrink? Is the entire immune system really set into decline by a single organ's aging?

Also, can its aging really be so easily reversed? If interleukin 7 can restore it so easily then why doesn't the body make more interleukin 7? I'm suspicious that there's got to be a downside to supplying more of a single hormone.

I wonder if the thymus declines as a way to reduce the risk of leukemia and other blood cancers that would come from more stimulus for immune cell division.

John Schloendorn said at January 29, 2006 7:09 PM:

"thymus aging is why? What causes it to shrink?"

The t-cell immune response consists of both "naive" cells generated in the thymus (those searching the "antigen-space" for new things foreign to the body) and "memory" t-cells that already "know" one or the other pathogen. The thymus is only good for the naive generation of new t-cells.
Now what's important is that the memory response is much more efficient at dealing with known pathogens than the naive de-novo searching (or else vaccinations wouldn't work). So it seems to make some evolutionary sense to shut down de-novo generation of t-cells in favor of memory t-cells as an animal acquires an increasing repertoire of efficient memory t-cells.

So thymus aging comes only at the sacrifice of dealing with really new things, but we used to be much less mobile in the past when these things evolved, so it might have been pretty unlikely to run into something genuinely new once you'd been around for a couple of decades.

And in addition, as we get very old, in most people the memory t-cells develop their own problems (subsumed as "anergy"), which is quite independent of what happened earlier to the thymus and naive t-cell generation, but it does break the last backbone of your defense.

Randall Parker said at January 29, 2006 7:16 PM:


Thanks for the info. Perhaps you can address another question about aging immune systems: I've read that as the immune system gets older some of those memory T cells grow excessively in number. T cells aimed at fairly small number of targets just divide too much and therefore excessively decrease the diversity of the memory T cells.

Do you know anything about this? Seems a little like cancer in the sense that these cells divide too much. I wonder if some T cell lines develop a reduced ability to respond to signals that limit their proliferation or whether the problem is more from other cells telling them to divide too much, perhaps due to inflammation?

Is "anergy" that process or is "anergy" something else?

Lou Pagnucco said at January 29, 2006 9:57 PM:

This is certainly a very complex topic.

Possibly, loss of naive T-cell production is only part of the problem, since the thymus produces many
hormone-like substances with poorly understood functions.
(See "Introduction to Basic Immunity" at http://www.bioproteinplus.com/images/AHC-Thymus%20Report.doc)

It is worth noting that transplanting a juvenile thymus into a old animal can reduce symptoms of autoimmunity
even though memory T-cells produced earlier still continue circulating.
(See "Thymus transplantation, a critical factor for correction of autoimmune disease in aging MRL/+mice"
at http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=38711)
If major human autoimmune diseases could be suppressed with thymic regeneration/transplantation, at least quality of life would be improved. I am not aware of any studies examining longevity for this type of transplant.

I haven't found any studies in which an old thymus was grafted into a young immunologically compatible animal, but it would be interesting to know how it effects autoimmunity and longevity.

Randall Parker said at January 30, 2006 3:40 PM:


Thinking about the reduction in autoimmune response when a young thymus is transplanted I wonder if a young thymus transplant would generally reduce immunity. Maybe it would reduce immunity against some pathogens the host had previously encountered but would be better at responding to first exposures to new pathogens.

With development of a larger set of vaccines one could train a transplanted youthful immune system to make it have more of the advantages of an older immune system in terms of "experience" while retaining the advantages of a more youthful immune system.

Lou Pagnucco said at January 30, 2006 10:57 PM:


You could be correct. It would be interesting to see what results when a young thymus is transplanted next to the
already existing thymus in an old animal.

Here are some additional questions I'd like to have answered:

If a involuted thymus is rejuvenated in an old animal (e.g., by interleukin 7, or by anti-androgens) so
that it is "histologically normal",
-- does it atrophy again immediately when the treatment is stops, or does it resume
atrophying at a normal rate? (i.e., does temporary therapy reset the thymus aging clock?)
-- when transplanted into a younger animal, does it function as a young thymus?

John Schloendorn said at January 31, 2006 8:05 PM:


Yes, you got it. Unfortunately it is precisely the anergic ones that expand. Someone on the SENS2 conference (was it Campisi?) mentioned some interesting work regarding the identification of anergy-driven promoters in those T-cells. If you could charge those with a suicide gene, maybe that can take care of some of the problem.
But to get such engineered t-cells into the body one would first need a form of bone-marrow transplantation that doesn't do more damage that it is supposed to fix... I think current "reduced intensity conditioning" regimen might be getting there slowly. If they are ever perfected, it could become a very powerful platform for tampering with the blood cells for this and many other ends.

Lou, as far as I know, a transplanted young thymus will atrophy rather rapidly and the benefit to thymopoiesis is transient. I think someone (mackall?) was trying to engineer T-cells to secrete IL-7 in the thymus to prevent this from happening, but I'm not sure what happened.

Lou Pagnucco said at February 1, 2006 8:40 AM:


Thanks for the information.

Do you know whether the atrophy was observed when the transplant was from a highly immunologically compatible animal?

I wonder if a thymus transplant would fare better between clones.

John Schloendorn said at February 1, 2006 1:21 PM:

I believe this was done in a strain of lab mice, so they should be genetically identical. Check out work by Mackall though, it's pretty fascinating.

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