May 13, 2013 | 1
Aging happens. As you get older, your body slows down, eventually your brain slows down, too. Some things go gradually, and some go suddenly.
To many people, this might seem like a pretty random process. We used to think of aging this way, as just…well cells get old, which means we get old, too. DNA replication after a while starts making errors in repair, the errors build up, and on the whole body scale the whole thing just kind of goes downhill. It seems random.
But in fact, it’s not. There are specific proteins which can help control this process. And one of these, NF-kB, in one particular brain region, may have a very important role indeed.
Zhang et al. “Hypothalamic programming of systemic ageing involving IKK-b,NF-kBandGnRH” Nature, 2013.
(Source by Chalmers Butterfield)
NF-kB (which stands for nuclear factor kappa-light-chain-enhancer of activated B cells, which is why we use NF-kB) is a protein complex that has a lot of roles to play. It’s an important starting player in the immune system, where it helps to stimulate antibodies. It’s important in memory and stress responses. NF-kB is something called a transcription factor, which helps to control what DNA is transcribed to RNA, and therefore what proteins will eventually be produced. Transcription factors, as you can see, can have a very large number of functions.
But in the hypothalamus, NF-kB may have the added function of helping to control aging. The hypothalamus is an area of many small nuclei (further sub areas of neurons) located at the base of the brain. It’s been coming more and more into vogue lately among neuroscientists. In the past, we were interested in the hypothalamus mostly for its role in controlling hormone release from the dangling pituitary gland before it, but now we are learning that the hypothalamus can play roles in fear, mood, food intake, reproduction, and now…aging.
Zhang et al, from the Albert Einstein College of Medicine, were interested in what role NF-kB played in mouse aging. They looked at mice where NF-kB was labeled with GFP (to may it glow a nice green).
You can see above that as mice become old (the bottom panel), the amount of NF-kB increases drastically. So increases in NF-kB in the hypothalamus are definitely correlated with aging.
Now the question becomes: what does this mean? Is it just a correlation, is NF-kB a side-product of some other aspect of aging, say? Or does NF-kB have a significant role to play in aging itself?
To look at this, the authors used gene transfer (using a harmless virus that inserts a gene into the mouse genome where you inject it), that either specifically increased NF-kB in the hypothalamus, or specifically decreased NF-kB in the hypothalamus of middle-aged mice (you want to use middle-aged mice in this case, so that you avoid potential developmental differences, and can just look at aging). Then they just got simple: they looked at how long the mice ended up living.
What you can see above is a survival graph, something you see a lot of in things like aging study and toxicity. The descending lines are the % of animals still alive at the time point (on the x axis). So you can see that control mice (in red) lived around 1000 days (a little less than three years, old mice!), while if you INCREASE NF-kB (in blue) they don’t live as long. On the other hand, if you DECREASE Nf-kB (in green), the animals lived a bit longer (about 7 months longer, which is a good while in mice).
The mice didn’t just live longer. They also had better memories, stronger muscles, and stronger skin. So while they still aged, they appeared to age slower than normal mice.
And it’s not just NF-kB. If you decrease IKK-beta, which activates NF-kB, you get something similar: longer lived mice.
Here you can see that the normal mice still lived about 1000 days, while the mice without IKK-beta lived longer.
Now the question becomes how this was working. NF-kB, after all, plays a lot of different roles in stress response and inflammation. The authors decided to look at GnRH, gonadotropin releasing hormone, a hormone that many of us scientists usually associate with things like control of ovulation. But GnRH has other functions, and one of them, as the authors of this paper discovered, was in promoting the birth of new neurons in adult mice.
GnRH is released during puberty and adulthood, and is inhibited by high levels of IKK-beta and NF-kB. So it is possible that, by going downstream of IKK-beta and NF-kB and increasing GnRH, you might be able to get the aging effects seen in the other experiments.
And sure enough, injecting GnRH directly into the hypothalamus increased neurogenesis, increased muscle endurance, and increased the memory capacity of the aged mice, very similar to the effects seen with IKK-beta and NF-kB (though they did not check to see if these mice also lived longer).
So it looks like IKK-beta stimulates NF-kB, which inhibits GnRH, and that this pathway could help mediate longevity, as well as the age related changes in mice. It’s a nice way to show a potential mechanism. This research gives you a question (what is the role of NF-kB in aging?), an answer (higher levels of NF-kB promote aging, and lower appears to slow aging), and then provides a mechanism (how does it work? through GnRH).
Now, this is not the fountain of youth. All the mice eventually died. And all of the peptides involved, NF-kB, IKK-beta, GnRH, have far more things to do in the body than simply controlling aging, so changing levels of these proteins in humans could have effects that are far outside the desired ones. But still, this has lots of implications. For one, it could be important when looking at diseases where premature aging occurs (progeria). I’m also particularly interested in the changes that the authors of this study got in hippocampal neurogenesis (the birth of new neurons they saw when they gave GnRH). As you might know, hippocampal neurogenesis can be very important, not only for memory, but for things like mood. It might be interesting to look at NF-kB and GnRH in people with severe age-related memory loss, for example, and see if new treatments might be possible. It would also be interesting to look at things like age-related depression, and how NF-kB and GnRH might play into it.
While these results are still young (heh), they reveal an interesting new target for research on how, and why we grow old. It will be interesting to see how it ages.
<span title=”ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Nature&rft_id=info%3Adoi%2F10.1038%2Fnature12143&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Hypothalamic+programming+of+systemic+ageing+involving+IKK-%CE%B2%2C+NF-%CE%BAB+and+GnRH&rft.issn=0028-0836&rft.date=2013&rft.volume=497&rft.issue=7448&rft.spage=211&rft.epage=216&rft.artnum=http%3A%2F%2Fwww.nature.com%2Fdoifinder%2F10.1038%2Fnature12143&rft.au=Zhang%2C+G.&rft.au=Li%2C+J.&rft.au=Purkayastha%2C+S.&rft.au=Tang%2C+Y.&rft.au=Zhang%2C+H.&rft.au=Yin%2C+Y.&rft.au=Li%2C+B.&rft.au=Liu%2C+G.&rft.au=Cai%2C+D.&rfe_dat=bpr3.included=1;bpr3.tags=Neuroscience”>Zhang, G., Li, J., Purkayastha, S., Tang, Y., Zhang, H., Yin, Y., Li, B., Liu, G., & Cai, D. (2013). Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH <span style=”font-style: italic;”>Nature, 497</span> (7448), 211-216 DOI: <a rev=”review” href=”http://dx.doi.org/10.1038/nature12143″>10.1038/nature12143</a></span>