A Different Take on NF-κB and the Hypothalamus

As reported a couple of days ago, researchers have again demonstrated a link between aging and NF-κB, altering its levels in the hypothalamus it to both modestly lengthen and shorten life in mice. This may be completely a matter of dialing down chronic inflammation in later life, or it may also touch on other common ground in the overlap between metabolism and aging such as insulin signaling.

In the course of their work, the researchers followed some of the connections in this biological jigsaw puzzle to study other proteins and genes involved in generating extended life in mice via inhibition of NF-κB in the hypothalamus. One of these is gonadotropin-releasing hormone (GnRH), and the researchers found that enhancing its levels in the hypothalamus has much the same effect as inhibition of NF-κB. This side of the research gained the attention of the fellow who runs Extreme Longevity:

Can GnRH Administration Reduce Aging?

[The scientists] showed that regular GnRH administration to middle aged mice increased the number of brain cells and reduced signs of aging in the animals. To wit they specially said "GnRH treatment (peripheral) reduced the magnitude of ageing histology in control mice," and "GnRH led to an amelioration of ageing-related cognitive decline."

But of course the holy grail question here is simply can regular peripheral administration of GnRH increase lifespan? I contacted lead author Dongshen Cai MD-PhD and asked if the group had any lifespan data on regular GnRH treatment.

"We don't have lifespan data regarding GnRH treatment," he replied.

Too bad. Imagine if simply a weekly or so injection of GnRH from early middle age onwards could lead to decades more good health and reduction of disease? [Clearly] this is an experiment that should be tried in animals right away. Fortunately Dr. Cai agrees, "it is in our plan," he says.

It has to be said that I generally don't think of this sort of study in these terms. I'm not looking to see whether there's a treatment that can be pulled out, because in most cases a 20% life extension in mice by some form of metabolic manipulation (gene therapy, altering levels of proteins, and so forth) isn't going to be all that relevant to the future of human longevity. For one, it's not rejuvenation, it's only slowing aging. Secondly, mice have very plastic life spans, as is the case for most shorter-lived species. All sorts of things that are either known to do very little to nothing for human life span or are expected to do very little to nothing for human life span can nonetheless extend life by 10%-30% in mice.

So what I see here in the NF-κB / GnRH work is the potential for a therapy that might be applied to modestly reduce inflammation or improve the metabolic profile of older people. Something comparable to rapamycin, in other words, a marginal gain. Perhaps it's a little better than today's best therapies that produce similar effects, and perhaps it's not. I'll wager that it's not going to be as good as regular exercise and calorie restriction. So overall it's not something that I'd give a lot of time and interest to. As a general rule if a research result isn't producing actual rejuvenation then it's not going to have the potential to be a part of greatly extending lives in humans. We have a medical industry presently near-entirely focused on picking mechanisms like this and then using them to produce palliative, marginally effective patches to slap over some of the end stage consequences of aging. The dominant paradigm is to try to alter metabolism late in the game for a small benefit, and without attempting repairing the underlying damage that caused all the harm in the first place. This is a paradigm doomed to poor results, high costs, and ultimate failure.

We have to move on past this methodology of medicine and clinical application of research. The future is SENS and similar projects that aim to repair the causes of aging rather than putting patches on the consequences. It seems fairly clear to me from the performance of the medical establishment to date that only repair can be reliably expected to grant us additional decades of healthy life.


I digested this paper in the context of older results that demonstrate the role of the brain in regulating aging. This is striking, and worth pointing out, even if it isn't new. The hypothalamus is the brain's press secretary, transducing nervous signals into endocrine signals for transmission through the body. The brain can decide the body needs to age faster, and send signals via the hypothalamus to make us older. To the extent that the story is really so simple, we have a promising target for intervention.


Posted by: Josh Mitteldorf at May 5th, 2013 6:27 PM
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