In genetic experiments with worms in the 1990s, DAF-2 was one of the first genes discovered that curtails life span. Delete the DAF-2 gene, and the worm lives longer. But by what mechanism? No one had the least idea. Gary Ruvkun’s lab at Harvard found a way to ask a fundamental question , using genetic manipulations that were just becoming available at the time.
Normally, of course, every cell in the body has exactly the same DNA. But Ruvkun was able to prepare “mosaic” worms with different genes in different areas of the body. Lab worms are simple creatures with just three kinds of tissue comprising most of their 959 cells. So he had three kinds of worms, with
- DAF-2 genes only in the intestinal and digestive cells
- DAF-2 genes only in the muscle cells
- DAF-2 genes only in the nerve cells
What he learned (2000) was that it was only through the nerve cells that DAF-2 shortens life span.
This was the first indication that maybe there are nerve networks that calculate life span, based on many sensory inputs, internal and external. Maybe the length of our lives is decided in our neurons. That’s an over-statement to be sure, but what has become clear is that the nervous system has a substantial role in dictating life span, and this is true in mammals as well as worms.
The biggest factor affecting life span from the outside is availability of food. Of course, it’s a conundrum for the traditional view of aging (based on accumulated damage): why is the body able to protect itself from damage better when it is starving? Biologists have looked and looked for metabolic effects, and traced the biochemistry through the metabolism of the blood-sugar regulating hormone insulin, and the fat cells that signal to ignite self-destructive inflammation. So we are able to understand how, but not why the metabolism is not able to protect itself from these effects when food is plentiful..
But it’s not about “able” so much as “willing”. The body is programmed to die on schedule when the population has what it needs to be fruitful and multiply, but to hold off the genetic source of death at the individual level when famine is more of a threat than overpopulation. As if to underscore that this is a choice, rather than a direct consequence of biochemistry, life extension through caloric restriction is found to be mediated through the nervous system. The UCSF laboratory of Cynthia Kenyon has reported (1999) that destroying the worm’s tiny chemical sensor, the smeller/taster that detects the presence of food, can extend the worm’s life span even as though it were starving even though it has plenty to eat.
Soon it was discovered that, in mammals, too, the signals that mediate the effect of food in shortening life span are also coordinated through the central nervous system. In response to eating, the body secretes insulin to make sure that blood sugar doesn’t get dangerously high. But in addition to this short-term effect, the insulin signaling has a long-term effect that hastens the aging process. Holzenberger (2004) first suggested that the hypothalamus is the switchboard in the brain from which endocrine signals are sent that shorten life span in response to food. In a 2009 review, Susan Broughton and Linda Partridge summarized the case against the CNS as culprit in translating the body’s insulin signals into a pro-aging message. It’s complicated, they add, because the nerves themselves seem to benefit from insulin signaling, so that insulin might protect the aging CNS, even as the CNS does the dirty work of generating the signals that age the rest of the body. They express hope that the protective benefit of insulin can be separated from the pro-aging signal. The knockout experiment (excuse the pun) was performed in 2007 in the Harvard lab of Morris White. A gene that receives insulin signals was knocked out not in the whole mouse but just in the brain (by now mosaic experiments are routine). The result was mice that are obese and diabetic and insulin-resistant but still their life spans were extended, compared to controls. Despite being published in Science, this experiment has not received attention commensurate with its promise, perhaps because its methods were so technical.
Outside of diet, some of the primary factors that predict life span in humans are social. People live longer when they are needed, when they have in close family ties, when they have status and importance in their communities. This seems to be true even after the access to good food, healthy environments, and better medical care are factored out. And it may be true in other non-human primates. This doesn’t tell us anything about mechanism, but again it is suggestive of a central role for the brain in regulation of aging.
This brings us to the results published this week in Nature from the lab of Dongsheng Cai at Einstein College of Medicine in New York. Excess inflammation has been recognized for a long time as a direct mechanism of aging. Inflammation increases cancer risk, destroys arteries, and plays a role in Alzheimer’s disease (here is my blog post on the subject).
The new study shows that there is also an indirect effect of inflammation that magnifies its pro-aging effect. Inflammation is detected in the hypothalamus*, and pro-aging signals are sent out as a result. Since these signals further increase inflammation, this could be one of those self-reinforcing loops that accelerate our demise, and are relatively easy to disrupt via medical intervention. (Cai spoke of ‘cascading benefits’.) The mechanism described in Cai’s paper involve two more ingredients from the genetical alphabet soup: NF-kappa-B is emitted in response to danger, and switches on the gene transcription in a cell in a manner appropriate to emergency response. NF-kappa-B increases with age and promotes higher levels of inflammation — Boooo! GnRH is a signal that commands the reproductive cycle (M as well as F) and incidentally works to protect the body from aging — Yeaaa! Inflammation increases NF-kappa-B in the hypothalamus, and this, in turn, reduces the flow of GnRH.
When the researchers added GnRH to the hypothalamuses of old mice, they saw that it promoted adult neurogenesis. When they injected mice with GnRH, the mice showed reduced signs of aging. (from The Scientist)
The one-line take-home is that blocking NF-kappa-B in the hypothalamus increased the life span of mice by 20% (press release). And that’s as close as I can come to a simple story with a single magic bullet.
*The hypothalamus is a tiny organ in the lower midbrain that takes nerve signals (electrical) and transduces them into hormonal signals (chemical) for transmission throughout the body.
This article originally appeared here: http://joshmitteldorf.scienceblog.com/2013/05/05/role-of-the-nervous-system-in-deciding-how-long-we-live/