A new report this week about signals from hypothalamus reminds us that some of the biggest influences on longevity are mediated through the nervous system. To this extent, the decision about how long to live comes from a calculation made in the brain. The new research suggests a hormone known as GnRH as a relatively simple signal by which aging might be slowed, and another signal called NF-kappa-B promotes aging and might be blocked to slow aging.
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.
FightAging.org has a radical take on anti-aging technology. They’re going for the gold – shutting down aging at its source – and they’re not so interested in interventions that might add a few decades to our lives.
In this week’s post, they ask the most practical question: can administration of GnRH lengthen life span of mice? Dr Cai responded by saying he doesn’t know, but asking that question is a priority for his next round of experiments.
I often use thymic protein A , Pro-Boost, for immune enhancement; also 1,3 beta glucan.
The most effective substance at safely down regulating NFkB is anatabine citrate. More effective than NSAIDs, Cox-2 inhibitors, Steroids, or Statins. See Roskamp Institute and watch the March 2014 investor conference at Star Scientific. The video demonstrates some amazing science and experiments with mice.
WEB search anatabine NFkB then look for Anatabloc. Take as directed, sublingually, daily, 2 x 4hrs, and it will be the first nutraceutical to make a material difference in how your body feels.
Anablock must work good; because the FDA called it it a drug and the company suspended sales. 🙁
Resveratrol and curcumin both down regulate NF-kB, as well as does dietary restriction. NF-kB is an emergency response factor that when activated enters the nucleus, and activates any of several sets of genes such as anti-pathogen, growth, inflammation and other necessary pathways. However, as we age NF-kB gets over-activated (probably by one or more of the AGE genes) and causes too much inflammation, leading to atherosclerosis, arthritis, and even cancer, among other diseases.
When the DAF2 gene (insulin receptor gene) is knocked out in the worm C. elegans, the worm lives significantly longer. However, if at the same time the DAF16 gene (homolog to the mammalian FOXO gene) is also knocked out, then there is no life extension. This indicates that it is the action of DAF16 in activating a set of good genes in the nucleus that gives the extra lifespan. So one of the functions of DAF2 is to down regulate DAF16. This is probably also the function of the AGE1 and AGE2 genes.
Since it has been shown that knocking out DAF2 only extends lifespan when it happens in the neurons, I would suspect it is not the neurons themselves; but rather a gland in the neurons that secretes a hormone affecting the rest of the animal, a Death Hormone!
It is all so very complicated; but there is the possibility that some simple intervention will be discovered, maybe by accident, that completely eliminates aging. Then we can all live happily ever after. Oh wait, my bad! I forgot, dying in a violent accident is not aging.
How much curcumin. Per day?
No one has done the study.
A bottle of curcumin (with black pepper for greater absorption) from the company Curcumin2K recommends two per day of their 1330 mg caps with something oily or fatty when you eat; since curcumin is fat soluble. I suspect, if one is also taking resveratrol, that one cap per day might be adequate; because they both work by the same pathway.