A mechanism that controls aging has been identified in the hypothalamus, a part of the brain that controls most of the basic functions of life. By manipulating this mechanism, researchers have both shortened and lengthened the life span of mice. The discovery reveals several new drug targets that, if not quite an elixir of youth, may at least delay the onset of age-related disease.
The hypothalamus is an almond-size puppet master in the brain. “It has a global effect,” says Dongsheng Cai at the Albert Einstein College of Medicine in New York. Sitting on top of the brain stem, it is the interface between the brain and the rest of the body and is involved in, among other things, controlling our automatic response to the world around us, hormone levels, sleep-wake cycles, immunity and reproduction.
While investigating aging processes in the brain, Cai and his colleagues noticed that aging mice produce increasing levels of nuclear factor kB (NF-kB) — a protein complex that plays a major role in regulating immune responses. The protein is barely active in the hypothalamus of 3-to-4-month-old mice but becomes very active in old mice, ages 22 to 24 months.
To see whether it was possible to affect aging by manipulating levels of this protein complex, Cai’s team tested three groups of middle-aged mice. One group was given gene therapy that inhibits NF-kB, the second had gene therapy to activate NF-kB and the third was left to age naturally.
This last group lived, as expected, between 600 and 1,000 days. Mice with activated NF-kB all died within 900 days, while the animals with NF-kB inhibition lived for up to 1,100 days.
The mice that lived the longest also remained mentally and physically fit for longer. Six months after receiving gene therapy, all the mice were given a series of tests involving cognitive and physical ability.
In all of the tests, the mice that subsequently lived the longest outperformed those in the control group, while the short-lived mice performed the worst.
Postmortem examinations of muscle and bone in the longest-living rodents also showed that they had many chemical and physical qualities of younger mice.
Further investigation revealed that NF-kB reduces the level of a chemical produced by the hypothalamus called gonadotropin-releasing hormone (GnRH) — better known for its involvement in the regulation of puberty and fertility, and the production of eggs and sperm.
To see if they could control life span using this hormone, the team gave another group of mice — 20 to 24 months old — daily injections of GnRH for five to eight weeks. These mice lived longer, too, by a length of time similar to that of mice with inhibited NF-kB.
GnRH injections also resulted in new neurons in the brain. What’s more, when injected directly into the hypothalamus, GnRH influenced other brain regions, reversing widespread age-related decline and further supporting the idea that the hypothalamus could be a master controller for many aging processes.
GnRH injections even delayed aging in the mice that had been given gene therapy to activate NF-kB and would otherwise have aged more quickly than usual. None of the mice in the study showed serious side effects.
So could regular doses of GnRH keep death at bay? Cai hopes to find out how different doses affect life span, but he says the hormone is unlikely to prolong life indefinitely since GnRH is only one of many factors at play. “Aging is the most complicated biological process,” he says.
“There are dozens of pathways that people will look at thanks to this work,” says Richard Miller at the University of Michigan in Ann Arbor. Miller has previously demonstrated that an immunosuppressant drug called rapamycin can also extend life in mice.
Since the hypothalamus and GnRH regulate several major biological processes, it may be possible to influence aging through related mechanisms, Miller says. He wants to look at possible dietary interventions, such as the indirect effect that spikes in glucose may have on the hypothalamus.
Stuart Maudsley at the National Institute on Aging agrees that the hypothalamus could be the route in for age-controlling drugs. “The body is all one big juicy system,” he says. The ideal drug would hit that system at its center. “Activate that keystone and everything falls into place,” he says.
Maudsley posits that we could see drugs that slow aging in the next 20 years. Initially, though, research is likely to focus on delaying the onset of age-related diseases.
But since the hypothalamus has an effect on every cell in the body, Maudsley warns that interfering with it could lead to unwanted sequences of events. “You’re playing with fire,” he says.
— New Scientist