Almond-Sized Brain Region is Control Centre for Ageing

In a New York laboratory, a special group of mice is destined to outlive their cage-mates. Their muscles will stay strong for longer. Their brains will stay sharp for longer. When they eventually die, they will have seen more months than their peers.

The secret to their longevity isn’t a drug or a special diet. Instead, Dongsheng Cai from the Albert Einstein College of Medicine simply reduced the levels of a single protein called NF-kB in part of the brain called the hypothalamus. That was enough to extend their lives.

The hypothalamus is an almond-sized structure on the floor of the brain. It’s a control centre for many aspects of our lives that we don’t actively think about. The nervous system feeds it with information about the state of our body and the world around us, and it uses these to coordinate the release of hormones that influence our hunger, thirst, temperature, sleep cycles, and more.

Now, Cai has discovered yet another vital duty on the hypothalamus’ already impressive CV—it’s a command centre that coordinates the ageing process across the entire body. By manipulating proteins within it, Cai managed to speed up or slow down the pace of ageing in mice.

Headlines will inevitably talk about scientists discovering fountains of youth, but that would be hype. As Cai emphasises, “We can’t prevent ageing.” Although his experiments point to ways of extending life or avoiding the health problems that accompany old age, there’s a long history of supposed breakthroughs in ageing research that have led down false turns and dead ends. Other scientists need to repeat these experiments to show that the result aren’t one-offs and that they apply to humans as well as mice.

As we get older, our organs start to deteriorate across the board. It’s possible that this all happens independently and randomly. But studies of worms and flies suggest that parts of the brain might help to coordinate this body-wide decline. Cai suspected that the hypothalamus might play this role in the brains of mammals.

His team showed that as mice get older, the NF-kB protein becomes more active throughout their brains, but especially in the hypothalamus. Next, the team delivered genes into their mice that reduced the levels of NF-kB in their hypothalamus. Even if the animals were already well into middle-age, the loss of the protein still extended their lives by around 10 percent. And if they had less NF-kB from birth, they lived 20 percent longer—a gain of around 7 months.

Better still, those extra months were healthier ones. The mice performed better in maze tests that tested their learning and memory, their muscles and tendons were stronger, their bones were heavier and their skins were thicker. And when Cai’s team delivered genes that increased levels of NF-kB, they saw the opposite effects. The rodents’ bodies declined more quickly, and they died after an average of 30 months.

“This is a brilliant study,” says Caleb Finch from the University of Southern California, who studies ageing. In the 1970s, he suggested that the hypothalamus might contain pacemakers of ageing, and these experiments support his ideas.

Changing an animal’s lifespan is cool enough, but the results are also important because they support a close connection between ageing and the immune system. NF-kB is a key part of the immune system and plays the role of ‘first responder’. It’s activated by everything from radiation to infectious microbes to stress, and coordinates the immune system’s response to these potential threats. This includes setting up a state of inflammation, where teams of cells can destroy invaders and repair damage. In the short term, this saves our lives, but in the long term, chronic inflammation can contribute to many diseases of old age, such as cancer and heart disease. Could it also age the entire body?

Cai’s team found that the ageing hypothalamus builds up more microglia—a dedicated brand of inflammatory immune cells in the brain, which destroy infectious microbes and vacuum up debris. They also produce NF-kB, which tells neighbouring neurons to do the same. This flood of NF-kB switches off the gene for a hormone called GnRH.

That’s a surprise—GnRH is best known as a reproductive hormone. It controls the development of our sexual organs and the making of eggs and sperm. Why does it affect ageing?

To find out, Cai’s team injected GnRH into the hypothalamus of old mice. They found that the hormone triggers the birth of new neurons (neurogenesis), not just in the hypothalamus but also in other areas like the hippocampus, involved in memory. As mice get older, this production line grinds to a halt, but GnRH can rev it back into action. The team even managed to increase the lifespan of mice, and delay the decline of their muscles, brains and bones, by injecting them with GnRH.

Howard Chang from Stanford University says, “If reproduced by others, this work provides further evidence that aging is a regulated rather than a [random] process.” As mice age, microglia build up in their hypothalamus and raise local levels of NF-kB. This reduces the levels of GnRH, and stops the creation of new neurons. What happens next is unclear. It’s possible that the newborn neurons affect many different organs, and their loss leads to the widespread decline that we experience as we age. The next step is to work out exactly what these new neurons do and the connections they form.

But let’s recap what we already know, just to appreciate how bizarre this chain of results is. You have a life-support centre in the brain, a protein that coordinates the immune system, and a hormone that controls our sex organs, all working together to influence… the pace of ageing?

At first, Cai’s discovery feels like a unifying or simplifying one—just one small part of the brain can influence ageing in a broad range of organs. In fact, it just makes things even more complicated than they were before.

Reference: Zhang, Li, Purkayastha, Tang, Zhang, Yin, Bo, Liu & Cai. 2013. Hypothalamic programming of systemic ageing involving IKK-b,NF-kB and GnRH.

Update: The original version of this post implied that increasing levels of NF-kB led to longer lifespan, and reducing those levels led to shorter lifespan. In fact, it’s the opposite. Obviously. Sorry. Sometimes, I suck. Regret the error, etc. Thanks to Emily Willingham for pointing out the flaw.