Conscilience

Overview | Planetary Collective

Age-defying: Master key of lifespan found in brain

The brain’s mechanism for controlling ageing has been discovered – and manipulated to shorten and extend the lives of mice. Drugs to slow ageing could follow

Tick tock, tick tock… A mechanism that controls ageing, counting down to inevitable death, 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 lifespan 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-sized puppetmaster 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, our hormone levels, sleep-wake cycles, immunity and reproduction.

While investigating ageing processes in the brain, Cai and his colleagues noticed that ageing mice produce increasing levels of nuclear factor kB (NF-kB)   – a protein complex that plays a major role in regulating immune responses. NF-kB is barely active in the hypothalamus of 3 to 4-month-old mice but becomes very active in old mice, aged 22 to 24 months.

To see whether it was possible to affect ageing 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, while the third was left to age naturally.

This last group lived, as expected, between 600 and 1000 days. Mice with activated NF-kB all died within 900 days, while the animals with NF-kB inhibition lived for up to 1100 days.

Crucially, the mice that lived the longest not only increased their lifespan but 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 the controls, while the short-lived mice performed the worst.

Post-mortem 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 lifespan using this hormone, the team gave another group of mice  – 20 to 24 months old  – daily subcutaneous 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 ageing processes.

GnRH injections even delayed ageing 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 lifespan, but says the hormone is unlikely to prolong life indefinitely since GnRH is only one of many factors at play. “Ageing 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 (see “A guide to defying age”).

Since the hypothalamus  – and GnRH in particular  – regulate several major biological processes, it may be possible to influence ageing through related mechanisms, says Miller. 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 in Baltimore, Maryland, 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 centre. “Activate that keystone and everything falls into place,” he says.

Though this is the first time that an explicit role has been found for GnRH in the ageing process, previous studies in humans have hinted at a link between longevity and fertility – in which the hormone is known to play a significant role.

As GnRH levels drop, so too does egg production and fertility. In a study presented this month at the annual meeting of the Population Association of America in New Orleans, Graziella Caselli at the University of Rome, Italy, and colleagues found that mothers in Sardinia who’d had their last child over the age of 45  – so were still fertile at a late age  – were significantly more likely to reach 100 than those who’d had their last child at a younger age. Since late fertility could be linked to higher levels of GnRH, Cai says those findings are a good match for his own. “There is likely to be some kind of biological correlation between ageing and reproduction,” he says.

“There are maybe 10 steps to controlling ageing,” says Miller. “We’ve taken the first two or three.” The first is simply accepting the idea that ageing can be slowed down, he says. “Many think it can’t. They are wrong.”

Maudsley reckons that we could see drugs that slow ageing in the next 20 years. Initially, though, research is likely to focus on delaying the onset of age-related diseases. “That could solve some real problems,” says Cai.

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.

3 Waterbears by *Banvivirie

Tardigrades are represented by more than 1000 different species, and here are just three. They are distinguished mainly by the shape of their pharynx and the shapes of their claws.

Say hello to the stunning results of CLARITY — a new technique that enables scientists to turn brain matter and other tissues completely transparent. It’s already being hailed as one of the most important advances for neuroanatomy in decades, and it’s not hard to see why.

Cut off a mouse’s head. Carefully remove its brain, wash it gently, and you’ll wind up with something resembling the sample pictured above, on the left. Grey matter, it so happens, lives up to its name. Due in large part to molecules known as lipids, organs like the brain are usually opaque. Lipids comprise cell membranes and provide structural support to a variety of organs and tissues throughout the body – but they also scatter light. As a result, most microscopes are lucky if they can peer even a millimeter into biological matter before images in the viewfinder get blurry.

One of the more popular techniques scientists use to get around this hangup is called “sectioning.” It’s brutally straightforward in practice: a researcher will freeze a chunk of tissue (a mouse brain, for example) in liquid nitrogen, and then slice it into scores of little sheets, each one just a fraction of a millimeter thick. This turns a single 3-dimensional problem (otherwise inscrutable, due to its non-transparent nature) into a series of 2-dimensional ones. Go through a brain layer by layer, and you can cobble together a volumetric picture of everything from cellular structure, to the spatial distribution of proteins, to the various connections that form between neurons. But the tradeoff is substantial. You’re literally cutting your sample into a bunch of tiny little pieces. With every slice, tissue is deformed, connections are severed, information is lost.

CLARITY does away with the slicing and dicing entirely. The technique, described in the latest issue of Nature by a team led by Stanford researchers Kwanghun Chung and Karl Deisseroth, works by stripping away all of a tissue’s light-scattering lipids, while leaving everything else right where it belongs. You’ll recall, however, that lipids play an important structural role in organs like the brain; if you remove them, everything else falls apart — a fact that has plagued past attempts at making tissues see-through. But that’s where CLARITY is different.

CLARITY works by virtue of a bait and switch. In their study, Chung and Deisseroth submerge a mouse brain in a mixture of formaldehyde and acrylamide. The former attaches important cellular structures and components to the latter, which solidifies into a gel when heated. An electrical current is then coursed through the gel, stripping it of anything not hanging on. The lipids go bye-bye, and the brain goes clear as Jell-O. More importantly: all of its significant structures remain intact and in place. Neurons, synapses, proteins, DNA. Every last component is exactly where it should be.

The ability to strip a brain of its lipids and nothing else gives rise to remarkable research possibilities. In the image above, a mouse brain turned transparent with CLARITY has been made visible again by labeling specific neurons with a fluorescent marker that glows green. Researchers have been using this technique (called “immunolabeling”) to highlight certain molecular and structural features for years, but with CLARITY, labeled cells can be seen in three dimensions, all at once.

In fact, the process of removing the brain’s lipids actually makes the tissues more permeable, making it easier to not only tag them with fluorescent markers in the first place, but untagthem and then tag them again with an entirely different label. What’s more, the fact that you don’t have to cut a brain up to see how it was stained means that you can add more tags to the same brain. The picture below shows a region of the brain known as the hippocampus that has had its different neurons labeled in a variety of fluorescent colors. A brain that was once impermeable to light has been made invisible, only to be made visible again – but this time with remarkable specificity.

There’s nothing that says this technique couldn’t be used on human brains, so long as you have the time. Coloring-in a clarified brain like the one above requires soaking it in solution with the fluorescent labels you want to tag it with. For a mouse brain, that can take a month or more. For a brain as voluminous as a human’s, it would take much longer. (While Chung and Deisseroth did demonstrate their technique could be used on human brains, they did so with a small block of tissue, not an entire brain.)

Likewise, there’s nothing that says CLARITY could not be used on tissues besides the brain, though the organ certainly shows the most immediate promise. The ability to visualize the neuronal connections throughout a transparent brain, for example, could spur incredible growth in the field of connectomics, which seeks to map the brain’s neuronal wiring. In neuroscience, few tools are as coveted as those that enable you to see the part and the whole simultaneously – CLARITY could enable researchers to study the structure and distribution of individual neurons in the context of the whole brain. “This is the kind of innovation that will slingshot neuroscience far beyond today,” said Henry Markram, leader of Europe’s recently unveiled Human Brain Project, in an interview with NatGeo’s Ed Yong. “This new method of whole-brain imaging across all levels of the brain provides a way to acquire much of the key data we will need.”

New Research on How the Brain Makes Decisions

Neuroscience researchers at Trinity College Dublin have opened a new avenue for research on how the brain enables us to make decisions about our environment. By observing the gradual formation of a decision in brain activity before the particular decision was actually reported, the findings also have the potential to contribute to improved understanding and diagnosis of numerous brain disorders that are associated with impaired perceptual decision making. The discovery was recently published in Nature Neuroscience.

When interacting with our environment, we need to be sure about what we’re seeing, feeling or hearing in order to decide how to act. What does that road sign ahead say? Is that a train I hear approaching? Is it too dark for me to cycle home without a light? Somehow the brain enables us to make concrete decisions about the vast and often unreliable array of information it continually receives through the senses. One influential theory about how this might be achieved proposes that the brain allows information from the senses to accumulate over time and only commits to a particular decision once a reliable quantity has been gathered. While this theory has existed for several decades Assistant Professor, Redmond O’Connell at the Trinity College Institute of Neuroscience and colleagues are the first to have identified exactly how this occurs in the human brain.