Turning Down the Aging ‘Rheostat’ in Mice

by Jim Schnabel

June 18, 2013

What if a single clump of neurons in the brain could “program” your rate of aging, affecting your brain and in the rest of your body, too? What if you could seize control of this program to extend your lifespan and “healthspan,” holding Alzheimer’s and other debilitating age-related diseases at bay for an extra decade or two?

These tantalizing possibilities have just been raised by the laboratory of Dongsheng Cai at the Albert Einstein College of Medicine in New York. In a study published in Nature on May 1, Cai and his colleagues found evidence that a brain region called the hypothalamus is a major regulator of aging processes. Although these experiments were done in mice, Cai predicts the results will apply to other mammals, including people.

“The [natural] life span of mice is much shorter than that of humans, but mice and humans are pretty compatible in terms of the hypothalamus and even the physiology of the aging process,” Cai says.

A hypothalamic fountain of youth, stoppered by inflammation

Aging is partly a consequence of time’s relentless march. Random unrepaired damage occurs to DNA and other important components of cells, and these flaws accumulate. Eventually, essential systems in the body—including repair and maintenance systems—stop working properly, and the spiral of damage and dysfunction accelerates.

On the other hand, animal species have such widely varying natural lifespans—weeks for mosquitoes and houseflies, four score years for H. sapiens, and well over a century for some clams and giant tortoises—that aging must be partly “programmed.” Over the past few decades researchers have begun to find some of the key molecular elements of these aging programs, at least in smaller lab animals such as roundworms, fruit flies, and mice. These include the hormone IGF-1, sirtuin and FOXO proteins, mitochondrial MRP proteins, and a transcription factor (a protein that activates other genes) called nuclear factor kappa B (NF-κB).

NF-κB is widely known as a basic sensor of inflammation, stress, and other signals associated with cell damage. When activated, it can trigger hundreds of separate cellular processes including the increased expression of immune system genes. Its chronically increased activity has so far been linked to cancers, arthritis, asthma, colitis, Alzheimer’s disease, and the appearance of accelerated tissue aging. In general, NF-κB seems to become more active in animals as they age, and researchers have begun to experiment with compounds that lower its activity as a way to treat various age-related conditions.

Cai and his colleagues recently found evidence that NF-κB activity helps mediate the development of obesity and diabetes from within the hypothalamus, a multifunctional cluster of nuclei in the evolutionarily older part of the brain, just above the brainstem. Though tiny in humans (about four cubic centimeters) compared with the cognitive parts of the brain, the hypothalamus helps regulate some of our most basic bodily processes, including insulin secretion, growth, circadian rhythms, sexual development, ovulation, and spermatogenesis.

When Cai’s team fed mice a high-fat diet, NF-κB activity in their hypothalamuses rose, and the population of hypothalamic stem cells declined. The loss of those cells impaired the normal hypothalamic regulation of the mice’s metabolism, leading to obesity and a pre-diabetes condition. That led Cai to the hypothesis that NF-κB activity in the hypothalamus might control aging-related processes more generally.

In the new study, he and his team showed that NF-κB activity in the mouse hypothalamus rises sharply after middle age. When the researchers reduced hypothalamic NF-κB activity by blocking its chief activator, the inflammatory enzyme IKK-β, they extended the average lifespan of mice by about 10% (when the IKK-β-blocking started in middle age) and 23% (when it started from conception), compared to control mice. Boosting IKK-β and NF-κB activity had the opposite effect, shortening lifespan.

Cai’s group found that NF-κB activity in the hypothalamus suppresses the normal secretion of a hormone called gonadotropin-releasing hormone (GnRH). Delivering GnRH therapy to old, NF-κB-boosted mice restored their cognitive performance, slowed their tissue aging, and enhanced neurogenesis—the production of neurons from resident stem cells—in the hypothalamus, the memory-related hippocampus, and other brain regions. Neurogenesis in the hippocampus is known to decline in Alzheimer’s as well as ordinary neural aging.

Therapeutic possibilities

Cai believes that the NF-κB / GnRH pathway may be just one influence that the hypothalamus brings to bear on the aging process. “The whole [aging-process-regulating] network could be larger than this,” he says. But already his results suggest some obvious potential therapies for treating or preventing Alzheimer’s and other age-related conditions.

One possibility is  using GnRH itself—a relatively simple ten-amino-acid peptide—as well as “agonists” that mimic GnRH’s effect by activating GnRH receptors. Remarkably, Cai’s team was able to produce an anti-aging effect in older mice by injecting GnRH directly into the body, not the brain. (An important caveat is that GnRH agonists, if delivered at high enough and frequent enough doses, can quickly desensitize GnRH receptors, reducing the activity of GnRH-dependent systems instead of boosting them. GnRH agonists now are typically used this way, against testosterone-driven prostate cancers, for example.)

Inhibitors of NF-κB’s principal trigger, IKK-β, which is produced in the brain by brain-resident immune cells called microglial cells, are a second possibility. IKK-β inhibitors are already being investigated as treatments for cancers, asthma, and other conditions.

In principle, inhibiting the inflammatory activation of IKK-β-producing microglial cells should have the same effect. Chronic microglial activation has been linked to aging-related neurodegenerative conditions such as Alzheimer’s, and scientists have begun to develop drugs that nudge inflamed microglial cells back into a less harmful, more nourishing mode of activity. (See “A New Look at Brain Inflammation in Alzheimer’s.”) Drugs that achieve this effect should have the added benefit—if Cai and his colleagues are right—of quieting the IKK-β/NF-κB pathway and thus slowing the aging process more broadly, within the brain and in the rest of the body as well.

Bruce Yankner, a longtime neurodegeneration researcher at Harvard Medical School, and a co-author of a recent commentary on the Cai laboratory findings, notes that hypothalamic NF-κB activity might also be targeted by quenching inflammation elsewhere in the body. Hypothalamic neurons apparently can detect not only local brain inflammation but also systemic inflammation. “The dendrites [input branches] of neurons in the hypothalamus extend through the blood-brain barrier into the bloodstream, so presumably they would be able to sense inflammatory metabolic signals in the blood,” Yankner says.

The evolutionary logic

How much does all this apply to humans, who—unlike short-lived mice—may be already nearing the biological limits of their lifespan? “I think the safe answer is that we’ll just have to wait and see,” says Yankner.

But there has long been a linkage between inflammation and the major age-related illnesses in humans, including atherosclerosis, Alzheimer’s, and Parkinson’s. Many scientists have assumed that this linkage—“inflammaging,” some call it—exists because inflammation in an older body is apt to stay “on” inappropriately, causing damage that wouldn’t have occurred at younger ages. “Inflammation can be induced by multiple mechanisms—oxidative stress, local injury, infection—and it is less well controlled during aging, so it doesn’t always turn off when it should,” Yankner says.

If Cai’s results are right, however, inflammation is not just a source of damage that runs increasingly amok with age; it is also a signal that controls the effective rate of aging. Yankner speculates that this signal—indicating infection or some other source of significant damage—may have evolved to dial down growth and reproduction while an organism shifts its resources towards defense. In environments where life is normally nasty, brutish, and short, the extended activation of such a program could be an advantage. In more benign environments, such as those many humans in developed countries live in today, it could well be a disadvantage, making a potentially longer life shorter.

Cai says that he and his group—along with other aging-research laboratories—are setting up experiments to confirm that hypothalamic NF-κB signaling influences the rate of human aging, not just mouse aging.

“I think that the most straightforward evidence for [these findings’] relevance to humans would come from genetics,” says Yankner. “For example, if you found that certain genetic variants of the GnRH gene are associated with aging and lifespan in people, then that could be very powerful evidence in support of this model.”