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Vol. LXI, No. 24
November 27, 2009

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Lions, Tigers & Bullies
Sapolsky Limns Science of Stress, Bane of Neurons

  Dr. Robert Sapolsky  
  Dr. Robert Sapolsky  

Whether you are an olive baboon luxuriating on the savannas of Africa or a middle-aged policy wonk buried midlevel in Foggy Bottom, stress is going to enter your life in virtually similar chemical ways. But one’s physiological makeup largely determines whether the stress of either life ultimately proves invigorating or withering.

The fact that a large crowd turned out Oct. 28 for Dr. Robert Sapolsky of Stanford’s talk on “Stress and Health: From Molecules to Society,” prompted NIH director Dr. Francis Collins, who introduced this year’s Florence S. Mahoney Lecture on Aging, to quip, “Maybe people at NIH are interested in stress—I’m sure I don’t know why.”

The problem with us humans, Sapolsky noted drily, is that “we spend 75 years having our bodies go to hell on us.” Unlike most mammals, whose lives are cut short either by predators, or more likely by tainted food or drink, “humans die slowly due to an accumulation of damage.” But why, he asked, do some last to 85 and others only to 50?

A person’s psychological makeup is important, as is social status and how one behaves when feeling unloved, Sapolsky explained. All involve how we handle stress, which has been proven to worsen any number of human ailments.

Seven decades of neuroscience have demonstrated how stress works: down at the far end of the hypothalamic-pituitary-adrenal axis, hormones known as glucocorticoids (GCs, including corticosterone and hydrocortisone) exert their effect on hippocampal neurons. Like most of life’s powerful elements, however, GCs are a double-edged sword: while they are essential for life (the adaptive stress response helps you run away from the unleashed hound, mobilizing energy, increasing cardiovascular tone, suppressing digestion and sharpening cognition), they can also produce such stress-related disorders as myopathy, fatigue, hypertension and impotence. It does a body no good, Sapolsky suggested, when GCs ramp up not in response to the bared fang, but to the ambivalent hallway social interaction, the plumber who shows up 2 hours late, the spouse whose text messages divulge a straying partner.

Stress produces neuron atrophy and loss in the hippocampus, actually aging it. Sapolsky and his colleagues have shown that a neuronal “energy crisis” is what ultimately undoes the neuron, regardless of upstream cause, be it stroke, Alzheimer’s, AIDS or depression.

Sapolsky lingered after his lecture for a reception in the south lobby of the CRC, where attendees asked questions and enjoyed refreshments.

Sapolsky lingered after his lecture for a reception in the south lobby of the CRC, where attendees asked questions and enjoyed refreshments.

“Neurons suffer energy collapse,” he said, and glucose uptake is inhibited. Neurons themselves have defenses, he continued, “but these too are weakened by glucocorticoids.” It turns out that GCs, long thought, like other steroids, to be anti-inflammatory, are actually pro-inflammatory in some parts of the brain after an abrupt injury, Sapolsky said.

Seeking strategies to bolster neurons, his team has investigated the use of drugs to inhibit the genesis of steroids, in addition to blocking GC receptors. It would also make sense to counter neuronal energy loss by supplementing with excess energy, using mannose and ketones.

None of these avenues struck Sapolsky’s team as more promising than their effort of the past decade to “build a better neuron.” They are using gene therapy to induce over-expression of a variety of different genes that have the potential for protecting the nervous system from stress and from neurological insults. The delivery vector they chose is herpesvirus. They engineered a version that is stress-responsive, thus it kicks in just when it is needed—in response to stress.

The Stanford team made a family of three genes to insert, including an artificial gene that binds GCs but acts as if it had bound estrogen, which has a variety of beneficial effects in the nervous system.

Regarded as a potential therapy for psychiatric disorders, the gene therapy strategy is, of course, only testable in tissue culture and experimental animals so far; there are problems with delivery and safety, Sapolsky noted. “We are lurching in the right direction,” he said, then showed a slide depicting how high the clinical Matterhorn now looms: the vector penetrates far too feebly into human brain tissue at present.

The last quarter of Sapolsky’s 70-minute presentation reviewed the accumulated insights of his past 31 summers studying baboons, chiefly males, in Africa. The goal of his observation is to determine why the stress response differs from person to person. Which animals, in a mammalian society, suffer stress damage?

Since baboons only spend 3 hours a day gathering food, that leaves 9 daylight hours for social shenanigans. “Like us,” Sapolsky noted, “they have the luxury of generating psychosocial stress.”

He found that social rank is “a very powerfully organizing feature of their society—it stabilizes their world.” Baboon life, it turns out, is amok with “high rates of violence and threats of violence” but there also exists a subtle savvy in the way violence is used and avoided. The males that end up attaining high rank tend to be as much diplomats as brawlers; personality and personal experience are crucial to success among these hairy politicians.

Sapolsky delighted in taking the packed hall to the verge of existential abysses then back to therapeutic promise, but he did offer an observation that every baboon in the hall should find useful: social isolation is the single biggest predictor of high stress. If you’re a hurtin’ monkey, don’t bear your sorrows alone. NIHRecord Icon

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