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Roy Smith

Stayin’ Alive

Roy Smith, chair of the Department of Metabolism and Aging at The Scripps Research Institute (TSRI), divides the world into good hormones and bad hormones, and lays the troubles of human aging, the heartache and the thousand natural shocks that flesh is heir to, squarely on the bad ones.

While many believe that the age-dependent decline in the production of sex steroids, growth hormones and insulin-like growth hormones is nature's way of protecting us from cancer and heart disease, Smith is having none of it. A far more likely scenario, he says, is that once we reach our reproductive capacity, Nature begins programming us for death and that if we wish to maintain a higher quality of life as we age, we have no choice but to oppose what Nature has in mind—tooth and nail.

"Aging is all hormonally related," he says. "There are the good hormones—testosterone, estrogen, growth hormones—which, when we are young, buffer the action of stress-induced hormones, such as cortisol and proinflammatory cytokines. While the stress-induced hormones are essential, they behave as ‘bad hormones’ when present in excess. When you're young, they get shut off quickly once the stress recedes. But as you age, the feedback pathways that regulate hormone release become sluggish, and the bad hormones tend to hang around—not a good thing.”

Smith's basic thesis is that if we could understand how to restore our body's hormonal patterns to what they were when we were young adults, then we might really have something worthwhile. There is ample scientific evidence that this is the right approach, he argues. For example, if brain tissue from very young animals is transplanted into the brain of old animals, the young cells will establish links to other parts of the old brain and restore lost neuronal function.

“My idea is to find a way to replace the good hormones that are depleted by aging in a way that mimics normal physiology,” he says. “We have demonstrated the feasibility of this approach by developing a small molecule that rejuvenates the growth-hormone axis."

Growth hormone (GH) is released in pulses every three hours, but as we age the size of these pulses continues to decline. With this in mind, Smith focused on understanding why. He found that GH production in the pituitary gland does not decline markedly during aging, but that the signal initiated in the brain that stimulates GH release weakens. With his team at Merck Research Laboratories, Smith used reverse pharmacology to develop a small molecule that rejuvenates the GH axis in elderly people. Taken as a pill once daily, this molecule reverses the decline in pulsatile GH release in older people (70-94 years) such that their blood profile is indistinguishable from that of young adults. The same molecule was used to isolate the receptor that regulates its action, which was a previously undiscovered orphan receptor, the growth hormone secretagogue receptor. The production of this receptor is attenuated during aging.

A few years later, a natural activator of this receptor was discovered and named “ghrelin.” Ghrelin is an endocrine hormone produced primarily in the stomach that plays a physiological role in energy homeostasis and GH release. While the full extent of its physiological role remains relatively unknown, we do know that ghrelin promotes weight gain and fat storage through its metabolic actions. Ghrelin protects neurons from oxidative damage and small-molecule ghrelin mimetics are being tested for preventing progression of Parkinson’s and Alzheimer’s diseases. Ghrelin also regulates immune function and inhibits the release of proinflammatory cytokines.

"In young animals, when you inactivate ghrelin, there is no difference in the production of thymocytes or T-cell precursors—part of our immune system—but that changes dramatically during aging and can be partially restored by ghrelin replacement," Smith says. "So, ghrelin and its receptor play a role in both immune function and neuronal function during aging. If you give this small-molecule long-acting ghrelin mimic to obese people and increase the secretion of growth hormone, it puts their metabolism on a normal and youthful footing—which includes restored and increased muscle mass and bone turnover and decreased body fat. After age 35, if you don't change your exercise or eating habits, what you eat goes to fat. When you're younger, it doesn't. Think of what we might be able to do with something like that."

Smith also recently discovered that the interaction between ghrelin and dopamine receptors can lead to pleasure-producing behavior and memory formation; dopamine is a neurotransmitter that plays a key role in the brain's reward centers. This complex partnership has an impact on other signaling pathways linked to neuropsychiatric disorders as wide-ranging as Parkinson's disease, schizophrenia, addiction and Prader-Willi syndrome. In response to all he has learned, Smith has been working with small molecules that modify dopamine action in selective areas of the brain by targeting interactions between ghrelin and dopamine receptors.

Most aging research is designed to look at longevity, but Smith looks at improving quality of life—not necessarily how much longer we can live, but how much better we might live while we're still around.

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“My idea is to find a way to replace the good hormones that are depleted by aging in a way that mimics normal physiology,” says Roy Smith, chair of the Department of Metabolism and Aging.