Stayin' Alive

By Eric Sauter

Roy Smith, the recently named head of Scripps Florida's new Department of Metabolism and Aging, 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.

In a long review of aging research that Smith wrote in 2005 for Endocrine Reviews, he pointed out that 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, he was having none of it. A far more likely scenario, he wrote, 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 then we have no choice but to oppose nature—tooth and nail.

Smith has been in opposition to nature's agenda for some time and will continue the fight as he settles into his new offices and laboratories on the new Scripps Florida campus.

"Aging is all hormonally related," he said. "There are the good hormones— testosterone, estrogen, growth hormones, and there are the bad hormones—cortisol, stress hormones, inflammatory cytokines. My idea is to find a way to replace the good hormones depleted by aging in a physiological way."

Stress hormones, for example, are substances set loose in times of anxiety. When you're young, they get shut off quickly once the stress recedes. But as you age, the feedback pathways get sluggish and the bad hormones tend to hang around. Not good.

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. If you transplant young tissue into older animals, you restore the older tissue. Young cells implanted in old brains will establish links to other parts of the brain and restore lost neuronal function.

"What this tells you is that there are circulating factors that can help reprogram tissues," he said. "The animal work on this is very encouraging.'"

At Merck, where he was a senior director, then vice president for basic research for 11 years, in collaboration with medicinal chemists Smith developed a small molecule, named MK-0677, that increased the amplitude of episodic growth hormone release. Smith and his colleagues closely monitored the impact of MK-0677 on a population of frail, elderly patients. According to Smith, "The results of this study were quite encouraging, as these subjects exhibited modest improvements in strength at the large muscle groups of the knees and shoulders. Meanwhile, their placebo-matched cohorts continued to decline at the normal physiologic rate. Likewise, the MK-0677-treated subjects showed increases in lean-body mass and decreased fat deposition." Subsequently, Smith's lab cloned and characterized the MK-0677 receptor and it was identified as a new orphan receptor.

Although Merck placed the project on hold, Smith continued to pursue the research at Baylor College of Medicine's Huffington Center on Aging, which he joined as director in 1998. He was still intrigued by the growth hormone secretagogue receptors in the brain, through which all of his synthetic molecules were acting to increase growth hormone secretion. And while his studies at Merck had concluded that the receptor was expressed primarily in the brain, the identity of its natural ligand (a molecule that binds to and activates the receptor) remained a mystery.

The receptor was expressed in brain areas that control biological rhythms such as learning, memory, mood, cognitive function, and appetite, in addition to being expressed in hypothalamic neurons that regulate growth hormone release. So, it seems like a safe bet that it plays a role in regulating central nervous system function during aging.

A Novel Ligand

Moreover, the idea that this receptor plus an endogenous ligand plays a critical role in aging is supported by recent findings. The MK-0677 receptor was "de-orphanized" by Kojima and colleagues who isolated the endogenous ligand for the receptor and named it ghrelin.

Ghrelin, first identified in 1999, is an endocrine hormone produced primarily in the stomach, which plays a physiological role in energy homeostasis, although the full extent of that role remains relatively unknown. What is known is that ghrelin promotes weight gain and fat storage through its metabolic actions, decreasing the breakdown of stored fat for energy as well as energy expenditure itself. During periods of weight loss such as dieting, the body produces high levels of ghrelin to encourage eating. 

Smith has been working with small molecules that mimic ghrelin.

"The hormone ghrelin protects neurons against damage," he said. "In animals where the ghrelin gene was knocked out, the animals had memory deficits that could be restored by restoring the hormone. The thymus would also partially regenerate in response to small molecules based on ghrelin."

The thymus produces T-cells, the immune system's warriors. It also gradually declines after puberty until it becomes a mere shadow of itself later in life.

"In young animals, when you delete ghrelin there is no difference in the production of thymocytes or T-cell precursors, but that changes significantly during aging," Smith said. "So, ghrelin and its receptor play a role in both immune function and neuronal function during aging. If you give this small-molecule 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 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."

Born to Die

Smith acknowledges, cheerfully, that not everyone agrees with him on his rejuvenation work, or even that the goal is worthwhile.

"When I first showed this data," he said, "someone asked me, 'Why do you want to turn back the physiological clock and prevent aging? When we get old, we're supposed to feel terrible.' I replied that it would be nice to have a choice in the matter."

Smith, who was born in England but has spent much of his adult life in the United States, speaks with an accent that combines the distinctively broad British accent slathered with Texas twang. It occasionally comes out sounding vaguely Australian.

Having spent so much time in the United States, he is fairly observant of its cultural tendencies, particularly when it comes to aging. 

"A lot of the aging research in the U.S is focused on the cosmetic aspects," he said. "I think it's important not get the cosmetic confused with function. When I think of healthy aging, it's not how you look; it's how well you function, most importantly your mental capacity."

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 can live while we're still around.

As examples, Smith cites his old friend, Michael Debakey, the world-famous physician and surgeon who recently died just before his 100 birthday. Or Roy Huffington, the man who endowed the aging center at Baylor.

"We had Roy's 90th birthday party at my house," he said. "He died recently while in Venice. He was very active and would fly all over the world. I wouldn't mind having a heart attack at 92 in Venice."

As Huffington and Debakey demonstrate, the idea of staying active, both mentally and physically, excites Smith. Smith himself is essentially starting over from scratch by moving to Florida. He brought none of his Baylor colleagues with him, and spent the summer and much of the fall interviewing candidates for positions in his new department, a daunting task for anyone. Smith's department will initially have 12 faculty members plus laboratory staff, which will mean a department of somewhere between 120 and 150 people.

"It's very exciting because this is the beginning of a unique science campus, with the Max Planck Institute next door," he said. "We have a great combination here—the ability to do high-volume screening, the chemistry support, and the close collaborations with Scripps in La Jolla. The focus of the campus is very timely, considering the NIH is focused more and more on taking discoveries in basic science and carrying them through to the clinic."

Smith's focus will be on metabolic diseases such as diabetes and obesity; as well as prevention of age-dependent functional decline caused by loss of skeletal muscle mass and strength, osteoarthritis, stroke, and neurodegenerative diseases such as Parkinson's and Alzheimer's diseases

"We're taking more of a preventive approach," he said. "We have some good leads and are looking at how to actively develop them."

That active part is so attached to his enthusiasm for science that it's impossible to separate them.

"People ask me what my hobby is," he said. "I tell them, 'My job is my hobby.'"

Roy Smith turned 66 this December.

Send comments to: mikaono[at]scripps.edu

"My idea is to find a way to replace the good hormones depleted by aging in a physiological way," says Roy Smith, chair of the Scripps Research Department of Metabolism and Aging.