Only as old as your arteries

CU physiologists, experts on the age-mitigating effects of diet and exercise, turn their focus to ‘nutraceuticals’

By Clint Talbott

Douglas Seals, integrative physiologist and a professor of distinction in the University of Colorado’s College of Arts and Sciences.

Douglas R. Seals has amassed scientific evidence indicating that exercise, weight loss, good nutrition, including salt restriction, can cut your chances of getting cardiovascular disease. That is no trivial point. Heart disease is the United States’ number-one killer.

But Seals knows that exhorting people to exercise and lose weight, no matter how well the case is buttressed with rigorous scientific data, will go only so far. For that reason, Seals’ laboratory has begun researching “nutraceuticals,” food extracts or vitamin supplements that could mimic the effects of a healthful lifestyle.

“Let’s face it. Despite our best efforts, some people are not going to exercise or improve their diet,” Seals observes, “but they might take a pill.”

Seals is an integrative physiologist and a professor of distinction in the University of Colorado’s College of Arts and Sciences. Much of his research has helped scientists and physicians understand why cardiovascular diseases are worse among sedentary, overweight and older adults.

Seals emphasizes that his laboratory continues to study exercise and other behavioral changes. “There’s value and a need to do additional lifestyle studies,” he says.

“The problem is when I present data on lifestyle changes to a group of physicians, they’ll listen politely, and they’ll agree … but what I’m presenting is really of limited help” to them. “The fact that I prove that you can take a middle-aged or older adult and improve health with exercise” doesn’t alter the fact that many of their patients simply will not adopt healthy lifestyle practices.

Seals’ physician colleagues often respond with comments such as, “You’ve got to give me something that I can work with in my clinic.”

For many people, the advice to eat better and exercise more is as unpersuasive as the surgeon general’s warnings on smoking. Nonetheless, Seals cites compelling reasons that he has spent his scholarly life working to explain why such lifestyle changes are effective.

About 80 percent of cardiovascular disease is linked to dysfunction of the arteries, Seals notes. The rate of dysfunction increases with age and is worsened by poor diet and sedentary living.

Seals’ laboratory has been focused on three areas. First, it has worked to understand what changes occur in arteries with aging that increase our risk of cardiovascular diseases. Second, once it understands the nature of the changes—such as stiffening arteries—the Seals lab strives to understand why and how these changes occur. Third, the group works to understand how to prevent or reverse these changes.

As old as your arteries

A human subject in Douglas Seals' Integrative Physiology of Aging Laboratory has his blood drawn for testing. From left, Nurse Claire Gibson, Research Assistant Molly Russell and human subject Kevin Strickfaden. Photo by Noah Larsen.

In public presentations, Seals lays out the scientific evidence: As people age, their large arteries tend to become less elastic, and this stiffening increases their risk of developing hypertension, stroke and heart disease.

Also with aging, the smaller arteries exhibit progressively less ability to dilate. Older adults tend to have about half of the dilation capacity of young adults. This, too, is associated with higher rates of cardiovascular diseases.

Degenerative arterial aging can be facilitated by a number of factors. Seals’ lab has studied two in depth: oxidative stress and inflammation. Oxidative stress can result from normal food consumption or from the activation of certain enzymes, which can cause excessive production of reactive oxygen species.

Those reactive compounds can damage proteins, DNA and other molecules, causing the cells to malfunction.  Seals’ group has sampled cells of arteries from young people and older adults. Older adults have much higher levels of oxidatively damaged proteins in their cells.

Giving these older adults vitamin C, an antioxidant, can restore arterial dilation to levels approximating those of young adults, Seals notes.

Another factor in arterial aging is inflammation, which might be caused by oxidative stress and the activation of immune cells. Such stressors activate genes that produce inflammatory proteins. Seals’ laboratory finds much higher concentrations of inflammatory proteins in older adults than in young adults.

That effect can be almost entirely reversed when older adults take an anti-inflammatory agent (such as an aspirin-like drug they have studied recently) for a few days.

Citing a quote from Gary Gerstenblith at Johns Hopkins University, Seals says: “Successful aging refers to individuals whose biological age is younger than their chronological age.” Seals notes that arterial stiffness is highly variable among older adults. While some adults have exceptionally stiff large arteries, others show arterial elasticity similar to that of people in their 20s.

Fountain of arterial youth?

Seals and others have evidence of four ways to help one’s arteries age successfully.

The first is no surprise: “It would be helpful to exercise,” he says. “One of the most potent influences in all of our research in this area is simple, aerobic exercise.”

Seals notes an experiment in which impaired arterial dilation was shown in a group of older compared with young sedentary adults. Remarkably, older adults who exercise had arterial dilation much more similar to that of young adults than to their sedentary peers.

A second indicator of successful arterial aging is the amount of body fat around the midriff. Arterial dilation decreases with an expanding waistline, experiments show.

Workers in Douglas Seals' Integrative Physiology of Aging Laboratory monitor a human subject who is being tested for arterial elasticity. Clockwise from left: Ph.D. student Ashley Walker, Postdoctoral Fellow Brad Fleenor, Researh Assistant Molly Russell and test subject Kevin Strickfaden. Photo by Noah Larsen.

In a recent study, Seals’ laboratory divided adults with excessive abdominal fat into two groups: one that lost weight and another that didn’t. Those who lost weight regained much of the arterial dilation capacity they had lost while being chunkier.

“So we think abdominal fatness is somehow related to at least this expression of arterial aging,” Seals said.

A third major influence on arterial aging is diet, including salt intake, which has been correlated with increasing stiffness in large arteries. In a 2004 experiment, Seals and his colleagues studied older adults showing arterial stiffness. In the experimental group, salt intake was cut in half.

Within one week, arterial stiffness dropped by about 25 percent.

“So we think that diet in general and specifically dietary sodium intake is a very important component of how your arteries age.”

A fourth factor they have studied is human levels of LDL or “bad” cholesterol. As LDL levels rise in adults’ blood, Seals notes, the risk of cardiovascular diseases also rises.

In recent history, a clinically “high” level was considered to be 160 milligrams per deciliter of blood or higher. But 160 is no magic number. Older adults with “high-normal” LDL—between 130 and 160—have considerably less arterial dilation than older adults with “low-normal” levels.

“The take-home message here is even within clinically normal levels of LDL cholesterol, you need to be mindful of where you are,” Seals observes.

All of these data indicate that exercise, diet, body weight and cholesterol levels affect arterial health and may predict cardiovascular disease. As Seals suggests, there is often a straight line between aging, arterial dysfunction and heart disease.

Two kinds of intervention

Lifestyle interventions—including better diet, more exercise and weight control—may well break the “second step” between the dysfunction of arteries and the development of heart disease, Seals notes.

“Our research is attempting to identify interventions, lifestyle interventions and pharmacological interventions, that we can use to treat middle-age and older adults who already have dysfunctional arteries.”

Seals is careful to note the importance of further studying, and better understanding, lifestyle changes to improve human cardiovascular health. “No one disputes that it’s important work … when you can get people to adhere to it. But if you can’t, it doesn’t matter that you’ve shown that arterial function improves with exercise.”

That’s why Seals’ lab is expanding its focus to include non-traditional pharmacological strategies. These strategies are called nutraceuticals, diet-based pharmaceuticals.

Out of hundreds of potential compounds the Seals lab could study, it has chosen to focus on a few of the most promising substances.

One is vitamin D. In recent years, several studies have found evidence that vitamin D may slow the aging process. In one experiment, scientists in Britain found that adults with the lowest levels of vitamin D showed higher rates of biological aging. Another study, also from Europe, found evidence that higher levels of vitamin D were associated with better functioning of the brain.

Seals is beginning similar studies on the effect of vitamin D on cardiovascular health in middle-aged and older adults.

Another nutraceutical receiving a lot of attention is resveratrol, a compound found in the skin of red grapes and other plants. The compound is found in red wine, though in low doses generally not thought to be therapeutic.  Seals’ laboratory  is now studying a new experimental agent that represents a more concentrated form of resveratrol.

Typically, Seals notes, nutraceuticals can reduce inflammation or oxidative stress. “If we can prove that one or more of these compounds is effective, then the question is, ‘What is their mechanism of action?’”

Curcumin, the active ingredient in the curry spice turmeric, is a third nutraceutical the Seals lab is studying. Recent investigations on curcumin have shown powerful anti-inflammatory effects in other tissues, and Seals is expecting to find similar benefits for reversing arterial aging.

One aim of these experiments is to see if nutraceuticals can “mimic” the positive effects of exercise, calorie restriction/weight loss and a healthful diet. There are many more potential anti-aging compounds than the lab could ever hope to study, Seals notes. “It becomes a process of not just trying to identify promising agents, but trying to figure out which of a large number of intriguing candidates to assess.”

In some cases, the compounds are tested first in arterial cells (in culture) or mice. “The real end game is to translate these studies to humans,” Seals says. “One of the strengths of our lab is that we can do that ourselves.”

If you are interested in participating in a human study conducted by Seals’ Integrative Physiology of Aging Laboratory, see www.colorado.edu/intphys/research/cv%20volunteers.html or call 303-492-3485.

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