Blood, Iron, and Gray Hair

The life of a red blood cell is brief but fast paced. Each heartbeat pumps millions of the tiny cells into the body’s vascular system at speeds of more than a meter per second. In about a minute, they can carry oxygen from the lungs to tissues in the rest of the body and return to the lungs. And they die before they’re 4 months old. The body replaces old red blood cells by generating fresh ones, typically producing about 2 million cells per second.

For a variety of reasons, however, the production of new red cells can fall behind the loss of old ones.

The resulting deficiency, called anemia, turns up among people of all ages, but recent research shows that it disproportionately affects seniors. One study estimates that after age 85, 26 percent of men and 20 percent of women are anemic. And while symptoms in young and old people alike include fatigue, headache, and pale skin, the new findings link anemia in elderly people to additional effects, including accelerated physical and mental decline and a shorter life span.

Far from being an innocuous part of old age, anemia may reflect a serious health problem, recent studies show.

“If you’re anemic [and elderly], you won’t live as long as a person who’s not anemic,” says hematologist Jerry L. Spivak of Johns Hopkins University in Baltimore.

“[Anemia] is associated with higher mortality, disability, higher risk of falls in the elderly, poorer quality of life, increased hospitalization risk, and increased health care utilization,” says geriatrician and epidemiologist Luigi Ferrucci of the National Institute on Aging (NIA) in Baltimore.

Furthermore, in about one-third of anemia cases among elderly people, no obvious cause can be found. That makes treating anemia difficult, if not impossible.

Researchers have begun to investigate the causes of anemia in the elderly population and to explore possible treatments. So far, they have more questions than answers. But one early result suggests that injections of the hormone erythropoietin may relieve anemia’s consequences in relatively healthy elderly people. If further trials bear out that finding, a vast number of senior citizens could have reason to seek the treatment.

Prevalent problem

Premenopausal women are much more likely to be anemic than are their male peers. About 12 percent of U.S. women between the ages 17 and 49 have anemia, while barely 1 percent of similarly aged men do, according to national data.

The study that yielded those figures, the National Health and Nutrition Examination Survey (NHANES), employed a widely used definition of anemia that the World Health Organization (WHO) developed decades ago. Anemia is typically measured in terms of blood concentration of hemoglobin, the red blood cell molecule that binds to oxygen in the lungs and releases it where it’s needed. According to WHO, a man is anemic if he has a hemoglobin concentration lower than 13.0 grams per deciliter (dl), whereas a cutoff of 12.0 g/dl applies to women.

By comparison, average hemoglobin concentrations exceed 15.0 g/dl and 13.5 g/dl in non-elderly white men and white women, respectively. Average concentrations for black men and women are slightly lower than are those for whites.

In contrast to the pattern seen in younger adults, “older men tend to have lower hemoglobin than older women,” says geriatrician Claudia Beghé of the James A. Haley VA Medical Center in Tampa, Fla.

Two years ago, an analysis of the NHANES data found that 10 percent of women between 75 and 84 years old—and 16 percent of men in that age range—are anemic. In people 85 or older, each gender faced a 10 percent greater risk, Ferrucci and his colleagues reported in the Oct. 15, 2004 Blood. That research excluded people who were hospitalized or living in nursing homes.

In segments of the elderly population, anemia is even more prevalent than that. Beghé and two colleagues reviewed 71 studies in 2004, including the Blood study and some studies that examined only hospital patients or nursing home residents. They found that among people in some medical wards as many as 61 percent are anemic.

Overall, among those over age 65, “anemia is affecting 3 million people in the United States,” says Ferrucci.

Pattern of risk

For the senior population, anemia is not a benign condition. In one research effort, for example, geriatrician Harvey Jay Cohen of Duke University Medical Center and the VA Medical Center in Durham, N.C., and his colleagues tested blood-hemoglobin concentrations in 1,744 North Carolina residents who were at least 71 years old. By the WHO criteria, 24 percent of the volunteers were anemic when the study began.

At the study’s outset in 1992 and again in 1996, the researchers assessed each volunteer’s cognitive and physical status, including his or her memory and handling of life’s daily activities.

“People with anemia had lower physical function and lower cognitive status,” Cohen says. They were also more likely than the others to deteriorate during the 4-year interval. “Having anemia predicted further declines in physical function and cognitive status,” Cohen says.

Furthermore, participants who had anemia in 1992 were 70 percent more likely than the others to have died by 2000, Cohen’s team reports in the April American Journal of Medicine.

Some fraction of the anemia-associated deaths can be blamed on factors other than the low hemoglobin concentration that was disproportionately common among those with anemia. But even after taking into account obesity and other background differences, Cohen’s team found that anemia was associated with a 40 percent increase in death rate.

Over a 4-year period, Brenda Penninx of Wake Forest University in Winston-Salem, N.C., and her colleagues, including Ferrucci, found that people over 70 who initially had anemia were 20 percent more likely to be hospitalized and about 75 percent more likely to die than were initially nonanemic participants (SN: 1/10/04, p. 30: Available to subscribers at Age-related anemia hastens death).

Penninx and her colleagues have also found that elderly people with anemia lose more muscle strength over a 4-year period than do people who don’t have anemia.

In another recent study, hematologist Mary Cushman of the University of Vermont College of Medicine in Burlington and her colleagues measured hemoglobin in men and women age 65 or older who were well enough to be living at home. Of nearly 5,800 volunteers, 8.5 percent were anemic by WHO criteria when the study began.

The volunteers remained in the study for 11.2 years on average. By 2001, 2,350 of them had died. Deaths were least frequent in people with moderately high hemoglobin concentrations—about 14 g/dl in women and slightly more than 15 g/dl in men.

Compared with those people, volunteers who were anemic but otherwise of similar health at the outset were 38 percent more likely to die during the study, the researchers reported in the Oct. 24, 2005 Archives of Internal Medicine.

Death rates were also elevated among people who were not anemic by WHO criteria but who had low-normal hemoglobin concentrations, Cushman’s team found. Penninx and other researchers have made similar observations, which cast doubt on the clinical relevance of the WHO criteria’s cutoff for defining anemia.

Physicians should seek to diagnose anemia and, when possible, reverse it in their elderly patients, Cushman says. However, she cautions that the data don’t prove that anemia contributes to mortality risk. Some underlying factor might both cause the anemia and shorten lifespan.

Anemia weighs particularly heavily on blacks, several studies show. That’s true among elderly people as well as other age groups. “Anemia in the old is threefold more common in blacks than in whites,” Cohen says. In his study, elderly people with anemia had similar rates of death, regardless of their race.

Seeking cause

Anemia occurs when the body produces insufficient amounts of hemoglobin. Sometimes, the cause is a shortage of iron, the metal in hemoglobin that permits the molecule to bind and release oxygen.

In children, common causes of anemia are inadequate iron intake and genetic diseases. In women of childbearing age, loss of menstrual blood can remove iron more quickly than it can be replaced. Bleeding robs the body of iron that otherwise would get recycled into the next generation of red cells.

“Correction of the underlying disorder is the most effective means of alleviating the anemia,” says Spivak.

A test called a complete blood count identifies anemia and sometimes hints at its cause. Roughly one-third of anemia cases in elderly people are caused by deficiencies of iron or of vitamin B12 and folic acid, which the body needs in order to make red blood cells. These deficiencies can often be corrected by dietary changes or inexpensive treatments, Ferrucci says.

Another one-third of elderly cases, he says, are related to underlying chronic diseases that lead to inadequate utilization, rather than deficient intake, of iron.

Specific causes of poor iron utilization include various cancers and chronic kidney disease, which results from advanced diabetes. Many scientists are focusing on the role of inflammation, such as that seen in rheumatoid arthritis and during chronic infections, in causing the anemia associated with chronic disease.

Some of these conditions are an aftermath of the aging process and defy correction, says Spivak.

Diabetes, chronic kidney disease, and chemotherapy all seem to impair the kidneys’ production of erythropoietin, a hormone that’s essential for red-cell production. Synthetic erythropoietin can boost the body’s manufacture of red blood cells and ameliorate symptoms of anemia in people who have severe kidney disease or who are undergoing chemotherapy. Trials have demonstrated that injecting epoetin alfa, a form of erythropoietin, improves brain function and quality of life in these people.

Even with thorough diagnostic testing, the underlying problem is unclear in about a third of elderly people with anemia, Ferrucci says. Some recent data suggest that, as a group, elderly people whose anemia can’t be explained tend to have mild kidney dysfunction and impaired production of erythropoietin. That raises the possibility that erythropoietin therapy could be useful in that large group of currently untreatable people.

Test treatment

No published trial has tested whether synthetic erythropoietin works against unexplained anemia or anemia caused by a variety of chronic ailments, says geriatrician Parag Agnihotri of Michael Reese Hospital in Chicago. Two years ago, he and his colleagues set out to determine whether epoetin alfa could improve quality of life in patients who were at least 65 years old and had chronic anemia.

For 16 weeks, they gave Procrit, a brand of epoetin alfa, in a weekly injection to 58 volunteers who had less than 11.5 g/dl blood hemoglobin. Either before or after that treatment, they gave the same people a placebo for 16 weeks. Neither the volunteers nor the doctors who administered the medication knew during the trial which patients were getting the drug and which the placebo. Procrit’s maker, Ortho Biotech of Bridgewater, N.J., sponsored the study.

Blood-hemoglobin concentrations improved dramatically during erythropoietin treatment but not during placebo treatment, Agnihotri says. About two-thirds of the patients attained a hemoglobin concentration above 13 g/dl, he and his colleagues reported last December at a meeting in Atlanta of the American Society of Hematology. The anemia wasn’t reduced during the placebo treatments.

“Based on this study, we can say that … epoetin alfa does increase hemoglobin among chronic-anemic elderly patients,” Agnihotri says.

Among the elderly patients whose hemoglobin concentrations went up, their self-assessments of quality of life and energy levels “improved dramatically,” says Agnihotri.

Most of the patients in the trial were African American women, but Agnihotri suspects that the results are relevant to all anemic people over age 65, regardless of sex or race.

“This is the first intervention trial to look at correction of chronic anemia in elderly patients,” he says. “Before this study, it was unclear whether we should correct anemia in elderly people.”

Agnihotri notes that future studies will be needed to determine whether the drug produces lifesaving health benefits and whether it’s cost-effective. Currently, each injection costs hundreds of dollars. The benefits of treatment wore off quickly when patients switched to the placebo, so continuous treatment would be necessary to permanently relieve patients’ symptoms, Agnihotri says.

Ferrucci says that it will take large trials to justify widespread use of erythropoietin to treat elderly people with anemia. Even then, he says, “it is not a broad solution.”

Many elderly people make more than normal amounts of erythropoietin, but their bone marrow doesn’t respond by making as many red cells as it should. Ferrucci suggests that chronic inflammation reduces the marrow’s responsiveness to the hormone.

Two branches of the National Institutes of Health in Bethesda, Md., last August offered an incentive for further research. The NIA and the National Heart, Lung, and Blood Institute plan to fund up to $10 million of research over a 4-year period.

“The goal of the program is to advance our knowledge about this unexplained anemia, to try to determine why it happens to some older people and not to others, [and to] develop better ways of treating it,” says Susan G. Nayfield, chief of the NIA’s geriatrics branch.

The institutes have received more than 2 dozen research proposals, Nayfield says. With the scope of anemia in the elderly growing evident, researchers in the field are ready to focus on what to do about it.