Blood has many roles in the metaphorical life of the human body. It’s the organ of kinship (“blood ties”), the seat of emotion (“blood lust”) and a vehicle for identity (“travel is in his blood”). But might it also be a window on the body’s fate?
Many scientists are trying to answer that question as a practical matter, not a metaphor. They are scouring the blood for biomarkers — easily measured substances that illuminate what’s going on in hard-to-reach places.
Biomarkers aren’t new to medicine. Many lab tests are, in fact, tests of biomarkers. Sugar or protein in a sample of urine can shed light on what’s happening in the kidneys or pancreas. The concentration of cholesterol in the blood may hint at disease in the arteries. What’s changed is medicine’s ability to measure more molecules, with greater precision and less cost, than was possible in the past.
The result is a storehouse of information on millions of people, most of it available at the prick of a hypodermic needle. When the health and longevity of those people are correlated with the readings of their biomarkers, it becomes possible to find biomarker profiles that predict risk of future disease or early death.
A recent attempt to do just that was described this year in the journal Aging Cell by Paola Sebastiani, a biostatistician at the Boston University School of Public Health. Her subjects were members of the Long Life Family Study — 5,000 people in 550 families with a predilection for longevity.
The volunteers in the study were subjected to many blood tests. Sebastiani and her colleagues focused on 19 that proved to be most informative. The tests included common ones (hemoglobin concentration, serum albumin) and exotic ones (C-reactive protein, insulinlike growth factor). Together, the tests shed light on six domains of physiology, including inflammation, kidney function and blood-sugar metabolism.
A computer algorithm analyzed the test results in the thousands of volunteers and determined that they fell into 26 patterns, or clusters. Each cluster contained people with similar test results. The biggest one had 2,200 people, all of whom had test readings close to the average for the whole study population. They became the reference group.
“The methodology that I used is to look at multiple markers simultaneously, which is challenging. You have to have a lot of data to be able to do this,” Sebastiani said. The researchers found the clusters differed from each other, and from the reference group, in their rates of cancer, heart disease, diabetes and premature death, and also in measures of aging, such as grip strength and walking speed. As expected, one cluster was considerably healthier than the average, with a low incidence of disease and early death. Its members seemed to have biological ages younger than their chronological ages.
In short, the 19 blood tests together formed a biomarker that told people whether they were aging prematurely, and predicted in general terms the chances of developing serious illness or dying early.
Sebastiani and her team then looked to see whether the biomarkers worked in a different population.
They chose the Offspring Cohort of the Framingham Heart Study — several thousand men and women who had had blood tests done periodically since the 1970s. The biomarkers held up. They divided that population into clusters with the same patterns of disease risk, premature aging and early death as seen in the Long Life Family Study.
The research didn’t address whether people could move from one biomarker cluster to another, and in so doing change their risk for a bad outcome. But Sebastiani suspects they can — and do.
“There are a lot of things you can do to improve biomarkers. They are not all hard-wired, like genetic mutations,” she said.
Such biomarker profiling would be useful in clinical trials of anti-aging treatments because it would allow researchers to measure the efficacy of a drug by seeing whether a person taking it shifted from a cluster with advanced biological age and elevated risk for disease, to a more youthful, lower-risk one.
The more obvious use, however, is in the routine doctor visit, where it could provide patients a peek at what may lie ahead and a chance, Ebenezer Scroogelike, to alter their fates. There is, of course, much more in blood than what the Boston University researchers were looking at. For example, there are white blood cells containing thousands of genes in various states of activity. It turns out they, too, can be biomarkers.
In a study published in 2009, Richard A. Kerber at the University of Louisville and two collaborators looked at 2,100 genes that are always turned on in cells, most of them doing molecular housekeeping. The researchers measured the amount of activity of each gene in blood samples drawn from about 100 people in the 1980s and then frozen. The people were 57 to 97 years old at the time.
Even though all the genes were active, for many of them the amount of activity varied by a person’s age. In all, 10 percent tended to become more active as a person got older, and 6 percent became less active. Using that information, the researchers were able to say what biological age based on gene activity looked like for each year of middle and old age.
Many of the people had since died — a fact that allowed the researchers to calculate what the risk of death had been over the decades for people with various biological ages at the time the blood was drawn. It turned out that for every “extra” year of biological age, a person’s risk of dying was about one-third higher than it would normally have been. For example, a 55-year-old with the gene-activity profile of a 56-year-old had a 33 percent greater risk of dying at age 55 than a 55-year-old person whose biological age matched his chronological age.
As with the blood biomarkers, this one will probably be more useful as a signpost than as a crystal ball.
“I don’t think it’s ever going to be very accurate in terms of predicting how long someone is going to live,” Kerber said. “There are too many random factors; too much stuff can happen. But if it’s monitored at several time points, it could tell you whether you’re going in the right direction or not.”
Other ways of measuring gene activity are also proving to be useful gauges of disease risk and longevity, at least in research studies. Just last month, a team of scientists led by Yan Zhang at the German Cancer Research Center in Heidelberg reported that a phenomenon called DNA methylation may be one.
In methylation, a methyl group (a cluster of one carbon and three hydrogen atoms) attaches to the DNA strand, repressing the gene at that spot. Patterns of methylation are strongly influenced by age, sex, and environmental and lifestyle exposures, including smoking and exercise. Methylation also plays a role in the onset and course of many chronic diseases, including cancer, diabetes and autoimmune disorders.
The German team found that specific methylation patterns at just 10 sites (out of thousands), when measured in people in their 60s, strongly predicted a person’s risk of dying over the next 10 years.
So, blood biomarkers that predict longevity — hemo-augury, you might call it — are a hot topic in medical research. But can they tell us anything useful that we don’t already know?
Various studies have shown that genes are responsible for only 30 percent of our longevity. The other 70 percent is determined by diet, exercise, weight, habits such as smoking and drinking, family and social life, along with access to medical care, and luck.
How much difference nongenetic factors can make is evident in the experience of Seventh-Day Adventists.
The members of that Christian sect don’t smoke or drink, tend to be vegetarians and have strong family and church-community bonds. Life expectancy is 86 for Adventist men and 89 for Adventist women, compared with 76 for American men overall and 81 for American women. Adventists come from many ethnic and racial backgrounds, so the big increase in longevity is presumably the consequence of behavior, not genes.
“What that says is that we humans have, on average, a genetic blueprint that allows us to get to a very old age,” said Thomas T. Perls, a geriatrician at Boston University who directs a study of very old people called the New England Centenarian Study. “If we take advantage of that blueprint, we get to almost 90. If we fight it, then we’re going to die in our 50s or 60s.”
Biomarkers that hint at our chances for a long life are scientifically interesting. Perls’s research, for example, has found that people who live to age 105 share many rare variants of just 130 genes out of the 20,000 they all carry.
But as a practical matter, we don’t need to wait for hemo-augury to show up at our doctor’s office. We already know what to do to make ourselves healthier.
Brown is a physician and journalist.