Our Bodies Age in 3 Distinct Shifts

The carnival worker who tries to guess your age relies on aspects of your appearance, such as your posture and whether any wrinkles emanate from the corners of your eyes and lips. If the carny’s guess is more than a few years off, you win a stuffed koala.

But a team of Stanford University School of Medicine scientists doesn’t need to know how you look to guess your age. Instead, it watches a kind of physiological clock: the levels of 373 proteins circulating in your blood. If the clock is off, you don’t win a plush toy. But you may find out important things about your health.

We’ve known for a long time that measuring certain proteins in the blood can give you information about a person’s health status — lipoproteins for cardiovascular health, for example,” said Tony Wyss-Coray, PhD, professor of neurology and neurological sciences, the D. H. Chen Professor II and co-director of the Stanford Alzheimer’s Disease Research Center. “But it hasn’t been appreciated that so many different proteins’ levels — roughly a third of all the ones we looked at — change markedly with advancing age.

Changes in the levels of numerous proteins that migrate from the body’s  tissues into circulating blood not only characterize, but quite possibly cause, the phenomenon of aging, Wyss-Coray said. A paper describing the research was published Dec. 5 in Nature Medicine. Wyss-Coray is the senior author. The lead author is neurology instructor Benoit Lehallier, PhD.

The researchers analyzed plasma — the cell-free, fluid fraction of blood — from 4,263 people ages 18-95. “Proteins are the workhorses of the body’s constituent cells, and when their relative levels undergo substantial changes, it means you’ve changed, too,” Wyss-Coray said. “Looking at thousands of them in plasma gives you a snapshot of what’s going on throughout the body.”

The study’s results suggest that physiological aging does not simply proceed at a perfectly even pace, but rather seems to chart a more herky-jerky trajectory, with three distinct inflection points in the human life cycle. Those three points, occurring on average at ages 34, 60 and 78, stand out as distinct times when the number of different blood-borne proteins that are exhibiting noticeable changes in abundance rises to a crest. This happens because instead of simply increasing or decreasing steadily or staying the same throughout life, the levels of many proteins remain constant for a while and then at one point or another undergo sudden upward or downward shifts. These shifts tend to bunch up at three separate points in a person’s life: young adulthood, late middle age and old age.

The investigators built their clock by looking at composite levels of proteins within groups of people rather than in individuals. But the resulting formula proved able to predict individuals’ ages within a range of three years most of the time. And when it didn’t, there was an interesting upshot: People whose predicted age was substantially lower than their actual one turned out to be remarkably healthy for their age.

The researchers obtained their samples from two large studies. One of them, known as the LonGenity study, has assembled a registry of exceptionally long-lived Ashkenazi Jews. It was able to provide many blood samples from people as old as 95. On measuring the levels of roughly 3,000 proteins in each individual’s plasma, Wyss-Coray’s team identified 1,379 proteins whose levels varied significantly with participants’ age.

Source: https://med.stanford.edu/
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Most Metastatic Colorectal Cancers Have Spread Before Diagnosis

Colorectal cancers often spread before the initial tumor is detected, according to a new Stanford study. Identifying patients in whom early metastasis is likely could better guide treatment decisions. Up to 80% of metastatic colorectal cancers are likely to have spread to distant locations in the body before the original tumor has exceeded the size of a poppy seed, according to a study of nearly 3,000 patients by researchers at the Stanford University School of MedicineIdentifying patients with early-stage colorectal tumors that are born to be bad may help doctors determine who should receive early treatments, such as systemic chemotherapy, to kill cancer cells lurking far from the tumor’s original location.

This finding was quite surprising,” said Christina Curtis, PhD, assistant professor of medicine and of genetics at Stanford. “In the majority of metastatic colorectal cancer patients analyzed in this study, the cancer cells had already spread and begun to grow long before the primary tumor was clinically detectable. This indicates that metastatic competence was attained very early after the birth of the cancer. This runs counter to the prevailing assumption that metastasis occurs late in advanced primary tumors and has implications for patient stratification, therapeutic targeting and earlier detection.”

Researchers and clinicians have assumed that cancers acquire the ability to metastasize through the gradual accumulation of molecular changes over time. These changes, the thinking goes, confer specific traits that eventually allow cancer cells to escape the surrounding tissue, enter the bloodstream and take up residence in new locations. In this scenario, metastasis, if it occurs, would be a relatively late event in the evolution of the primary cancer.

Curtis, who co-directs the molecular tumor board at the Stanford Cancer Institute, is the senior author of the study, which was published online June 17 in Nature Genetics. Postdoctoral scholar Zheng Hu, PhD, is the lead author.

Source: http://med.stanford.edu/

Blocking Protein Curbs Memory Loss

Impeding VCAM1, a protein that tethers circulating immune cells to blood vessel walls, enabled old mice to perform as well on memory and learning tests as young mice, a Stanford study found. Mice aren’t people, but like us they become forgetful in old age. In a study  published online May 13 in Nature Medicine, old mice suffered far fewer senior moments during a battery of memory tests when Stanford University School of Medicine investigators disabled a single molecule dotting the mice’s cerebral blood vessels. For example, they breezed through a maze with an ease characteristic of young adult mice.

The molecule appears on the surfaces of a small percentage of endothelial cells, the main building blocks of blood vessels throughout the body. Blocking this molecule’s capacity to do its main job — it selectively latches onto immune cells circulating in the bloodstream — not only improved old mice’s cognitive performance but countered two physiological hallmarks of the aging brain: It restored to a more youthful level the ability of the old mice’s brains to create new nerve cells, and it subdued the inflammatory mood of the brain’s resident immune cells, called microglia.

Scientists have shown that old mice’s blood is bad for young mice’s brains. There’s a strong suspicion in the scientific community that something in older people’s blood similarly induces declines in brain physiology and cognitive skills. Just what that something is remains to be revealed. But, the new study suggests, there might be a practical way to block its path where the rubber meets the road: at the blood-brain barrier, which tightly regulates the passage of most cells and substances through the walls of blood vessels that pervade the human brain.

 

We may have found an important mechanism through which the blood communicates deleterious signals to the brain,” said the study’s senior author, Tony Wyss-Coray, PhD, professor of neurology and neurological sciences, co-director of the Stanford Alzheimer’s Disease Research Center and a senior research career scientist at the Veterans Affairs Palo Alto Health Care System. The lead author of the study is Hanadie Yousef, PhD, a former postdoctoral scholar in the Wyss-Coray lab. The intervention’s success points to possible treatments that could someday slow, stop or perhaps even reverse that decline. Targeting a protein on blood-vessel walls may be easier than trying to get into the brain itself. “We can now try to treat brain degeneration using drugs that typically aren’t very good at getting through the blood-brain barrier — but, in this case, would no longer need to,” Yousef said.

Source: http://med.stanford.edu/