Stanford Medicine-led study finds way to predict which organs will fail first

A Stanford Medicine-led study has found a way to predict which organs in individuals will fail first, which could lead to early interventions that would improve health and extend lives, according to newly published research in the journal Nature. The study was published online Dec. 6.

The study of 5,678 people found that human organs age at different rates. Comparing an organ with its counterpart in other people of the same age, researchers can predict if a person is at a higher risk of diseases associated with the organ and at greater risk of dying, according to the study.

Senior author Tony Wyss-Coray and lead authors and graduate students Hamilton Oh and Jarod Rutledge developed a new way of thinking about organ aging. They looked at the biological age of organs as opposed to the person’s chronological age.

The findings are striking. About 1 in every 5 reasonably healthy adults 50 or older is walking around with at least one organ aging at a strongly accelerated rate, the study found.

“We can estimate the biological age of an organ in an apparently healthy person. That, in turn, predicts a person’s risk for disease related to that organ,” Wyss-Coray, a professor of neurology, said.

Many previous studies have come up with single numbers representing individuals’ biological age, which is determined by various biomarkers in the blood as opposed to chronological age, which is represented by the number of years a person has lived since their birth.

The new study took these numbers a step further and designated distinct numbers for each of 11 key organs, organ systems or tissues: the heart, fat, lungs, immune system, kidney, liver, muscle, pancreas, brain, vascular system (blood vessels in an organ) and intestine.

“When we compared each of these organs’ biological age for each individual with its counterparts among a large group of people without obvious severe diseases, we found that 18.4% of those age 50 or older had at least one organ aging significantly more rapidly than the average. And we found that these individuals are at heightened risk for disease in that particular organ in the next 15 years,” Wyss-Coray said.

Only about 1 in 60 people in the study had two organs undergoing aging at the accelerated rate, but those who did had 6.5 times the mortality risk of somebody without any pronouncedly aged organs, he said.

The researchers used commercially available technologies coupled with an algorithm they designed to assess the levels of thousands of proteins in people’s blood. They determined that nearly 1,000 of those proteins originated within one or another single organ, and tied abnormal levels of those proteins to corresponding organs’ accelerated aging and susceptibility to disease and mortality.

In the brain, for example, an increase or a decrease in certain synaptic or neuronal proteins in the blood and sampled brain tissues above or below what a particular age group might typically have could indicate a biologically rapidly aging brain.

They first checked the levels of nearly 5,000 proteins in the blood of about 1,400 healthy people ages 20 to 90 (but who were mostly in mid- to late stages of life). The researchers flagged all proteins with genes that were four times more highly activated in one organ compared with any other organ. They found nearly 900 organ-specific proteins, which they whittled down to 858 to be reliable, they said.

A machine-learning algorithm they developed guessed people’s ages based on the levels of the nearly 5,000 proteins. The algorithm tried to pick proteins that best correlate with a trait of interest, such as accelerated biological aging in a person or in a particular organ.

The scientists verified the algorithm’s accuracy by assessing the ages of another 4,000 people who were somewhat representative of the U.S. population. They used the proteins they’d identified to hone in on each of the 11 organs, measuring levels of organ-specific proteins within each individual’s blood.

The team came up with an “age gap” for each of the 11 organs, which is the difference between an organ’s chronological age and its estimated biological age based on the organ-specific proteins found in the researchers’ calculations.

The age gaps for 10 of the 11 organs studied — with the exception of the intestine — were significantly associated with future risk of death from all causes over 15 years of follow-up, the researchers found.

A single, standard deviation higher than the biological age of the organ compared to that of other people in the same age group carried a 15% to 50% higher mortality risk over the next 15 years, depending on which organ was affected.

“We found that among people with no active disease or clinically abnormal biomarkers at baseline, every 4.1 years of additional (biological) heart age (one standard deviation) conferred an almost 2.5-fold increased risk of heart failure over a 15-year follow-up,” the study found.

They made similar findings regarding other organs. Those with “older” brains were 1.8 times as likely to show cognitive decline over five years than those with “young” brains. Accelerated brain or vasculature (blood vessels in an organ) aging — either one — predicted risk for Alzheimer’s disease progression as well as the best currently used clinical biomarkers, the study found.

There were also strong associations between an extreme-aging (more than 2 standard deviations above the norm) kidney score and developing hypertension and diabetes; and also between an extreme-aging heart score and developing atrial fibrillation and heart attack.

The age difference in organs between those who have organs that aren’t aging rapidly and those with rapidly aging organs also doesn’t have to be wide to be detrimental.

“The two most significant associations between disease and age gap were between the kidney age gap and metabolic disease traits. Individuals with hypertension had kidneys that were approximately one year older than their same-aged peers, while individuals with diabetes had kidneys approximately 1.3 years older,” the study found.

But it’s not all bad news. It might be possible for a blood test to determine which, if any, organs in a person’s body are aging rapidly, the researchers said.

“If we can reproduce this finding in 50,000 or 100,000 individuals, it will mean that by monitoring the health of individual organs in apparently healthy people, we might be able to find organs that are undergoing accelerated aging in people’s bodies, and we might be able to treat people before they get sick,” Wyss-Coray said.

Identifying organ-specific proteins that best indicate excessive organ aging could also lead to new drugs, he said. The trio of researchers have co-founded a company, Teal Omics Inc., to explore commercializing their findings. Stanford University’s Office of Technology Licensing has also filed a patent application related to their work.

Researchers from Washington University; the University of California, San Francisco; the Albert Einstein College of Medicine; and Montefiore Medical Center contributed to the study.