A recent American study demonstrates a simple way of studying organ ageing by analysing distinct proteins, or sets of them, in blood, enabling the prediction of individuals’ risk for diseases, the researchers suggest.
Like any typical car or house or society, the pace at which parts of our bodies fall apart varies from part to part.
The study, involving 5 678 people and led by Stanford Medicine investigators, has shown that our organs age at different rates – and when an organ’s age is especially advanced in comparison with its counterpart in other people of the same age, whoever is carrying it is at heightened risk both for diseases associated with that organ and for dying.
According to the researchers, about one in every five reasonably healthy adults 50 or older is walking around with at least one organ ageing at a strongly accelerated rate.
The silver lining: it may be possible that a simple blood test can tell which, if any, organ, is ageing rapidly, guiding therapeutic interventions well before clinical symptoms manifest.
“We can estimate the biological age of an organ in an apparently healthy person,” said senior author, Tony Wyss-Coray, PhD, a professor of neurology and the DH Chen Professor II, “which, in turn, predicts the risk for disease related to that organ.”
Hamilton Oh and Jarod Rutledge, graduate students in Wyss-Coray's lab, are lead authors of the study, which was published in Nature.
Biological versus chronological age
“Numerous studies have come up with single numbers representing someone’s biological age – the age implied by a sophisticated array of biomarkers – as opposed to their chronical age, the actual numbers of years that have passed since birth,” said Wyss-Coray, who is also the director of the Phil and Penny Knight Initiative for Brain Resilience.
The new research went a step further, coming up with distinct numbers for each of 11 key organs, organ systems or tissues: heart, fat, lung, immune system, kidney, liver, muscle, pancreas, brain, vasculature and intestine.
“When we compared each organ’s 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 50 or older had at least one organ ageing significantly faster than the average,” Wyss-Coray said.
“And we found that these people are at heightened risk for disease in that particular organ in the next 15 years.”
Only about one in 60 people in the study had two organs undergoing ageing at that fast clip. But, Wyss-Coray said: “They had 6.5 times the mortality risk of somebody without any pronouncedly aged organ.”
Using commercially available technologies and an algorithm of their own design, the researchers assessed the levels of thousands of proteins in people’s blood, determined that nearly 1 000 of those proteins originated within one or another single organ, and tied aberrant levels of those proteins to corresponding organs’ accelerated ageing and susceptibility to disease and mortality.
They started by checking the levels of nearly 5 000 proteins in the blood of just under 1 400 healthy people aged 20 to 90 but mostly in mid- to late stages of life, and flagging all proteins whose genes were four times more highly activated in one organ compared with any other organ.
They found nearly 900 such organ-specific proteins, which they whittled down to 858 for purposes of reliability.
To do this, they trained a machine-learning algorithm to guess a person’s age based on the levels of those nearly 5 000 proteins.
The algorithm tries to pick proteins that best correlate with a trait of interest (in this case, accelerated biological ageing in a person or in a particular organ) by asking, one by one, “Does this protein enhance the correlation?”
The scientists verified the algorithm’s accuracy by assessing the ages of another 4 000 or so people who were somewhat representative of the US population.
Then they used the proteins they’d identified to zero in on each of the 11 organs they’d selected for analysis, measuring levels of organ-specific proteins within each individual'’s blood.
While there was some modest aging synchrony among separate organs within any person’s body, that person’s individual organs largely went their separate ways along the ageing path.
Organ age gap
For each of the 11 organs, Wyss-Coray’s team came up with an “age gap”: the difference between an organ’s actual age and its estimated age based on the algorithm’s organ-specific-protein-driven calculations.
The researchers found that the identified age gaps for 10 of the 11 organs studied (the only exception being intestine) were significantly associated with future risk of death from all causes over 15 years of follow-up.
Having an accelerated-ageing organ (defined as having a 1-standard-deviation higher algorithm-scored biological age of the organ than the group average for that organ among people of the same chronological age) carried a 15% to 50% higher mortality risk over the next 15 years, depending on which organ was affected.
People with accelerated heart ageing, but initially exhibiting no active disease or clinically abnormal biomarkers, were at 2.5 times as high a risk of heart failure as people with normally ageing hearts, the study showed.
Those with “older” brains were 1.8 times as likely to show cognitive decline over five years as those with “young” brains. Accelerated brain or vasculature aging – either one – predicted risk for Alzheimer’s disease progression as well as the best currently used clinical biomarkers do.
There were, likewise, strong associations between an extreme-ageing (more than two standard deviations above the norm) kidney score and both hypertension and diabetes, as well as between an extreme-ageing heart score and both atrial fibrillation and heart attack.
“If we can reproduce this finding in 50 000 or 100 000 individuals,” Wyss-Coray said, “it would mean that by monitoring the health of individual organs in apparently healthy people, we might be able to find organs that are undergoing accelerated ageing in people’s bodies, and we might be able to treat them before they get sick.”
Identifying the organ-specific proteins that best indicate excessive organ ageing and, consequently, elevated disease risk, could also lead to new drug targets, he said.
Wyss-Coray, Oh and Rutledge have co-founded a company, Teal Omics Inc, to explore the commercialisation of their findings. Stanford University’s Office of Technology Licensing has filed a patent application related to this work.
Study details
Organ ageing signatures in the plasma proteome track health and disease
Hamilton Se-Hwee Oh, Jarod Rutledgeo, Stephen Montgomery, Tony Wyss-Coray, et al.
Published in Nature on 6 December 2023
Abstract
Animal studies show ageing varies between individuals as well as between organs within an individual but whether this is true in humans and its effect on age-related diseases is unknown. We utilised levels of human blood plasma proteins originating from specific organs to measure organ-specific ageing differences in living individuals. Using machine learning models, we analysed ageing in 11 major organs and estimated organ age reproducibly in five independent cohorts encompassing 5 676 adults across the human lifespan. We discovered nearly 20% of the population show strongly accelerated age in one organ and 1.7% are multi-organ agers. Accelerated organ ageing confers 20–50% higher mortality risk, and organ-specific diseases relate to faster aging of those organs. We find individuals with accelerated heart ageing have a 250% increased heart failure risk and accelerated brain and vascular ageing predict Alzheimer’s disease (AD) progression independently from and as strongly as plasma pTau-181, the current best blood-based biomarker for AD. Our models link vascular calcification, extracellular matrix alterations and synaptic protein shedding to early cognitive decline. We introduce a simple and interpretable method to study organ ageing using plasma proteomics data, predicting diseases and ageing effects.
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