Protein Signatures Of Organ Aging Could Aid Disease Prevention Efforts
By Deborah Borfitz
January 23, 2024 | Stanford Medicine investigators are leading the development of a test measuring organ-specific proteins in the blood as a simple and sensible way to estimate biological age. Among the potential applications are screening people for conditions such as heart failure and Alzheimer’s disease, personalizing the intervention they’re prescribed, and signaling sooner the efficacy of investigational drugs based on how well they rejuvenate certain organs, according to Hamilton Oh, graduate student in the lab of neurology professor Tony Wyss-Coray, Ph.D. and scientific cofounder and advisor to startup Teal Omics Inc.
The effort is part of a broader movement in the field away from representing aging with a single number and instead acknowledging that individual organs in the body largely go their separate ways along the aging path. But while other groups are measuring biological age using epigenetic markers from blood cells or clinical and functional measurements, here the focus is squarely on the proteins that drive biology on a molecular level. In this way, says Oh, “instead of just measuring [organ] function we can understand it.”
In a study recently published in Nature (DOI: 10.1038/s41586-023-06802-1), proteomics was used to come up with distinct numbers representing the biological age for each of 11 key organs, organ systems, or tissues—heart, fat, lung, immune system, kidney, liver, muscle, pancreas, brain, vasculature, and intestine. One in five reasonably healthy adults 50 or older was found to have an especially aged organ, Oh says.
Much work remains to be done to “flush out if having an older organ is truly indicative of a real health problem,” he adds, although there is some solid evidence that this is true. Increased organ age is associated with mortality, as is brain age with Alzheimer’s and heart age with heart failure, hypertension, diabetes, atrial fibrillation, and heart attack.
However, people with chronic liver disease were missing in the 5,678-person study, says Oh. Investigators were therefore unable to assess if an older liver based on the blood plasma proteins originating from that organ means something for liver function.
The study found a significant association between the identified age gap—the difference between an organ’s actual and estimated age—and future risk of death from all causes over 15 years of follow-up for 10 of the 11 organs. For the 1 in 60 people in the study having two fast-aging organs, their mortality risk was 6.5 times that of individuals without any pronouncedly aged organ.
A notable exception here was the intestines. The mortality risk assessment was done on about 900 people, perhaps too small of a cohort in which to spot a connection, Oh says. “It could also be that the proteins we are measuring aren’t necessarily indicative of intestinal health.”
Newer technologies enable the measurement of 11,000 proteins, more than double the number quantified by the proteomics assay used in the study, and are getting better every year, says Oh. “So, it is not that intestines don’t age. It’s that maybe we are not able to measure it yet.”
Investigators are “definitely not at the stage where we can give clinical advice or have interventions based on [our study’s methods],” Oh says. “But it is coming. Hopefully, this will be standard of care in the future.”
It was only a few years ago that anti-aging scientists came to collectively realize that biological age—how fast a person’s body is deteriorating compared to the rest of the population—is a much more accurate measure of health span than the number of years lived. Different groups started coming up with their own aging clock or model, primarily based on blood biomarkers and epigenetic patterns in immune cells, but the problem was that they were all assigning one score to represent the entire body, says Oh.
The perspective of the Stanford Medicine team is that “the body is made up of thousands of different cell types, all super unique, and each form tissues and ultimately organ systems that all have their own crucial functions and respective age-related diseases,” he continues. “How could blood cells possibly represent this complexity?”
It still makes sense to look in circulating blood, which is “connected to pretty much every cell in the body,” but with the goal of detecting the proteins derived from specific organ systems, says Oh. Many proteins can be matched to specific organs based on the gene expression of organs.
The idea to identify proteins that could be mapped to certain organs and cell types was first suggested by a bioinformatician post-doc, Benoit Lehallier, in the Wyss-Coray lab a few years ago, says Oh. He and first co-author Jarod Rutledge expanded on the concept for the study, which was completed inside of about 18 months.
Other groups working to pin down age-related processes most notably include Morgan Levine, Ph.D., principal investigator at the Altos Lab, San Diego Institute of Science. She has been a pioneer in the development of aging clocks and measuring biological age. Levine is currently working on estimating the age of different organs using epigenetic markers from blood cells, as described in a 2023 paper on the preprint server bioRxiv (DOI: 10.1101/2023.07.13.548904).
Researchers in Australia also published a paper last April in Nature Medicine (DOI: 10.1038/s41591-023-02296-6) where they instead looked at clinical measurements such as respiratory function, kidney filtration, and brain volume MRI scans from different organ systems across a large cohort from the UK Biobank. It revealed the multisystem nature of human aging in health and chronic disease, suggesting the potential to identify individuals at increased risk of aging-related morbidity and to limit their organ-specific aging.
“What separates our study from those is that we did this all with a blood test and with proteins,” says Oh. “It really is quite simple; people already measure proteins when they go to the doctor’s office. Now we’re measuring more and doing a little fancier modeling with them.”
For many years, anti-aging science was focused on assessing the ability of an intervention to extend lifespan in a model organism, Oh says. But what people die from are different diseases, including ones like Alzheimer’s that mice don’t even get, so “it is crucial to think about aging under this lens of the functional decline of an organ system.” That shift in thinking is what is going to both change medicine and how clinical trials for anti-aging are done, he adds.
If a drug is thought to extend lifespan, it might be hard to know if that benefit reflects individuals not getting cancer or having healthier hearts and arteries. Research is underway to better elucidate what aging interventions are doing in mice, says Oh, “but it would be great to assess that in humans as well.” Exploring how these drugs work in people might help explain the unintended side effects, such as an intervention intended to help the heart adversely impacting the liver.
The proteomics-based test has many possible applications, including as an additional screening tool for heart disease to enable earlier intervention, he says. It might also be deployed in clinical trials to measure the efficacy of drugs based on their ability to revitalize certain organs associated with positive functional outcomes in the future—a strategy that could shave years off the wait time on results.
Measuring organ aging signatures in the plasma holds great potential for personalizing medicine, notably for individuals suffering from heterogenous diseases such as Alzheimer’s, he adds. “Maybe people with especially old brains are more susceptible to cognitive decline and respond better to a certain kind of drug than people with younger brains, or... maybe if you have an old vascular or cardiovascular heart age taking this drug is not the best thing to do [because of the risk of a brain bleed].”
More insights are expected from a larger study now underway where the Stanford Medicine team is analyzing data from 50,000 people in the UK Biobank. “Our results are actually quite striking,” says Oh, and are expected to be available on the bioRxiv preprint server in early 2024. “Preliminarily, everything is pretty much holding up.”
Teal Omics is among several groups on the hunt for new drugs targeting organ aging, he adds. The venture-backed startup, founded in 2022, holds patents for specific proteins in the blood for the purpose of measuring aging in different organs.
“The goal of all of this is ultimately to better understand health, the biology of how we age, and to address aging to prevent disease... [to] help our families stay cognitively youthful without getting dementia... [and] to keep people from getting heart disease,” says Oh. Recent research suggests this is possible, and much sooner than anyone thought.