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New tool measures the degree of chronic inflammation in a person’s body to determine their “immunological age”; this number indicates when and if that person will become fragile or develop heart disease later in life, scientists report.
The tool, called iAge, uses a type of artificial intelligence (IA) called a deep neural network to analyze blood markers of inflammation, according to the new study, published Monday (July 12) in the journal Natural aging. These markers include proteins called cytokines, which transmit messages between immune cells and to other cells in the body. Using blood samples from 1,001 people, ages 8 to 96, the team discovered patterns between these circulating inflammatory markers and various age-related conditions.
Of the 50 cytokines assessed, the team reported a handful that appeared to have the strongest influence on a person’s iAge score; in particular, a cytokine called CXCL9 stood out as the largest contributor. The substance usually rallies immune cells to the site of an infection, but among study participants, CXCL9 levels began to climb rapidly around the age of 60, on average. In follow-up experiments with cells in lab dishes, the team linked this age-related spike in cytokines to functional problems in endothelial cells, the main components of some blood vessel walls.
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But they discovered that, at least in the lab dishes, “if you reverse the genes [for] CXCL9, you can recover those functions, “helping cells to contract and build vascular networks as usual, said David Furman, lead author of the study, director of the Stanford 1000 Immunomes Project and head of the Center for AI and Data Science of Aging at Buck Institute for Research on Aging. This suggests that in the future, medical treatments may be developed to stop age-related increases in CXCL9, the authors suggested in their report. .
That said, until scientists better understand the underlying triggers for age-related inflammation, it will be difficult to develop drugs that target inflammation without disturbing them. immune system in general, experts told Live Science.
Making the connection between inflammation and aging
The new study stems from the Stanford 1000 Immunomas Project (1KIP), an effort to understand how the signatures of chronic inflammation change with age. Scientists collected blood samples from people of different ages between 2009 and 2016, then passed those samples through a series of tests, assessing cytokine levels, gene activation, and immune responses in the cells collected. .
With these measurements, the team hoped to identify the parts of the immune system that contribute to the persistent, low-intensity inflammation that appears with age, Furman said. This chronic inflammation has been linked to various diseases, from cancer to Alzheimer’s, and linked to signs of aging, including increased cellular senescence, where cells stop functioning and proliferate and instead sound alarm bells for immune cells.
While these links between inflammatory markers and aging are not new, “the problem on the ground is that ‘inflammation’ is too much. [much] of an umbrella term, and we can’t really reduce inflammation without serious health consequences, ”said Dr. Luigi Ferrucci, scientific director of the National Institute on Aging at the National Institutes of Health, who did did not participate in the study. The new study takes a “step forward” in using AI to sift through mountains of data collected from 1KIP participants, identifying specific cytokines that may play a key role in aging, Ferrucci told Live Science in an email.
“I don’t agree that this is a measure of immunological aging” because iAge cannot predict how well a person’s immune system will respond to vaccination or infection , for example, added Ferrucci. But the tool could still be useful as a clue to track biological aging as it relates to inflammation, he said.
After the deep neural network generated an iAge for each participant, the team wanted to see how accurately the metric reflected people’s health status. Initially, the group found that, in participants aged 60 and older, higher ages correlated with a higher risk of people with two or more chronic conditions at the same time. (The chances of being diagnosed with at least two chronic conditions increase dramatically with age, affecting about 95% of primary care for people aged 65 and older, according to a 2016 report in the Journal of Multimorbidity and Comorbidity.)
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The team also revisited around 30 participants aged 65 and over whose blood had been drawn in 2010; in 2017, researchers asked these same participants to complete a questionnaire about their ability to live independently, asking if they needed help dressing or getting around their house, for example. They also measured how quickly participants could get up from a chair and cross a room.
This helped researchers measure frailty, a state marked by fatigue, slow gait, poor balance, weakness, and muscle loss that often occurs in older people. Ultimately, individuals’ iAge scores predicted how fragile they were seven years after collecting blood samples in 2010, and did so more accurately than their chronological age alone.
“One of the most exciting things I think about iAge and other aging clocks is their predictive abilities,” said Emily Goldberg, assistant professor who studies age-related inflammation at the University of California at San Francisco, which was not involved in the study. IAge’s predictive power has yet to be tested in large groups of diverse people, “but it has the potential to predict health outcomes in time for people to change their behaviors to prevent chronic age-related diseases. “Goldberg told Live Science in an email.
After the frailty test, the team wanted to zoom in on individuals who were aging exceptionally well, surviving beyond 100 years. They examined the blood of a group of 37 individuals in Italy, 18 of whom were centenarians at the time of the blood sample. The researchers compared these centenarians – plus a 99-year-old man – to 18 people aged 50 to 79, and assessed how their iAges matched their chronological ages. Almost 70% of the older group had a lower than average iAge for their actual age, while only around 23% of the younger group had the same.
This suggested that while high iAge scores predict frailty and chronic disease, low scores may be predictive of healthy aging, the authors reported. Although, given that about 30% of centenarians were not abnormally low in age, inflammation is probably not the only factor at play.
‘Play with fire’
To begin to understand why immune scores seem to predict age-related decline, the team began to analyze how individual cytokines contribute to the overall score; Once again, they found that CXCL9 stood out as a key iAge booster. The same cytokine has been linked to cardiovascular aging in the past, researchers therefore sought to understand better.
They first recruited around 100 healthy adults, aged 25 to 90, and assessed both their CXCL9 levels and their cardiovascular health. As in their main study cohort, CXCL9 levels appeared to be the major factor in age-related inflammation in this small group, and in particular, the cytokine was linked to signs of cardiovascular deterioration, such as thickening of the walls of the left ventricle and arterial stiffness. , which can increase the risk of a heart attack.
At this point, the researchers went to the lab to see how high levels of CXCL9 might trigger these effects. The team found that the cytokine turns on genes related to inflammation in endothelial cells that line blood vessels, while turning off genes involved in cell division. “It’s a signature for cellular senescence,” Furman said. By pushing cells into senescence, the cytokine also made cells less able to contract, expand, or build microvascular channels. Conversely, inhibiting the production of CXCL9 allowed cells to function normally again.
In theory, this points to a path for treatments for CXCL9-related inflammation, although the triggers that cause CXCL9 to skyrocket remain a mystery, Furman said. When it comes to finding treatments for age-related inflammation, in general, “it’s a start, not an end,” Ferrucci told Live Science. Deducing the exact causes of the inflammation is important because scientists can then carefully target these specific systems, while leaving the rest of the immune system intact, he said.
Although AI has identified which cytokines may be important for age-related inflammation, it has not provided any information on why specific cytokines are linked to aging, said Alan Cohen, assistant professor at the University of Sherbrooke in Quebec, which did not participate in the study. Because the immune system acts as a multi-level network, where a single cytokine can trigger an elaborate cascade of events, understanding which network-wide changes lead to chronic inflammation will take a lot more work, he said. he declares. But that’s the only way to identify solutions that control age-related inflammation, while allowing useful immune functions to continue, he added.
For example, “many of these inflammatory cytokines are also essential components of the host’s defense mechanisms to protect against infection,” noted Goldberg. “Targeting these factors will therefore be [require] very thorough validation and careful planning. ”
“We’re playing with fire… because a lot of these molecules can help in some cases, hurt in others,” Cohen said. “We should be quite careful moving into therapeutics until we have a better understanding of the networks.”
Originally posted on Live Science.
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