AI used to generate an immune system “clock” that predicts health and mortality

Researchers at Stanford University School of Medicine and the Back Institute for Aging Institute have used artificial intelligence to build an inflammatory aging clock (iAge). This suggests that it is more accurate in predicting immunity than the number of candles in a birthday cake. The system is how quickly it becomes frail or if there are still no cardiovascular problems that may be clinically relevant in the future.

Scientists have also identified chemokines associated with heart aging through collaboration with the 1000 Immunome project and other cohorts. It can be used for early detection of age-related medical conditions and may be a potentially modifiable target for intervention. ..

“There is a great shortage of standard immunometric criteria that can be used to identify individuals at greatest risk of developing one or more chronic aging diseases,” said Back Institute associate professor and artificial intelligence. Dr. David Ferman, director of the intelligence platform, said. A visiting researcher at the Stanford University School of Medicine’s 1001 Immunome Project, the Stanford University School of Immunotransplantation and Infections, and a senior author of the team’s research. Nature aging.. “By incorporating biology into a completely unbiased approach, we were able to identify many indicators, including age-related chronic systemic inflammation and the small immune proteins involved in heart aging. Now has the means to detect dysfunction and the route to intervention before a full-blown medical condition develops. “

The team described the findings as “Deep Learning Based Inflammatory Aging Clock (iAge) Tracks Multiple, Immunosenescent, Weak, and Cardiovascular Aging.. The lead authors of this study are Nazish Sayed, MD, PhD, assistant professor of vascular surgery at Stanford University, and Yingxiang Huang, PhD, senior data scientist at Buck Institute.

“Every year, the calendar shows that we are one year older,” Ferman explained. “But not all humans are biologically aging at the same rate. This can be seen in clinics. Some older people are very vulnerable, and it’s a picture of their health. Some people. ”According to Ferman, this difference is primarily due to the difference in the rate at which people’s immune system declines. The immune system, which has evolved to address threats such as injuries and pathogen infections, is excellent at initiating a rapid, intense, local, short-term resistance and repair response called acute inflammation. .. This positive inflammatory response usually plays its part and diminishes within the next few days. However, as the authors pointed out, the important role of the immune system in maintaining human health and protecting against infectious diseases has been recognized for over 100 years, but “… it has been revealed in the past. For decades, the inflammatory components of the immune system are often chronically elevated in the elderly and are associated with an increased incidence of cancer, cardiovascular disease, neurodegenerative disease, etc. ” These observations led to the notion that inflammation plays an important role in the regulation of physiological aging.

Therefore, as we grow older, it seems that low-grade, constant systemic “bad inflammation” is beginning to begin. This systemic and chronic inflammation causes organ damage, autoimmunity, cancer, heart attack, stroke, and neurodegeneration. “In contrast to the acute reactions that are usually caused by infection, chronic and systemic inflammation are physical, chemical, or metabolic stimuli (” sterile “agents,” such as those released by damaged cells or environmental damage. ) Is believed to be caused by. “Damage-associated molecular patterns” (DAMP), the team explained. This type of inflammation is associated with aging and is characterized by being mild, persistent and ultimately resulting in concomitant damage to tissues and organs.

Researchers studying aging have previously identified nine “characteristics” of the aging process. “… Nine established features of aging: (1) genome instability, (2) shortened telomere length, (3) epigenetic modification, (4) loss of protein homeostasis, (5) dysregulated nutrients Sensation, (6) mitochondrial dysfunction, (7) cellular senescence, (8) stem cell depletion, and (9) altered intracellular communication have all been shown to be associated with persistent systemic inflammation. “I will,” said the team. However, age-related immune system dysfunction was not part of the mix.

To date, there have been no metrics to accurately assess an individual’s inflammatory status in a way that can predict future clinical problems and show how to deal with them or avoid them, Ferman said. Said. But he argued that the new study produced a single numerical quantitative measure that could do just that.

The 1000 Imnom Project collected blood samples from 1,001 healthy people aged 8-96 years between 2009 and 2016. Samples were subjected to various analytical procedures to determine the level of immune signaling cytokines, the state of multiple immune activations. The types of cells that respond to different stimuli, and the overall activity level of thousands of genes in each of those cells.

In a newly reported study, researchers used artificial intelligence to extract a complex from all this data to generate an effective inflammatory clock, iAge. The strongest predictor of inflammatory age they found was a set of about 50 immune signaling cytokines. Using levels of these cytokines condensed using complex algorithms, a single inflammatory score that adequately tracks a person’s immune response and the likelihood that any of a variety of age-related diseases will occur. Can be generated.

In 2017, scientists evaluated approximately 30 1000 immunome project participants aged 65 and over who were drawn in 2010. They measured the speed at which participants got up from their chairs and walked a certain distance, and their ability through questionnaires. Live independently (“Can I walk alone?” “Do I need help getting dressed?”). The age of inflammation proved to be superior to the chronological age in predicting frailty after 7 years.

Ferman and his colleagues obtained blood samples from an ongoing study of very long-lived people in Bologna, Italy, and found that 29 such (all but 100) had an inflammatory age of 50-79 years, 18 years. Compared with people. They found that the age of inflammation in these older people was on average 40 years lower than the calendar age. One was a 105-year-old man with an inflamed age of 25. Ferman said that when it comes to health and longevity, the “age” of the immune system definitely outweighs the chronological information that can be derived from a driver’s license. .. “On average, the immune age of a person over 100 is 40 years younger than what is considered” normal, “one outlier, a super-healthy 105-year-old man (living in Italy) has an immune system. I have. 25 years old, “he said.

To further assess the effect of inflammatory age on mortality, Ferman’s team turned to a Framingham study that has been tracking the health outcomes of thousands of individuals since 1948. Framingham studies lacked sufficient data on blood-derived protein levels, but it is well known that their activity levels predominantly direct the production of cytokines in the inflammatory clock. Researchers measured the activity levels of genes encoding these cytokines in the cells of Framingham subjects. This surrogate at the cytokine level was significantly correlated with all-cause mortality in Framingham participants.

Scientists have observed that blood levels of one substance, CXCL9, contribute more strongly to the inflammatory age score than any other watch component. They found that on average, levels of CXCL9, a cytokine secreted by certain immune cells that attract other immune cells to the site of infection, begin to rise sharply after age 60.

In a new cohort of 97 individuals aged 25-90 years selected from the 1000 Immunomes Project for apparently good health and no signs of illness, researchers show subtle signs of cardiovascular deterioration. I searched. Using a sensitive test of arteriosclerosis that increases the risk of stroke, heart attack, and renal failure, a high inflammatory age score and high CXCL9 levels are another precursor to unexpected arteriosclerosis and adverse effects on the heart. The wall of the left ventricle. “These people are all healthy according to all available lab tests and clinical assessments, but with iAge, they may suffer from left ventricular hypertrophy (enlargement and thickening of the wall of the heart’s main pump chamber). I was able to predict a person. Vascular dysfunction, “he said.

CXCL9 was previously involved in cardiovascular disease. A series of in vitro experiments showed that CXCL9 is secreted not only by immune cells, but also by endothelial cells, the main component of the vessel wall. Researchers’ results show that older age correlates with a significant increase in CXCL9 levels of endothelial cells, reducing the ability of endothelial cells to form, dilate, and contract microvascular networks.

However, the team showed through laboratory experiments with mouse tissues and human cells that lowering CXCL9 levels restores youthful endothelial cell function, with CXCL9 directly affecting the dysfunction of these cells. It was suggested that contributing and inhibiting it could prove to be effective in reducing sensitive individuals. Risk of cardiovascular disease. “Our inflammatory aging watch’s ability to detect asymptomatic accelerated cardiovascular aging suggests its potential clinical consequences,” Ferman said. “All disorders are best treated when treated early.”

The authors conclude that: “… By applying artificial intelligence to deep immune monitoring of human blood, it produces an inflammatory aging clock, especially to inform doctors about the patient’s inflammatory burden and overall health. Can be used as a companion diagnosis. Chronic diseases… Our immunometric criteria for human health identify healthy elderly people at risk of premature cardiovascular aging without clinical or evidence of cardiovascular disease. can.”

According to Ferman, the tool can be used to track the risk of developing multiple chronic diseases by assessing cumulative physiological damage to the immune system. For example, age-related vulnerability is predicted by comparing biological immunometric criteria with information about how long it takes someone to get up from a chair and walk a certain distance, and the degree of autonomy and independence. I can do it. “With iAge, we can predict who will be frail seven years ago,” he said. “It leaves us a lot of room for intervention.”

The authors conclude that “artificial intelligence was used to create a compact representation of these biomarkers, leading to an aging” inflammatory clock “that took into account the non-linear relationships and redundancy of cytokine networks.” I did. “This metric has great potential in translational medicine because it is tracked across multiple aging phenotypes in the general population and can be used as a diagnostic tool to identify people at risk for both non-communicable diseases and infectious diseases. I have sex. “