Immune system ‘clock’ predicts illness and mortality (2022)

You’re as old as your immune system.

Investigators at the Stanford University School of Medicine and the Buck Institute for Research on Aging have built an inflammatory-aging clock that’s more accurate than the number of candles on your birthday cake in predicting how strong your immune system is, how soon you’ll become frail or whether you have unseen cardiovascular problems that could become clinical headaches a few years down the road.

In the process, the scientists fingered a bloodborne substance whose abundance may accelerate cardiovascular aging.

The story of the clock’s creation published July 12 in Nature Aging.

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“Every year, the calendar tells us we’re a year older,” said David Furman, PhD, the study’s senior author. “But not all humans age biologically at the same rate. You see this in the clinic — some older people are extremely disease-prone, while others are the picture of health.”

This divergence, Furman said, traces in large part to differing rates at which people’s immune systems decline. The immune system — a carefully coordinated collection of cells, substances and strategies with which evolution has equipped us to deal with threats such as injuries or invasions by microbial pathogens — excels at mounting a quick, intense, localized, short-term, resist-and-repair response called acute inflammation. This “good inflammation” typically does its job, then wanes within days. (An example is that red, swollen finger you see when you have a splinter, and the rapid healing that follows.)

Chronic inflammation

As we grow older, a low-grade, constant, bodywide “bad inflammation” begins to kick in. This systemic and chronic inflammation causes organ damage and promotes vulnerability to a who’s who of diseases spanning virtually every organ system in the body and including cancer, heart attacks, strokes, neurodegeneration and autoimmunity.

To date, there have been no metrics for accurately assessing individuals’ inflammatory status in a way that could predict these clinical problems and point to ways of addressing them or staving them off, Furman said. But now, he said, the study has produced a single-number quantitative measure that appears to do just that.

Furman directs the Stanford1000 Immunomes Projectand is a visiting scholar at Stanford’sInstitute for Immunity, Transplantation and Infection. In addition, he’s an associate professor at the Novato, California-based Buck Institute for Research on Aging and director of the Artificial Intelligence Platform at the same institute.

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Lead authors of the study areNazish Sayed, MD, PhD, assistant professor of vascular surgery at Stanford, and Yingxiang Huang, PhD, senior data scientist at the Buck Institute.

For the 1000 Immunomes Project, blood samples were drawn from 1,001 healthy people ages 8-96 between 2009 and 2016. The samples were subjected to a barrage of analytical procedures determining levels of immune-signaling proteins called cytokines, the activation status of numerous immune-cell types in responses to various stimuli, and the overall activity levels of thousands of genes in each of those cells.

The new study employed artificial intelligence to boil all this data down to a composite the researchers refer to as an inflammatory clock. The strongest predictors of inflammatory age, they found, were a set of about 50 immune-signaling proteins called cytokines. Levels of those, massaged by a complex algorithm, were sufficient to generate a single-number inflammatory score that tracked well with a person’s immunological response and the likelihood of incurring any of a variety of aging-related diseases.

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In 2017, the scientists assessed nearly 30 1000 Immunomes Project participants ages 65 or older whose blood had been drawn in 2010. They measured the participants’ speed at getting up from a chair and walking a fixed distance and, through a questionnaire, their ability to live independently (“Can you walk by yourself?” “Do you need help getting dressed?”). Inflammatory age proved superior to chronological age in predicting frailty seven years later.

Next, Furman and his colleagues obtained blood samples from an ongoing study of exceptionally long-lived people in Bologna, Italy, and compared the inflammatory ages of 29 such people (all but one a centenarian) with those of 18 50- to 79-year-olds. The older people had inflammatory ages averaging 40 years less than their calendar age. One, a 105-year-old man, had an inflammatory age of 25, Furman said.

To further assess inflammatory age’s effect on mortality, Furman’s team turned to the Framingham Study, which has been tracking health outcomes in thousands of individuals since 1948. The Framingham study lacked sufficient data on bloodborne-protein levels, but the genes whose activity levels largely dictate the production of the inflammatory clock’s cytokines are well known. The researchers measured those cytokine-encoding genes’ activity levels in Framingham subjects’ cells. This proxy for cytokine levels significantly correlated with all-cause mortality among the Framingham participants.

A key substance

The scientists observed that blood levels of one substance, CXCL9, contributed more powerfully than any other clock component to the inflammatory-age score. They found that levels of CXCL9, a cytokine secreted by certain immune cells to attract other immune cells to a site of an infection, begin to rise precipitously after age 60, on average.

Among a new cohort of 97 25- to 90-year-old individuals selected from the 1000 Immunomes Project for their apparently excellent health, with no signs of any disease, the investigators looked for subtle signs of cardiovascular deterioration. Using a sensitive test of arterial stiffness, which conveys heightened risk for strokes, heart attacks and kidney failure, they tied high inflammatory-age scores — and high CXCL9 levels — to unexpected arterial stiffness and another portent of untoward cardiac consequences: excessive thickness of the wall of the heart’s main pumping station, the left ventricle.

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CXCL9 has been implicated in cardiovascular disease. A series of experiments in laboratory dishware showed that CXCL9 is secreted not only by immune cells but by endothelial cells — the main components of blood-vessel walls. The researchers showed that advanced age both correlates with a significant increase in endothelial cells’ CXCL9 levels and diminishes endothelial cells’ ability to form microvascular networks, to dilate and to contract.

But in laboratory experiments conducted on tissue from mice and on human cells, reducing CXCL9 levels restored youthful endothelial-cell function, suggesting that CXCL9 directly contributes to those cells’ dysfunction and that inhibiting it could prove effective in reducing susceptible individuals’ risk of cardiovascular disease.

“Our inflammatory aging clock’s ability to detect subclinical accelerated cardiovascular aging hints at its potential clinical impact,” Furman said. “All disorders are treated best when they’re treated early.”

Other Stanford study co-authors are Robert Tibshirani, PhD, professor of biomedical data science and of statistics; Trevor Hastie, PhD, professor of statistics and of biomedical data; senior research scientist Lu Cui, PhD; Human Immune Monitoring Center Immunoassays director Yael Rosenberg-Hasson, PhD; former neurology instructor Benoit Lehalier, PhD; former postdoctoral scholar Shai Shen-Orr, PhD; Holden Maecker, PhD, professor of microbiology and immunology; Cornelia Dekker, MD, professor of pediatric infectious diseases, emeritus; Tony Wyss-Coray, PhD, professor of neurology and neurological sciences; Francois Haddad, MD, clinical professor of cardiovascular medicine; Jose Montoya, MD, former professor of infectious diseases; Joseph Wu, MD, professor of radiology and director of the Stanford Cardiovascular Institute; and Mark Davis, PhD, professor of microbiology and immunology and director of the Institute for Immunity, Transplantation and Infection.

Researchers from the Buck Institute, Edifice Health, the University of North Carolina, Technion-Israel Institute of Technology, the University of Leuven, the University of Bologna, the University of Florence and the Institute of Neurological Sciences of Bologna also contributed to the work.

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The work was funded by the Stanford Alzheimer’s Disease Research Center, the Buck Institute for Research on Aging, the Ellison Foundation, the National Institutes of Health (grants U19 AI057229, U19 AI090019, UL1 RR025744, K01 HL135455 and P50 AG047366) and the Paul F. Glenn Foundation.


How does the immune system predict danger? ›

The immune system detects “danger” through a series of what we call pathogen-associated molecular patterns (PAMPs) or damage-associated molecular pattern molecules (DAMPs), working in concert with both positive and negative signals derived from other tissues.

What determines longevity of immune response? ›

Genetic factors play a relevant role in the attainment of longevity because they are involved in cell maintenance systems, including the immune system. In fact, longevity may be correlated with optimal functioning of clonotypic and natural immunity.

What is the immune system theory? ›

The Quantal Theory of immunity 5 states that individual cells of the immune system recognize and react to antigens (both nonself and self) by proliferating and differentiating into effector cells in an all-or-none (quantal) fashion.

What time of day is your immune system strongest? ›

Immune function is at its peak just before the activity of the day starts—early morning in humans and mid-afternoon for nocturnal creatures like mice—as demonstrated in a study performed by scientists at the University of Geneva (UNIGE) in Switzerland and the Ludwigs-Maximilians University (LMU) in Germany.

What is the immune system response to a threat? ›

Antibodies attach to a specific antigen and make it easier for the immune cells to destroy the antigen. T lymphocytes attack antigens directly and help control the immune response. They also release chemicals, known as cytokines, which control the entire immune response.

What happens when your immune system is strong? ›

What if Your Immune System is Too Strong? There are some conditions where an immune system can get too strong. For example, allergies, asthma or eczema can occur if an immune system is too strong. Autoimmune disease is also thought to happen due to an overactive immune system.

At what age is your immune system at its peak? ›

The function of the immune system peaks at around puberty and gradually declines thereafter with advance in age.

Which immune cells live the longest? ›

Neutrophil cells (a type of white blood cell) might only last two days, while the cells in the middle of your eye lenses will last your entire life.

How do you know if your immune system is out of whack? ›

6 Signs You Have a Weakened Immune System
  1. Your Stress Level is Sky-High. ...
  2. You Always Have a Cold. ...
  3. You Have Lots of Tummy Troubles. ...
  4. Your Wounds Are Slow to Heal. ...
  5. You Have Frequent Infections. ...
  6. You Feel Tired All the Time.
16 Feb 2022

What are 3 interesting facts about the immune system? ›

Six Fascinating Fun Facts About the Immune System
  • Our immune system remembers every microbe it has ever fought and defeated. ...
  • The immune system is made up of two different systems: the innate immune system and the adaptive immune system. ...
  • Getting a fever means that your immune system is working.

Which is the most accepted theory of immune response? ›

The clonal selection hypothesis is a widely accepted model for the immune system's response to infection.

What are the two main goals of the immune system? ›

The main job of the innate immune system is to fight harmful substances and germs that enter the body, for instance through the skin or digestive system. The adaptive (specific) immune system makes antibodies and uses them to specifically fight certain germs that the body has previously come into contact with.

At what sleep stage is your immune system strengthened? ›

The deep sleep stage of the sleep cycle helps to boost immune function and aids in controlling stress and anxiety.

Does sleeping late weaken your immune system? ›

Yes, lack of sleep can affect your immune system. Studies show that people who don't get quality sleep or enough sleep are more likely to get sick after being exposed to a virus, such as a common cold virus. Lack of sleep can also affect how fast you recover if you do get sick.

What are the 3 defenses of the immune system? ›

Humans have three types of immunity — innate, adaptive, and passive: Innate immunity: Everyone is born with innate (or natural) immunity, a type of general protection. For example, the skin acts as a barrier to block germs from entering the body.

What are the 4 phases of the immune response? ›

The adaptive immune response in B cells, Helper T cells and Cytotoxic T cells involved four phases: encounter, activation, attack, and memory.

What are the three defenses of the immune system? ›

The immune system's three lines of defense include physical and chemical barriers, non-specific innate responses, and specific adaptive responses.

What weakens the immune system the most? ›

Stress and worry aren't great germ fighters. Just having anxious thoughts can weaken your immune response in as little as 30 minutes. Constant stress takes an even bigger toll and makes it harder to fend off the flu, herpes, shingles, and other viruses.

At what age does your immune system weaken? ›

The bad news is that as we age, our immune systems gradually deteriorate too. This “immunosenescence” starts to affect people's health at about 60, says Janet Lord at the University of Birmingham, UK.

What diseases cause overactive immune system? ›

Autoimmune disease affects 23.5 million Americans, and nearly 80 percent of those are women. If you're one of the millions of women affected by this group of diseases, which includes lupus, rheumatoid arthritis and thyroid disease, you may be wondering why your immune system is attacking itself.

What vitamins make your immune system stronger? ›

Vitamins B6, C and E are all known for their immune-boosting properties. You can get all of these vitamins from a well-balanced diet, so you don't need supplements. Some foods rich in these vitamins include eggs, bell peppers, spinach and almonds.

Does your immune system get better or worse with age? ›

The strength of the immune response declines with age.

The number of B cells that respond to influenza is reduced, and antibody avidity in response to carbohydrate antigens is diminished.

How do you stop an overactive immune system? ›

Eating a well-balanced diet and getting regular exercise may also help you feel better. BOTTOM LINE: The main treatment for autoimmune diseases is with medications that bring down inflammation and calm the overactive immune response.

What living thing has the strongest immune system? ›

Ostriches have the most powerful immune system of any land animal,” Ms. Anikeyeva said. “For some people, ostrich oil works like a miracle.

What is the largest immune system organ? ›

Spleen. The spleen is the largest internal organ of the immune system, and as such, it contains a large number of immune system cells. Indeed, about 25 percent of the blood that comes from the heart flows through the spleen on every beat.

Which organ has the most immune cells? ›

Bone marrow

That is where most immune system cells are produced and then also multiply. These cells move to other organs and tissues through the blood.

What are the 3 causes of weakened immune systems? ›

Also, infections like the flu virus, mono (mononucleosis), and measles can weaken the immune system for a brief time. Your immune system can also be weakened by smoking, alcohol, and poor nutrition.

Does Covid ruin your immune system? ›

“While this was a small pilot study, it does suggest that some people with long COVID may actually have underactive immune systems after recovering from COVID-19, which means that boosting immunity in those individuals could be a treatment,” said senior author Dr.

Can the immune system fight every disease? ›

The main feature of the innate immune system is to respond quickly, which can lead to inflammation and fever. It does not recognize specific strains of bacteria or viruses; it attacks broadly, which is why it is unable to get rid of all pathogens.

What has biggest impact on immune system? ›

Several factors like sleep, diet, stress and hygiene can affect the immune system's performance, and any offsets in these behaviors can cause havoc on immune function.

What are the 4 main organs in the immune system? ›

The key primary lymphoid organs of the immune system are the thymus and bone marrow, and secondary lymphatic tissues such as spleen, tonsils, lymph vessels, lymph nodes, adenoids, and skin and liver.

Who is the father of immune system? ›

As a student of immunology, I learned that Louis Pasteur was really the father of immunology, despite Edward Jenner's pioneering introduction of vaccination to prevent smallpox in 1798 (Smith, 2011).

Which immune response is first? ›

Innate immunity is the first immunological, non-specific mechanism for fighting against infections. This immune response is rapid, occurring minutes or hours after aggression and is mediated by numerous cells including phagocytes, mast cells, basophils and eosinophils, as well as the complement system.

What is the first line of immune response? ›

The innate immune system is the body's first line of defense against germs entering the body. It responds in the same way to all germs and foreign substances, which is why it is sometimes referred to as the "nonspecific" immune system.

What happens when your immune system fails? ›

When your immune system fails completely, you're left without any natural protection against illness. This leaves you open to “opportunistic infections” — sicknesses that can even come from things that ordinarily wouldn't harm you.

Is your immune system always working? ›

Even though you may be unaware that your immune system is functioning, it is always working. You may notice it when an infection or irritation you can see or feel occurs. An example is when a bug bites your skin.

What are the 3 phases of immune function? ›

The cellular immune response consists of three phases: cognitive, activation, and effector. In the cognitive phase, macrophages display foreign antigens on their surface in a form that can be recognized by antigen-specific TH1 (T helper 1) lymphocytes.

Why do some people rarely get sick? ›

Why Some People Evade Colds And Others Don't People who have built up immunity to common viruses are less likely to get sick. But researchers say it's also possible some people are genetically less susceptible to catching a common cold.

What foods weaken the immune system? ›

10 Foods That May Weaken Your Immune System
  • Added sugar. There's no doubt that limiting how much added sugar you consume promotes your overall health and immune function. ...
  • Salty foods. ...
  • Foods high in omega-6 fats. ...
  • Fried foods. ...
  • Processed and charred meats. ...
  • Fast food. ...
  • Foods that contain certain additives. ...
  • Highly refined carbs.
22 Mar 2021

Does napping help immune system? ›

The nitty-gritty about napping

Sleep is essential for your mind and body. It keeps you alert and focused. It helps cement memories. It may even boost your immune system, protecting you from illnesses such as diabetes and heart disease.

What stage of sleep restores body? ›

Stage 3: Non-REM sleep

In stages 3 and 4, deep sleep begins. Your eyes and muscles don't move, and your brain waves slow down even further. Deep sleep is restorative. Your body replenishes its energy and repairs cells, tissues, and muscles.

Does your body fight infection when you sleep? ›

In a recent study, scientists say they discovered that quality sleep can bolster the T cells in your body that fight off infection. Good sleep does this by enhancing the ability of T cells to adhere to and destroy cells infected by viruses and other pathogens.

Do colds make your immune system stronger? ›

There is actually some truth to this. A child exposed to colds and viruses earlier in life will develop a stronger immune system and is less likely to become sick in his or her later years.

Is 6 hours sleep enough? ›

Recommended Hours of Sleep by Age

The Centers for Disease Control and Prevention (CDC) considers less than seven hours per night to be short sleep5, which means for most people, six hours of sleep is not enough.

How do you know if something is attacking your immune system? ›

BOTTOM LINE: Symptoms like fatigue, muscle aches, swelling, and redness could be signs of an autoimmune disease. Symptoms might come and go over time.

How do you know if your immune system is attacking you? ›

Joint pain and swelling. Skin problems. Abdominal pain or digestive issues. Recurring fever.

How does immune status increase risk of infection and why? ›

The immune system may not immediately recognize harmful germs, which increases the risk of infection. Glucose Levels: High glucose levels suppress the function of white blood cells that fight off infection, increasing the risk of contracting a foodborne illness.

How does the immune system fight an invasion? ›

As soon as the injury occurs, immune cells in the injured tissue begin to respond and also call other immune cells that have been circulating in your body to gather at the site and release cytokines to call other immune cells to help defend the body against invasion.

What are the 7 autoimmune diseases? ›

Common autoimmune disorders include:
  • Addison disease.
  • Celiac disease - sprue (gluten-sensitive enteropathy)
  • Dermatomyositis.
  • Graves disease.
  • Hashimoto thyroiditis.
  • Multiple sclerosis.
  • Myasthenia gravis.
  • Pernicious anemia.
24 Apr 2021

How can I reset my immune system naturally? ›

Here are 9 tips to strengthen your immunity naturally.
  1. Get enough sleep. Sleep and immunity are closely tied. ...
  2. Eat more whole plant foods. ...
  3. Eat more healthy fats. ...
  4. Eat more fermented foods or take a probiotic supplement. ...
  5. Limit added sugars. ...
  6. Engage in moderate exercise. ...
  7. Stay hydrated. ...
  8. Manage your stress levels.
1 Apr 2020

What are the most serious autoimmune diseases? ›

Four of the most frequently fatal ones include:
  • Giant cell myocarditis.
  • Anti-NMDA receptor encephalitis.
  • Mixed connective tissue disease.
  • Autoimmune vasculitis.
16 Oct 2022

Do immunocompromised people get sick faster? ›

Some people who are immunocompromised (have a weakened immune system) are more likely to get sick with COVID-19 or be sick for a longer period.

What organ is responsible for immunity? ›

Primary lymphoid organs: These organs include the bone marrow and the thymus. They create special immune system cells called lymphocytes. Secondary lymphoid organs: These organs include the lymph nodes, the spleen, the tonsils and certain tissue in various mucous membrane layers in the body (for instance in the bowel).

How do you calm an overactive immune system? ›

Use nutrients such as fish oil, vitamin C, vitamin D, and probiotics to help calm your immune response naturally. Exercise regularly — it's a natural anti-inflammatory. Practice deep relaxation like yoga, deep breathing, biofeedback, or massage, because stress worsens the immune response.

What destroys the body's immune system? ›

Your immune system can also be weakened by smoking, alcohol, and poor nutrition. AIDS. HIV, which causes AIDS, is an acquired viral infection that destroys important white blood cells and weakens the immune system. People with HIV/AIDS become seriously ill with infections that most people can fight off.

What are the 3 main defenses of your immune system? ›

Humans have three types of immunity — innate, adaptive, and passive: Innate immunity: Everyone is born with innate (or natural) immunity, a type of general protection. For example, the skin acts as a barrier to block germs from entering the body.

What are the three main enemies the immune system defends against? ›

The human body has three primary lines of defense to fight against foreign invaders, including viruses, bacteria, and fungi. The immune system's three lines of defense include physical and chemical barriers, non-specific innate responses, and specific adaptive responses.


1. How to Stop (And Even Reverse) Aging
(PBS Terra)
2. Turning Back the Clock: The Science of Staying Young
(SITN Boston)
3. Hallmarks of Aging: The Immune System Takes the Lead
(Cleveland Clinic)
4. The New Science of Sleep and Dreams | Professor Matthew Walker
(How To Academy Mindset)
5. Dr. Steve Horvath on epigenetic aging to predict healthspan: the DNA PhenoAge and GrimAge clocks
6. Epigenetic Clocks Help to Find Anti-Aging Treatments | Steve Horvath | TEDxBerkeley
(TEDx Talks)

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