Uncovering and attending to patients’ immune age
LONGEVITY — THE COMBINATION OF HEALTH AND LIFE SPAN — is the goal of patients and practitioners alike. The higher goal is a long health span, the period of life that is free of poor health and disability.
However, we don’t all age biologically at the same rate. Some become visibly aged and prone to disease, while others the same age are enjoying a long health span, where they remain vigorous and largely disease-free. While life span has increased in the past decades, health span has not. Today, the gap between health span and life span is estimated at around nine years.1
What makes the difference between aging poorly and longevity? Research into aging points to a robust immune system as the key to a long and healthy life. A 2023 study led by researchers from Tufts Medical Center and Boston University School of Medicine, for example, found that many centenarians have immune systems that are highly functional, as if they were chronologically decades younger.2
Aging is characterized by immunosenescence, or a series of immune-related changes that play an important role in many age-related diseases and chronic conditions, especially infectious disease, autoimmunity, heart disease, stroke, cancer and neurodegeneration. Healthy older adults have an immune age — the immune system’s functional capacity — that is younger than their chronological age. Their immune systems continue to function efficiently, without the impairments that typically come with age.3
A powerful immune system helps avoid or delay some crucial hallmarks of aging, particularly inflammaging, the chronic, low-level inflammation that often accompanies aging. And because the immune system directly correlates to mitochondrial function, a decline in immune health can lead to mitochondrial dysfunction, which can result in accelerated aging.
Biomarkers for longevity
To help determine someone’s immune age, I start with standard blood tests for inflammatory markers, including interleukin 1 beta, interleukin 6, interleukin 8, tumor necrosis factor (TNF) alpha, and hs-C-reactive protein. Elevated levels tell me that inflammaging is at work — and some disease processes may also be happening. Elevated TNF alpha, for example, is associated with chronic inflammatory diseases such as arthritis and diabetes. Elevated hs-CRP is linked to an increased risk of a heart attack, particularly in people who have already had one.
I also check for gut health by examining blood levels of zonulin and occludin, two markers of tight junctions in the gut wall. When these markers are elevated, the gut becomes leaky, allowing undigested food particles, bacteria, lipopolysaccharides (LPS), and other intestinal contents to enter circulation. The immune response this creates is a significant source of chronic inflammation. An interesting 2023 study of centenarians in China showed that many have a gut microbiome with the bacterial makeup of a younger person. Their longevity and relatively good health support the idea that a long and healthy lifespan is associated with youth-associated signatures in the makeup of the gut microbiome.4 A lifetime healthy eating pattern may play an important role. The study is another example of how a healthy gut microbiome plays an essential role in keeping systemic inflammation under control as we age.
Maintaining immune vigor
A healthy diet, maintaining a normal weight and regular exercise are critical for longevity. Many studies, such as the long-running Nurses’ Health Study and the Health Professionals Follow-up Study, have confirmed the importance of these factors.
In the Nurses’ Health Study, for example, women who followed these three healthy habits at age 50 lived about 34 years longer and remained free of diabetes, cardiovascular disease, or cancer; women at age 50 who didn’t follow these healthy habits lived only 24 disease-free years. The results were very similar for men.5
Longevity arises from the impact of a healthy lifestyle on the immune system. Negative lifestyle factors such as overconsumption of sugar, gluten and alcohol, environmental toxins, and lack of sleep cause inflammation, which can lead to an imbalance in immune homeostasis. The result is decreased resistance to infection and a reduced ability to detect and remove damaged cells. These factors make the immune system age in step with, or even faster than, an individual’s chronological age.
Each factor negatively affects immunity; combined, the aging effect on the immune system is compounded. Conversely, improving any one element will help enhance immunity; improving more than one will help turn back the clock even more. For example, overweight or obese people often also suffer from sleep apnea, significantly affecting their sleep quality. Improving either factor (preferably both) will enhance immunity as well.
We can use lifestyle to slow the inevitable impacts of aging on the immune system, but we can’t stop them. As we age, our bodies inevitably build up senescent cells, which have naturally stopped dividing but don’t die. They continue to consume nutrients and produce metabolic waste but are no longer truly functional. As senescent “zombie” cells accumulate in the body, they fuel chronic inflammation, contributing to aging-associated diseases such as cancer, degenerative disorders and autoimmunity.
Along with other cells in the body, immune system cells become senescent. Old, ineffective T cells accumulate in the adaptive immune system, while innate immune cells such as macrophages, neutrophils, and natural killer cells become impaired.6 Immune senescence is a significant factor in reduced immunity as we age.
I recommend a two-pronged approach to clear out old or damaged immune cells to help rejuvenate the immune system and improve immune protection: exercise and intermittent fasting.
Exercise and immunity
Regular moderate exercise improves immune surveillance by macrophages and T cells at any age, leading to better protection against infection. Exercise stimulates the production of leukocytes, increasing them anywhere from 2-4 times, making them more mobile: They can migrate faster within the bloodstream and lymphoid tissues in the body in response to an attack. Exercise also improves anti-inflammatory signaling and recognizing of antigens promptly and accurately.
Even a moderate exercise session is enough to stimulate the immune system positively. Regular exercise improves immunity by reducing chronic low-level inflammation, increasing T cell proliferation and cytokine production, promoting the production of anti-inflammatory M2 macrophages, and increasing phagocytosis in neutrophils.
Regular exercise leads to beneficial changes in body composition and metabolism, improving immunity as well. The improved cardiovascular and endothelial function lets circulating immune cells enter and quickly leave the bloodstream. Most importantly, regular physical activity throughout a lifetime may help prevent or limit immunosenescence. Exercise is another powerful way to rejuvenate the immune system and clear out old immune cells. The more intense the exercise, the more the immune system is stimulated to rejuvenate.
Muscle mass and immunity
Sarcopenia, or the loss of muscle strength and mass, usually begins as we reach our 40s and can accelerate rapidly in older people, leading to frailty and poor quality of life.7 Regular exercise emphasizing resistance training is a powerful tool to fight sarcopenia and improve longevity.
As Gabrielle Lyon, DO, founder of the Institute for Muscle-Centric Medicine, says, “Muscle is the organ of longevity.” A recent study of 16,221 participants in the Nurses’ Health Study and Health Professionals Follow-up Study shows the importance of physical activity and the muscle it builds. An analysis of their physical activity levels over 30 years showed that those who were consistently moderately active for 150-300 minutes a week had a 19-25% lower risk of death from any cause.8
Recent research suggests that skeletal muscle is a central regulator of immune system function. Aging skeletal muscle plays a central role in developing immunosenescence by disrupting the interplay between the muscles and the immune system. This exciting research suggests that maintaining or increasing well-toned muscle mass through regular resistance exercise pays off not only in better body composition, increased strength, more endurance and improved quality of life, but also increased immunity.9
Regular exercise is also crucial for autophagy, the normal process of breaking down and removing damaged or dysfunctional cells, including damaged immune cells. In addition to activating autophagy, exercise activates mitophagy or removes damaged mitochondria within cells.
Any consistent form of regular exercise will improve these functions. Still, a recent meta-analysis of 26 studies assessing the autophagic response to exercise in humans showed that autophagy and mitophagy increase most following long-term resistance exercise.10 The value of weight-training for immunity and its many benefits is why I prescribe weight-training exercises for my patients in addition to aerobic exercise. In my extensive experience, this combination has synergistic effects that improve immunity and well-being beyond what each type of exercise alone can accomplish.
To combat immunosenescence and improve immune resilience, we need to restore a better balance of effective immune cells and replace worn-out immune cells with new ones. The evidence that exercise increases immunity through autophagy and mitophagy and helps delay immune system aging is powerful, but it’s only part of the reset equation. We need to add intermittent fasting (also known as time-restricted eating) to help rejuvenate the immune system, improve the balance of new and old immune cells, and reboot your immune system’s function.
Fasting is a well-known method for stimulating immunity by removing old or damaged immune cells through autophagy and mitophagy. Stimulating autophagy breaks down old immune cells and encourages the production of new immune cells that are more resilient, a process that helps reset the immune system.11 The damaged parts are discarded, and the remaining macromolecules are recycled throughout the body. Autophagy appears to be particularly effective in destroying immunosenescent cells that can cause autoimmunity.12
Intermittent fasting can increase the rate of autophagy. The faster you remove senescent leukocytes and replace them with newly generated cells, the quicker you decrease the amount of inflammation in the body.13
Fasting also deletes old leukocytes (white blood cells). Eating again stimulates your stem cells to generate new leukocytes when you stop fasting (Yoshinori Ohsumi won the 2016 Nobel Prize in physiology or medicine for his discoveries in the mechanisms of this critical process).
Similarly, the mitochondria within immune cells can become damaged and dysfunctional. Fasting triggers mitophagy, allowing the remaining mitochondria to function better. At the same time, mitophagy helps reduce the production of undesirable inflammatory cytokines from the cell.14
Fasting and immune benefits
The mechanisms behind enhanced mitophagy are still being explored. Several transcription factors that promote mitochondrial biogenesis and improve function are involved. One example is the nuclear factor 2 (Nrf2) pathway, which regulates reactive oxygen species production by mitochondria. Fasting may enhance the activity of the Nrf2 pathway and improve the expression of antioxidant regulatory genes.15
While fasting for 24 hours or longer is an effective technique for boosting immune system regeneration, it is difficult for most people. Extensive fasting may also lead to the loss of muscle mass and a negative impact on immunity. To maintain and improve immunity, I recommend regular intermittent fasting instead. By fasting after the evening meal until the following day (approximately 14 to 16 hours) and eating a healthy diet with appropriate nutrient intake during the eating window, you get the immune benefits of fasting while maintaining and even building skeletal muscle mass.
Uncovering the secrets of longevity and health span has always been the goal of humanity. From alchemy and elixirs to modern-day supplements and genetic engineering, we have always sought the secrets of longevity and health span. For me, the key to longevity is turning on the health switches in the body. A robust and resilient immune system is the master switch.
ROBERT G. SILVERMAN, DC, DACBN, DCBCN, MS, CCN, CNS, CSCS, CIISN, CKTP, CES, HKC, FAKTR, is a chiropractic doctor, clinical nutritionist, national/international speaker, author of Amazon’s #1 bestseller “Inside-Out Health,” and founder and CEO of Westchester Integrative Health Center. He graduated magna cum laude from the University of Bridgeport College of Chiropractic and has a Master of Science in human nutrition. The ACA Sports Council named him “Sports Chiropractor of the Year” in 2015. He is on the advisory board for Functional Medicine University and is a seasoned health and wellness expert on both the speaking circuits and the media. He is a thought leader in his field and practice, and a frequently published author in peer-reviewed journals and other mainstream publications.
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 Karagiannis TT, Dowrey TW, Villacorta-Martin C, et al. Multi-modal profiling of peripheral blood cells across the human lifespan reveals distinct immune cell signatures of aging and longevity. EBioMedicine. 2023;90:104514. doi:10.1016/j.ebiom.2023.104514.
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 Xiang-Ke Chen, Chen Zheng, Parco Ming-Fai Siu, Feng-Hua Sun, Stephen Heung-Sang Wong & Alvin Chun-Hang Ma (2023) Does Exercise Regulate Autophagy in Humans? A Systematic Review and Meta-Analysis, Autophagy Reports, 2:1, DOI: 10.1080/27694127.2023.2190202.
 Brandhorst, Sebastian et al. “A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan.” Cell metabolism vol. 22,1 (2015): 86-99. doi:10.1016/j.cmet.2015.05.012.
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