Introduction
The immune system is considered one of the most highly developed and sophisticated systems in the human body. Significant age changes in immune function, termed immunosenescence, have been known for decades but only recently have studies revealed how such age changes can be minimized. This blog will discuss the positive effects of exercise as a prescription on how to retard aging of the immune system, that is how to retard immunosenescence. While there are other means to enhance immune function e.g. optimizing intestinal bacteria, the wealth of data accumulated over the past ten years points to exercise as the most convincing means, on how to retard aging of the immune system.
This blog presents the positive effects of exercise on the immune system in three parts: A) basics of immune function, B) immunosenescence and C) positive effects of exercise that retard aging of the immune system (immunosenescence).
A. Basics of Immune Function
The immune system functions to suppress and/or destroy pathogens, foreign debris and aberrant cells (e.g. cancer cells). The system has two main components, termed adaptive and innate (1).
Adaptive Immunity
Adaptive immunity encompasses repertoires of two types of cells, designated T-cells or B-cells. These cells, also called lymphocytes, respond to unique components of pathogens, foreign debris and malignant cells. T-cells destroy unwanted invaders or malignant cells out right, secrete soluble factors that kill or assist other cells to kill; B-cell produce antibodies that bind and eventually destroy pathogens and foreign debris.
The distinctiveness of adaptive immunity is its long term memory. That is, each encounter with a new foreign entrant (scientifically termed an antigen), generates “memory” in select cells such that the next encounter with this antigen is faster, more robust and potentially lifesaving. Immune memory is a highly effective means to prevent repeat infections and is the rationale for vaccine efficacy.
Innate Immunity
Innate immunity consists of many different cell types such as neutrophils, natural killer cells, dendritic cells and monocyte-macrophages. This diverse group of cells represents the “first line of defense” against invading foreign pathogens, chemicals or mutated cells.
The monocyte, a circulating sentinel has the ability to migrate into tissues and morph into a macrophage, a potent tissue resident. The macrophage engulfs antigenic material, degrades it and specifically alerts lymphocytes (adaptive immunity, described above) to assist with final destruction. Dendritic cells, also tissue residents, detect antigenic material and cross-talk with lymphocytes, thus another alarm signal for adaptive immunity. Natural killer cells do exactly as their name implies. They have the potential to directly annihilate foreign cells e.g. cancer cells or microbes.
The immune system, adaptive and innate, is fully fortified with a first alert system, effective destructive devices and memory to continuously protect against a variety of harmful insults, be they pathogens, chemicals, cancer cells.
B. Immunosenescence
Both age and environment remodel the immune system. This is immunosenescence. Cells of the immune system lose their normal functions as described above and gain less or adverse functions. Such changes are driven in part by chronic viral infections e.g. cytomegalovirus (considered 85% population exposure (2)) or chronic chemical exposures, that the body encounters throughout life. Additionally, immune cells are sensitive to chronic stress (steroid hormones in particular) that can damage these cells and even kill them. Negative exposures throughout life drive immunosenescence and collectively is termed immunobiography (3)
Aging of Adaptive Immunity
The most remarkable age-related change in the immune system is the dramatic shrinkage of the thymus, a key lymphoid gland located in the upper chest in front of the heart and aorta. By age 30, the thymus size has decreased by 75% and consists mostly of fat. Thymic atrophy is serious because the thymus is the site where naive T-cells become “trained and educated” to handle future unknown antigens. With thymic shrinkage, the output of new T-cells decreases and hence T-cell replacement continues to decline. Similarly, new naive B-cells, derived from the bone marrow, also decrease over the years. Therefore, as adaptive lymphocytes wear out, they are not replaced and immune function suffers.
Aging of Innate Immunity
Innate cells also age. These cells respond superbly for many years but with repeated stimulation as noted above and even with limited “memory”, their ability to kill pathogens, produce valuable mediators and alert the adaptive system eventually reaches exhaustion.
Overall Consequences of Immunosenescence
There are several serious consequences arising from the lack of replenishment of T- and B-cells, the overworking of the older T- and B-cell repertoires and the diminished functions of the various innate cells. The major consequences are:
1) age-associated increase in infectious diseases,
2) reduced response to vaccinations,
3) increased incidence of cancers and poor response to cancer therapy and
4) elevated presence of pro-inflammatory factors supporting an internal milieu of low grade inflammation (inflammaging) that underpins all major disease.
Inflammaging is one of the thirteen hallmarks of aging (4) (see Blog 26)
C. Positive Effects of Exercise that Retard Aging of the Immune System
One of the best ways to maintain optimal function of the immune system is through physical exercise. The long held view that a single bout of acute exercise suppressed the immune system, has been debunked. More recent data show that physical exercise, acute and chronic ” improves immune competency across the lifespan” (5).
A summation of recent findings indicates that the intensity of the exercise affects the impact on the immune system (6). Immune benefits accrue from moderate and high intensity exercises.
Moderate Intensity Exercise
The definition of moderate intensity exercise is attainment of 40-70% of maximal breathing capacity (VO2 max) with an elevated heart rate to a similar extent and performed for 150 minutes per week (American College of Sports Medicine). An example is brisk 30 minute walking, 5 days per week plus resistance exercises twice weekly.
Moderate intensity exercise improves the functionality of the various immune cells. Neutrophils become better at disposing of unwanted material, the quality and number of monocytes and natural killer cells increase, macrophages are less proinflammatory and assist with cell repair, B-cell number and function increases (better antibody specificity) and T-cell clones change to better handle immune responses (6). These changes affect both innate and adaptive immunity and clearly retard immunosenescence (7).
High Intensity Exercise
High intensity exercise is generally denoted as high intensity interval training. This entails achieving 80-100% VO2 max for several minutes followed by low intensity recovery at 40% VO2max for several minutes. This is repeated for various periods of 10-30 minutes. Similar to this, but slightly less challenging is vigorous intensity exercise (150 minutes per week) with elevated heart rate at 70-85% of max and heavy breathing as in running, jogging, fast cycling, uphill climbing plus resistance exercise 2 or more times weekly.
Engagement in high intensity exercise produces positive changes in the immune system similar to those produced with modest intensity exercise. However, additionally, the number of neutrophils increases and the number of proinflammatory monocytes declines. There is temporary enhancement of the number of natural killer cells, production of antibodies is increased and the ratio of various T-cell clones is optimized along with their decrease in inflammatory mediators (8). Taken together, high intensity exercise dramatically stalls immunosenescence and optimizes detection and elimination of pathogens, cancer cells or unwanted chemical debris.
Overall Benefits
Retarding immunosenescence produces numerous rewards.
Firstly, a significant outcome is an enhanced antibody production to vaccination in older individuals who exercise compared to those who do not (9-11). Vaccines against pneumonia, respiratory syncytial virus, shingles (resurgence of chicken pox virus as herpes zoster), influenza and novel viruses e.g. SARS-CoV-2 and variants benefit the older adult immensely (12). Hence, optimal protection is highly desirable. Whereas adjuvants and higher vaccine doses help improve protective response of vaccines, exercise is a significant addition.
Secondly, chronic physical exercise is strongly linked to cancer prevention (13). This is not a causal effect but as reviewed by Zhu et al., (2022), results of hundreds of trials show a reduced risk of many cancers (breast, colorectal, gastric, lung, kidney, endometrial) of about 20% in those committed to 3-5 hours of moderate-vigorous exercise per week.
Additionally, physical exercise is beneficial in improving the efficacy of various types of cancer therapy (chemotherapy, radiation, surgery, immune modulators). It reduces fatigue, increases the therapeutic killing power, optimizes immune function, and reduces severity of side effects (13). Hence it “enhances the curative effect of cancer treatment” (13).
Thirdly, a program of serious exercise prevents the inflammatory output of immunosenescence. Low grade inflammation (inflammaging) underpins all major diseases (atherosclerosis, diabetes, cancers, dementias, psychological diseases). Immune cells secrete inflammatory mediators, usually in response to acute assaults. Continued production of inflammatory substances is harmful. As noted above, exercise prompts immune cells to decrease production of these damaging factors such that they help out acutely but do not persist chronically. Clearly, the data show that exercise is the best prescription to prevent all major diseases (14). As discussed in many blogs, it also prevents skeletal muscle loss and assures independence (see Blogs 2, 3 ,33 )
Conclusions
Optimal function of the immune system is incredibly important for the older adult in maintaining a good quality of life. This highly evolved immune system protects the body not only from both outside insults e.g. parasites, bacteria, viruses, and chemicals and also inside insults (mutated malignant cells). Immunosenescence compromises this protection. Fortunately, chronic physical exercise of modest and high intensity retards aging of the immune system. The benefits of exercise are many: improved response to vaccines, decreased cancer risk, better response to cancer therapy and reduced inflammaging, the bases of all major diseases. An exercise program is well worth the effort.
References (pubmed)
1. Bilder Glenda E. Human Biological Aging: From Macromolecules to Organ Systems. John Wiley & Sons Publishers, Hoboken, New Jersey, 2016.
2. https://cytogam.com/cmv-landscape-cmv-seroprevalence/
3. Fulop T, Larbi A, Pawelec G et al., Immunology of Aging: the Birth of Inflammaging Clinical Reviews in Allergy & Immunology (2023) 64:109–122 https://doi.org/10.1007/s12016-021-08899-6
4. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G.Hallmarks of aging: An expanding universe. Cell. 2023 Jan 19;186(2):243-278. doi: 10.1016/j.cell.2022.11.001
5. Campbel JP, Turner JE. Debunking the Myth of Exercise-Induced Immune Suppression: Redefining the Impact of Exercise on Immunological Health Across the Lifespan Front Immunol. 2018 Apr 16:9:648. doi: 10.3389/fimmu.2018.00648.6 Shi et al., 2025
7. Despeghel M, Reichel T, Zander J et al., Effects of a 6 Week Low-Dose Combined Resistance and Endurance Training on T Cells and Systemic Inflammation in the Elderly Cells . 2021 Apr 8;10(4):843. doi: 10.3390/cells10040843
References continued
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9. Pascoe AR, Fiatarone Singh MA, Edwards KM.The effects of exercise on vaccination responses: a review of chronic and acute exercise interventions in humans.
Brain Behav Immun. 2014 Jul;39:33-41. doi: 10.1016/j.bbi.2013.10.003
10. Dinas PC, Koutedakis Y, Ioannou LG, Metsios G, Kitas GD Effects of Exercise and Physical Activity Levels on Vaccination Efficacy: A Systematic Review and Meta-Analysis. .Vaccines (Basel). 2022 May 12;10(5):769. doi: 10.3390/vaccines10050769
11. Barni L, Carrasco-Vega E, Olivieri M, Galán-Mercant A, Guiducci S, Picariello F, González-Sánchez M.Does Physical Exercise Enhance the Immune Response after Vaccination? A Systematic Review for Clinical Indications of COVID-19 Vaccine. Int J Environ Res Public Health. 2023 Mar 15;20(6):5183. doi: 10.3390/ijerph20065183
12. Bilder, Glenda Elaine and Brown-O’Hara, Patricia. Drug Use in the Older Adult: Guide for Nurses, Other Practicing Clinicians and Interested Older Individuals. Springer Nature, Cham, Switzerland, 2025
13. Zhu C, Ma H, He A, Li Y, He , Xia Y. Exercise in cancer prevention and anticancer therapy: Efficacy, molecular mechanisms and clinical information. Cancer Lett. 2022 Sep 28; 544:215814. doi: 10.1016/j.canlet.2022.215814.
14. Pedersen BK, Saltin B Exercise as medicine – evidence for prescribing exercise as therapy in 26 different chronic diseases. .Scand J Med Sci Sports. 2015 Dec;25 Suppl 3:1-72. doi: 10.1111/sms.12581