Thymic involution is the process by which the thymus shrinks with age and produces fewer T cells, impairing immunity and increasing the risk of infection in older adults. In addition, thymic involution increases the risk of cancer and autoimmunity with age.

However, research has identified some of the mechanisms of thymic involution and highlighted possible strategies to improve immunity:

  • By activating PPAR-gamma, a protein that regulates fat metabolism, caloric restriction reduced the rate of thymic involution in mice and increased the number and diversity of circulating T cells.[1]
  • T cells from participants with obesity tended to be less diverse, a finding supported by a study in mice that found that diet-induced obesity increased immunosenescence, a type of advanced cell aging, and thymic involution in mice. This suggests maintaining a healthy weight may slow thymic involution and loss of T cell immunity.[2]
  • Stress increased the rate of thymic involution in mice due to an increase in circulating glucocorticoids (e.g., the stress hormone, cortisol), which induce programmed cell death in thymic cells. This suggests that preventing stress or utilizing stress reduction tools (e.g., mindfulness, talk therapy, social support) has the potential to slow thymic involution.[3]

Role of T cells in cancer, autoimmunity, and fighting infection

The thymus is a lymphoid organ located behind the sternum and near the heart. Its primary purpose is to produce mature T cells, a type of white blood cell involved in allergies, autoimmunity, and immunity against pathogens. T cell maturation begins at birth and is most active in early life when pathogens and allergens are encountered by the immune system for the first time. T cell production drops sharply after adolescence, followed by a sharp rise in the rate of thymic involution after age forty.

New T cells arise from hematopoietic progenitor cells (i.e., blood stem cells) in the bone marrow and migrate to the thymus for maturation. In the thymus, naive T cells will mature into one of four main populations.

  • T helper, type 1 (Th1) cells amplify the infectious response to intracellular bacteria and viruses by recruiting phagocytic (i.e., cell eating) cells, such as macrophages, to the site of infection.
  • T helper, type 2 (Th2) cells coordinate with eosinophils, mast cells, and other immune cells to attack extracellular pathogens such as parasites. However, when the immune system reacts abnormally, these immune cells play a central role in the development of allergies to foods, pets, pollen, and other environmental triggers. One theory suggests allergic diseases are so prevalent in the industrialized world because parasitic infections are so rare, creating an imbalance in Th2 immunity.[4]
  • Cytotoxic T (Tc) cells deliver molecular signals that induce cellular death (i.e., apoptosis) to foreign cells, cancer cells, and cells infected with intracellular bacterial and viral pathogens.
  • T regulatory (Treg) cells promote tolerance to self-antigens and are vital for preventing autoimmunity, a condition where the immune system confuses molecular patterns from human tissue as foreign antigens and causes chronic illness.

With such an important set of responsibilities, it is unsurprising that a decline in T cell-mediated immunity contributes to debilitating age-related illnesses:

  • Reduced infectious immunity – Immunosenescence, a cellular process integral to thymic involution, is associated with reduced immunity to influenza and other respiratory infections and less effective response to influenza vaccination.[5]
  • Autoimmunity – Immunosenescence reduced production of naive T cells (which react to new antigens) and increased production of clonal T cells (which react to previously encountered antigens), increasing the risk of developing autoantibodies, which are central to the development of rheumatoid arthritis, multiple sclerosis, and other autoimmune diseases.[6]
  • Cancer – In addition to DNA mutations, which accumulate throughout the lifespan, thymic involution and dysfunctional cancer immunity, which occur with aging, are important drivers of cancer incidence.[7]
  • Chronic inflammation – In states of advanced thymic involution, T cells become active and pro-inflammatory shortly after leaving the thymus due to impairment of negative selection, the process by which aberrant and autoimmune T cells are destroyed before reaching circulation.[8]
  • Heart disease – Thymic involution and altered T cell immunity increase the blood concentrations of proinflammatory cytokines and activated macrophages, which increase the rate of cholesterol deposition in the arteries (i.e., atherosclerosis).[9]

Summaries

Below is a selection of summaries from recent research investigating the role of thymic involution in health and disease.

People tend to be less physically active with age; however, older adults who exercise slow the progression of aging and disease. In addition to the well-documented effects of exercise on cardiovascular health, exercise training improves immunity through a variety of mechanisms, including the increased production of naive T cells, which can be programmed to help fight infection. Findings of one report demonstrate better T cell immunity among older adult cyclists.

The authors recruited 125 trained amateur cyclists and 75 adults who did not participate in regular intense exercise between the ages of 55 and 80 years old for the study. They also recruited 55 young adults between 20 and 36 years old who did not exercise vigorously. The researchers collected a blood sample from each participant in order to measure hormones, cytokines, and the type and number of peripheral blood mononuclear cells, white blood cells in the blood that include monocytes, T cells, B cells, and natural killer cells.

The number of young T cells (those that had recently migrated from the bone marrow to the thymus) and naive T cells was greater in older adults who cycled than older adults who did not cycle. Older adult cyclists had the same number of young T cells as the young adult participants. While older adult non-cyclists had a greater number of senescent immune cells, which are proinflammatory aged cells, than young adults, older adult cyclists did not have increased cellular senescence compared to young adults. Finally, older adult cyclists had markedly lower levels of the pro-inflammatory cytokine interleukin-6 and higher levels of interleukin-7, which slow thymus shrinkage.

These results demonstrate that intense exercise training in older adults increases naive T cell release, reduces the burden of senescent cells, and lowers inflammation, which may translate to slower thymic involution and better immunity with aging.

Experimental drug protocol demonstrates reversal of epigenetic aging.

The human immune system loses function with age in a process known as immunosenescence. Previous research has reported on the ability of a number of drugs to impact the aging process; however, these studies have not measured the ability to reverse epigenetic aging. Research from epigenetics expert Steve Horvath is the first to demonstrate the reversal of epigenetic aging and immunosenescence of the thymus with drug therapy.

Nine participants between the ages of 51 and 65 years were given a drug protocol that included recombinant human growth hormone to reverse signs of immunosenescence. Because growth hormone can increase insulin production to a harmful degree, the investigators used metformin, a common diabetes drug, and dehydroepiandrosterone, a steroid precursor, to control symptoms of diabetes. They collected white blood cells to measure immune characteristics and epigenetic age.

Following one year of treatment, the investigators reported an average decrease in epigenetic age of 1.5 years over baseline, meaning they reversed epigenetic age by 2.5 years over the course of the study. Participants demonstrated an increase in T cell production and an increase in the leukocyte/monocyte ratio, a measure of immune cell populations that is associated with less inflammation and lower rates of several cancers. Monocytes use large quantities of nicotinamide adenine dinucleotide (NAD+), which is an important energy source for cells. The investigators suggested this decrease in monocytes and subsequent increase in NAD+ may be responsible for the reversal of epigenetic aging.

The main purpose of this pilot trial was to determine the safety and efficacy of the intervention. Larger studies with a control group are needed to expand on these results.

Frequently Asked Questions

Q: What does emerging science say about the causes and treatment of autoimmune diseases such as multiple sclerosis, lupus, and others?

A: Research describes the gut microbiota as a central mediator of immune dysfunction in the development of autoimmune diseases. Therefore, probiotics and intestinal microbiota transplantation may be novel therapeutic targets.[10] Fasting is another therapy under investigation for treating autoimmunity. One report in humans showed that a fasting-mimicking diet reduced autoimmunity and promoted immune regeneration.[11] To learn more about the fasting-mimicking diet used by the researchers in this study, see our episode with fasting and longevity expert, Dr. Valter Longo.

  1. ^ Inhibition of Thymic Adipogenesis by Caloric Restriction Is Coupled with Reduction in Age-Related Thymic Involution The Journal of Immunology 183, no. 5 (July 2009): 3040–52. https://doi.org/10.4049/jimmunol.0900562.
  2. ^ Obesity accelerates thymic aging Blood 114, no. 18 (October 2009): 3803–12. https://doi.org/10.1182/blood-2009-03-213595.
  3. ^ Malformed reference
  4. ^ Allergy, Parasites, and the Hygiene Hypothesis Science 296, no. 5567 (April 2002): 490–94. https://doi.org/10.1126/science.296.5567.490.
  5. ^ T-Cell Immunity to Influenza in Older Adults: A Pathophysiological Framework for Development of More Effective Vaccines Frontiers in Immunology 7 (February 2016). https://doi.org/10.3389/fimmu.2016.00041.
  6. ^ Aging of the immune system: A risk factor for autoimmunity? Autoimmunity Reviews 5, no. 2 (February 2006): 136–39. https://doi.org/10.1016/j.autrev.2005.09.008.
  7. ^ Thymic involution and rising disease incidence with age Proceedings of the National Academy of Sciences 115, no. 8 (February 2018): 1883–88. https://doi.org/10.1073/pnas.1714478115.
  8. ^ Thymic Involution Perturbs Negative Selection Leading to Autoreactive T Cells That Induce Chronic Inflammation The Journal of Immunology 194, no. 12 (May 2015): 5825–37. https://doi.org/10.4049/jimmunol.1500082.
  9. ^ The Pivotal Role of Thymus in Atherosclerosis Mediated by Immune and Inflammatory Response International Journal of Medical Sciences 15, no. 13 (2018): 1555–63. https://doi.org/10.7150/ijms.27238.
  10. ^ The microbiome in autoimmune diseases Clinical and Experimental Immunology 195, no. 1 (December 2018): 74–85. https://doi.org/10.1111/cei.13158.
  11. ^ A Diet Mimicking Fasting Promotes Regeneration and Reduces Autoimmunity and Multiple Sclerosis Symptoms Cell Reports 15, no. 10 (June 2016): 2136–46. https://doi.org/10.1016/j.celrep.2016.05.009.

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