In a recent review, Geisel School of Medicine professors Jingang Gui and Ruth Craig collaborated to summarize the factors that determine the function and age-related involution of the human thymus.

Age-related thymic involution, the progressive shrinking of the thymus, is closely associated with the natural decline of the immune system over time, or immunosenescence. This decrease in thymic sizereduces the amount of thymopoiesis—the process by which thymocytes differentiate into mature T-cells—that occurs. The result is impaired antigen-recognition and thus failure of the body’s primary immune response.

The review was motivated by the need to treat the rapidly aging world population. In the U.S. alone, experts predict that people over the age of 60 will make up 25 percent of the U.S. population by 2050. According to the CDC, approximately 80 percent of people in this age group suffer from one or more chronic disorders caused by immunodeficiency, often as a result of thymic involution.

The thymus and its T-cell receptor repertoire—the collection of molecules on the surface of T-cells responsible for antigen-recognition—are both built during fetal and early post-natal development. Thus, early “programming” is critical to determining adult immunity and age-related thymic involution. A host of factors, including genetics, environment, and sex, influence this development. The authors emphasized the need to understand these variables and how they affect people on an individual basis in order to develop better treatments.

The genes controlling thymus size and involution rate differ among individuals, which helps explains our differential susceptibility to pathogens. Not surprisingly, genetic disorders like Down’s syndrome and DiGeorge syndrome can significantly impact early programming by impairing thymic growth. Thymic involution also changes the gene expression profile of thymic cells. Interestingly, recent studies found temporary improvement in thymocyte function in mice following therapeutic treatment; however, the treatment did not affect gene expression profiles. This finding suggests that age-related thymic deterioration may never be reversed completely, or at least without altering gene expression.

Environmental factors experienced during development have a significant impact on thymic function in later years. For example, zinc deficiency can cause thymic atrophy, which results in increased risk of infection. In general, malnutrition during development adversely affects thymic function and structure. According to the authors, even the amount of breastfeeding a child receives, and the duration of each feeding, can determine thymic function.

Differences in male and female development also influence thymic function, contributing to gender-dependent disease susceptibility. Compared to men, women experience lower risk of bacterial, viral, and fungal infection, but have increased risk of autoimmune disorders such as multiple sclerosis. This difference is caused by the location of thymic programming genes, such as T-cell regulator FOXP3, on the X chromosome, among other factors. Whereas women have two X chromosomes, men have only one, a difference that results in distinct inheritance and expression patterns.

Hormones, such as sex steroids like estrogen and testosterone, also influence thymic size and function, especially during puberty. As such, the rate of involution varies by sex as well. In mice, researchers observed a biphasic rate of involution in males and a constant, one-way rate of involution in females. Rate of involution was also found to be increased by excessive caloric intake and obesity.

The process by which naïve T-cells—mature T-lymphocytes before they have encountered an antigen—are produced is critical for determining the strength of the immune system. The thymic microenvironment, or stroma,is vital to the growth and development of thymocytes, which eventually mature into T-cells. Deterioration of the stroma in aged subjects is caused by the loss of thymic epithelial cells. These cells are regulated by the gene FOXN1, the expression of which decreases with age. Moreover, when FOXN1 is overexpressed in mice, it delays the declination of thymopoiesis, supporting its role in this pathology.

While the aging process affects all of us, this wealth of information brings hope for improved therapeutics in the future.