A critical immune organ called the thymus shrinks rapidly with age, putting older individuals at greater risk for life-threatening infections. A study published August 6 in Cell Reports reveals that thymus atrophy may stem from a decline in its ability to protect against DNA damage from free radicals. The damage accelerates metabolic dysfunction in the organ, progressively reducing its production of pathogen-fighting T cells.
The findings suggest that common dietary antioxidants may slow thymus atrophy and could represent a promising treatment strategy for protecting older adults from infections.
“The thymus ages more rapidly than any other tissue in the body, diminishing the ability of older individuals to respond to new immunologic challenges, including evolving pathogens and the vaccines that may otherwise offer protection from them,” says senior study author Howard Petrie of the Scripps Research Institute. “We provide, for the first time, a mechanistic link between antioxidants and normal immune function, opening new avenues for potential treatment strategies that could improve immune defenses in the aging population.”
The thymus produces essential immune cells called T cells, which are continuously lost and must be replaced throughout life. But starting around the time of puberty, the thymus rapidly decreases in size and loses its capacity to produce enough new T cells. This loss is partially offset by the duplication of existing T cells, but the resulting population of cells becomes more and more biased toward memory T cells, which recognize pathogens from previous or ongoing infections. As a result, broad-spectrum immunity against new pathogens and protective immune responses elicited by new vaccines diminish with age.
The development of interventions to slow the progression of thymus atrophy has been limited by the lack of knowledge about the underlying mechanisms. The prevailing theory suggests that sex hormones play a key role, but this explanation does not account for the accelerated speed at which the thymus diminishes in size in comparison to other tissues. Moreover, the body of scientific evidence clearly indicates that other factors must be involved in age-related thymus atrophy.
To address this question, Petrie and first author Ann Griffith, currently at the University of Texas Health Science Center at San Antonio, developed a computational approach for analyzing the activity of genes in two major thymic cell types–stromal cells and lymphoid cells–in mouse tissues, which are very similar to human thymic tissues in terms of function and the properties of atrophy. They found that stromal cells were deficient in an antioxidant enzyme called catalase, resulting in the accumulation of free radical and metabolic damage.
To test whether catalase deficiency plays a causal role in thymus atrophy, the researchers performed genetic experiments to enhance catalase levels in mice. By 6 months of age, the size of the thymus of the genetically engineered mice was more than double that of normal mice. Moreover, mice that were treated with two common antioxidants from the time of weaning achieved nearly normal thymus size by 10 weeks of age.
Taken together, the findings provide support for the free-radical theory of aging, which proposes that reactive oxygen species such as hydrogen peroxide cause cellular damage that contributes to aging and a variety of age-related diseases. These toxic molecules, which form in cells as a natural byproduct of the metabolism of oxygen, have been linked to progressive atrophy in many organs and tissues as part of the normal aging process. However, these are generally slow, progressive processes that do not become apparent until late in life and often go mostly unnoticed.
“In the case of the thymus, atrophy is more rapid than other tissues, which we now show is a consequence of stromal catalase deficiency in the context of a highly metabolic environment designed to support the demands of T-cell proliferation,” Petrie says. “Our studies show that, rather than an idiosyncratic relationship to sex steroids, thymic atrophy represents the widely recognized process of accumulated cellular damage resulting from lifelong exposure to the oxidative byproducts of aerobic metabolism.”
In future studies, the researchers will investigate whether antioxidant supplementation improves the functioning of the thymus and the immune system during aging. If these studies provide support for this idea, then they could lead to the development of new clinical recommendations for the prevention or treatment of age-related thymus atrophy in humans.