Fight Aging!

The thymus is a small organ, and the location in which thymocytes created in the bone marrow mature into T cells of the adaptive immune system. Unfortunately, the thymus atrophies steadily with advancing age. Active tissue is replaced with fat, reducing the supply of new T cells to a tiny fraction of what it was in early adult life. This process is a major factor in the aging of the immune system, leading over time to an adaptive immune system packed full of exhausted, senescent, malfunctioning T cells, the consequence of a lack of replacements.

A range of approaches are under development aimed at producing regrowth of the aged thymus, and consequent restoration of the adaptive immune system. In today's open access paper, researchers here comment on a novel approach to the regrowth of the aged, atrophied thymus. It involves delivery of RANKL, a transmembrane protein that also has a circulating form. RANKL appears necessary for sustained thymic function, and levels are reduced with age. It is likely that selective delivery of RANKL to only cells relevant to thymic function would be necessary in order to produce a viable therapy, however, as the protein is known to be involved in other processes throughout the body.

Rejuvenating the immune system

A recent study elucidates the role of the RANK-RANKL axis in the thymus during aging. The study demonstrates that decreased RANKL levels occur in thymocytes, leading to impaired cellularity and function of thymic epithelial cells (TECs) and endothelial cells (ECs), and subsequently to thymic involution. Their findings were recapitulated in young mice by neutralizing RANKL levels, while exogenous RANKL administration in aged mice restored thymic architecture, TEC and EC abundance, and their functional properties. Similarly, RANKL stimulated cellularity and maturation of epithelial and endothelial cells in human thymic organocultures. Moreover, RANKL treatment in aged mice improved T-cell progenitor homing to the thymus and boosted T-cell production. As an outcome, peripheral T-cell renewal and effective antitumor and vaccine responses were achieved.

In the aging thymus, apart from reduced key thymocyte subsets, diminished RANKL expression in these cells was also evident. The aging process is characterized by accumulation of DNA lesions, due to impaired efficiency of DNA repair networks with age as well as by epigenetic changes. Overall, these changes result in profound chromatin modifications reflected by global heterochromatin loss and redistribution. These events subsequently drive transcriptional changes that are anticipated to affect potent RANKL regulators such as hormones, cytokines, and signaling cascade components. As an example, histone demethylases influence lifespan by modulating components of cardinal longevity routes, such as the IGF-1 axis. IGF-1 induces RANKL and its levels are known to decrease with age, thus providing a possible explanation of low RANKL expression during thymic involution.