Researchers here demonstrate that mice with lower levels of PPAR-γ exhibited reduced atrophy of the thymus with age, and as a consequence also exhibit improved measures of immune function. The thymus is where T cells mature in the final stages of their creation before being released to duties in the body. Unfortunately it has evolved to atrophy, its active tissue replaced with fat tissue. This initially occurs immediately following childhood in a process called thymic involution, and then the remaining functional thymic tissue steadily declines over the course of later life. This places an ever-lower limit on the supply of new T cells, and in turn that limit contributes to immune system aging. In later life, T cells become dysfunctional or overspecialized faster than their ranks can be augmented with new, fully functional cells.
Thus there is interest in finding ways to rejuvenate the thymus, such as via tissue engineering of new thymic tissue, or delivering signals to the thymus that instruct it to regenerate, as in the case of work on FOXN1. The research here is of the latter type, an investigation of the controlling mechanisms that determine whether the thymus atrophies into fat tissue or continues to maintain active tissue of the sort that can host maturing T cells. Unfortunately, PPAR-γ can't just be globally reduced, as the effects are fairly ugly - when it occurs in humans due to rare mutation of the gene, the outcome is the condition known as type 3 familial partial lipodystrophy (FPLD3). Any therapy built upon this research would have to accurately target inhibition or blockade of PPAR-γ to the thymus.
Thymic senescence contributes to increased incidence of infection, cancer, and autoimmunity at senior ages. This process manifests as adipose involution. As with other adipose tissues, thymic adipose involution is also controlled by PPARgamma. This is supported by observations reporting that systemic PPARgamma activation accelerates thymic adipose involution. Therefore, we hypothesized that decreased PPARgamma activity could prevent thymic adipose involution, although it may trigger metabolic adverse effects.
We have confirmed that both human and murine thymic sections show marked staining for PPARgamma at senior ages. We have also tested the thymic lobes of PPARgamma haplo-insufficient and null mice. Supporting our working hypothesis both adult PPARgamma haplo-insufficient and null mice show delayed thymic senescence. Delayed senescence showed dose-response with respect to PPARgamma deficiency. Functional immune parameters were also evaluated at senior ages in PPARgamma haplo-insufficient mice (null mice do not reach senior ages due to metabolic adverse affects). As expected, sustained and elevated T-cell production conferred oral tolerance and enhanced vaccination efficiency in senior PPARgamma haplo-insufficient, but not in senior wild-type littermates.
Of note, humans also show increased oral intolerance issues and decreased protection by vaccines at senior ages. Moreover, PPARgamma haplo-insufficiency also exists in human known as a rare disease (FPLD3) causing metabolic adverse effects, similar to the mouse. When compared to age- and metabolic disorder-matched other patient samples (FPLD2 not affecting PPARgamma activity), FPLD3 patients showed increased measures of T cell activity suggesting delayed thymic senescence, in accordance with mouse results and supporting our working hypothesis. In summary, our experiments prove that systemic decrease of PPARgamma activity prevents thymic senescence, albeit with metabolic drawbacks. However, thymic tissue-specific PPARgamma antagonism would likely solve the issue.