The pituitary gland is the size of a pea, but it plays a major role in the endocrine system. It is often called the master gland because it controls several other hormone glands in the body. Almost all pituitary hormones are altered by aging in humans, often in a manner dependent upon sex, body composition, stress, comorbidity, intercurrent illness, medication use, physical frailty, caloric intake, immune status, level of exercise, and neurocognitive decline. Now in a mouse-model study, researchers at KU Leuven have discovered that the pituitary gland in mice ages as the result of an age-related form of chronic inflammation. Their findings suggest the potential to one day slow down this process or help repair it.

Their findings are published in the journal Proceedings of the National Academy of Sciences (PNAS) in a paper titled, “Interleukin-6 is an activator of pituitary stem cells upon local damage, a competence quenched in the aging gland.”

“My research group discovered that the pituitary gland ages as a result of a form of chronic inflammation that affects tissue and even the organism as a whole, explained Hugo Vankelecom, PhD, professor in the department of development and regeneration at KU Leuven. “This natural process usually goes unnoticed and is referred to as ‘inflammaging’—a contraction of inflammation and aging. Inflammaging has previously been linked to the aging of other organs.”

The researchers applied single-cell transcriptomics to start revealing the acute pituitary stem cell activation process as occurring upon targeted endocrine cell-ablation damage.

“This stem cell reaction was contrasted with the aging (middle-aged) pituitary, known to have lost damage-repair capacity,” wrote the researchers. “Stem cells in the aging pituitary show regressed proliferative activation upon injury and diminished in vitro organoid formation. Single-cell RNA sequencing uncovered interleukin-6 (IL-6) as being up-regulated upon damage, however only in young but not aging pituitary.”

“As a result of this new study, we now know that stem cells in the pituitary do not lose this regenerative capacity when the organism ages,” explained Vankelecom. “In fact, the stem cells are only unable to do their job because, over time, the pituitary becomes an ‘inflammatory environment’ as a result of the chronic inflammation. But as soon as the stem cells are taken out of this environment, they show the same properties as stem cells from a young pituitary.”

The findings open a number of potential therapeutic avenues, posing the question whether it would be possible to reactivate the pituitary.

“Administering IL-6 to young mice promptly triggered pituitary stem cell proliferation, while blocking IL-6 or associated signaling pathways inhibited such reaction to damage,” wrote the researchers. “By contrast, IL-6 did not generate a pituitary stem cell activation response in aging mice, coinciding with elevated basal IL-6 levels and raised inflammatory state in the aging gland (inflammaging). Intriguingly, in vitro stem cell activation by IL-6 was discerned in organoid culture not only from young but also from aging pituitary, indicating that the aging gland’s stem cells retain intrinsic activatability in vivo, likely impeded by the prevailing inflammatory tissue milieu. Importantly, IL-6 supplementation strongly enhanced the growth capability of pituitary stem cell organoids, thereby expanding their potential as an experimental model.”

Further research will be needed to determine if this work can be applied to humans. “Mice have a much greater regeneration capacity than humans. They can repair damaged teeth, for instance, while humans have lost this ability over the course of their evolution. Regardless, there are plenty of signs suggesting that pituitary processes in mice and humans are similar, and we have recent evidence to hand that gene expression in the pituitaries of humans and mice is very similar. As such, it is highly likely that the insights we gained will equally apply to humans.”

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