D-Mannose Treatment Reduces Senescent Cell Burden in the Aging Bladder
Researchers here show that D-mannose treatment can upregulate autophagy in bladder and urinary tract epithelial cells, reducing inflammation and other cellular dysfunction. Like other approaches that increase autophagy, such as the use of mTOR inhibitors and calorie restriction, this appears to reduce the burden of cellular senescence over time in aged tissues. This likely results from a slowdown of the pace at which cells become senescent, allowing the immune system to catch up in its task of destroying lingering senescent cells. The end result of this improvement in tissue quality is a greater resistance to urinary tract infection. Normally, risk of such infections increases with age.
Aging poses a number of challenges to the body's well-being, one of the most important being an increased susceptibility to multiple diseases, including urinary tract infections (UTIs). Researchers have now shown that, compared to the younger counterpart, the aging urinary tract in animal models changes how it functions at the cellular level in ways that seem to favor the establishment and recurrence of UTIs. The researchers investigated a process called autophagy that all cells naturally use to clean up old or defective cellular materials by digesting and recycling them in structures called lysosomes. "We found that the recycling process naturally slows down as urothelial cells age. Older cells accumulate larger lysosomes that are less effective at degrading cellular materials, which leads to their toxic accumulation inside the cell."
Aged urothelial cells also accumulate more damaging reactive oxygen species (ROS) than younger tissues. "ROS are molecules that can harm tissues, and the redox response that normally neutralizes ROS in younger cells is dampened in aging urothelial cells. Consequently, an inflammatory process builds up, leading to cell death. Dead urothelial cells leave their location, exfoliating the bladder and disrupting its integrity, which further exacerbates age-related dysfunction."
Importantly, researchers also discovered that treating aged mice with D-Mannose, a natural sugar, restores autophagy and mitigates ROS and urothelial cell shedding, suggesting that mannose supplementation could counter age-associated human urothelial dysfunction. Researchers then compared bacterial UTIs in older animals versus younger animals. "We found that aged mice have more bacterial reservoirs in the urinary tract and are more prone to spontaneous recurrent UTI than younger mice, suggesting that the age-related dysfunction of the tissue could explain the higher recurrence of UTIs observed in older age. Collectively, our results demonstrate that normal aging affects bladder physiology, with aging alone increasing baseline cellular stress and susceptibility to infection. We suggest that mannose supplementation could counter age-associated urothelial dysfunction in addition to limiting recurring UTIs."