A Novel Approach to Restoring Lysosomal Function in Old Cells
Lysosomes are the recycling units in the cell, responsible for breaking down damaged structures and proteins into their component parts. Unfortunately, their function declines with age, and most of the evidence associated with this decline indicates that it is important in determining the pace of aging. Less recycling of damaged molecular machinery means greater dysfunction and greater accumulation of further damage. One reason for this progressive failure of lysosomal function, prevalent in long-lived cell populations, is that certain byproducts of metabolism are hard to break down. They accumulated in lysosomes, making them bloated and inefficient. There are numerous other less direct issues as well, associated with the functioning of the cellular maintenance system of autophagy as a whole, not just the lysosome at the end of the recycling path.
As an illustration of that second point, researchers have in the past managed to boost faltering lysosomal function in the aged liver via a gene therapy to increase the number of lysosomal receptors used in the delivery of waste to the lysosome. The research noted here has high-level similarities to that effort, in that researchers are adjusting an aspect of cellular biochemistry that boosts lysosomal activity or efficiency, but without addressing the underlying reasons as to why it fails with age. Nonetheless, some degree of slowed aging and restored tissue function results.
Aging is a phenomenon in which a cell’s ability to divide and grow deteriorates as it gets older, and this causes degradation of the body and senile diseases. The inhibition and recovery of aging is an instinctive desire of humans; thus, it is a task and challenge of biologists to identify substances that control aging and analyze aging mechanisms. Researchers have been conducting research to reverse the aging process by shifting the existing academia’s ‘irreversibility of aging’ paradigm. To reverse the aging process, the research team searched for factors that could control aging and tried to discover substances that could restore cell division capacity. As a result, it was confirmed that KU-60019, an inhibitor of ATM protein, which is a phosphorylation enzyme, recovers the functions of aging cells through activation of lysosomal functions and induction of cell proliferation.
The degradation of lysosomes, which are intracellular organelles responsible for autophagy and decomposition of biopolymers such as proteins and lipids in the cell, leads to cell senescence by accumulating biomolecules that must be removed in cells and causes instability of the metabolism such as removal of dysfunctional mitochondria that do not function. The research team was the world’s first to confirm that as cell aging progresses, the vacuolar ATPase (v-ATPase) protein involved in the lysosomal activity regulation is phosphorylated by the ATM protein, and the binding force between the units constituting the v-ATPase is weakened, so consequently the function of lysosomes deteriorates.
In addition, the team has proven that the reversible recovery of aging is possible through its experiment that shows the regulation of ATM protein activation by KU-60019 substances induces the reduction of phosphorylation of v-ATPase, thereby inducing recovery of mitochondrial function and functional recovery of the lysosome and autophagy system as well as promoting wound healing in aging animal models.