Researchers here provide evidence that points to declining autophagy as a cause of the faltering stem cell activity that accompanies aging. Autophagy is an important process of cellular maintenance, a part of recycling damaged structures and proteins within cells. Increased levels of autophagy are a feature of numerous methods of modestly slowing aging demonstrated in mice and other laboratory species. Unfortunately autophagy fails with age; like all systems it is impacted by the accumulation of molecular damage, and in particular in this case, by the growing amounts of metabolic waste making up lipofuscin, a mix of various compounds that mammalian biochemistry struggles to break down. Lipofuscin ends up accumulated in lysosomes, recycling systems in the cell that play an important role in autophagy, and degrades their function. If repairing this problem will not only improve the quality of cells, but also restore more youthful levels of stem cell activity, that would be a considerable victory. It is all the more reason to support the work of the SENS Research Foundation and others on ways to safely clear out the constituents of lipofuscin and thus restore lysosomal function in aged tissues.
Researchers have discovered that in addition to its normal role in cellular waste-processing, autophagy also is needed for the orderly maintenance of blood-forming hematopoietic stem cells (HSCs), the adult stem cells that give rise to red blood cells, which carry oxygen, and to platelets, which prevent bleeding, as well as the entire immune system, which fights infections and disposes of pathogens. The researchers found that autophagy keeps HSCs in check by allowing metabolically active HSCs to return to a resting, quiescent state akin to hibernation. This is the default state of adult HSCs, allowing their maintenance for a lifetime.
Failure to activate autophagy has profound impacts on the blood system, leading to the unbalanced production of certain types of blood cells. Defective autophagy also diminished the ability of HSCs to regenerate the entire blood system when they were transplanted into irradiated mice, a procedure similar to bone marrow transplantation. The researchers determined that 70 percent of HSCs from old mice were not undergoing autophagy, and these cells exhibited the dysfunctional features common among old HSCs. However, the 30 percent of old HSCs that did undergo autophagy looked and acted like HSCs from younger mice.
In a large series of experiments and analyses, the scientists compared characteristics of HSCs from old mice with those of HSCs from younger mice that had been genetically programmed so that they could not undergo autophagy. They found that loss of autophagy in young mice was sufficient to drive many of the defects that arise naturally in the blood of old mice, including changes in the cellular appearance of HSCs and a disruption in the normal proportions of the various types of blood cells, characteristics of old age. Previous research had shown that autophagy causes the formation of "sacs" within cells that can engulf and enzymatically digest molecules and even major cellular structures, including mitochondria, the cell's biochemical power plants. But in the new study, the researchers found that genetically programmed loss of autophagy resulted in the accumulation of activated mitochondria with increased oxidative metabolism that triggered chemical modifications of DNA in HSCs.
These "epigenetic" DNA modifications altered the activities of genes in a way that changed the developmental fate of HSCs. They triggered disproportionate production of certain blood cells and reduced the ability of HSCs to regenerate the entire blood system when transplanted. This result was similar to what the researchers observed in the majority of old HSCs that failed to activate autophagy. In contrast, the minority of old HSCs that still exhibited significant levels of autophagy were able to keep their mitochondria and metabolism in check, and could re-establish a healthy blood system following transplantation, similar to HSCs from young mice. However, in a hopeful sign for potential future therapies to rejuvenate blood stem cells, the researchers succeeded in restoring autophagy to old HSCs by treating them with pharmacological agents in a lab dish.