Enhanced Lysosomal Activity Turns Back the Decline in Neural Stem Cell Function

Stem cell activity falters with age. This is a feature of all of the stem cell populations studied to date, though whether this is the result of declining cell count or increasing quiescence varies by tissue type. Stem cells are responsible for providing a supply of daughter somatic cells to replenish losses and maintain tissue function. Their progressive failure to do so is one of the important contributing causes of aging.

Why do stem cells undergo this decline? Intrinsic damage to the stem cells themselves is certainly a factor, but in many populations it isn't as important as changes in the signaling environment that take place in reaction to rising levels of molecular damage throughout a tissue. That said, in the research here, improved lysosomal activity is demonstrated to improve neural stem cell function. This implies that improved autophagy, increased removal of wastes and damaged components, is the cause of restored function. Autophagy declines with age, and there have been other examples in which enabling greater lysosomal function restores loss of organ function - such as in the liver, by adding more receptors essential to lyosomal activity.

Protein homeostasis, or proteostasis, is critical to maintain cellular integrity and function. Dysregulation of the proteome, including accumulation of damaged and aggregated proteins, is a major hallmark of aging. Accumulation of protein aggregates is also associated with pathological conditions, including neurodegenerative diseases. Though not much is known about the etiology of aggregates in many cases, their clearance can extend lifespan and alleviate the symptoms of neurodegeneration in some model systems.

There are three main mechanisms or branches of the protein homeostasis and clearance network: the lysosome-autophagy proteolytic system, molecular chaperones, and the proteasome. Macroautophagy, generally referred to as autophagy, is a tightly regulated process by which cellular organelles, proteins, and cytoplasm are engulfed into autophagosomes for degradation and recycling. The lysosomal-autophagy pathway is also important for the degradation of potentially toxic protein aggregates. Cellular quality control through this system may be particularly important in tissue-specific stem cells, which are used for lifelong tissue regeneration and repair.

Evidence suggests that the flux through the autophagy-lysosomal system is necessary for the maintenance and lineage progression of the adult neural stem cell (NSC) pool. These findings also raised a number of interesting questions regarding the precise role of autophagy in the NSC lineage in the adult and aging brain. For example, is autophagy critical for all stages of neurogenesis, or are specific transitions during lineage progression particularly dependent on this process?

Comparison of the activated (aNSC) and quiescent (qNSC) neural stem cells revealed striking differences in the expression of genes involved in protein homeostasis between the two cell types. Further analysis revealed that genes specifically associated with lysosomal function were selectively upregulated in the quiescent population. This is in contrast to aNSCs, which had higher expression of various molecular chaperones and displayed a signature associated with the proteasome and ubiquitin-mediated proteolysis. The use of a reporter system with manipulation of autophagic flux revealed that qNSCs degrade their lysosomal contents at a much slower rate than aNSCs.

The correlation between lysosome activation and NSC activation raises the question of whether activation of lysosomes is sufficient to drive NSCs out of the quiescent state. NSC activation involves cell cycle re-entry in response to intrinsic or extrinsic cues from the neurogenic microenvironment, although the molecular mechanisms are not fully understood. Could lysosome activation be a novel intrinsic stimulus to break quiescence? Recent work provides compelling evidence that this may be the case.

The authors observed that blocking lysosomal acidification induced aggregate accumulation in qNSCs and significantly reduced their ability to become activated. In contrast, induction of autophagic flux reduced the quantity of aggregates and enhanced the response of qNSCs to activation cues. This evidence suggests that clearance of protein aggregates is sufficient to induce activation of qNSCs in response to growth factor stimulation, although it cannot be ruled out that other unidentified cargo are critical for activation. Nevertheless, pathological lysosome dysfunction and aggregate buildup may have a causative role in the age-associated decrease in NSC activation and neurogenesis.

Link: https://doi.org/10.1177/1179069518795874


I recall from the book Ending Aging that a superfund project was underway to find enzymes that could be transferred into human lysosomes somehow to allow for better cleanup of various kinds of intracellular and extracellular junk. Where are we on that project?

Posted by: Nathan at September 6th, 2018 9:42 AM

@Nathan: One branch of that ended up becoming LysoClear, targeting A2E in the retina. Another branch was picked up for 7-ketocholesterol and atherosclerosis by Jason Hope's company human.bio and we don't really know what became of it. The rest is still a work in progress at the SENS Research Foundation, but similarly not a great deal has been said about whether things stand of late.

Posted by: Reason at September 6th, 2018 10:08 AM

Possibly relevant -- A web search turned up a number of papers indicating that olive phenols (e.g., oleuropein, hydroxytyrosol) activate both autophagy and neurogenesis.

Posted by: Lou Pagnucco at September 6th, 2018 12:20 PM
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