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The Road to the Fountain of Youth May Pass through Neuronal Lysosomes

By Gabby Escalante
​

​Spanish explorer Juan Ponce de Leon got his name in the history books because he scoured the Americas looking for the fountain of youth. Instead, Ponce de Leon discovered Florida, a small consolation prize for failing to find the mythical land of Bimini, said to contain a river whose waters could restore youth to anyone who bathed in it or drank its waters. Hundreds of years later, humanity is no closer to finding the fountain of youth—but not through lack of effort or interest. Aging and its mechanisms have been the target intense study by scientists for decades. And unveiling the secrets of aging will, by association, disclose the secrets of youth.  Although the evidence does not suggest that those secrets will be found in the waters of any fountain or river, scientists have made progress, inch by inch, toward a full understanding of the process of aging.

Researchers at Stanford University have gotten humanity a step closer to defeating one of the direst consequences of aging—cognitive decline. In doing so, they may have also opened the door for a new strategy to restore stem cell function that is lost in the aging process.  In a paper published in Science, researcher Dena Leeman and her colleagues report on an extensive series of experiments that studied neural stem cells (NSC) obtained from the sub-ventricular zone in adult laboratory mice. The sub-ventricular zone is one of the key neurogenic niches of the mouse brain, where a subset of astrocytes acts as a source of quiescent NSC. These NSC can give rise to activated NSC and, eventually, neurons which help preserve olfactory function and repair the brain after injury.

Yet, the ability for quiescent NSC to transform into activated NSC declines with age, as does neurogenesis, olfactory discrimination, and memory.  This deficit is thought to be due to impaired protein homeostasis, a process known as proteostasis.  Deficient proteostasis leads to the accumulation of protein aggregates, a development that has been linked to the onset of  neurodegenerative diseases such as Huntington’s chorea and Alzheimer’s disease.

How do our brain cells protect against the formation of these aggregates? One key mechanism helps maintain proteostasis by incorporating protein aggregates into intracellular, double-membraned vesicles known as autophagosomes.  These vesicles then pour their contents into lysosomes, where the proteins are broken down by proteolytic enzymes. In their paper, Leeman and colleagues show that quiescent NSC show heightened expression of genes that regulate lysosomal function and, as a result, have larger lysosomes with greater quantities of insoluble protein aggregates than do activated NSC.  Moreover, subjecting lysosomes to a low-nutrient environment for a brief period of time actually cleared protein aggregates from lysosomes and enhanced activation of quiescent NCS. These findings suggest that disposing of lysosomal protein aggregates is a necessary step in the transition from quiescent to activated NSC.

As a next step, Leeman and her colleagues compared young mice—aged 3 to 4 months—and old mice—aged 19 to 22 months (the lifespan of a mouse extends to a maximum of about two years). Using mice that were genetically modified to express a fluorescent version of a protein found in autophagosomes, the authors were able to visualize under the microscope that quiescent NSC from old mice have large amounts of protein aggregates outside of lysosomes, whereas cells from young mice did not display this abnormality. The authors found that quiescent NSC differ substantially between young and old mice, but that once they become activated, NSC of young and old mice show little difference. Thus, aging seems to preferentially affect quiescent cells.  Moreover, neither young nor old activated NSC displayed extra-lysosomal protein. These findings suggest that old quiescent NSC are unable to process accumulated proteins, and that this inability impairs their activation and subsequent development into replacement neurons.

Leeman and colleagues showed that protein accumulation and defective NSC activation seen in old mice can be corrected by procedures that stimulate lysosomal function, making old quiescent NSC behave like their younger counterparts.  In one experiment, the authors deprived old mice of food for two days (which would be equivalent to about 2 months in mouse years— don’t try this at home!) The result was a reduction in protein aggregates in the mice’s quiescent NSC. Protein aggregates were also reduced by expression of a transcription factor known as TFEB that regulates lysosomal function.  Thus, stimulating lysosomes can restore the ability of old NSC to go from a quiescent to an activated state.

How is it that lysosomal processing of protein aggregates could be important to NSC activation? The authors suggest that digestion of protein aggregates in lysosomes in quiescent NSC may provide energy needed for the activation process. Alternatively, it may prevent the accumulation of dangerous protein aggregates that could be toxic to the neuronal descendants of activated NSC.  In any case, the findings described in this paper may open new avenues for restoring the stem cell function that is lost in aging by means of stimulating lysosomal function. Indeed, it has long been known that caloric restriction extends the lifespan of laboratory mice, and that starvation followed by refeeding regenerates stem cell pools. The findings by Leeman and colleagues may provide an explanation for those intriguing observations and may help identify specific approaches to re-establishing stem cell function in aging.

Although Leeman’s work brings us closer to fulfilling Ponce de Leon’s quest, some caution is warranted. The work described was performed entirely in laboratory mice, which differ in many ways from humans. Although the authors showed impressive changes in protein aggregates and in the number of activated NSC in response to nutrient restriction and treatment with a drug called rapamycin, they did not examine the mice’s cognitive function.  We therefore should look toward future research in this area before Leeman’s findings are applied to humans. When we do, we will undoubtedly arrive at the veritable fountain of youth, whether literal or figurative.

​​

Works Cited
[1] Leeman DS, Heberstreit K, RuetzT et al. Lysosome activation clears aggregates and enhances quiescent neural stem cell activation during aging. Science 2018;359:1277-1283

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  • Home
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    • Spring 2020
    • Fall 2019: Mind & Matter
    • Spring 2019: Fight or Flight
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    • Spring 2018: Transform
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    • Spring 2017: Power
    • Fall 2016: Origins
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    • Fall 2015: Immortality
    • Spring 2015: War
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