Enhancing Lysosomal Function and PADK in the Latest Rejuvenation Research

The April 2012 edition of Rejuvenation Research includes the proceedings of the SENS5 conference, so there's a lot of material you'll have already seen there. The sole open access paper is worth reading as an update on research into the use of Z-Phe-Ala-diazomethylketone (PADK) to boost lysosomal function. The lysosome, you will recall, is a form of roving recycling unit that exists within the cell. Its task is to break down waste and unwanted materials - and that function is vital, as demonstrated by the many ultimately fatal conditions caused by lysosomal dysfunction. Unfortunately for all of us, lysosomal functionality deteriorates with age. This is most likely due in large part to accumulating waste materials, such as lipofuscin, that lysosomes cannot break down. They instead bloat and malfunction.

One body of research aiming to fix this issue is organized and advocated by the SENS Foundation, and focuses on ways to safely break down the waste materials that cannot be handled by lysosomes. For example, through biomedical remediation and the use of tailored bacterial enzymes. Meanwhile, other research groups have worked on boosting lysosomal activity in various ways, which seems to have generated some benefits where successful. For example, reversing decline in liver function, and restoring mental capacity in mice engineered to generate the signs of Alzheimer's disease.

It is that second example that is the subject of this open access paper, showing that enhancing lysosomal activity can potentially help with aggregates of damaging material outside cells, as well as the state of the cell interior:

Positive Lysosomal Modulation As a Unique Strategy to Treat Age-Related Protein Accumulation Diseases

Knowing the link between lysosomal dysfunction and selective pathogenesis, one logical step toward therapeutic intervention is the enhancement of enzymatic activity in lysosomes. [Some age-related diseases] may be slowed or reversed by the positive modulation of the lysosomal system. Many studies suggest that lysosomal activation occurs with age and in diseased brains, but not to the necessary extent that would prevent the gradual loss of neuronal integrity and brain function.

Enhancement of lysosomal function has been proposed as a plausible strategy to reduce protein accumulation events in age-related disorders, including those events in Alzheimer disease, Parkinson disease, and Huntington disease. Several of the studies indicate that induction of protein degradation processes is an attempt to clear amyloid peptides and tau species, as well as α-synuclein and mutant huntingtin. Another potential therapeutic strategy that may involve the endosomal-lysosomal system is the disaggregation of extracellular Aβ peptide, with the idea that the disaggregation would promote uptake of monomers and small oligomers into neurons and microglia where they are trafficked to lysosomes for degradation.

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Of the list of lysosomal modulatory agents [provided in the paper] only PADK, diazoacetyl-dl-2-aminohexanoic acid methyl ester, glycyl-phenylalanyl-glycine-aldehyde semicarbazone, and bafilomycin A1 have been reported to elicit protection against protein accumulation pathology under appropriate low-dose conditions.

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From the in vitro and in vivo findings, unique lysosomal modulators represent a minimally invasive, pharmacologically controlled strategy against protein accumulation disorders to enhance protein clearance, promote synaptic integrity, and slow the progression of dementia.

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