Combating Iron in the Brain: Researchers find anti-aging micromolecule

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1. Schematic model of miR-29 action in brain aging. During aging an accumulation of iron in neurons occurs. This induces expression of miR-29 that in turn represses expression of IRP-2 thereby limiting iron uptake. This mechanism counteracts aging-related damages. MiR-29 may also counteract effects aging-related phenotypes by additional mechanisms, for example modulation of pro-apoptotic BCL-2 family members 2. MiR-29 is up-regulated with age in neurons. a Genomic organization of miR-29 family in N. furzeri. Three different clusters were isolated (pri-mir-29 1, 2, 3) encoding four different mature members miR-29a, b, d, e. In red, seed sequence is reported, single nucleotide differences in blue. b Age-dependent expression of miR-29 primary transcripts (Pri-miR-29-1, 2, 3) in the brain of N. furzeri. The relative expression was evaluated by RT-qPCR, data were normalized on TATA binding protein (TBP), pri-miR-29-2 results much more expressed than the other clusters and shows a clear age-dependent up-regulation (1 way ANOVA with post-test for trend: R = 0.5285 P < 0.0001, n = 4 animals for age group). c Correlation of miR-29 with its predicted targets. Blue bars show the distribution of Pearson’s correlation coefficients between miR-29a and its predicted target. Light-blue bars show the distribution of correlation values extracted from a bootstrap (P = 10–14, Kolmogorov–Smirnoff). d, e Pri-miR-29-2 expression pattern in N. furzeri brain. d Pri-miR-29-2 signal (red) and HuC/D expression (green) in the optic tectum (TeO). Pri-miR-29-2 shows a nuclear staining and a co-localization with neuronal marker HuC/D along the periventricular gray zone (PGZ), white arrows show neurons in the optic tectum (TeO) negative for pri-miR-29-2. Scale bar = 50 μm. Cerebellum overview picture (e) shows a clear and strong expression of pri-miR-29-2 just in the granular cell layer (GCL), it is instead absent in the Purkinje cell (white arrow) and molecular layer (ML). Scale bar 100 μm

1. Schematic model of miR-29 action in brain aging. During aging an accumulation of iron in neurons occurs. This induces expression of miR-29 that in turn represses expression of IRP-2 thereby limiting iron uptake. This mechanism counteracts aging-related damages. MiR-29 may also counteract effects aging-related phenotypes by additional mechanisms, for example modulation of pro-apoptotic BCL-2 family members
2. MiR-29 is up-regulated with age in neurons. a Genomic organization of miR-29 family in N. furzeri.

The older we get, our brain ages. Cognitive abilities decline and the risk of developing neurodegenerative diseases like dementia, Alzheimer’s and Parkinson’s disease or having a stroke steadily increases. A possible cause is the accumulation of iron molecules within neurons, which seems to be valid for all vertebrates. In a collaborative research project within the consortium JenAge, researchers from the Leibniz Institute on Aging – Fritz Lipmann Institute (FLI) in Jena, Germany, and the Scuola Normale Superiore (SNS) in Pisa, Italy, found that this iron accumulation is linked to a microRNA called miR-29, known to act as a tumor suppressor, hindering the proliferation of cancer cells.

However, clearly, miR-29 also regulates whether or not iron can be deposited in neurons. Using the African fish Nothobranchius furzeri – the shortest-living vertebrate that can be kept under laboratory conditions – the team showed a large increase of iron deposits in fish where miR-29 had been suppressed, which led to premature brain aging. In contrast, healthy fish showed the more miR-29 in their neurons, the older they were. Hence, miR-29 acts as a kind of anti-aging molecule during aging, inhibiting the accumulation of iron in neurons.

“We strongly believe that our results are relevant for humans as well,” says Prof. Alessandro Cellerino. In fact, the link between an increased iron accumulation and neurodegenerative diseases or strokes in humans has been known for some time; there are also results showing a reduced concentration of miR-29 in these diseases. However, it is totally new that miR-29 acts as molecular switch that inhibits iron accumulation. “These results are surprising – and very promising, because the development of miR-29-based pharmaceuticals for cancer therapy is already ongoing. This may offer a head start for the development of new therapies for Parkinson’s or Alzheimer’s disease and for the treatment of strokes as well,” Cellerino adds.

African killifish Nothobranchius furzeri has only recently been introduced as animal model in aging research. It was the deciphering of the fish’s genome in late 2015 by the Leibniz Institute on Aging (FLI) that laid the foundation for genetic studies in this fast-aging vertebrate. Mario Baumgart, a Postdoc at the FLI adds: “There’s no other vertebrate showing such a rapid aging as this little fish. It is like aging in fast motion. Moreover, 90% of human genes can be found in the fish as well, making almost all knowledge gained from N. furzeri transferable to humans.” This is why the results about the molecular switch miR-29,published on February 13, 2017 in the journal BMC Biology are so promising and mean a further step towards the treatment of neurodegenerative diseases. http://www.leibniz-fli.de/institute/public-relations/detailpage/?tx_news_pi1%5Bnews%5D=3371&cHash=460957fd5bb10f68ed71202baa06d905