Analysis of Longevity Enhancing Loss of Function Mutations in the E(z) Gene

This open access paper is a good example of the sort of work that follows identification of a longevity-enhancing mutation in a laboratory species, flies in this case. Finding such a mutation is just the first step on a long road towards a better understanding of metabolism. Unfortunately, most such work will have little relevance to the practical matter of extending human life span. Short-lived species have a great plasticity of longevity in response to metabolic changes, while we humans do not. The operation of cellular metabolism and tissue function is enormously complex, and it is rarely the case that any of the connections between proteins and mechanisms and function are either simple or easy to establish. This is why much of the field of aging research moves slowly indeed, being focused on (a) interventions that cannot possibly do much for human life span, and (b) trying to understand all of the details of the way in which aging progresses.

The E(z) histone methyltransferase heterozygous mutation in Drosophila is known to increase lifespan and stress resistance. However, the longevity mechanisms of E(z) mutants have not been revealed. In the present research we studied the effects of E(z) histone methyltransferase heterozygous mutation on lifespan, stress-resistance, fecundity, and genome-wide transcriptional profile dynamics in Drosophila imagoes. We observed 22-23% lifespan extension in both sexes, and E(z) mutants were significantly more resistant to hyperthermia, oxidative stress, and endoplasmic reticulum stress, and demonstrated enhanced fecundity.

The genome-wide transcriptome analysis identified 239 genes, which expression level was altered more than 2 times by E(z) mutation. Several of the most differentially expressed genes had never been described before as pro-longevity genes. Most likely, these genes may be associated with E(z) mutation, but not related to aging and longevity. The exception is a differential expression of antimicrobial peptides and the Turandot family of genes. These humoral innate immunity factors have been previously discussed in the context of aging and stress-resistance.

A mutation in the E(z) gene surprisingly neither activated nor repressed canonical pro-longevity or anti-longevity genes like mTor or insulin/IGF-signaling elements and either determinants of DNA repair, Sod, Sirtuins, etc. We also did not find strong changes in the expression of the Hox family of genes, for which gene repression by polycomb group proteins such as E(z) was previously shown.

We observed that the E(z) mutation leads to modulation of many genes related to the immune response, ribosome biogenesis, and cell cycle. Although age-dependent changes in the expression of these genes are similar to changes in control flies, it is most likely that mutations in E(z) lead to positive perturbations in the pathways for which age-associated gene expression changes are shown. In addition, the gene expression is sex-specific, despite the fact that the increase in median lifespan for both sexes was broadly similar, which emphasizes the importance of separate preparation and analysis of females and males.



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