How to address a mistake in an old paper in a very prestigious scientific journal? A Nature paper published in 2000 currently has around 400 citations, but there is a mistake in the paper and surprisingly, still it gets citations. The mistake affects the result of the paper in a way that half of the arguments in the paper are invalid. 

I warned the authors two years ago and they confirmed the mistake. I expected them to put some announcement that there is a mistake in the paper to avoid misleading researchers, but unfortunately they have not done so.

How should we address these situations? Should we send a comment and report it to the editor? Is it rude? Or should we simply dismiss it because it is an old paper?
Some journals accept a type of short correspondence or comment in which objections to some published material can be submitted. If you can articulate your objections in a scientific way suitable for publishing you may try this approach. For example, imagine the original analysis has some error. Reanalyzing the data gives different results and invalidates the previous publication. Conversely in this approach the authors of the original study have the opportunity to reply to your complaints.

An example of this is a commentary published in Nature Genetics, where the authors highlight important deficiencies in the design of the experiments in an earlier publication that can lead to incorrect conclusions. Of course, the authors of the original paper are allowed to respond to the comments.

Correspondences have the advantage that can be very short. I am not sure at this moment if Nature also accepts this format.

If the material that demonstrates the error in the original publication is substantial it may grant an additional publication. This is for example what happened with the paper that demonstrated the divergence between human and mice inflammatory responses, which led to a response paper analyzing the same data, and arriving at the opposite results.