Sunday, August 16, 2009

Paper review: A Human Protein Interaction Network Shows Conservation of Aging Processes between Human and Invertebrate Species

Stumbled across this (another blog - but looks interesting, so let's see what we can make of it.

"A Human Protein Interaction Network Shows Conservation of Aging Processes between Human and Invertebrate Species"

(a) created a protein interaction network of longevity-related genes using human homologues of yeast/worm/fly known to increase longevity
(b) compared the genes encoding these "longevity network proteins" to genes change in expression during human muscle aging
(c) 6 of 18 homologs of 18 human FRAP1-interacting proteins that differ between young and old muscles extended worm life-span

So we have (1) evidence that there is good shared gene networks between worm and human, so it's a good model and (2) a list of interesting additional candidate longevity genes

The authors put it better; "we show that human homologs of invertebrate longevity genes change in their expression levels during aging in human tissue" and "These observations taken together indicate that the broad patterns underlying genetic control of life span in invertebrates is highly relevant to human aging and longevity. We also present a collection of novel candidate genes and proteins that may influence human life span."

It makes sense that we should share the same basic longevity repetoire with worm, given that the aging process affects most of life.

They focused mainly on FRAP1 then, with strong evidence that FRAP1 homologues are important for longevity in other species.

They tested 18 homologs of FRAP1 interacting genes in yeast (basically they fed worms with bacteria expressing double stranded RNA corresponding to genes encoding the different FRAP1 interacting proteins). Generally, extension of lifespan was obtained (Fig 6). This quote discusses the most interesting candidate:
  • "Knock-down of rps-27 expression in nematode resulted in 50% and 44% increases in life span in two independent experiments. Mammalian RPS27 encodes a zinc finger-containing protein component of the 40S ribosomal subunit [39]. Several studies have established that TOR signaling can modulate life span in yeast [30,32] and fly [40]. It has been demonstrated further that inhibition of translation can also extend life span indicating that loss-of-function in TOR signaling modulates aging through an effect on rates of translation [41–43]. Since RPS27 is a component of the ribosome and interacts with FRAP1 (Tor), it is likely that the life span extension seen in the rps-27 knock-down is due to an effect on rates of translation either through TOR signaling, direct effects on ribosome structure, or a combination of the two."
Interesting! I wonder what the "side effects" of inhibiting rates of translation might be? From GeneCards, the gene is implicated in various cancers. Generally, the gene doesn't scream out:

"Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 40S subunit. The protein belongs to the S27E family of ribosomal proteins. It contains a C4-type zinc finger domain that can bind to zinc. The encoded protein has been shown to be able to bind to nucleic acid. It is located in the cytoplasm as a ribosomal component, but it has also been detected in the nucleus. Studies in rat indicate that ribosomal protein S27 is located near ribosomal protein S18 in the 40S subunit and is covalently linked to translation initiation factor eIF3. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome."

More investigation needed, for instance perhaps the entire S27E family of proteins are integral to the aging process? Anyway, sticking to RPS27 or MPS-1,
Metallopanstimulin-1, the gene that encodes the protein it seems to reduce the growth of tumours, see this article. So, the gene could protect against cancer formation. How this relates to an increase in life span when the gene is knocked down in worm is not readily clear. In human, might knocking it down increase the risk of tumours?

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