Longevity Briefs: Are These The Genes That Drive Ageing?

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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Our genes play a fundamental role in the ageing process – and it’s not just a matter of which gene variants we are born with, but also how the activity of different genes changes throughout life. Scientists can compare gene activity between young and old individuals, but such studies only reveal associations – correlations between gene activity and age – without distinguishing whether a gene is a true “driver” of ageing, whether the gene activates as a response to ageing and is in fact beneficial, or whether it is merely a downstream effect of ageing that plays no actual role in the process.

These distinctions are important, because knowing which genes actually drive or counter ageing might allow us to develop therapies that would target these genes or their downstream effects. Unfortunately, identifying the important genes from among the sea of genetic changes that occur throughout life is not easy. In this study, scientists devise a new method in an attempt to pinpoint genes that causally affect lifespan, by combining data from different pre-existing studies and then testing the standout genes in an animal model.

The discovery:

First, researchers conducted a comprehensive meta-analysis, which is a statistical analysis of the combined results from multiple existing scientific studies. They analysed 25 gene expression datasets from healthy mammals including humans, dogs and rodents, across various tissue types. By pooling this extensive data, they identified genes that consistently showed increased or decreased activity with age across many different datasets. The top 4 genes whose activity increased with age were:

• TMEM176A, which encodes a membrane protein that plays a role in the immune system and in cancer
• EFEMP1, which helps maintain the integrity of the extracellular matrix (the ‘web’ of proteins that exists between cells)
• CP, which plays a crucial role in transporting iron and copper in the blood
• HLA-A, which encodes part of a structure on the surface of cells called MHC. MHC allows the immune system to distinguish between our own cells and pathogens. Some variants of HLA-A are associated with autoimmune disease.

The top 4 genes whose activity decreased with age were:

• CA4, which encodes an enzyme that helps CO2 exchange in the lungs and is important for maintaining blood pH
• SIAH, which has numerous roles including regulating inflammation and apoptosis (cells suicide). It is important for suppressing cancer.
• SPARC, which is important for wound healing, though it can also aid the spread of cancers
• UQCR10, which is important for the functioning of the mitochondria, the power plants of the cell

Next, to determine if the expression of genes actually caused changes in lifespan, the researchers turned to C. elegans, a small nematode worm that has a short lifespan, meaning that lifespan extension is quick to observe. They used genetic techniques to silence the expression of each gene of interest, allowing them to observe the impact of reduced gene activity.

They tested the top 10 age-upregulated and 9 age-downregulated genes, and found that six of those genes produced significant and reproducible increases in lifespan (by 9-15%) when their expression was inhibited. Most of these genes were not among the 8 genes listed above. The genes that were age-upregulated were CASP1 and RSRC1, which are involved in inflammation and gene regulation respectively, while there were four age-downregulated genes that extended lifespan when inhibited: DIRC2, SPARC, CDC20 and CA4. SPARC and CA4 have already been described. DIRC2 plays a role in vitamin B6 transport and in kidney cancer, while CDC20 regulate cell division and is also involved in cancer.

The implications:

By combining data from many studies in different mammals, the researchers in this study were able to narrow down their search to genes whose activity consistently changed in the same way across different species and in different tissues. This lends credence to the idea that these genes could have an important part to play in ageing that is conserved across different species. However, when the researchers looked at the effects of blocking the activity of these genes in worms, they found that the genes whose expression changed the most throughout life were not necessarily the ones that produced the greatest effects on lifespan. This is not particularly surprising – if a gene plays a very important and fundamental role in the ageing process, small changes in activity might still have a larger effect on lifespan than greater changes in a less consequential gene.

The more surprising finding was that whether the activity of a gene went up or down during ageing didn’t seem to predict its effect on lifespan – every gene tested in the C.elegans worms resulted in lifespan extension when it was inhibited, regardless of how its expression changed naturally. The most likely explanation for this is that the genes that are downregulated during normal ageing are being suppressed as a response to ageing – it’s the body’s natural way of trying to limit age related damage. Suppressing them further in worms only served to help them survive even longer. Aside from identifying potential gene targets, one takeaway from this study is that we need to be casting a wide net over genes that show a relationship with ageing, not just those that have large changes in activity or whose activity increases.