Pooled Genome-Wide Data Analysis Finds Link Between Blood Iron Levels and Aging

Pooled Genome-Wide Data Analysis Finds Link Between Blood Iron Levels and Aging
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Ageing drives development of many of the world’s most common fatal diseases, including heart disease, dementia, and cancers, which makes this a hot research topic. However, it’s also a very challenging because aging is so varied and influenced by so many biological and other factors. To get dependable data, researchers need very large sample sizes.

Now scientists from the University of Edinburgh and the Max Planck Institute for Biology of Ageing in Germany have studied genetic influences on aging used anonymized datasets downloaded from the publicly available Zenodo, Edinburgh DataShare, and Longevity Genomics servers. The study combined genome-wide association summary statistics for healthspan (or how long patients have good health), parental lifespan, and longevity.

The researchers identified 10 genomic loci that appear to influence all three of those phenotypes. The majority of those loci are associated with cardiovascular disease, others affect the expression of genes whose activity is known to change with age. Five of these loci (near FOXO3SLC4A7LINC02513ZW10, and FGD6) have not been reported previously at genome-wide significance. Further, gene sets linked to iron were overrepresented in the analysis of all three measures of ageing.

In total, the study implicates 78 genes that are enriched for ageing pathways previously highlighted in model organisms, such as the response to DNA damage, apoptosis, and homeostasis. The group also determined that the heme metabolism pathway appears to be promising for further ageing research. Blood iron is affected by diet and abnormally high or low levels are linked to age-related conditions such as Parkinson’s disease, liver disease, and a decline in the body’s ability to fight infection in older age.

The researchers suggest that a drug designed to mimic the influence of genetic variation on iron metabolism might help overcome some of ageing’s effects, but they caution that more work is required. The study was published this week in the journal Nature Communications.  DOI 10.1038/s41467-020-17312-3.

Lead author Paul Timmers, from the Usher Institute at the University of Edinburgh, said: “We are very excited by these findings as they strongly suggest that high levels of iron in the blood reduces our healthy years of life, and keeping these levels in check could prevent age-related damage. We speculate that our findings on iron metabolism might also start to explain why very high levels of iron-rich red meat in the diet has been linked to age-related conditions such as heart disease.”

For their study, the University of Edinburgh and Max Planck Institute researchers pooled and analyzed information from three public databases, creating a combined dataset equivalent to studying 1.75 million lifespans or more than 60,000 extremely long-lived people. This allowed them to examine the data “in unprecedented detail,” they wrote in their paper.

In addition to pinpointing ten regions of the genome linked to long lifespan, healthspan, and longevity, the researchers also found that gene sets linked to iron metabolism were overrepresented in their analysis. This finding was confirmed using a statistical method – known as Mendelian randomization. Genes involved in metabolizing iron in the blood, they suggest, may be partly responsible for a healthy long life.

Joris Deelen from the Max Planck Institute for Biology of Ageing in Germany, and also a study author, said: “Our ultimate aim is to discover how ageing is regulated and find ways to increase health during ageing. The ten regions of the genome we have discovered that are linked to lifespan, healthspan and longevity are all exciting candidates for further studies.”