Is IRON the next anti aging target?

https://www.nature.com/articles/s41467-020-17312-3

Several of the genes we identify have previously been shown to influence lifespan in experiments on model organisms. For example, knockouts of the orthologs of APOE, LDLR, CDKN2B, and RBM38 in mice shortens their lifespan24,25,26,27, while knockout of IGF1R has the opposite effect28. Similarly, overexpression of the FOXO3 orthologue in Drosophila melanogaster29 and the SNCA orthologue in Caenorhabditis elegans30 have shown to extend their respective lifespans. Many of our genes are also enriched for pathways previously related to ageing in eukaryotic model organisms, including genomic stability, cellular senescence, and nutrient sensing31. For example, FOXO3 and IGF1R are well-known players modulating survival in response to dietary restriction32, but we also highlight genes involved in the response to DNA damage and apoptosis, such as CDKN2B, USP28, E2F2, and BCL3. In addition to hallmarks discovered in model organisms, our results suggest that haem metabolism may play a role in human ageing. This pathway includes genes involved in processing haem and differentiation of erythroblasts33. Although the enrichment is largely driven by genes linked to the LDLR locus, genes linked to other loci of interest (such as FOXO3, CDKN2B, LINC02513) are involved in similar biological pathways: myeloid differentiation, erythrocyte homeostasis, and chemical homeostasis.

The pathway analysis has potential limitations due to the correlative nature of the genes used to test for enrichment, which can inflate type 1 errors34. However, the strong signal for haem metabolism, in combination with the MR results, suggests the evidence for the involvement of this pathway in human ageing is reasonably robust. Haem synthesis declines with age and its deficiency leads to iron accumulation, oxidative stress, and mitochondrial dysfunction35. In turn, iron accumulation helps pathogens to sustain an infection36, which is in line with the known increase in infection susceptibility with age37. In the brain, abnormal iron homeostasis is commonly seen in neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease and multiple sclerosis38. Plasma ferritin concentration, a proxy for iron accumulation when unadjusted for plasma iron levels, has been associated with premature mortality in observational studies39, and has been linked to liver disease, osteoarthritis, and systemic inflammation in MR studies40,41.