The secret to a long life has always been a topic of intrigue and fascination. Genome-wide studies of people with different life spans have revealed key genes that contribute to a longer life. Moreover, genes involved in longevity were found to be correlated with coronary heart disease, type-2 diabetes and father’s age at death.
In recent years, science has made advances in identifying key genes and connecting them to a function in the body. Traits are often classified as influenced by genetics or by the environment, often known as the debate between nature vs nurture. However, as we begin to further understand the composition of organisms, we come to understand that nature and nurture work together to produce our phenotypes.
Longevity is often defined as life expectancy. Scientists have recently identified the importance of genetics on human longevity. Previous studies described the heritability of lifespan as ranging from 15–30%, meaning that 15–30% of our lifespan is defined by our genes. Other experts in the area are investigating the impact of our choice in mates on heritability. They have suggested that assortative mating, or choosing mates with traits similar to our own, can account for some of the apparent heritability. However, it is still undisputed that genes are a main determinant for lifespan. A particular area of interest is associating possible genes responsible for determining longevity.
A study by Deelen et al. in 2019 did just that. To identify key genes, they used Genome-Wide Association Studies (GWAS). As seen in Figure 1 below, they selected individuals and controls based on their survival percentile. The subjects chosen were from a variety of ethnicities, including European, East Asian or African American and they all belonged to the 90th or 99th survival percentile. The DNA of these subjects was extracted and sequenced. Using GWAS, they used computer programs and statistical analyses to compare the association between survival percentile and the genetic variants of the participants.
Method for Genome-Wide Association Studies (GWAS). GWAS require a selection of individuals and controls based on a specific characteristic. Researchers collect a sample from the subjects and extract DNA for sequencing. Based on the characteristics portrayed by the individuals and their whole genome, computer programs process the association between the two. Lastly, statistical analyses are used to understand the significance of the association. The researchers interpret the results to draw conclusions regarding genetic variations that contribute to those characteristics.
A single-nucleotide polymorphism, or SNP is a change in a nucleotide of the genome. In databases, SNPs have a unique number prefixed with rs for Reference SNP. In the figure below, we can see some of the SNPs identified by Deelen et al. and their impact on the chances of survival to the 90th and 99th percentile. Some of these are located in known genes, whereas others are not. The figure also shows some key diseases/traits and their genetic correlation with survival to the 90th percentile.
Results of study demonstrating correlation between gene variants and survival, and genetic correlation between diseases/traits with survival. Deelen et al. used GWAS to find the correlation between loci and the chance of survival to the 90th and 99th percentile. The two most significant variants were rs429358 and rs7412, which decrease and increase the chance of survival, respectively. This study used genetic correlation analysis to find diseases and traits with significant correlation to the survival to the 90th and 99th percentile. The most significant diseases/traits were coronary artery disease and father’s age at death.
Their study identified two important variants of the apolipoprotein E (APOE) as having a significant impact on longevity. They found an allele of ApoE ε4 that decreases the chances of survival to 90th and 99th percentile, and an allele of ApoE ε2 that increases those chances. ApoE has been shown to be the main cholesterol carrier in the brain and mediate cholesterol metabolism in peripheral tissues. Moreover, the two variants are correlated with the risk of developing cardiovascular disease and Alzheimer’s disease. Since the two are age related diseases, the researchers suggested that is the reason why ApoE significantly impacts longevity. In addition, ApoE ε2 protein shows high stability and ApoE ε4 shows low stability upon folding. The opposite effects of the two on survival could be due to their stability.
The GPR78 gene was also identified as an important determinant of survival to the 90th percentile. The GPR78 protein is part of a family of receptors that mediate responses to extracellular signals such as neurotransmitters and hormones. Although the function of the GPR78 protein is unknown, studies have shown that it is involved in lung cancer metastasis. Mutations in this gene have been shown to cause a series of complications, including death. Further research into this gene and its mutations could give insight into its function and role in longevity.
Another important finding of the study was the identification of diseases and traits that play a role in human longevity. Importantly, they found a significant negative genetic correlation between coronary artery disease and type-2 diabetes. This was expected as it has been previously shown that families with longer life spans have a decreased prevalence of coronary heart disease and type-2 diabetes. Their study also found that father’s age at death has a higher genetic correlation to longevity than mother’s age at death. The researchers attribute this to the difference in prevalence of diseases such as coronary artery disease, type-2 diabetes and habits such as smoking, between men and women in the last century.
We reached out to the author of the paper to ask about some challenges faced in the study. Joris Deelen stated that the two main challenges were “coming up with a good definition of longevity and finding appropriate control groups.” In comparison to other studies, longevity has often been investigated using a cut off age of 85, 90 or 100. In this case, using a percentile allowed the investigators to study a larger sample size. For the control group, they used a similar approach by using survivors to the 60th percentile, granting a larger sample size. “We struggled with getting all the cohorts to participate in our effort”, added Joris Deelen and it took over 2 years to complete the study.
The study conducted by Deelen et al. gave us insight into genes, diseases and traits associated with longevity. Some of the genes identified directly correlate to the diseases connected with lower life spans. Many of the genetic variants identified belong to genes with unknown functions. Further research could be done in this area as it would help correlate genes with traits and understand the mechanisms which determine longevity.
About the author
This blog post was written by Matilde Gomes. She is a fourth year student at the University of Toronto doing a specialist major in Molecular Biology and Biotechnology. She hopes to pursue a masters in epigenetics or mitochondrial DNA. In her free time, she enjoys playing basketball and spending time with family and friends.
The Genomic Odyssey 
Fascinating! I am quite interested in seeing more about the correlation between father’s age at death and longevity.
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