Genetic study improves life expectancy and scientific understanding of aging

By studying the effect of genetic variations on lifespan in the human genome, researchers have developed a way to estimate whether an individual can hope to live longer or shorter lives than average and have acquired an advanced scientific understanding of the diseases and cellular pathways involved in aging. Their findings were presented at the 2018 annual meeting of the American Society of Human Genetics (ASHG) in San Diego, California.

Presenting author Paul Timmers, MRes, a graduate student from the University of Edinburgh and an international group of collaborators undertook to identify the key genetic factors of lifespan. In the largest association study ever conducted on the entire genome to date, they coupled genetic data from over 500,000 participants from the British Biobank and other cohorts with data. on the life of the parents of each participant. Rather than studying the effects of one or more selected genes on lifespan, they examined the entire genome to answer the question more openly and identify new avenues to explore in future work.

Because the effect of a given gene is so small, the size of the sample was important to identify genes relevant to life with sufficient statistical power, explained Timmers. Using this sample, the researchers validated six associations previously identified between genes and aging, such as the APOE gene, linked to the risk of neurodegenerative disease. They also discovered 21 new genomic regions that influence lifespan.

They used their results to develop a polygenic risk score in terms of lifespan: a unique personalized genomic score that estimates a person's genetic probability of living longer. Based on the weighted contributions of relevant genetic variants, this score allowed researchers to predict which participants were likely to live longer.

"By using only one person's genetic information, we can identify the 10% of people with the most protective genes, who will live on average five years longer than the less protected 10%," said Mr. Timmers.

The researchers also wanted to know if the genetic variants directly affected the aging process or the risk of individual diseases that could lead to death. They found that among the common variants – variants found in at least 1 in 200 people – those associated with Alzheimer's disease, heart disease and smoking-related conditions were related to overall life span. In particular, they have not found an association of life expectancy for other cancers, suggesting that susceptibility to death caused by other cancers is due to rare genetic variants or to the environment.

"It was an interesting result," said Timmers. "We suspect that the variants we found, such as smoking and Alzheimer's disease, belong only to the modern period of human history.For example, a genetic propensity to smoke has not harmed us before the discovery of tobacco, but it is now.Since natural selection has not yet had many generations to act on these variants, the variants are still quite common, "he explained.

In addition, the researchers looked at cell types and protein pathways in which lifetime gene variants had the strongest effect. They found that genes play a key role in adult fetal brain cells and prefrontal cortex cells, with particular effects on the pathways associated with fat metabolism. Together, Timmers noted, these findings highlight the brain as an important organ in determining lifespan and represent a good opportunity for follow-up studies.

To capitalize on their discoveries, researchers plan to study how the variants and functional pathways they have identified affect lifespan. For example, they plan to investigate whether these pathways are associated with single diseases with implications for longevity or a broader spectrum of age-related diseases. By better understanding the interactions between these pathways, they ultimately hope to find ways to slow down aging and the emergence of diseases that can improve the duration and quality of life.

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More information:
Timmers P et al. (October 20, 2018). Abstract: The genomic basis of life span can predict and reveal the foundations of modern risks. Presented at the 2018 Annual Meeting of the American Society of Human Genetics. San Diego, California. eventpilot.us/web/page.php?pag… = ASHG18 & id = 180120478