Genetic study improves lifespan predictions and scientific understanding of aging

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

Presenting author Paul Timmers, MRes, graduate student at the University of Edinburgh, and an international group of collaborators set out to identify the key genetic factors in lifespan. In the largest genome-wide association study of lifespan to date, they matched genetic data from more than 500,000 participants from the UK Biobank and other cohorts with lifespan data. life of the parents of each participant. Rather than studying the effects of one or more selected genes on lifespan, they looked at the whole 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 large sample size was needed to identify genes relevant to lifespan with sufficient statistical power, Timmers explained. Using this sample, the researchers validated six previously identified associations between genes and aging, such as the APOE gene, which has been linked to the risk of neurodegenerative disease. They also discovered 21 new genomic regions that influence lifespan.

They used their findings to develop a Polygenic Lifespan Risk Score: a unique, personalized genomic score that estimates a person’s genetic likelihood of living longer. Based on the weighted contributions of the relevant genetic variants, this score allowed the researchers to predict which participants were likely to live the longest.

“Using only a person’s genetic information, we can identify the 10% of people with the most protective genes, who will live an average of five years longer than the least protected 10%,” Timmers said.

The researchers also wanted to know if the genetic variants directly affect the aging process or affect the risk of individual diseases that can lead to death. They found that among common variants – variants found in at least 1 in 200 people – those associated with Alzheimer’s disease, heart disease and smoking-related conditions were linked to overall lifespan. Notably, they did not find associations of lifespan for other cancers, suggesting that susceptibility to death from other cancers is due to rarer genetic variants or the environment.

“It was an interesting result,” Timmers said. “We suspect that the variants we have found, such as for smoking and Alzheimer’s disease, relate only to the modern period of human history. For example, a genetic propensity to smoke was not harmful before we were discovering tobacco, but now it is. Since natural selection hasn’t had many generations to act on these variants yet, the variants are still quite common,” he explained.

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

To build on their findings, the researchers plan to study how the functional variants and pathways they identified affect lifespan. For example, they plan to investigate whether these pathways are associated with single diseases that have implications for longevity or with a broader spectrum of age-related diseases. By better understanding how these pathways interact with each other, they hope to ultimately identify ways to slow aging and the onset of disease that will improve the length and quality of life.

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