The Genetic Drivers Of Longevity In Mice, Humans And Worms – Science 2.0

Since the dawn of civilization, people have searched for the secret to long life. Famously, Gianni Pes, Michel Poulain and Dan Buettner proposed that diet drives a persons longevity. Other researchers have favored a genetics based explanation for longevity. Recently, a study published in Science found that a mouses genes determine its lifespan, and that there are human orthologs, or analogous genes. The study also found that female and male mice have different genes controlling their lifespans, which is interesting considering that female mice have longer lifespans. The study firmly lands on the side of those who have argued that genes directly determine lifespan. This means that reducing the risk of disease alone is not enough to increase longevity.

While the idea of aging is universal, in scientific terms, it does not have a precise measure. Much as Socrates asked us to investigate the real meaning of widely discussed concepts, scientists have had to work out ways to measure aging, and, this implies, asking what aging really is. Broadly, as the authors of the study note, it is a progressive decline in physical, mental and reproductive capacities, in which a person accumulates morbidities and the risk of dying increases. However, it is not known what the exact interplay is between genes, sex and environment, in determing lifespan.

Researchers have measured aging through a number of traits, such as lifespan, and age-related disease onset. Researchers believe that if they can figure out what the genetic and nongenetic drivers of longevity are, they can develop treatments to improve not just quality of life, but longevity.

A team of scientists led by Robert Williams, looked at the determinants of longevity in 3276 UM-HET3 mice, a type of, or genetically diverse mice that the National Institute on Agings (NIA) Interventions Testing Program (ITP) had been studying. The NIAs TIP had collected this data in 2003, when they were trying to see if dietary interventions would affect the longevity of mice. The mice were raised in closely controlled, homogeneous conditions, and the program collected tissue from them, so they could isolate the impact of genes on the lifespan of mice. The diversity of mice was a result of the need to mirror the diversity in the human genepool. Typically, mice do tend to inbreed, and this warps studies on longevity.

The NIAs TIP did not study the genetic drivers of longevity, and that is the point at which Robert WIlliams and his team began their study. The team were charged with figuring out whether the genetic drivers of longevity are related to sex and age, and whether the nongenetic drivers, such as litter size, or having a good diet from early in life, was important to longevity. In studying these drivers, they were able to classify the changes in liver gene expression of mice in the same genetic cross, according to whether they were driven by age or genotype. The last step in the study was to bring those results together with the orthogonal or itnesecting datasets, to undertake quantitative trait locus mapping, associating phenotypes with genotypes. This would allow the team to figure out which genes are associated with increased longevity.

The team was able to determine genetic loci important for longevity. Sevel of these loci were found in female mice, but, at first, no genetic loci linked specifically to longevity in male mice, were found. When the scientists removed the data for male mice who died at the beginning of the study, they then found genetic loci associated specifically with longevity in male mice. They also found that the factors such as body weight and litter size also impact longevity. For instance, mice with larger body weights and who grew up in smaller litters, died earlier. Consequently, genes linked to body weight and litter size could arguably be linked to longevity. Longevity could be indirectly impacted by the effect of these genes on those factors. However, it is important to note that not all longevity genes are correlated with those factors, opening up the door to the possibility that there are other genes influencing longevity.

The goal of this study was to say something meaningful about longevity in humans, so the study then went to human genome biobanks, and the researchers found sequences that mirrored those in mice. In addition, there was a similar relationship between early development and longevity. They then looked at genes in worms, to see if a similar relationship existed, and if broader conclusions could be drawn about the association of these genes and longevity. Ultimately, they concluded that genes are the primary determinants of longevity.

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The Genetic Drivers Of Longevity In Mice, Humans And Worms - Science 2.0