Lifespan study reveals age-specific biological changes in Down Syndrome

In a groundbreaking new study published in Nature Communications, researchers from the Linda Crnic Institute for Down Syndrome (Crnic Institute) at the University of Colorado Anschutz discovered important differences in the physiological changes observed in over 300 individuals with Down syndrome across the lifespan.

The study is part of the ongoing Human Trisome Project, a large, detailed cohort study of people with Down syndrome, including deep annotation of clinical data, multi-omics datasets, and the largest biobank for the study of this condition to date.

The Crnic Institute team analyzed hundreds of blood samples to identify physiological differences between research participants with Down syndrome versus control participants without Down syndrome at different life stages. They observed that triplication of chromosome 21, or trisomy 21, the genetic condition that causes Down syndrome, leads to age-specific effects during childhood, adolescence, and various stages of adult life. They identified key biological processes that are consistently dysregulated at all ages as well as those that are dysregulated only during specific age ranges.

These results reveal for the first time that trisomy 21 changes human biology in unique ways as persons with Down syndrome grow and age. Whereas some effects of the extra chromosome are observed throughout life, such as immune hyperactivity and dysregulated oxygen metabolism, other effects occur only in children or only in adults."

Joaquín Espinosa, PhD, executive director of the Crnic Institute, professor of pharmacology, principal investigator of the Human Trisome Project, and one of the senior authors of the paper

"The magnitude of these age-specific changes is remarkable," explained Neetha Paul Eduthan, MS, one of the lead authors of the paper. "When examining the genes, proteins, metabolites, and immune cell types affected by trisomy 21 in children versus adults, the changes that are unique to one age group always outnumber those that are conserved across the lifespan."

To put these observations into perspective, the team also analyzed the temporal effects of the sex chromosomes, or sex karyotype, defined as XX for females and XY for males.

"This analysis revealed the profound impacts of puberty on human biology," explained Micah Donovan, PhD, instructor of pharmacology and co-lead author of the study. "The molecular differences between young boys and girls are negligible in the first decade of life, but with the onset of puberty and gonad activation, vast biological changes are observed across the sexes, including important differences in gene expression, metabolism, and immune function."

The study team also employed advanced computational approaches to elucidate how human biology changes from early childhood to late adult life, and how these temporal changes are affected by trisomy 21.

"We identified eight major temporal trajectories for gene expression, protein levels, metabolite levels, and immune cell frequencies in the bloodstream," said Matthew Galbraith, PhD, associate research professor of pharmacology, director of the Data Sciences Program at the Crnic Institute, and one of the senior authors of the paper. "Biological aging is not a linear process, and our analyses provide an unprecedented view of the developmental trajectories of more than 20,000 biological data points from 6-month-old babies to sexagenarians."

The Crnic Institute study team has already embarked on several follow-up studies, including new investigations of impaired musculoskeletal growth and accelerated immune aging characteristic of Down syndrome.

"This is another important breakthrough from our scientists at the Crnic Institute that we hope will lead to more personalized medicine and effective treatments for people with Down syndrome at different ages," said Michelle Sie Whitten, president & CEO of Global Down Syndrome Foundation (GLOBAL), a partner and an affiliate organization of the Crnic Institute. "As a mother of a brilliant 22-year-old with Down syndrome, I am eager to understand how this new knowledge may elongate life and improve the health of millions of people with Down syndrome across the world. We are proud that GLOBAL's advocacy work with Congress and with the National Institutes of Health (NIH) has led to the establishment of the trans-NIH Down syndrome funding initiative, the INCLUDE Project, that underwrites this and numerous other groundbreaking studies and clinical trials."