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Circadian Gene Expression Variation Across Tissue Types May Offer Aging, Disease Clues

NEW YORK – A new analysis of circadian clock-related gene expression rhythms in a wide range of human tissue types over the course of a day suggests that age and sex may influence these expression patterns in ways that may inform future studies of aging and disease.

"A stratification by sex and age revealed a rich picture of group-specific rhythms, especially in metabolic and cardiovascular tissues, that may provide insight into differential disease incidence rates," senior and corresponding author Felix Naef, with the EPFL's Institute of Bioengineering, and his colleagues reported in Science on Thursday, noting that "differences in 24-hour rhythmic processes across sexes and ages may help improve patient-specific chrono-pharmacology."

Using an algorithm designed to temporally organize gene expression profiles found with data from efforts such as the Genotype-Tissue Expression (GTEx) project, researchers at the Swiss Federal Institute of Technology Lausanne (EPFL) teased apart circadian gene expression patterns across 46 tissue types in 914 GTEx participants.

"The algorithm exploits the fact that the circadian phases of tissue samples (typically 10 to 20 per individual) from the same donor are correlated and assumes that relative circadian phases of tissues are conserved across donors," the authors explained, noting that the computational approach established a skeletal muscle circadian pattern known as the "donor internal phase" for each individual.

Bringing in transcript marker clues from human muscle samples tracked over time, the team showed that it was possible to estimate the gene expression fluctuations taking place over a 24-hour stretch for tissues from GTEx donor individuals.

Overall, the team noted that molecular clocks in these tissues tended to have synchronous gene expression activity, with both morning- and evening-related expression waves. Even so, gene expression waves were particularly pronounced in adrenal gland tissues and metabolic tissue types, such as adipose, esophageal, or cardiovascular tissues, but far more muted in brain tissue samples.

Such expression variability was further enhanced when the investigators analyzed the circadian clock patterns with an eye to individual's age and biological sex, despite an overall conservation in molecular clock structure.

Their results suggested female participants had more genes following rhythmic expression patterns, for example, including genes expressed in the adrenal gland and liver, potentially offering insights into the outsized role that liver conditions such as nonalcoholic fatty liver disease play in males compared to females.

Gene expression rhythms appeared to get dialed down with age in their analysis, on the other hand, differing in donors over 60 years old compared to their younger counterparts. That reduced rhythmicity was especially obvious in coronary artery tissue or tissues with ties to cardiovascular function or disease.

Similarly, the team saw an apparent age-related shift from 24-hour gene rhythms to gene expression fluctuations operating on a 12-hour clock in some tissues, including the liver, pituitary gland, and colon.

"Such destabilization of 24-hour periodicity … as a result of aging might reflect differences in the reception of external cues in older individuals," the authors speculated, adding that "the loss of [messenger RNA] rhythms with age in coronary arteries correlates with age-dependent incidence rates of cardiovascular disease."