A gene-activity atlas of the prefrontal cortex reveals three age periods and a near-complete loss of neuronal circadian rhythm after 60
A gene-activity atlas of the prefrontal cortex reveals three age periods and a near-complete loss of neuronal circadian rhythm after 60
On 23 September, the PsychAD consortium published a study in Nature. The researchers profiled gene activity in 1.3 million cell nuclei from a region of the frontal cortex involved in planning, working memory, and impulse control, collected from 284 neurologically healthy donors ranging in age from birth to 97 years. They identified three periods of age-related change along with a separate shift in the daily oscillation of gene activity.
The authors chose the dorsolateral prefrontal cortex because it is particularly vulnerable to age-related decline. By restricting the sample to healthy donors, they established a reference for how cells change during ordinary aging, independent of changes driven by brain disease.
During childhood and adolescence, the activity of 8223 genes changed with age; more than 80% of these genes were active in neurons. Around age 24, the proportions of different cell types stopped shifting appreciably. The study's lead investigator, Panos Roussos, describes this age as a transition to a more stable cellular composition in this cortical region; other aspects of brain biology continue to change throughout life.
In young and middle adulthood, only 27 genes and then just one gene were associated with age, respectively. After 60, changes resumed: 735 genes showed altered activity, and nearly 60% of them were active in glia, the cells that support and protect neurons.
The same transition appeared across the course of the day. Using each donor's time of death, the authors reconstructed how gene activity varied by hour. In donors aged 20 to 59, dozens of neuronal genes oscillated in a coordinated pattern; in donors over 60, only a single gene retained this rhythm. In the glial cells of the older group, new oscillations emerged in genes involved in the unfolded protein response, a cellular hallmark of stress.
Among the genes whose glial activity changed after 60, those linked to heritable risk for Alzheimer's disease were overrepresented beyond what chance would predict. The findings were replicated in an independent set of 306 donors and validated on tissue sections from donors at four different ages.
The authors suggest that future interventions should target the cell types and age windows where these changes are most pronounced.