A cell-by-cell map of the brain’s planning region from birth to 97

Just behind your forehead, on each side, sits the dorsolateral prefrontal cortex, a part of the brain involved in planning, working memory and keeping attention on a task. It is one of the last regions to mature in youth and one of the most sensitive to decline in old age.

The brain is made of many kinds of cells. Neurons carry signals; some excite their neighbours, others calm them down. Around them are support cells, together called glia: astrocytes, which feed and tidy up after neurons; oligodendrocytes, which wrap nerve fibres in insulating fat (myelin); and microglia, the brain’s resident immune cells. Earlier studies of the aging brain often ground up whole pieces of tissue, which blurs these cell types together, or covered only part of life.

What they did

A team at the Icahn School of Medicine at Mount Sinai, as part of a consortium called PsychAD, used brain tissue from 284 people aged 0 to 97 who had died without any diagnosed brain disease, from two US brain banks. For older donors, they excluded brains with more than minimal signs of Alzheimer’s disease.

From a piece of prefrontal cortex from each person, they isolated the nuclei of individual cells and read which genes were active in each one, a method called single-nucleus RNA sequencing. After strict quality checks, 1,307,674 nuclei remained, sorted into 27 cell types. The team grouped donors into development (0–19 years), young adulthood (20–39), middle adulthood (40–59) and late adulthood (60 and over), and also modelled changes as smooth curves over age. They checked key results in a separate dataset of 306 donors from earlier studies and with tissue staining.

What they found

• Three phases. In childhood and adolescence, 8,223 genes changed activity with age, mostly in neurons. In young and middle adulthood almost nothing changed: 27 and 1 genes. After 60, change resumed with 735 genes, and this time mostly in glia (426) rather than neurons (246).
• The mix of cells settles early. The proportions of cell types shifted a lot in youth and then levelled off; the team identified about age 24 as a turning point. Two groups kept changing later in life: a type of calming neuron (marked by a gene called SST), which became less common, and the cells that give rise to oligodendrocytes.
• Late-life glia turn to immune and stress programs. In older brains, astrocytes, microglia and oligodendrocytes switched on genes for immune responses and for handling misfolded proteins. Genes linked to Alzheimer’s disease and other neurological conditions were over-represented among these late-life changes. Genes tied to psychiatric conditions such as schizophrenia were concentrated in the changes of early life.
• Neurons grew more alike. With age, the different kinds of excitatory neurons changed in an increasingly similar way, with shared changes in genes for DNA repair.
• Daily rhythms faded. Using each donor’s time of death, the team looked for genes whose activity rises and falls over 24 hours. In people aged 20 to 59, 64 genes showed a clear rhythm, many of them parts of the body’s internal clock and most in one type of neuron. In people 60 and over, only one gene passed the same strict test. In older brains, some glia instead showed rhythms in stress-response genes.

What to keep in mind

• Gene activity only. The authors note that reading gene activity does not capture changes in the proteins themselves or in other layers of control, so it doesn’t show how cells actually work.
• A snapshot of different people. Each donor gave tissue once, after death. Differences between age groups are comparisons of different people, not changes followed within the same brain.
• Healthy brains only, one region. The donors had no brain diagnosis, so the study describes normal aging rather than disease, and only one area of the cortex was studied.
• Links to disease are statistical. Overlaps with risk genes for Alzheimer’s or schizophrenia point to where these conditions may act; they don’t show cause.
• Rhythms from time of death. The 24-hour patterns are reconstructed by comparing people who died at different times of day, not measured in living people.

Why it matters

The picture that emerges is of a brain that is busily rebuilt in youth, holds steady through midlife, and starts to change again after 60, mainly in its support and immune cells rather than in the neurons themselves. The loss of coordinated daily rhythms in older neurons is a lead for researchers studying how the body clock changes with age. Because the data are shared with other scientists, the atlas gives other researchers a baseline of normal aging against which to compare brains with dementia or psychiatric illness.