At 24 the brain seems to close a long season of work in progress. Decades of relative stability follow, then, after the age of 60, molecular activity changes again: this time it is mainly the cells that support, protect and monitor the neurons that move. It is the trajectory reconstructed by a large study published in Naturewhich tracked cellular changes in the dorsolateral prefrontal cortex across nearly a century of human life.
The researchers analyzed more than 1.3 million cell nuclei from the brains of 284 people, from infancy to age 97, building one of the most detailed maps available of how neurons and glial cells change with age. The sequence identified is quite clear: major transformations during development, an adjustment around the age of 24, a long relatively stable phase and then a new wave of molecular activity after the age of 60.
At age 24 the brain enters its long stable phase
The region observed by the researchers is the dorsolateral prefrontal cortex, involved in functions such as planning, working memory, cognitive control and decision-making. During childhood and adolescence its cellular composition changes significantly. Neurons and glial cells go through maturation phases, gene expression programs change and many cell populations continue to settle. Then the curve slows down.
The authors identify a point of inflection around the age of 24, after which the composition of most cellular subclasses becomes much more stable. The brain naturally continues to change and adapt, while above all slowing down the great cellular and molecular remodeling that had characterized the previous phases. This relative quiet accompanies much of adulthood.
Between the ages of 20 and 59, for example, researchers also observed well-coordinated circadian rhythms in neurons, with several genes following regular patterns throughout the 24 hours. A sort of long phase of ordinary cerebral administration. Then you get above 60 and something starts to move again.
After the age of 60, the cells that support the neurons change in particular
In late adulthood, a new wave of molecular activity appears. This time it is above all astrocytes, microglia, oligodendrocytes and other glial cells that are changing the most, which perform essential functions in supporting neurons, maintaining the brain environment and participating in the immune response. The authors describe a true reactivation of age-related molecular programs. The genes whose activity varies with aging increase and the processes linked to the immune response, inflammation and cellular stress become more evident.
The internal rhythm of the cells also changes. In the younger and middle-aged samples, the neurons showed very well-organized activity over 24 hours. After the age of 60 this synchronization attenuates, while some glial cells acquire new molecular rhythms linked to stress responses.
As researchers from the Icahn School of Medicine at Mount Sinai, involved in the largest collection of studies from which this atlas was born, explain, the aging brain therefore also seems to change the way in which it distributes some of its cellular activities over time.
Diseases follow different times
The map becomes particularly interesting when researchers overlay age-related changes with genes associated with certain neurological and psychiatric disorders. Genetic signals linked to schizophrenia and bipolar disorder are more closely associated with cellular programs active in early development. Those linked to Alzheimer’s, however, appear mainly in glial cells that change during late adulthood. It is therefore not just the cell type that matters. It also matters when, over the course of life, certain biological programs become more or less active.
A second work, published almost simultaneously on Scienceadds an interesting detail. By studying the hippocampus of adults of different ages, another group observed important changes in microglia, the immune cells of the brain, between the ages of about 50 and 75, together with modifications of the cells that contribute to the blood-brain barrier and of the three-dimensional organization of the genome.
It is a much closer zoom on a different region of the brain, which however falls in the same stretch of life in which the atlas of Nature sees molecular activity reignited. The two studies look at different things and with different tools, but they both end up showing how the second half of adult life is biologically more eventful than the old idea of slow and uniform aging suggests.
A brain that changes in stages
The photograph that comes out of the studio on Nature it therefore has little of the classic straight line that goes from growth to decline. At the beginning there are years of intense transformations. Around the age of 24 comes a phase of relative stability that lasts for decades. Then, after the age of 60, different cell populations start to modify their activity again and above all the support, protection and surveillance systems of the nervous tissue change.
A scan that could help better understand why some diseases appear more frequently in certain stages of life and which cells are most vulnerable in each period. For the identity card we become adults at 18 years old. For the brain, it seems, the calendar is a little less bureaucratic.
