Reports of old brains’ decrepitude have been greatly exaggerated, scientists reported on Monday, unveiling results that contradict a much-discussed 2018 study and instead support the idea that human gray matter is capable of generating new neurons up to the ninth decade of life.

The research, published in Nature Medicine, also found that old brains from people without dementia have much higher rates of such neurogenesis than do the brains of people with Alzheimer’s disease, offering a new clue to a field that is desperate for new ideas.

When scientists at the University of California, San Francisco, reported last year that they “couldn’t find a single new neuron” in human brains older than about 7, as one of the lead researchers told STAT, and that the rate of neurogenesis falls off a cliff during the first year of life, they were greeted skeptically. Their conclusion contradicted 20 years of research in rodents as well as humans showing that the adult brain can give birth to new neurons in the memory-forming structure called the hippocampus. (Claims of neurogenesis in other brain regions, in contrast, have not stood up.)

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Critics offered numerous explanations for why the UCSF team saw no neurogenesis, including the difficulty of using the molecular markers of neuron birth. Some of those markers degrade very quickly, for instance, meaning they might have vanished from the brains used in the study (donated to brain banks) before the scientists could detect them.

Because the UCSF study was published in a prominent journal (Nature) by a respected lab, it was not rejected out of hand. But the new research suggests that the critics’ hunch was right: The molecular markers of neurogenesis are as tricky to work with as soufflés in an earthquake.

In particular, said molecular neuropathologist María Llorens-Martín of Spain’s Universidad Autónoma de Madrid, who led the new study, the marker called DCX does very poorly during tissue fixation, the step when minuscule slices from a donated brain are prepared for analysis. “If you go over about 12 hours of fixation time, the markers of new neurons disappear,” she said. “The new cells are there but we cannot detect them.”

She knew new neurons were present because after not finding them in samples that had undergone a long fixation time, she and her colleagues looked again in samples from the same brain that were fixed quickly. Those, she said, showed clear molecular signs of having undergone neurogenesis until right before death — regardless of the age when that occurred — including the presence of a protein called doublecortin, which is associated with neuronal migration.

“We clearly demonstrated that if you go longer than 12 hours” of fixation time, “you lose the signal of neurogenesis,” Llorens-Martín said. She and her colleagues analyzed samples from 58 banked brains, with ages at death from 43 to 87.

In response, Shawn Sorrells, a lead author of the 2018 study failing to find adult neurogenesis, told STAT that although the new study “contains valuable data,” he and his co-authors did not find its evidence for ongoing neurogenesis “convincing.” Accurately identifying new neurons “is a complicated endeavor requiring multiple lines of evidence to rule out alternative explanations, none of which are presented in this study,” said Sorrells, now at the University of Pittsburgh.

He believes that what the Madrid scientists took to be new neurons “are actually a distinct set of mature hippocampal neurons that have been there since childhood.” The supposed new ones have a size and shape more like that of mature neurons, Sorrells added.

The Madrid group disagrees. And their analysis meshes with the more widely held view that healthy, adult brains produce new neurons, but at a rate that declines with age.

In a 43-year-old brain, for instance, the scientists measured roughly 42,000 new neurons per cubic millimeter of hippocampus (approximately the volume of nine grains of table salt). An 87-year-old had 20,000 new neurons per cubic millimeter.

Alzheimer’s disease was even worse for neurogenesis than age. One 78-year-old brain from a person who didn’t have Alzheimer’s had about 23,000 new neurons per cubic millimeter of hippocampus, while a brain of the same age but from someone who died with Alzheimer’s disease had 10,000.

That might solve a longstanding Alzheimer’s mystery: that some elderly people who died with brains full of amyloid showed no signs of dementia. That suggests some sort of resilience or compensatory mechanism: Inflammation, which more and more scientists believe causes Alzheimer’s, kills neurons, but high rates of neurogenesis supply replacements.

Although Llorens-Martín and her colleagues did not have enough brains of the same age to make definitive comparisons of individual neurogenesis rates, they saw hints of person-to-person variation. Among people in their 60s without Alzheimer’s, she said, rates of neurogenesis ranged from about 30,000 to 40,000 new neurons per cubic millimeter of hippocampus; in 80-somethings, it was 20,000 to 30,000.

“If you can increase the rate of neurogenesis, it might be protective” against Alzheimer’s, she said.

Research in both lab animals and people has found that aerobic exercise can increase the rate of neurogenesis in some brain regions; so can some antidepressants. Scientists are trying to figure out whether new neurons do any functional good in people, as research shows they do in rats. Llorens-Martín is planning experiments on that, she said, “but from their morphology and other signs, I would bet they’re doing something.”

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  • Very informing. Information transfer from old to new, does it slow down with age ? At present I am aiming for 82 years of age and do research in extractive mineral metallurgy and to some extent analytical chemistry.

  • That’s the first time I’m reading about how nuerogenesis plays a role in Alzheimer’s. So the rate of neurogenesis is inversely proportional to the age. Sounds logical. And I’m surprised that aerobics can have an effect on the neurogenesis ? Why is this possible, or rather how ?

  • Mental practices such as mindfulness also result in neurogenesis – please see the following studies:

    Last, N., et al. (2017). The effects of meditation on grey matter atrophy and neurodegeneration: A systematic review. Journal of Alzheimer’s Disease, 56(1), 275-286.

    Hölzel, B. K., et al. (2011). Mindfulness practice leads to increases in regional brain gray matter density. Psychiatry Research: Neuroimaging, 191(1), 36-43.

    There are several additional studies – too many to list here.

  • Thank you for this article! The information is intriguing, encouraging, and invaluable. Aerobic exercise! Who knew? And I will bet that evaluations of our nutrition and environmental quality will reveal many more controllable factors in addressing Alzheimer’s.

    It never ceases to amaze me how much we still do not know about the human body. I am very grateful for the research that will result in so many improvements in the lives of current and future generations.

    • Aerobic exercise on a regular basis throughout adulthood and even in children has been well-studied and, depending on the level of intensity (HIIT versus moderate-intensity, distance running), has shown to trigger neurogenesis. What’s more important for adults hoping to stimulate the birth of new neurons to improve cognition is to ensure those newly created neuronal connections (i.e. new neural “networks”) are built to last, with connectivity between neurons that doesn’t dissipate quickly after development. This is where one must consider the TYPE of aerobic exercise performed. To date, studies in rats indicate that while HIIT may be great for your wasteline, it does much less for your brain. In studies on rats, neuroscientists have identified a significant difference between the benefits of high-stress aerobic activity such as HIIT relative to moderate-intensity, endurance-based exercise. Here’s an example of just one of the many studies that have produced a somewhat surprising result: the rats subject to regular HIIT showed substantially lower cognitive improvement (and some in fact showed NO IMPROVEMENT against their sedentary peers) relative to the rats that ran a few miles each day at a relatively moderate pace. Moreover, the results were consistent with the conclusion that the further the distance, the greater the benefits of this aerobic exercise on the brain, reflecting a direct relationship between distance and lasting neurogenesis. I’d strongly recommend those interested in the subject, i.e. cognitive enhancement or the slowing or reversal of cognitive decline via exercise, Harvard’s Dr. John Ratey’s recent book on the subject: “SPARK: THE REVOLUTIONARY NEW SCIENCE OF EXERCISE AND THE BRAIN.” Also, Time Magazine did a special edition on The Science of Exercise: included therein are the results of a study on the impact of similar exercise on a a poor group of rats born with a genetic mutation that caused rapid aging and death. The study’s architects used a control group, who had the mutation and did not exercise (any more than naturally), and a test group who was enticed to exercise, running on the wheel a few times a week without much intensity. If it isn’t obvious, the study was intended to investigate whether exercise might slow the progression of this awful gene mutation’s impact on the aging process of the test mice. The results are nothing shy of extraordinary. Reading the results of that study alone should supply most with more than enough incentive to work aerobic exercise into their lives. For me, it signaled a game changer.

  • Could someone please do some correlations of the burden of heavy metals, chemicals, low grade infections, and low grade inflammation in people’s oral cavities with brain health? Perhaps with basket studies grouping people with weaker genetic methylation pathways, and lower immune Ig levels? Some routine housecleaning and greater vigilance may be in order.

  • Based on scientific literature mammals’ brain is made up only by one enormous hippocampus and nothing more! 😛

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