How physical exercise and fitness improves your brain function
Neurogenesis — the creation of new brain cells — occurs of course at a great rate in the very young. For a long time, it was not thought to occur in adult brains — once you were grown, it was thought, all you could do was watch your brain cells die!
Adult neurogenesis (the creation of new brain cells in adult brains) was first discovered in 1965, but only recently has it been accepted as a general phenomenon that occurs in many species, including humans (1998).
It's now widely accepted that adult neurogenesis occurs in the subgranular zone of the dentate gyrus within the hippocampus and the subventricular zone (SVZ) lining the walls of the lateral ventricles within the forebrain. It occurs, indeed, at a quite frantic rate — some 9000 new cells are born in the dentate gyrus every day in young adult rat brains — but under normal circumstances, at least half of those new cells will die within one or two months.
The neurons produced in the SVZ are sent to the olfactory bulb, while those produced in the dentate gyrus are intended for the hippocampus.
Adult neurogenesis might occur in other regions, but this is not yet well-established. However, recent research has found that small, non-pyramidal, inhibitory interneurons are being created in the cortex and striatum. These new interneurons appear to arise from a previously unknown class of local precursor cells. These interneurons make and secrete GABA (see below for why GABA is important), and are thought to play a role in regulating larger types of neurons that make long-distance connections between brain regions.
New neurons are spawned from the division of neural precursor cells — cells that have the potential to become neurons or support cells. How do they decide whether to remain a stem cell, turn into a neuron, or a support cell (an astrocyte or oligodendrocyte)?
Observation that neuroblasts traveled to the olfactory bulb from the SVZ through tubes formed by astrocytes has led to an interest in the role of those support cells. It's now been found that astrocytes encourage both precursor cell proliferation and their maturation into neurons — precursor cells grown on glia divide about twice as fast as they do when grown on fibroblasts, and are about six times more likely to become neurons.
Adult astrocytes are only about half as effective as embryonic astrocytes in promoting neurogenesis.
It’s been suggested that the role of astrocytes may help explain why neurogenesis only occurs in certain parts of the brain — it may be that there’s something missing from the glial cells in those regions.
The latest research suggests that the astrocytes influence the decision through a protein that it secretes called Wnt3. When Wnt3 proteins were blocked in the brains of adult mice, neurogenesis decreased dramatically; when additional Wnt3 was introduced, neurogenesis increased.
How are these new neurons then integrated into existing networks? Mouse experiments have found that the brain chemical called GABA is critical. Normally, GABA inhibits neuronal signals, but it turns out that with new neurons, GABA has a different effect: it excites them, and prepares them for integration into the adult brain. Thus a constant flood of GABA is needed initially; the flood then shifts to a more targeted pulse that gives the new neuron specific connections that communicate using GABA; finally, the neuron receives connections that communicate via another chemical, glutamate. The neuron is now ready to function as an adult neuron, and will respond to glutamate and GABA as it should.
The creation and development of new neurons in the adult brain is very much a "hot" topic right now — it's still very much a work-in-progress. However, it is clear that other brain chemicals are also involved. An important one is BDNF (brain-derived neurotrophic factor), which seems to be needed during the proliferation of hippocampal precursor cells to trigger their transformation into neurons.
Other growth factors have been found to stimulate proliferation of hippocampal progenitor cells: FGF-2 (fibroblast growth factor-2) and EGF (epidermal growth factor).
Recently it has been discovered that the normal form of the prion protein which, when malformed, causes mad cow disease, is also involved in neurogenesis. These proteins, in their normal form, are found throughout our bodies, and particularly in our brains. Now it seems that the more of these prion proteins that are available, the faster neural precursor cells turn into neurons.
The immune system's T cells (which recognize brain proteins) are also critically involved in enabling neurogenesis to occur. Among mice given environmental enrichment, only those with healthy T-cells had their production of new neurons boosted.
A number of factors have been found to affect the creation and survival of new neurons. For a start, damage to the brain (from a variety of causes) can provoke neurogenesis.
Moderate alcohol consumption over a relatively long period of time can also enhance the formation of new nerve cells in the adult brain (this may be related to alcohol's enhancement of GABA's function). Excess alcohol, however, has a detrimental effect on the formation of new neurons in the adult hippocampus. But although neurogenesis is inhibited during alcohol dependency, it does recover. A pronounced increase in new neuron formation in the hippocampus was found within four-to-five weeks of abstinence. This included a twofold burst in brain cell proliferation at day seven of abstinence.
Most drugs of abuse such as nicotine, heroine, and cocaine suppress neurogenesis, but a new study suggests that cannabinoids also promote neurogenesis. The study involved a synthetic cannabinoid, which increased the proliferation of progenitor cells in the hippocampal dentate gyrus of mice, in a similar manner as some antidepressants have been shown to do. The cannabinoid also produced similar antidepressant effects. Further research is needed to confirm this early finding.
If antidepressants promote neurogenesis, it won't be surprising to find that chronic stress, anxiety and depression are associated with losing hippocampal neurons. A rat study has also found that stress in early life can permanently impair neurogenesis in the hippocampus.
Showing the other side of this picture, perhaps, an intriguing rat study found that status affected neurogenesis in the hippocampus, with high-status animals having around 30% more neurons in their hippocampus after being placed in a naturalistic setting with other rats.
Also, a study into the brains of songbirds found that birds living in large groups have more new neurons and probably a better memory than those living alone.
Both physical activity and environmental enrichment (“mental stimulation”) have been shown to affect both how many cells are born in the dentate gyrus of rats and how many survive. Learning that uses the hippocampus has also been shown to have a positive effect, although results here have been inconsistent.
Inconsistent results from studies looking at neurogenesis are, it is suggested, largely because of a confusion between proliferation and survival. Neurogenesis is measured in terms of these two factors, which researchers often fail to distinguish between: the generation of new brain cells, and their survival. But these are separate factors, that are independently affected by various factors.
The inconsistency found in the effects of learning may also be partly explained by the complex nature of the effects. For example, during the later phase of learning, when performance is starting to plateau, neurons created during the late phase were more likely to survive, but neurons created during the early phase of more rapid learning disappeared. It’s speculated that that this may be a “pruning” process by which cells that haven’t made synaptic connections are removed from the network.
And finally, rodent studies suggest a calorie-restricted diet may also be of benefit.
A few years ago, we were surprised by news that new neurons could be created in the adult brain. However, it’s remained a tenet that adult neurons don’t grow — this because researchers have found no sign that any structural remodelling takes place in an adult brain. Now a mouse study using new techniques has revealed that dramatic restructuring occurs in the less-known, less-accessible inhibitory interneurons. Dendrites (the branched projections of a nerve cell that conducts electrical stimulation to the cell body) show sometimes dramatic growth, and this growth is tied to use, supporting the idea that the more we use our minds, the better they will be.
For more, see the research reports
A small UK study involving 28 healthy older adults (20 women with average age 70; 8 men with average age 67), has found that those with higher levels of aerobic fitness experienced fewer language failures such as 'tip-of-the-tongue' states.
The association between the frequency of tip-of-the-tongue occurrences (TOTs) and aerobic fitness levels existed even when age and vocabulary size was accounted for. Education level didn't affect TOTs, but only a few of the participants hadn't gone to university, so the study wasn't really in a position to test this out.
However, the larger the vocabulary for older adults, the less likely they were to have TOTs. Older adults also had more TOTs over longer words.
The test involved a 'definition filling task', in which they were asked to name famous people, such as authors, politicians and actors, based on 20 questions about them. They were also given the definitions of 20 'low frequency' and 20 'easy' words and asked whether they knew the word relating to the definition.
Aerobic fitness was assessed by a static bike cycling test.
The study included 27 young adults as a control group, to provide a comparison with older adults' language abilities, confirming that older adults did indeed have more TOTs. The young adults' fitness was not tested. All participants were monolingual.
Segaert et al (2018). Higher physical fitness levels are associated with less language decline in healthy ageing. Scientific Reports. https://www.nature.com/articles/s41598-018-24972-1
An Australian study involving 102 older adults (60-90) has concluded that physical fitness and arterial stiffness account for a great deal of age-related memory decline.
The study that, while both physical fitness and aortic stiffness were associated with spatial working memory performance, the two factors affected cognition independently. More importantly, and surprisingly, statistical modelling found that, taking BMI and gender into account, fitness and aortic stiffness together explained a third (33%) of the individual differences in spatial working memory — with age no longer predicting any of the differences.
While physical fitness didn’t seem to affect central arterial stiffness, the researchers point out that only current fitness was assessed and long term fitness might be a better predictor of central arterial stiffness.
It's also worth noting that only one cognitive measure was used. However, this particular measure should be a good one for assessing cognition untainted by the benefits of experience — a purer measure of the ability to process information, as it were.
It would also be interesting to extend the comparison to younger adults. I hope future research will explore these aspects.
Nevertheless, the idea that age-related cognitive decline might be largely, or even entirely, accounted for by one's physical fitness and the state of one's arteries, is an immensely appealing one.
Fitness was assessed with the Six-Minute Walk test which involved participants walking back and forth between two markers placed 10 metres apart for six minutes. Only participants who completed the full six minutes were included in the analysis.
 Kennedy, G., Meyer D., Hardman R. J., Macpherson H., Scholey A. B., & Pipingas A.
(2018). Physical Fitness and Aortic Stiffness Explain the Reduced Cognitive Performance Associated with Increasing Age in Older People.
Journal of Alzheimer's Disease. 63(4), 1307 - 1316.
A long-running study involving 454 older adults who were given physical exams and cognitive tests every year for 20 years has found that those who moved more than average maintained more of their cognitive skills than people who were less active than average, even if they have brain lesions or biomarkers linked to dementia.
Participants wore an activity monitor for a week, an average of two years before death. The range of physical activity was extreme, with the average being 155,000 counts/day and the standard deviation being 116,000 counts. Daily physical activity was affected by age (unsurprisingly) and education.
For every increase in physical activity by one standard deviation, participants were 31% less likely to develop dementia. For every increase in motor ability by one standard deviation, participants were 55% less likely to develop dementia.
191 had dementia and 263 did not. The participants donated their brains for research upon their deaths. The average age at death was 91 years. Almost all (95.6%) showed at least one brain pathology, with 85% having at least two, and the average being three. Pathologies include Alzheimer's pathology, Lewy Bodies, nigral neuronal loss, TDP-43, hippocampal sclerosis, micro- and macro-infarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy.
Buchman, Aron S. et al. 2019. Physical activity, common brain pathologies, and cognition in community-dwelling older adults. Neurology, 92 (8), e811-e822; DOI: 10.1212/WNL.0000000000006954
Data from the English Longitudinal Study of Aging, in which nearly 4,000 older adults (60+) had their walking speed assessed on two occasions in 2002-2003 and in 2004-2005, those with a slower walking speed were more likely to develop dementia in the next 10 years. Those who experienced a faster decline in walking speed over the two-year period were also more likely to develop dementia.
A long-running study involving 175 older adults (70-79) found that slowing in walking speed over a 14-year period was associated with cognitive impairment, and with shrinkage of the right hippocampus specifically.
Gait slowing over an extended period of time was a stronger predictor of cognitive decline than slowing at a single time point. All the participants slowed over time, but those who slowed by 0.1 seconds more per year than their peers were 47% more likely to develop cognitive impairment.
The finding held even when the researchers took into account slowing due to muscle weakness, knee pain and diseases, including diabetes, heart disease, and hypertension.
Typically, a slowing gait is seen as a physical issue, but doctors should consider that there may be a brain pathology driving it.
 Hackett, R. A., Davies‐Kershaw H., Cadar D., Orrell M., & Steptoe A.
(2018). Walking Speed, Cognitive Function, and Dementia Risk in the English Longitudinal Study of Ageing.
Journal of the American Geriatrics Society. 66(9), 1670 - 1675.
 Rosso, A. L., Verghese J., Metti A. L., Boudreau R. M., Aizenstein H. J., Kritchevsky S., et al.
(2017). Slowing gait and risk for cognitive impairment.
Neurology. 89(4), 336.
A study involving healthy older adults (55-85) found that recall was better after a session of moderately intense exercise, and several crucial brain regions showed greater activation.
The recall task involved identifying famous names and non famous ones. The test occurred 30 minutes after the exercise session (using an exercise bike) and on a separate day after a period of rest.
Brain activation while correctly remembering names was significantly greater in the hippocampus, middle frontal gyrus, inferior temporal gryus, middle temporal gyrus, and fusiform gyrus.
Data from the Framingham Heart Study has found that each additional hour spent in light-intensity physical activity was associated with higher brain volumes, equivalent to approximately 1.1 years less brain aging.
Data from 262 older adults (mean age 81) in the long-running Rush's Memory and Aging Project, found that higher levels of lifestyle physical activity (e.g., house cleaning, dog-walking, gardening, as well as exercise) are associated with more gray matter.
Participants wore an accelerometer continuously for seven to ten days, in order to accurately measure the frequency, duration and intensity of a participant's activities.
The association between physical activity and gray matter volumes remained after further controlling for age, gender, education levels, body mass index and symptoms of depression.
 Won, J., Alfini A. J., Weiss L. R., Michelson C. S., Callow D. D., Ranadive S. M., et al.
(2019). Semantic Memory Activation After Acute Exercise in Healthy Older Adults.
Journal of the International Neuropsychological Society. 25(6), 557 - 568.
 Spartano, N. L., Davis-Plourde K. L., Himali J. J., Andersson C., Pase M. P., Maillard P., et al.
(2019). Association of Accelerometer-Measured Light-Intensity Physical Activity With Brain Volume: The Framingham Heart Study.
JAMA Network Open. 2(4), e192745 - e192745.
 Halloway, S., Arfanakis K., Wilbur JE., Schoeny M. E., & Pressler S. J.
(Submitted). Accelerometer Physical Activity is Associated with Greater Gray Matter Volumes in Older Adults Without Dementia or Mild Cognitive Impairment.
The Journals of Gerontology: Series B.
A small pilot study, in which participants had brain scans and working memory tests before and after single sessions of light and moderate intensity exercise and after a 12-week long training program, has shown that immediate cognitive effects from exercise mirror long-term ones. Participants who saw the biggest improvements in cognition and functional brain connectivity after single sessions of moderate-intensity physical activity also showed the biggest long-term gains in cognition and connectivity.
The finding suggests that the brain changes observed after a single workout study can be a biomarker of sorts for long-term training.
The findings were presented by Michelle Voss at the Cognitive Neuroscience Society (CNS) in San Francisco, March 23-26, 2019.
Previous research uncovered a hormone called irisin that is released into the circulation during physical activity, and appeared to play a role in energy metabolism. Mice studies have now found that irisin protected memory and synapses in the brain — disabling irisin in the hippocampus resulted in synapses and memory weakening; boosting brain levels of irisin improved synapses and memory.
Mice who swam nearly every day for five weeks didn’t develop memory impairment despite getting infusions of beta amyloid — however, blocking irisin completely eliminated the benefits of swimming.
Samples from brain banks have confirmed that irisin is present in the human hippocampus and that hippocampal levels of the hormone are reduced in those with Alzheimer's.
A mouse study found that short-term bursts of exercise (equivalent to a game of pickup basketball, or 4,000 steps) activated a gene (Mtss1L) that promotes an increase in synapses in the hippocampus — which primes the brain for learning.
Lourenco, M. V., Frozza, R. L., de Freitas, G. B., Zhang, H., Kincheski, G. C., Ribeiro, F. C., … De Felice, F. G. (2019). Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models. Nature Medicine, 25(1), 165–175. https://doi.org/10.1038/s41591-018-0275-4
Chatzi, C., Zhang, Y., Hendricks, W. D., Chen, Y., Schnell, E., Goodman, R. H., & Westbrook, G. L. (2019). Exercise-induced enhancement of synaptic function triggered by the inverse BAR protein, Mtss1L. ELife, 8, e45920. https://doi.org/10.7554/eLife.45920
Data from 196,383 older adults (60+; mean age 64) in the UK Biobank found that a healthy lifestyle was associated with lower dementia risk regardless of genes.
Both an unhealthy lifestyle and high genetic risk were associated with higher dementia risk.
Lifestyle factors included smoking, physical activity, diet, and alcohol consumption. Bearing in mind that lifestyle factors were self-reported, 68.1% followed a healthy lifestyle, 23.6% were intermediate, and 8.2% followed an unhealthy lifestyle. Regarding genes, 20% were at high risk, 60% were intermediate, and 20% were at low risk.
Of those at high genetic risk, 1.23% developed dementia in the 8-year period (remember that these are people who are still relatively — the average age at study end would still only be 72), compared with 0.63% of those at low genetic risk. Of those at high genetic risk plus an unhealthy lifestyle, 1.78% developed dementia compared to 0.56% of those at low risk with a healthy lifestyle. Among those who had a high genetic risk but a healthy lifestyle, 1.13% developed dementia in the period.
I trust that these people will continue to be followed — it will be very interesting to see the statistics in another 10 years.
There were 1,769 new cases of dementia during the 8-year study period.
 Lourida, I., Hannon E., Littlejohns T. J., Langa K. M., Hyppönen E., Kuźma E., et al.
(2019). Association of Lifestyle and Genetic Risk With Incidence of Dementia.
JAMA. 322(5), 430 - 437.
A very long-running study, in which 800 Swedish women (aged 38-54) were followed for 44 years, found that women with a high level of mental activities in midlife were 46% less likely to develop Alzheimer's disease and 34% less likely to develop dementia overall, compared with women with the low level of mental activities. Women who were physically active were 52% less likely to develop dementia with cerebrovascular disease and 56% less likely to develop mixed dementia, compared with women who were inactive.
Mental activities included intellectual activities, such as reading and writing; artistic activities, such as going to a concert or singing in a choir; manual activities, such as needlework or gardening; club activities; and religious activity.
Participants were given scores in each of the five areas based on how often they participated in mental activities, with a score of zero for no or low activity, one for moderate activity and two for high activity. For example, moderate artistic activity was defined as attending a concert, play or art exhibit during the last six months, while high artistic activity was defined as more frequent visits, playing an instrument, singing in a choir or painting. Low activity was defined as scores of zero to two and high activity as scores of three to 10 (44% and 56% of participants, respectively).
The physically active group ranged from light physical activity such as walking, gardening, bowling or biking for a minimum of four hours per week to regular intense exercise such as running or swimming several times a week or engaging in competitive sports. Most (82%) were in the active group.
Of the 438 women with the high level of mental activity, 104 (23.7%) developed dementia, compared to 90 (25.9%) of the 347 women with the low level of activity. Of the 648 women with the high level of physical activity, 159 (24.5%) developed dementia, compared to 35 (25.5%) of the 137 women who were inactive.
I note that distinction between those with high and low levels of activity seems very broad-brush. I don’t know why the researchers didn’t analyze the data in a more refined manner — comparing the most active with the least active would be more usual, and would be more likely to show a greater effect. But perhaps that's the point — showing that even with this smaller distinction, a significant effect is still found.
During the study, 194 women developed dementia. Of those, 102 had Alzheimer's disease, 27 had vascular dementia, 41 had mixed dementia, and 14 had other dementias. 81 (41.8%) of those with dementia also had cerebrovascular disease.
Full text available at https://n.neurology.org/content/early/2019/02/21/WNL.0000000000007021
 Najar, J., Östling S., Gudmundsson P., Sundh V., Johansson L., Kern S., et al.
(2019). Cognitive and physical activity and dementia.
Neurology. 92(12), e1322.
Dr McPherson's practical, research-based books are instantly available as digital downloads from the Mempowered store (all formats), Kindle Store, Kobo Store, and iTunes. They are also available in paperback.