Physical activity (PA) has been central in the life of our species for most of its history, and thus shaped our physiology during evolution. However, only recently the health consequences of a sedentary lifestyle, and of highly energetic diets, are becoming clear.
It has been also acknowledged that lifestyle and diet can induce epigenetic modifications which modify chromatin structure and gene expression, thus causing even heritable metabolic outcomes.
About 50 years ago, scientists first learned that genetics has another layer, epigenetics. It matters not just what your genes are, but also on whether they are turned on or off.
Along with genes, you also inherit their epigenetic “switches”. This means that epigenetic changes due to behaviors and experiences can be inherited, directly contradicting what most of us were taught.
I remember being adamantly told that, counter to what most of us “assumed”, only your genes, not experience or behavior, could be inherited, that it was impossible.
Many studies have shown that PA can reverse at least some of the unwanted effects of sedentary lifestyle, and can also contribute in delaying brain aging and degenerative pathologies such as Alzheimer’s Disease, diabetes, and multiple sclerosis.
Most importantly, PA (physical activity)
- improves cognitive processes and memory,
- has analgesic and antidepressant effects, and
- even induces a sense of wellbeing,
giving strength to the ancient principle of “mens sana in corpore sano” (i.e., a sound mind in a sound body).
In this review we will discuss the potential mechanisms underlying the effects of PA on brain health, focusing on hormones, neurotrophins, and neurotransmitters, the release of which is modulated by PA, as well as on the intra- and extra-cellular pathways that regulate the expression of some of the genes involved.
we have only recently begun to understand the cellular and molecular reasons why sedentary life is detrimental for human health, and to realize that physical activity (PA) can be a powerful medicine to counteract its effects.
Actually, this is not surprising since the ability of our species to survive in many different environments, to escape predators, and to look around for food has depended on, and still depends on the ability to perform PA, and PA has thus shaped our physiology.
selective breeding in rodents for endurance running capacity affects both their general physiology and their brain, and also potentiates their cognitive abilities
There are clear indications that PA also has important effects on human brain health at any age.
PA is thus recommended as a non-pharmacologic therapy for different pathological afflictions as well as for the maintenance of general health status.
Habitual exercise improves cardiorespiratory fitness and cardiovascular health, helps reducing body mass index, and can represent a natural, anti-inflammatory “drug” in chronic diseases, such as type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD)
As discussed below, both endurance activity (i.e., long-lasting aerobic activity, such as running) and resistance exercise (i.e., exercise in which the predominant activity involves pushing against a force) have been shown to induce an increase of circulating growth factors (such as insulin-like growth factor 1, IGF-1), and neurotrophins (such as the brain-derived neurotrophic factor, BDNF) which have an effect on the brain both during development and in the adult.
This exposes a contradiction in the search for new non-opioid pain-relieving (seems an oxymoron) drugs:
- Exercise is always recommended for chronic pain, and this increases circulating amounts of NGF (nerve growth factor).
- Yet anti-NGF drugs are being developed to ease pain.
If NGF is increased with exercise and anti-NGF drugs are pain-relieving, then exercise should worsen pain, a contradictory and nonsensical conclusion.
In this review we will discuss the putative cellular and molecular mechanisms underlying the mentioned effects of PA on the nervous system, focusing on genes known to be involved, as well as on epigenetic effects due to DNA methylation, histone post-translational modifications and exchange, and on the possible role of non-coding RNAs.
2. Brain Plasticity, Adult Neurogenesis, and Physical Activity
The brain capacity to adapt to ever-changing conditions, known as brain plasticity, depends on the ability of neurons to modify the strength and composition of their connections in response to both external and internal stimuli. The long-term potentiation (LTP) in synaptic efficacy constitutes the physiologic base for learning and memory.
Now, increasing evidence suggests that PA, largely due to factors released by contracting muscles (Section 3; Figure 1), can improve brain functions, such as memory and attention, in both children and adults.
Hypothetical pathway for the exercise-mediated effects on brain functions: both endurance and resistance exercise, even if with different kinetics and properties, allow muscle synthesis, and release myokines (e.g., brain-derived neurotrophic factor, BDNF), as well as of metabolites (such as lactate) into the circulation; these molecules can cross the blood–brain barrier (BBB) at the level of the brain capillaries (grey arrows) and affect the functions of both neurons and glial cells, thus modifying neurotransmission in different regions of the brain. As explained in the text, neurotransmission can then activate pathways leading to modifications of gene expression. AS: astrocytes; BC: brain capillaries; Neu: neurons; OL: oligodendrocytes.
At the cellular level, it was found that treadmill exercise can increase hippocampal neurogenesis in aged mice.
In summary, while the genome of an organism is relatively stable over the lifespan, its expression (i.e., the phenotype) is influenced by many epigenetic factors.
Most important, we now know that inactivity is epigenetically deleterious: for example, it has been reported that nine days of bed rest can induce insulin resistance in otherwise healthy subjects.
2.1. Brain-Derived Neurotrophic Factor (BDNF)
BDNF is a neurotrophin involved in all the most important aspects of neuroplasticity, from neurogenesis to neuronal survival, from synaptogenesis to cognition, as well as in the regulation of energy homeostasis.
The BDNF increase seems to correlate with the exercise volume (given by “intensity + duration + frequency” of activity)
However, it was also reported that the greatest responses are given by well-trained individuals, while mainly sedentary subjects show lower or even no response
Interestingly, open-skill exercise (e.g., badminton) increases BDNF levels more than closed-skill exercise (e.g., running), probably because open-skill activities require additional attention to face ever-changing situations, and possibly also because they are more enjoyable.
Notably, the expression of the BDNF gene is also controlled at the epigenetic level.
2.2. microRNAs and Exercise
In summary, many differentially expressed miRNAs have been evidenced, when comparing the brain of exercising and non-exercising rodents, in a variety of brain areas, including the brain cortex and hippocampus.
We have to remember, however, that each miRNA can target a multiplicity of mRNAs, and each mRNA can be targeted by many different miRNAs, thus it is not yet immediately evident how exercise-induced modifications in the miRNA population fit into the general regulation of brain functions by PA.
2.3. Genes Involved in Mitochondrial and Lysosomal Biogenesis
Since the 1950s, the decline of mitochondrial oxidative functions has been considered one of the main causes of cell aging.
Moreover, mitochondrial DNA (mtDNA) accumulates mutations with age, and this is a further reason for an aberrant functioning of mitochondria.
On the other hand, PA has been reported to have anti-aging effects and can have a positive effect on mitochondrial biogenesis due to the increase of BDNF levels.
Autophagy is a physiological process which requires functional lysosomes, and that is involved in recycling proteins as well as in eliminating potentially toxic protein aggregates and dysfunctional organelles.
the autophagy increase, induced by exercise, not only contributes to the elimination of toxic protein aggregates accumulating in the brain, but also produces a specific increase of mitophagy.
3. Muscle Contraction and Production of Myokines
Skeletal muscle is the most abundant tissue in the body and plays a fundamental role in the maintenance of the correct posture and movement.
In addition, it has a central metabolic function, since, in response to post-prandial insulin, picks up glucose from the blood and accumulates it as glycogen.
Different kinds of fibres exist in skeletal muscle, which differs for both metabolic and contractile properties:
- slow-twitch oxidative (SO) fibres have a high content of mitochondria, and myoglobin, and are more vascularized,
- fast-twitch glycolytic (FG) fibres have a glycolysis-based metabolism, and finally
- fast-twitch oxidative glycolytic (FOG) fibres have intermediate properties
3.1. Muscle Contraction and Gene Regulation
This section is incomprehensible to me and deals with the details of biochemistry,
3.2. Release of Myokines and Metabolites by Contracting Muscles
As a whole, the data reported indicate that PA has several effects on the nervous system—it acts as an antidepressant and an anxiolytic, and can improve mood, self-esteem, and cognition.
The benefits induced by PA on the brain (as well as in other organs, such as the heart) are in part mediated by peptides (myokines) and metabolites released into the blood by the endocrine activity of contracting muscles.
I’m amazed that simply using our muscles can cause hormonal shifts. This only points to the incredible complexity of our bodies, a truly miraculous system constantly in flux.
This is followed by more incomprehensible biochemistry,
4. A Few Examples of Exercise Effects on Neurodegeneration:
Studies on Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease, and Multiple Sclerosis
The evidence that regular exercise can help to prevent and even treat neurological disorders has become stronger in recent years.
4.1. Alzheimer’s Disease (AD)
PA improves cognition in a mouse model of Alzheimer’s disease (AD), stimulating neurogenesis and the simultaneous increase of both BDNF and FNDC5
Another AD progression-slowing factor, known to be produced during physical activity and able to cross BBB is the insulin-like growth factor 1 (IGF-1).
Recently, it has been also reported that 4 weeks of exercise can revert the induction of gene encoding proteins involved in inflammation and apoptosis in the hypothalamus in a mouse model of AD.
After 6 weeks, an improvement in glucose metabolism was also observed, and after 8 weeks there was an evident reduction of apoptosis in some populations of hypothalamic neurons.
Finally, it has been suggested that the benefits noticed in early AD patients following aerobic exercise are due to the exercise-dependent enhancement of the cardiorespiratory fitness, which is in turn associated with improved memory performance and reduced hippocampal atrophy.
Unfortunately, most people with Alzheimer’s are already quite old and cannot start vigorous exercises.
4.2. Parkinson’s Disease (PD)
Parkinson’s disease (PD) is the second most common neurodegenerative disorder and involves a massive degeneration of the dopaminergic neurons in the substantia nigra, in the midbrain
Also, in the case of PD, it has been reported that association of the pharmacological therapy with exercise can help in managing the physical and cognitive decline typically associated with PD.
In PD animal models, exercise induces neuroprotective effects through the expression of some brain neurotrophic factors, including BDNF and glial-derived neurotrophic factor (GDNF).
In humans, the effects of PA have been studied on the basis of correlations found among acute effects of exercise on specific clinical variables.
Another study demonstrated that 4 weeks of aerobic exercise elicited a long-lasting improvement on both motor and non-motor functions of PD patients.
On the basis of these studies, we can conclude that PA can give PD-specific clinical benefits, but only if repeated habitually over time (i.e., exercise training)
My question would be which exercises, for how long, and how often repeated.
4.3. Huntington’s Disease (HD)
HD is a fatal genetic disorder, due to an autosomal dominant mutation that determines the expansion of poly-glutamine repeats in the huntingtin (HTT) coding region.
Clinical features of HD include significant motor defects together with non-motor changes, like cognitive, psychological, and behavioural disabilities, that may progressively get worse before diagnosis, and that results in limitations of daily activities.
Physical therapy and exercise interventions were integrated into the treatment decades ago, in order to maintain patient’s independence in daily life activities, while attenuating the damages in the motor function. It is indeed known that a passive lifestyle might lead to an earlier HD onset; while, as in other neurodegenerative diseases, exercise exerts a positive effect.
Recent studies have focused on both resistance and endurance exercise training modalities, based on the suggestion that both could be of help in HD patients.
All the results showed a significant increase in grey matter volume and significant improvements in verbal learning and memory, after long-training exercise.
4.4. Multiple Sclerosis (MS)
Patients with Multiple Sclerosis (MS) who perform regular physical activity have a better quality of life with less fatigue and less depression than those who are sedentary.
In addition to the PA-dependent increase of BDNF, VEGF, and IGF-1, in the context of MS, a specific increase in the expression of tight junction proteins, critical for the reestablishment of the BBB function, was also evidenced.
Actually, it has been also found that different training protocols act differently on gene expression; for example, while IGF1-R expression level decreases in the brain of MS mice subjected to forced-swimming protocol, IGF1-R mRNA level increases in the cerebellum of MS mice of a running group.
In parallel, a different pattern of myelin gene stimulation was also observed—in the mice that had performed running exercise, a smaller decrease of myelin was found in the brain, whereas swimming induced greater benefits in the cerebellum.
This is interesting to me because it makes clear that, like so many other human functions, exercise is not a monolithic factor. Different types of exercise definitely have differing effects.
In summary, these few examples of PA benefits in different neurodegenerative diseases reinforce the idea of a neuroprotective effect of exercise.
- increases expression of genes involved in enzymatic antioxidant responses,
- improves cognitive functions and memory, and
- can counteract the progression of diseases, or at least help patients to better perform daily life activities.
Moreover, specific differences in the responses of individual patients can be expected depending on genetic and epigenetic variability as well as even slight differences in the grade of the pathology.
Again, the specifics of the individual patient are of tremendous importance. Just like “exercise” isn’t a single activity, but varies according to which body parts are used in which ways, at what intensity, and at what frequencies.