Long Term Cognition via Exercise

Brain health is whole-person health. The idea that focusing on only one aspect of health, like diet or exercise, will result in a healthy older brain is naïve. We need to make sustained efforts across all aspects of wellness to remain cognitively vibrant into old age.

 

Aerobic exercise is the most transformative thing that you can do for your brain today. Aerobic exercise is beneficial at any age. The neuroprotective mechanisms induced by physical exercise are linked to an increased production of superoxide dismutase, endothelial nitric oxide synthase, brain-derived neurotrophic factor (BNDF), nerve growth factor, insulin-like growth factor, and vascular endothelial growth factor, and a reduction in the production of free radicals in brain areas such as the hippocampus, which is particularly involved in memory. Other mechanisms have also been reported in the prevention of Parkinson’s Disease: exercise limits the alteration in dopaminergic neurons in the substantia nigra and contributes to optimal functioning of the basal ganglia involved in motor commands and control by adaptive mechanisms involving dopamine and glutamate neurotransmission.

Evolution favored individuals with superior cognitive and physical abilities under conditions of limited food sources, and brain function can therefore be optimized by intermittent dietary energy restriction (ER) and exercise. Our evolutionary history suggests that we are, fundamentally, cognitively engaged endurance athletes, and that if we don’t remain active we’re going to have this loss of capacity in response to that, so there really may be a mismatch between our relatively sedentary lifestyles of today and how we evolved.”

 

The most promising strategy to keep one’s marbles as one ages is: not smoking, engaging in regular physical activity, controlling diabetes, hypertension and cholesterol, and maintaining a healthy diet and weight. Engaging in cognitively stimulating activities and avoiding social isolation also are probably beneficial.

 

In a study of more than 1,600 adults aged 65 and older, those who led a sedentary life seemed to have the same risk of developing dementia as those who carried the apolipoprotein E (APOE) gene mutation, which increases the chances of developing dementia. Conversely, people who exercised appeared to have lower odds of developing dementia than those who didn’t, the five-year study found. Being inactive may completely negate the protective effects of a healthy set of genes.

 

Physical activity also tends to counter some of the natural reduction in brain connections that occurs with aging. Chronic tradmill exercise in mice activates mTOR pathway, which is necessary for spinogenesis, neuronal activation, and axonal myelination leading to improved motor learning.

 

Alvaro Pascual-Leone, MD, professor of neurology at Harvard Medical School says that exercise is the best “prescription” for cognitive health. Conversely, Data from 105,206 adults aged 50 to 90 years indicate that cognitive functioning is important for exercise capacity.

 

Evolution did not prepare us to become couch potatoes.

 

Running enhances spatial pattern separation in mice.

 

Evolution favored individuals with superior cognitive and physical abilities under conditions of limited food sources, and brain function can therefore be optimized by intermittent dietary energy restriction (ER) and exercise.Aerobic exercise has positive effects on the right hippocampus and potentially beneficial effects on the overall and other parts of the hippocampus, the cingulate cortex and the medial temporal areas of the default mode network.

 

Exercise plays a role in maintaining insulin and BMI levels, which may help stave off dementia by protecting gray matter volume in the brain. Exercise is especially effective when combined with beet juice consumption.

 

Regular physical exercise modulates iron storage and trafficking in both the brain and skeletal muscle. This is important for keeping ones marbles.

 

Scientists are increasingly recognizing the capacity of physical activity to maintain and compensate for the deterioration of nerve cell function. The Mtss1L gene encodes a protein that causes bending of the cell membrane. Researchers discovered that when this gene is activated by short bursts of exercise, it promotes small growths on neurons known as dendritic spines—the site at which synapses form. In effect, the study showed that an acute burst of exercise is enough to prime the brain for learning.

 

Signals from stressed (via exercise) muscles rely on an enzyme called Amyrel amylase and its product, the disaccharide maltose. These stress signals can protect the brain and retina from aging. The signals work by preventing the buildup of misfolded protein aggregates.

 

Being social may be important to maximize benefits of exercise.

 

Comparing the brains of mice that exercised with those that did not, specific neurons switched their chemical signals, called neurotransmitters, following exercise, leading to improved learning for motor-skill acquisition. This study provides new insight into how we get good at things that require motor skills and provides information about how these skills are actually learned.

 

A study of the brains of mice shows that structural deterioration associated with old age can be prevented by long-term aerobic exercise starting in mid-life. Structural changes that make the blood-brain barrier leaky and result in inflammation of brain tissues in old mice can be mitigated by allowing the animals to run regularly.

 

Exercise improves mood and sleep, and reduces stress and anxiety. Problems in these areas frequently cause or contribute to cognitive impairment.

 

Higher fitness levels earlier in life may lower risk for dementia later in life.

 

Regions of the brain most vulnerable to aging were also the regions that benefitted most from aerobic exercise.

 

Using the legs, particularly in weight-bearing exercise, sends signals to the brain that are vital for the production of healthy neural cells, essential for the brain and nervous system.

 

Exercise can be overdone: endurance training such a marathon running increases tumor necrosis factor and IL-6.

 

The benefit of IGF -1 in the body and in the brain

Exercise works via IGF-1 induced by exercise. A reduction in insulin-like growth factor 1 signaling may moderate the vulnerability to Alzheimer’s disease of human Apolipoprotein E ε4 carriers.
Exercise significantly elevated proteins downstream to brain-derived neurotrophic factor activation important for synaptic function in the rat hippocampus. Exercise-derived IGF-1 interfaces with brain-derived neurotrophic factor-mediated synaptic plasticity to modulate aspects of exercise-induced cognitive function.

 

Physical activity and physical exercise influence the brain through circulating growth factors, which cross the blood barrier and modulate several mechanisms for cognition.4 Among these factors, brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF) have been indicated as the main factors, since they work in conjunction to produce functional effects related to plasticity, functioning and brain healthExercise works via cyclic AMP.

Exercise alone works better than (green tea-based) dietary polyphenols.

 

A moderate amount of exercise reversed bacterial infection-driven cognitive deficits in rats.

 

A more efficient, robust cardiovascular system

Lower cardiac output and worse left ventricular diastolic function are linked to executive function deficits.

 

CVD and dementia have shared risk factors, which might alter clearance of brain toxins or otherwise increase neurodegeneration. CVD might lead to clinical or subclinical strokes, leading to cognitive impairment. CVD might directly alter cerebral perfusion.

 

A long-term study of 1,449 people in Finland found that those who had better scores on standard metrics of cardiovascular health in midlife, especially for behavioral factors such as smoking, had a lower risk of dementia later in life. These findings suggest that maintaining lifelong cardiovascular health, particularly in the areas of smoking, exercise, and body mass index, could reduce dementia risk later in life.

 

“One of the key benefits of exercise is that it helps to control or modify many of the risk factors for heart disease,” says Dr. Kerry Stewart, director of Clinical and Research Exercise Physiology at Johns Hopkins Bayview.

 

Physically active individuals have lower blood pressure, higher insulin sensitivity, and a more favorable plasma lipoprotein profile. Acutely, exercise increases cardiac output and blood pressure, but individuals adapted to exercise show lower resting heart rate and cardiac hypertrophy.

 

Some benefits of exercise include enhanced mitochondrial function, restoration and improvement of vasculature, and the release of myokines from skeletal muscle that preserve or augment cardiovascular function.

 

 This study of 7,600 adults ages 45 and older compared the exercise data to the incidence of strokes in participants over seven years. tThose who were sedentary for 13 hours or more a day had a 44% increased risk of having a stroke.

 

This study of 35 individuals found that aerobic capacity was inversely related to stroke risk.

 

Keep at it

All the short-term cognitive benefits of exercise are amplified with long-term exercise.

 

The  brain/cognitive reserve built up by regular exercise in several stages of life, prepares the brain to be more resilient to cognitive impairment and consequently to brain pathology.

 

This study of master athletes between 50 and 80 showed that 10 days of no exercise hurts brain power & blood flow.

 

Three studies of 317, 95, and 107 participants showed that maintaining fitness through the practice of regular exercise improves health in old age, slowing the pace of damage to the brain and consequent cognitive decline.

 

387 Australian women from the Women’s Healthy Ageing Project were followed for for two decades. The women were aged 45 to 55-years-old when the study began in 1992. This study showed that the effect of exercise was cumulative. So every one of those 20 years mattered.

 

Make exercise a habit or, better yet, an obsession.

Greater clarity of thought, better executive functioning

One study showed that regular intensive lifelong exercise as a child and adult improved cognitive functioning at the age of 50 and that even exercise of a lower frequency could offer benefits for cognitive well-being.

 

A meta-analysis of 18 intervention studies published between 1966 and 2001 showed that fitness training has a robust benefits executive-control processes.

 

Studies show that people who are physically active are less likely to experience a decline in their mental function, have a lowered risk of developing Alzheimer’s disease, and possibly have improved thinking among people with vascular cognitive impairment.

 

Greater aerobic fitness, reduced CVD risk, and reduced sodium intake were associated with improvements in executive function in 160 sedentary men and women (age >55 years).

 

When muscles are put to work during exercise, they produced an enzyme that breaks down kynurenine – a compound that is present at higher levels in people with depression and other mental disorders. The enzyme produced by muscle converts kynurenine into kynurenic acid, which cannot cross the blood-brain barrier. In this way, the brain is protected from certain stress-induced changes that are thought to occur in depression.

Exercise vs. Arterial stiffness

Exercise works via reduced arterial stiffness and reduced blood pressure. Carotid artery stiffness is associated with cognitive impairment and dementia.

 

Cerebrovascular resistance index is the ratio of blood pressure to blood flow in the brain. Increased cerebrovascular stiffening, endothelial dysfunction  may drive or operate in parallel to these cerebrovascular abnormalities. This study of 232 older adults showed diminished inferior parietal and temporal cerebral blood flow for patients with Alzheimer’s disease. Cerebrovascular resistance index was significantly elevated in amyloid-positive versus amyloid-negative cases, with additional elevation in patients with Alzheimer’s disease.

 

This study used a control group (11 men and 15 women, 65 ± 7 years of age [mean ± SD]) or training group (9 men and 14 women, 67 ± 8 years). Aerobic training increased plasma nitric oxide concentrations  and decreased arterial stiffness  in the training group but there were no changes in the control group.

 

This study of 146 male and female volunteers 21 to 96 years old from the Baltimore Longitudinal Study of Aging found that interventions to improve aerobic capacity may mitigate the stiffening of the arterial tree that accompanies normative aging.

 

This study of 25 young healthy volunteers (18 men) concluded that intermittent, moderate-intensity aerobic exercise for only eight weeks reduces arterial stiffness.

 

This systematic review and meta-analysis of randomized controlled trials including 42 studies (1627 participants) concluded that aerobic exercise improved arterial stiffness significantly and that the effect was enhanced with higher aerobic exercise intensity and in participants with greater arterial stiffness at baseline.

 

40 elderly participants did mild-to-moderate aerobic exercise lasting for 30 min twice a week for 6 months. It was found that apparently healthy and sedentary elderly subjects may benefit from mild-to-moderate aerobic exercise to improve arterial stiffness.

 

This study of 146 male and female volunteers 21 to 96 years old from the Baltimore Longitudinal Study of Aging. It was found that arterial stiffness  varied inversely with VO2max, and this relationship was independent of age. In endurance trained male athletes, 54 to 75 years old, the arterial stiffness indexes were significantly reduced relative to their sedentary age peers.

Nitric Oxide

Exercise training has been shown, in many animal and human studies, to augment endothelial, nitric oxice-dependent vasodilatation in both large and small vessels. The extent of the improvement in humans depends upon the muscle mass subjected to training; with forearm exercise, changes are restricted to the forearm vessels while lower body training can induce generalized benefit. Increased nitric oxide bioactivity with exercise training has been readily and consistently demonstrated in subjects with cardiovascular disease and risk factors, in whom antecedent endothelial dysfunction exists. Exercise training may improve endothelial function by up-regulating endothelium nitric oxide protein expression and phosphorylation. Whilst the increase in NO bioactivity dissipates within weeks of training cessation, studies also indicate that if exercise is maintained, the short-term functional adaptation is succeeded by NO-dependent structural changes, leading to arterial remodelling and structural normalization of shear.

 

Running wheel exercise increased the amount of SIRT3 in neurons of normal mice and protected them against degeneration; in those lacking the enzyme, running failed to protect the neurons.

Aerobic exercise training increased nitric oxide generation, reduced blood pressure, and induced anti-oxidant enzymes via SIRT3 suggest that exercise training may be an important factor for the prevention of disease by inducing intrinsic nitric oxide and anti-oxidant enzymes.

 

Nine sedentary hypercholesterolemic volunteers aged 44±3 years participated in the study. Subjects performed 4 weeks of home-based cycle training. Basal release of endothelium-derived nitric oxide (NO) is increased with 4 weeks of home based training. This may contribute to the cardiovascular protective effects of exercise training, including reduced blood pressure.

 

This study of eight healthy young men showed that acute moderate-intensity exercise induces vasodilation through an increase in NO bioavailability in humans.

 

The calculated half-life of circulating nitrate up to 8 h in humans [34]. Nitric oxide decreases with age, so it may be wise for older people to get moving twice per day. Exercise does not have to be vigorous. Consider the Nitric Oxide Dump.

Blood flow to the brain is a major benefit of exercise

Acute physical exercise raises the cardiac output in response to increased needs for oxygen and energetic substrates compared to the state of rest, which increases the cerebral blood flow. The increased cerebral blood flow triggers various neurobiological mechanisms in the brain tissue. Repeated and regular physiological modifications related to exercise facilitate the synthesis of cerebral tissue.

 

Short (at least) bouts of vigorous exercise are essential to preserve the small capillaries in the brain.

 

Exercise was found to have a primary effect on dentate gyrus cerebral blood volume (CBV), and the CBV changes were found to selectively correlate with cardiopulmonary and cognitive function. Taken together, these findings show that dentate gyrus CBV provides an imaging correlate of exercise-induced neurogenesis and that exercise differentially targets the dentate gyrus, a hippocampal subregion important for memory and implicated in cognitive aging.

 

The effects of exercise on the brain can be enhanced by concurrent consumption of
natural products such as omega fatty acids or plant polyphenols. The potential synergy between diet and exercise could involve common cellular pathways important for neurogenesis, cell survival, synaptic plasticity and vascular function.

 

Inactivity reduces blood flow to the brain.

 

There is a clear link between blood supply to the hippocampus and cognitive performance. This suggests that brain blood flow might play a key role in the declining of memory performance, whether caused by age or disease.

Exercise improved cerebral and hippocampal blood flow in 12 weeks in 37 participants aged 57 – 75. Reduced exercise specifically increases hippocampal cell death during differentiation which then subsequently increases the risk for future cognitive decline.

 

Regular physical exercise (rPE) may thus increase angiogenesis, neurogenesis, synaptogenesis, and the synthesis of neurotransmitters in different cerebral structures involved in cognition due to an increase in the liberation of neurotrophic factors and the production of enzymatic antioxidants. There is an inversely proportional relationship between the amount of physical activity undertaken and the risk of cognitive decline and/or the development of neurodegenerative disease.
This study of 37 cognitively healthy sedentary adults (57–75 years of age) demonstrated an increased resting cerebral blood flow in the anterior cingulate region in the physical training. Cognitive gains were manifested in the exercise group’s improved immediate and delayed memory performance. These data suggest that even short term aerobic exercise can facilitate neuroplasticity to reduce both the biological and cognitive consequences of aging to benefit brain health in sedentary adults.

 

This study of 37 cognitively healthy sedentary adults (57–75 years of age) received supervised aerobic exercise for 3 sessions per week 1 h each for 12 weeks. Increases in both left and right hippocampal cerebral blood flow, VO2 max and rating of perceived exertion (RPE) were noted. This shows that shorter term aerobic exercise can facilitate neuroplasticity to reduce both the biological and cognitive consequences of aging to benefit brain health in sedentary adults.

 

Ainslie et al.¹⁹ measured cerebral blood flow (CBF_V) in the middle cerebral artery (MCA) in apparently healthy aerobic exercise trained and sedentary males. Their estimation of the annual decrease in CBF_V was 0.45%. However, CBF_V remained 17% higher in aerobic exercise-trained individuals compared to their age-matched sedentary counterparts, suggesting a difference in cerebrovascular function of 10 years between the active and sedentary individuals. Trained females had a higher VO₂max compared with the sedentary group and increased cerebrovascular conductance.

 

After mice exercise, their livers secrete a protein called Gpld1 into the blood. Gpld1 increases in the blood circulation of mice following exercise, and that Gpld1 levels correlate closely with improvements in the animals’ cognitive performance. Gpld1 is also elevated in the blood of healthy, active elderly adults compared to less active elders.

 

A study of 19 obese adolescents showed that exercise prevents vascular dysfunction which can precede decline.

 

A study of 749 Italian subjects aged 65 and older showed that exercise helps prevent vascular dementia.

Break a serious sweat

Exercise is most effective when it is intense or acute, such as running, or better: a loaded running wheel.

Vigorous (acute) and sustained exercise is best (break a sweat!): don’t overestimate effort. Vigorous exercise benefited mice cognition.

 

Cerebral neuronal activity and metabolism drive an increase in cerebral blood flow (CBF) during exercise. Increases in exercise intensity up to ∼60% of maximal oxygen uptake produce elevations in CBF.

Vigorous exercise activates mitochondrial biogenesis in aged mice, and a gene (VEGF-A) known to support neurogenesis.

 

People who exercise have greater brain volume in areas of the brain associated with reasoning and executive function.

Most, but not all, exercise benefits require circulating (serum) IGF-1.

 

In other studies, exercise increases mitochondrial biogenesis in the brain in mice and rats. Exercise enhances the proliferation of neural stem cells and neurite growth and survival of neuronal progenitor cells in dentate gyrus of middle-aged mice.

Exceed the lactate threshold. The lactate threshold raises with aerobic training. For most the lactate threshold is 60% of max heart rate. 60% of max oxygen consumption is 60% of max heart rate. Max heart rate is 207 – 0.7(age).

 

A study of 191 women 38 to 60 years of age showed that high cardiovascular fitness in midlife was associated with a decreased risk of subsequent dementia.

 

The lower the fitness level, the faster the deterioration of vital nerve fibers (white matter) in the brain.

 

Vigorous exercise saves time – it works fast – buys 10 years vs. mild exercise.

1 minute of intense exercise within a 10-minute time commitment provided more benefit than 50 minutes of continuous exercise per session.

 

This study of 191 women with an average age of 50 took a bicycle exercise test until they were exhausted to measure their peak cardiovascular capacity, measured at 103 watts.  92 women were in the medium fitness category; and 59 women were in the low fitness category, defined as a peak workload of 80 watts or less. Over the next 44 years, 5% of the highly fit women developed dementia, compared to 25% of moderately fit women and 32% of the women with low fitness. The highly fit women were 88% less likely to develop dementia than the moderately fit women.

 

Exercise may overcome the damaging effects of chronic inflammation.

 

Exercise works via adinopectin.

 

Exercise works by reducing bone morphogenetic protein (BMP).

 

Supplemental astaxanthin may help with cognitive function and neuronal plasticity when exercise is mild.

Brain-derived Neurotrophic Factor (BNDF)

Exercise promotes the expression of brain derived neurotrophic factor (BDNF) via β-hydroxybutyrate.

 

Myokines released by exercising muscles affect the expression of brain-derived neurotrophic factor synthesis in the dentate gyrus of the hippocampus.

 

Research has shown that the neuroprotective mechanisms induced by physical exercise are linked to an increased production of superoxide dismutase, endothelial nitric oxide synthase, brain-derived neurotrophic factor, nerve growth factor, insulin-like growth factor, and vascular endothelial growth factor, and a reduction in the production of free radicals in brain areas such as the hippocampus, which is particularly involved in memory.

 

Exercise may modulate BDNF gene expression in the hippocampus by inducing changes to the epigenetic landscape of its promoter.

 

Brain-derived neurotrophic factor (BDNF) signaling mediates adaptive responses of the central, autonomic, and peripheral nervous systems from exercise and dietary energy restriction (DER). In the hypothalamus, BDNF (a neurotrophin) inhibits food intake and increases energy expenditure. By promoting synaptic plasticity and neurogenesis in the hippocampus, BDNF mediates exercise- and DER-induced improvements in cognitive function and neuroprotection.
BNDF may protect one from dementia.

 

Exercise works via BNDF and other growth factors.  The effects of exercise on hippocampal plasticity are dependent on BDNF processing. BDNF happens via the PGC-1α/FNDC5 pathway.

HIIT is best for BNDF including those who are obese.

 

High-intensity exercise is the most efficient means to increase BDNF in circulation. Exercise-induced BDNF is best if vigorous (acute) or intense.

 

A morning bout of moderate-intensity exercise improves serum BDNF and working memory or executive function in older adults, depending on whether or not subsequent sitting is also interrupted with intermittent light-intensity walking.

 

This study of 78,430 of 103,684 eligible adults aged 40 to 79 years with valid wrist accelerometer data showed no minimal threshold for the beneficial association of step counts with incident dementia. Study findings suggest that approximately 9,800 steps per day may be optimal to lower the risk of dementia. The minimum dose may be approximately 3,800 steps per day, which was associated with 25% lower incident dementia.

 

Resistance exercise may transiently increase BNDF.

 

This study of 24 patients with schizophrenia showed that serum BDNF values significantly increased following a resistance + aerobic exercise program.

 

This randomized controlled study of 12 males, some of whom were diabetic, showed that 3 months of endurance training significantly increased serum BDNF.

 

BNDF ➝ bigger hippocampal volume and slower mental decline.

BDNF promotes adult neurogenesis – see below.

BDNF is also important for forming and functional memories.

BDNF protects neurons from injury and disease.

BDNF is important in neuronal growth and neuronal survival, participating in the synaptic processes of memory.

BDNF is important for synaptic plasticity. High levels of BDNF in the hippocampus are related to both survival and differentiation of dentate gyrus progenitor cells in the adult, and low levels of BDNF have been linked to deficient neurogenesis in aged animals.

Low-intensity aerobic exercise can promote neuroplasticity within the motor cortex of healthy adults but will not increase BNDF. Moderate exercise has no effect on BNDF.

BDNF signalling is linked to mitochondrial health because it upregulates antioxidant enzymes, and it mediates PGC-1α-induced mitochondrial biogenesis.

Vigorous exercise increases BNDF in parts of the brain not reached by mild exercise.

A short period of high-intensity cycling results in enhancements in performance of the face-name matching. These changes in cognitive function were paralleled by increased concentration of BDNF.

This study of 24 patients with schizophrenia showed that serum BDNF values significantly increased following a resistance + aerobic exercise program.

 

the production of BDNF, and in turn its effects upon neuronal survival/plasticity, can be modulated by circulating factors. As many of these factors decline with age, exercise may serve to enhance their presence and, in turn, their ability to reach the brain [29, 43, 192, 198, 200].

BNDF (in the brain) has a half-life of: “on the order of hours“, “> 40 minutes“, “3 hours“.

Resistance training had no effect on BDNF in this study.

 

 

Enjoying cognitive stimulation while exercising is super.

Exercise induces production of FNDC5, a protein found on the surfaces of certain cells. FNDC5 can activate neuroprotective genes in the hippocampus, the brain region in charge of memory formation.

Exercise, especially vigorous, can enlarge the hippocampus and other structures.

Vigorous exercise works via cathepsin B which has been shown to boost memory recall in mice. Cathepsin B is enriched in the circulation in an aerobic exercise intensity dependent manner. Cathepsin B, a myokine, and brain-derived neurotrophic factor (BNDF) have been found to possess robust neuroprotective effects.

 

Meta-analyses of randomized controlled trials (RCTs) of aerobic exercise in healthy adults were associated with significantly improved cognitive scores. One year of aerobic exercise in a large RCT of seniors was associated with significantly larger hippocampal volumes and better spatial memory; other RCTs in seniors documented attenuation of age-related gray matter volume loss with aerobic exercise. Cross-sectional studies similarly reported significantly larger hippocampal or gray matter volumes among physically fit seniors compared with unfit seniors. Brain cognitive networks studied with functional magnetic resonance imaging display improved connectivity after 6 to 12 months of exercise.

 

This systematic review and meta-analysis of 14 studies involving 737 participants provide evidence for exercise-induced volumetric retention in the left hippocampus. Aerobic exercise interventions may be useful for preventing age-related hippocampal deterioration and maintaining neuronal health.

 

Hippocampus size in physically fit adults accounts for about 40 percent of their advantage in spatial memory.
The cardiorespiratory fitness of 165 adults (109 of them female) between 59 and 81 years of age. Using magnetic resonance imaging, the researchers conducted a volumetric analysis of the subjects’ left and right hippocampi. They also tested the participants’ spatial reasoning. Even ignoring the hippocampus data, we see there is this significant and substantial relationship between how fit you are and how good your memory is, or at least a certain kind of memory, a certain kind of memory that we need all the time. An impairment of spatial memory is one of a number of reasons why older people end up losing their independence. Here is yet more evidence that becoming fit has implications for how well you’re going to live your life.

 

A study of 1,583 people enrolled in the Framingham Heart Study, with an average age of 40 and without dementia or heart disease showed higher brain volume in those who exercised the most.

 

This six month study of 59 sedentary volunteers, aged 60-79 years showed significant increases in brain volume, in both gray and white matter regions.

 

A study of 59 volunteers aged 60–79 years showed that aerobic fitness training produced significant increases in brain volume, in both gray and white matter regions.

 

Exercise increases grey matter and improves executive functioning even in 20-yr old people.
This study of 115 adults aged 50–70 years showed that exercise increases brain volume in the prefrontal and temporal cortex.
Exercise increases brain volume in the hippocampus of 165 nondemented older adults.

 

Hippocampal volume increased in patients with schizophrenia and healthy people in response to exercise.

Aerobic exercise Is the critical variable in an enriched environment that increases hippocampal neurogenesis.

Among all hippocampal subregions, exercise was found to have a primary effect on dentate gyrus.

A study of 2,013 adults showed that increases in peak oxygen uptake were strongly associated with increased gray matter volume.

A study of 52 healthy older adults aged 55-79 showed that higher levels of exercise over the past 10 years were related to larger superior frontal volumes. Most critically, exercise engagement selectively moderated age-related medial temporal lobe atrophy. Specifically, significant age-related atrophy was observed for older adults who engaged in low levels of exercise, but not for those who engaged in high levels of exercise.

A systematic review of 14 studies with 631 participants revealed that aerobic exercise could significantly increase hippocampal volume, decrease the atrophy of the medial temporal lobe, slow the anterior cingulate cortex (ACC) volume loss, increase functional connectivity within the hippocampus and improve signal activation in the cingulate gyrus and ACC.
A study of 1206 healthy, young adults showed that the physically fit have better white matter microstructure.

 

This systematic review of 14 clinical trials which examined the brain scans of 737 people before and after aerobic exercise programs or in control conditions. They studied a mix of healthy adults, people with mild cognitive impairment such as Alzheimer’s and people with a clinical diagnosis of mental illness including depression and schizophrenia. Ages ranged from 24 to 76 years with an average age of 66. Aerobic exercise significantly increase the size of the left region of the hippocampus.

 

This study of 1987 70-year old participants showed a reduced risk of dementia and higher brain volumes may be additional health benefits of maintaining physical activity into old age.

 

This study of 86 women between 70 and 80 years old were assigned to either twice weekly hour long sessions of aerobic training (brisk walking); or resistance training, such as lunges, squats, and weights; or balance and muscle toning exercises, for a period of six months. The total volume of the hippocampus in the group who had completed the full six months of aerobic training was significantly larger than that of those who had lasted the course doing balance and muscle toning exercises.

 

Exercise has recently been shown to enhance the frontal lobes of the brain, where executive functioning happens. Exercise also increases white matter which increases communication between hemispheres.

 

Exercise may be essential for the other neurogenesis agents to work.

Neurogenesis and neuroplasticity

Exercise works via rejuvenated neural stem cells which are essential for neurogenesis.

 

Physical exercise may trigger processes facilitating neuroplasticity and, thereby, enhances an individual’s capacity to respond to new demands with behavioral adaptations.

 

High-intensity interval training promotes neuroplasticity.

 

Animal studies indicate that exercise facilitates neuroplasticity via a variety of biomechanisms, with improved learning outcomes. Induction of brain neurotrophic factors by exercise has been confirmed in multiple animal studies, with indirect evidence for this process in humans.

 

Exercise training increases mitochondrial biogenesis and auto(mito)phagy in the brain. In mouse brains, exercise “fixed” mitochondria as shown by increased rates of mitochondrial respiration. Exercise mediates PGC-1α to induce mitochondrial biogenesis in the brain.

 

Aerobic exercise causes hippocampal neurogenesis in rats and mice.

 

Physical exercise as a well-known upregulator of hippocampal neurogenesis and angiogenesis: an increase in cerebral blood volume was specifically observed in the human hippocampus and correlated with cognitive improvement following a 12-week regime of physical training.

 

Exercise enhances neuroplasticity in the visual cortex of adult humans.
In a study at Columbia University, researchers showed that older men who exercised on a treadmill four times a week for 30 minutes grew new cells in their dentate gyrus, an important area of the brain related to memory and cognition such as executive function.

 

Exercise intervention has been shown to improve performance in a neurogenesis-dependent cognitive test, the visual pattern separation task in human subjects.

 

Exercise prevents temporal lobe atrophy via strong blood circulation – An intact temporal lobe keeps brainwaves in sync and allows consolidation of memory during sleep.

 

Exercise causes neurogenesis in rats even when forced.

 

This study in rats showed that running may facilitate contextual, spatial and temporal information encoding by increasing adult hippocampal neurogenesis and by reorganization of new neuron circuitry.

 

This study in mice showed that the morphology, physiology and early network of new neurons can be reorganized by physical activity.

 

Exercise can help induce more activity between neurons, which could in turn boost a person’s level of neuronal pentraxin-2. Participants with higher levels of neuronal pentraxin-2 showed little or no memory loss after two years. Exercise exerts its effects on cognition by affecting molecular events related to the management of energy metabolism and synaptic plasticity.

 

Exercise → testosterone →  adult neurogenesis within the dentate gyrus region of the hippocampus through an androgen-dependent pathway.

 

Physical exercise induced astroglial proliferation in the frontoparietal cortex and dorsolateral striatum of rats. This may protect blood-brain-barrier function following brain injury. Astrocytes support cells of the mammalian central nervous system, and also play an active role in higher neural processing.

 

Serotonin may be required for exercise-induced neurogenesis. Here is how to increase serotonin.

Exercise, especially vigorous exercise, can reduce the chance of type 2 diabetes.

Diabetes mellitus is associated with decrements in cognitive function and changes in brain structure. People with both type 1 and type 2 diabetes have been shown to have mild to moderate reductions in cognitive function as measured by neuropsychological testing compared to non-diabetic controls. Type 2 diabetes (T2DM) has also been associated with 50% increased risk of dementia.¹ Insulin resistance alone is linked to cognitive decline.

 

Exercise is ‘precision medicine’ for insulin resistance and its progression to type 2 diabetes.
While moderate intensity exercise may be capable of promoting weight loss and thus improving insulin resistance, studies have demonstrated that the impact of vigorous intensity exercise training may be more effective in mitigating insulin resistance.

 

Exercise lowers insulin resistance by decreasing visceral fat. Studies have shown that you can help trim visceral fat or prevent its growth with both aerobic activity (such as brisk walking) and strength training (exercising with weights). Spot exercises, such as sit-ups, can tighten abdominal muscles but won’t get at visceral fat. Exercise can also help keep fat from coming back. Visceral fat is a strong predictor of insulin resistance regardless of cardiorespiratory fitness in non-diabetic people.

Exercise is even more important when one is elderly.

Aged mouse runners showed faster acquisition and better retention of the maze than age-matched controls. The decline in neurogenesis in aged mice was reversed to 50% of young control levels by running.

 

A study of 100 healthy but low active older adults (aged 60-80 years) showed that engaging in higher intensity physical exercise may have protective effects on neural processing in aging.

 

Older adults who consistently get up early and remain active throughout the day are happier and perform better on cognitive tests.

 

Greater late-life physical activity is associated with higher presynaptic protein levels.

 

Brain scans and tests measuring memory and thinking skills were done 5 years apart in 876 seniors. The investigators found a greater mental decline for those who reported low-activity exercises, such as light walking and yoga, compared to those with high-activity levels and exercises like running and cardio workouts. Exercise produced a difference equivalent to 10 years of brain aging in 876 people over 65, and that was after taking into account other factors that can influence brain health, such as excess weight, high blood pressure, smoking and drinking.

 

A study of 93 people at risk for Alzheimer’s disease who do more moderate-intensity physical activity, but not light-intensity physical activity, are more likely to have healthy patterns of glucose metabolism in their brain.

 

Exercise improved focus and attention in 101 adults over 65. Improvement was best with exercise done in a way that bumps up overall fitness level.

 

This study of over 650,000 people, average age of 61. followed for 8.8 years showed that being physically fit lowers your risk of developing dementia.

 

Exercise suggestions for the elderly – don’t stop.

 

It is never too late: being elderly, even frailty, is no excuse!

 

Aerobic exercise and resistance training works in the elderly. Build some serious muscle!

 

A study of men over 60 showed that there is a strong link between handgrip strength, walking speed and cognition, indicating how improved physical health could boost elderly minds.

 

Long-term resistance training (important) in older people is feasible and results in increases in dynamic muscle strength, muscle size, and functional capacity.

 

In cohort study that included 8279 older adults, the presence of low muscle mass was significantly and independently associated with faster subsequent executive function decline over 3 years.

 

There is a direct relationship between brain activity, brain function and physical fitness in a group of older Japanese men. They found that the fitter men performed better mentally than the less fit men, by using parts of their brains in the same way as in their youth.

Shown by a study of 454 older adults showed that, in late life, there is a big jump in benefits when moving from very low activity to merely low activity.

 

This study of 649,605 military veterans showed that older adults with higher levels of cardiorespiratory fitness have a 33% reduced risk for developing Alzheimer’s.

 

This systematic review and meta-analysis of 36 studies representing data from 2750 participants showed that aerobic exercise positively influences episodic memory. Aerobic exercise as an accessible, non-pharmaceutical intervention to improve episodic memory in late adulthood.

 

In a stufy of 200 older adults who on average were 75 years old, patients with the highest levels of activity energy expenditure were 90 percent less likely to become cognitively impaired than those with the lowest levels of expenditure.

 

This study of 1324 cognitively normal subjects showed that any frequency of moderate-intensity exercise carried out in either midlife or late life was associated with a reduced chance of mild cognitive impairment (MCI).

 

High-intensity interval training is best for memory in the elderly. High-intensity interval training is doable at any age.

A study of 1740 persons older than age 65 years without cognitive impairment showed that the risk reduction associated with exercise was greater in those with lower performance levels.

Even low-intensity physical exercise for 30 min, three to six times a week for nine months, can significantly lower blood pressure in elderly adults. Because hypertension is a prominent risk factor, lowering blood pressure may be one of the mechanisms by which physical activity reduces the risk of many age-related neurodegenerative diseases.

 

A brisk walk three times per week reversed hippocampal shrinkage in elderly adults.

 

A study of 120 sedentary older adults without dementia showed that brisk walking for 40 minutes a day for three days a week increased the volume of the hippocampus by 2.12 per cent on the left side and 1.97 per cent on the right side via BDNF, a mediator of neurogenesis in the dentate gyrus.

 

Physical activity provided 470 older adults with an avenue to make new friendships and engage in more cognitive activities which, in turn, attenuates cognitive decline.

 

90 middle-aged and older (50- to 74-year-old) subjects who wore accelerometers while physically active and completed mobile cognitive testing from home. The data obtained showed a very linear relationship between physical activiy and cognitive performance.

 

Fitness in an older adult population can have substantial benefits to brain health in terms of the functional connections of different regions of the brain.

 

Elderly people who remained active had higher levels of proteins that facilitate the exchange of information between neurons. This result dovetailes with an earlier finding that people who had more of these proteins in their brains when they died were better able to maintain their cognition late in life. To their surprise, the researchers found that the effects ranged beyond the hippocampus, the brain’s seat of memory, to encompass other brain regions associated with cognitive function.

 

Sixteen adults (average age 63 years) engaged in aerobic activity, including treadmill, stationary bike or elliptical training, four times per week for six months. A control group of 19 adults (average age 67 years) participated in stretching exercises with the same frequency. Compared to the stretching group, the aerobic activity group had greater preservation of total brain volume, increased local gray matter volume and increased directional stretch of brain tissue. Participants in the aerobic exercise group showed statistically significant improvement in executive function after six months, whereas the stretching group did not improve.

 

Data obtained over five years from 876 people 65 or older found that individuals who burned the most calories had larger gray matter volumes in the frontal, temporal and parietal lobes of the brain, areas that are associated with memory, learning and performing complex cognitive tasks.

 

In a study involved 1,557 people with an average age of 75, those who engaged in the top third highest level of physical activity had a brain volume the equivalent of four years younger in brain aging than people who were at the bottom third activity level.

 

Elderly volunteers, with an average age of 68 were recruited to study two different types of physical exercise: dancing and endurance training. Both increase the area of the brain that declines with age. In comparison, it was only dancing that led to noticeable behavioral changes in terms of improved balance.”

Treating dementia and mild cognitive impairment (MCI)

Aerobic exercise increased blood flow to the brain in 30 older people with memory problems. A study of 70 men and women aged 55 to 80 who had been diagnosed with MCI showed that aerobic exercise increased blood flow to the brain. Exercise is a treatment for mild cognitive impairment per the American Academy of Neurology. Treating MCI with exercise demonstrated by a study of 33 adults (17 women) with amnestic mild cognitive impairment ranging in age from 55 to 85 years (mean age, 70 years). Exercise may prevent mild cognitive impairment from progressing to dementia.

 

Among 1159 participants with both high and low total tau concentrations, physical activity was associated with slower cognitive decline.

 

This 6-month randomised controlled trial involving 86 women aged 70-80 years with probable MCI showed that aerobic training significantly increased hippocampal volume along with significantly improved general balance and mobility performance.

 

Exercise is thought to play a vital role in not only preventing the pre-clinical stage of AD but also slowing the clinical progression of AD. It is also deployed as a treatment option for late-stage AD along with pharmacological treatment options. Various studies and clinical trials in both human and animal models are of the opinion that exercise slows the onset and progression of cognitive decline in AD patients. Some studies suggest that this effect is due to a decrease in neurofibrillary tangles and amyloid deposits in brain parenchyma. Others suggest that exercise causes an increase in angiogenesis, neurogenesis, and synaptogenesis mainly due to an increase in blood flow, brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), hormones, and second messengers.

 

Treadmill exercise can effectively prevent the decrease in hippocampal-dependent cognitive function and Aβ deposits in early AD progression possibly via modulating microglia-mediated neuroinflammation and oxidative stress.

 

In the most common, late-onset form of Alzheimer’s disease, beta-amyloid is produced in the brain at a normal rate but is not cleared, or removed from the brain, efficiently.

One of the most important beneficial effects of aerobic exercise on AD is modifying Aβ clearance. Accumulating evidence indicates that aerobic exercise not only upregulates the clearance of amyloid plaques and soluble Aβ in the brain but also increases its final removal from the periphery.

 

The Harvard Aging Brain Study assessed physical activity in its participants — 182 normal older adults, including those with elevated b-amyloid who were judged at high-risk of cognitive decline — through hip-mounted pedometers which counted the number of steps walked during the course of the day. “Beneficial effects were seen at even modest levels of physical activity, but were most prominent at around 8,900 steps, which is only slightly less than the 10,000 many of us strive to achieve daily,”

 

Post-exercise increase in glymphatic flow was observed in mice that were awake.  Prior to this study, such increases were only ever seen in mice that were either asleep or anesthetized.  This observation suggests that exercise and sleep are both independent and powerful drivers of brain waste disposal.

 

Exercise might help ward off Alzheimer’s in all of us, including those individuals who are at higher risk of the disease because they possess an e4 variant of the APOE gene.

 

4X exercise per week may cut dementia risk in half.

 

Mice that exercised made new brain cells, but that didn’t seem to help their memory. Only when they got an additional treatment—another gene to boost levels of a protein called brain-derived neurotrophic factor (BDNF)—did they outperform untreated control mice on the memory tests. BDNF, which encourages neural growth, also appeared to reduce inflammation in the diseased brain.

 

Physical exercise, particularly, moderate-intensity exercises seem to be more effective to promote increase the peripheral levels of BDNF in the elderly. A study of 120 older adults showed that aerobic exercise training increases the size of the hippocampus, leading to improvements in spatial memory via greater serum levels of BDNF.

 

A growing body of evidence also suggests that exercise interventions hold the potential to reduce the pathological features associated with AD. Animal and human studies indicate that exercise provides a powerful stimulus that can countervail the molecular changes that underlie the progressive loss of hippocampal function in advanced age and AD. Higher levels of fitness may reduce the brain atrophy in AD.

 

Older adults that improved their fitness through a moderate intensity exercise program increased the thickness of their brain’s cortex, the outer layer of the brain that typically atrophies with Alzheimer’s disease. MCI participants showed greater improvements in the left insula and superior temporal gyrus, two brain regions that have been shown to exhibit accelerated neurodegeneration in Alzheimer’s disease.

 

A study of 204 patients with mild cognitive impairment showed that participation in an exercise program can improve patients’ cognitive function, physical abilities, and body movement capacity.
This 6-month randomized controlled trial of 86 women aged 70-80 years with probable mild cognitive impairment showed that exercise can positively impact cognitive functioning and may represent an effective strategy to improve memory in those who have begun to experience cognitive decline.

 

Better memory for those who are healthy and those who have suffered decline

Aerobic exercise aids long–term memory.

 

Exercise counteracts age-related memory loss (different than Alzheimer’s).

 

Both acute and chronic exercise improve medial temporal lobe function with enhancements in performance of the face-name matching concomitant with increased concentrations of BDNF in the serum of young adult males.

 

Viscoelasticity, a measure of structural integrity in brain tissue, was correlated with fitness and memory performance – much more so than simply looking at the size of the hippocampus.

 

Aerobic exercise aids spacial memory. One year of aerobic exercise in a large randomized controlled trial of seniors was associated with significantly larger hippocampal volumes and better spatial memory; other RCTs in seniors documented attenuation of age-related gray matter volume loss with aerobic exercise.

 

Aerobic exercise may have a positive effect on the medial temporal lobe memory system (which includes the entorhinal cortex) in healthy young adults. The entorhinal cortex replays memories of movement independent of input from the hippocampus.

 

A study that involved 17,761 people aged 45 and older showed that poor cardiovascular health is linked to memory, learning deficits.

 

In a randomized controlled trial with 120 older adults, that aerobic exercise training increases the size of the anterior hippocampus, leading to improvements in spatial memory.

 

This systematic review and meta-analysis of nine studies (n = 547) showed that aerobic physical activity in individuals without ccognitive impairment had a large positive effect on memory.

Less chronic inflammation and less neuroinflammation

A common mechanism underlying the central and peripheral effects of exercise might be related to inflammation, which can impair growth factor signaling both systemically and in the brain. Exercise works by reducing brain inflammation.

 

The existence of anti-inflammatory exercise factors that are transferrable, target the cerebrovasculature and benefit the brain, and are present in humans who engage in exercise.

 

Exercise maintains homeostasis of the brain and prevents brain pathology by modulating the activation of glia, pro-inflammatory cytokines, and neuroinflammation, thereby preventing neurodegenerative diseases such as AD, PD, ALS, and MS.

Oxidative stress

Superoxide dismutase activity in response to acute exercise was significantly higher in young compared to (9) older adults. These data suggest that signal transduction of acute exercise may be impaired with aging. Repeated bouts of transient reactive oxygen species production as seen with regular exercise may be needed to increase resistance to oxidative stress in older individuals.

The following foods can decrease oxidative stress due to exercise: Curcumin + black pepper, watercress, beets or beet juice, all berries, cherries, spinach.

 

In a single bout of exercise, the magnitude of oxidative stress may be strongly influenced by an individual’s training history.

 

The preventive effect of regular exercise, at least in part, is due to oxidative stress-induced adaptation. The oxidative challenge-related adaptive process of exercise is probably not just dependent upon the generated level of ROS but primarily on the increase in antioxidant and housekeeping enzyme activities, which involves the oxidative damage repair enzymes. Therefore, the effects of exercise resemble the characteristics of hormesis.

Better Mitochondria

Physical exercise is considered a non-pharmacological strategy to protect mitochondrial health. Physical exercise regulates mitochondrial quality control allowing the repair/elimination of damaged mitochondria and synthesizing new ones, thus recovering the metabolic state.

 

Aerobic exercise promotes a large increase in mitochondrial mass, mitochondrial enzyme activity, and oxidation efficiency. One of the most defined energy sensors in skeletal muscle is the adenosine monophosphate (AMP)-activated protein kinase (AMPK). The activation of AMPK following exercise is intensity dependent with intensities of 60% VO₂ peak reported to consistently induce activation . AMPK activity is amplified during exercise in a fasted or glycogen depleted state, following which it acutely stimulates increased rates of fat oxidation. Once activated AMPK increases ATP production via an increase in lipid oxidation, by enhancing fatty acid uptake into skeletal muscle and increasing the transport of fatty acids into the mitochondria.

 

Exercise affects mitochondria via  rapid increases in expression of the transcription coactivator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and in mitochondrial biogenesis in skeletal muscle. PGC-1α regulates and coordinates mitochondrial biogenesis, and overexpression of PGC-1α in muscle cells results in increases in mitochondrial content.

 

Neurons are highly specialized post-mitotic cells that are inherently dependent on mitochondria due to their higher bioenergetic demand. Mitochondrial dysfunction is closely associated with a variety of aging-related neurological disorders, such as Alzheimer’s disease (AD). Accumulating evidence shows beneficial effects of appropriate exercise on improved mitophagy and mitochondrial function to promote mitochondrial plasticity, reduce oxidative stress, enhance cognitive capacity and reduce the risks of cognitive impairment and dementia in later life.

Any exercise is better than none, so what about walking?

In this study, brain connectivity was improved in 65 adults, aged 59 to 80, who joined a walking group.

 

This study shows that moderately vigorous physical activity, meaning more strenuous than walking, is associated with better cognition after an average of 25 years.

 

Walking has been shown to increase hippocampal volume in those with mild cognitive impairment. The key is consistency.

 

Walking reduces the risk of small vessel damage. That will delay the onset of dementia and help protect what function is left.

 

29 people 60 and older with memory complaints who walked more than 4,000 steps each day had a thicker hippocampus and thicker surrounding regions than those who walked less than 4,000 steps. Thickness in these regions correlates with better cognitive function.

 

The foot’s impact during walking sends pressure waves through the arteries that significantly modify and can increase the supply of blood to the brain, so doing exclusively low-impact exercise may not be a good idea.

 

After controlling for age, education, body mass index, cardiovascular disease risk factors, and the Mini Mental State Exam, we found that a greater amount, duration, and frequency of total daily walking activity were each associated with larger hippocampal volume among older women, but not among men.

 

This brain-imaging study, which included brain scans of more than 600 people in Scotland between the ages 70 and 73 found that those who participated in more physical exercise, including walking several times a week, had less brain shrinkage and other signs of aging in the brain than those who were less physically active. There was, however, no support for a beneficial effect of more intellectually challenging or socially orientated activities.

 

Exercise doesn’t have to be intense to make an impact. If you get more steps, if you’re moving around your environment a little bit more, that can be helpful to your brain health and keep you more independent as you age.

 

Older women who walked or partook in moderate-to-vigorous exercise each day had a reduced risk of developing mild cognitive impairment and dementia.

 

Any regular leisure time physical activity at any age is linked to better brain function in later life, but maintaining an exercise routine throughout adulthood seems to be best for preserving mental acuity and memory.

Fibroblast growth factor FGF-2

Exercise → FGF-2 – shown effective in rats.

 

Adult neurogenesis requires several neurotrophic factors to sustain and regulate the proliferation and differentiation of the adult stem cell population. The trophic system mediated by FGF-2 and its receptors contributes to create an important micro-environmental niche that promotes neurogenesis in the adult and aged brain.

 

In adult neurogenesis, FGF2 has been implicated based on its expression and regulation of neural stem and progenitor cells in the neurogenic niches, the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus.

 

Experiments in mice have shown that exercise regulates FGF-2 expression. Growth factors are likely mediators of the positive effects of exercise on the brain.

 

In adult neurogenesis, FGF2 has been implicated based on its expression and regulation of neural stem and progenitor cells in the neurogenic niches, the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus. FGFR1 signaling also modulates inflammatory signaling through the surface glycoprotein CD200, which regulates microglial activation.

 

Twenty four healthy older males: 12 higher fit (58 ± 1y) and 12 lower fit (59 ± 1y). Pre-exercise IGF-I was lower and FGF-2 was higher in the higher fit compared with lower fit individuals. Immediately ollowing anaerobic exercise, in both groups, FGF-2 decreased dramatically (p < 0.05); in the higher fit individuals FGF-2 level was 0.4 ± 0.1 pg·ml^-1 compared to 0.1 ± 0.02 pg·ml^-1 in the lower fit individuals.

 

Fibroblast growth factors (FGFs) are broad-spectrum mitogens and regulate a wide range of cellular functions, including migration, proliferation, differentiation, and survival. It is well documented that FGF signaling plays essential roles in development, metabolism, and tissue homeostasis. The malfunction of FGF/FGF receptor (FGFR) signaling axis is observed in a variety of human diseases, such as congenital craniosynostosis and dwarfism syndromes, as well as chronic kidney disease (CKD), obesity, insulin resistance, and various tumors.