A recent systematic review conducted in part for the 2018 Health and Human Services Physical Activity Guidelines for Americans Advisory Committee, summarized the existing evidence for the effects of exercise interventions on cognitive function across the life span, as well as in clinical disorders [11]. This umbrella review concluded that there is moderately strong evidence that moderate–vigorous exercise leads to improvements in cognition, especially processing speed, memory, and executive function. By far the strongest evidence for the cognitive-enhancing effects of exercise come from studies focusing on two age windows, that is, children aged 6–13 years and adults aged N50 years, as well as populations with dementia or other cognition-impairing condition (e.g., schizophrenia). Notably, although evidence for the effects of exercise in children and older adults is the strongest, it is still marred by inconsistencies and deficiencies in study design [12]. There is therefore still a need for rigorous and adequately powered RCTs in these groups to more definitively evaluate the effects of exercise on cognition. There is also emerging evidence that exercise has beneficial effects on cognition in nonneurological or psychiatric conditions, such as in women treated for breast cancer who experience co-occurring cognitive symptoms and complaints (Box 1). While there are complexities in defining specific age ranges for developmental periods such as adolescence [13], age groups are used to simplify the presentation of the studies discussed here. With that, there are major gaps in our understanding of the effects of exercise on cognition, particularly in early childhood (b6 years old), adolescence (approximate age range 14–17 years), and young to middle-age adulthood (ages 18–50 years). Work in these areas is emerging [14], but there is currently insufficient evidence from studies that used causal designs to support firm conclusions regarding the effects of exercise on cognitive outcomes in these age ranges.
What Is Known about Cellular and Molecular (Level 1) Mechanisms of Exercise? Aerobic exercise induces significant biochemical changes in the brains of animals [2,5,10]. Some of the most widely studied molecules in animal models are: (i) brain-derived neurotrophic factor (BDNF), which initiates a host of downstream effects including long-term potentiation and proliferation of neurons; (ii) vascular endothelial growth factor (VEGF), which supports blood vessel survival and growth; and (iii) insulin-like growth factor (IGF)-1, which influences several neural and angiogenic processes [2]. In humans, most studies on exercise-induced cellular/molecular changes have focused on analytes measurable in the bloodstream or cerebrospinal fluid. For example, meta-analyses and reviews have concluded that there are increases in BDNF after long-term exercise in children, adolescents, younger adults, older adults, Alzheimer’s disease patients, and those with psychiatric disorders, despite some inconsistency in the findings across individual studies [15,16]. In addition, circulating levels of BDNF in humans statistically mediate exercise-related improvements in executive functioning [17] in adults older than 71 years. This pattern of evidence supports the hypothesis that BDNF may be a mechanism of exercise that is conserved across species and age groups in humans (Figure 1, Key Figure). In older adults, there is also evidence that IGF-1 levels increase following exercise, although this effect is again somewhat inconsistent across studies (see [18] for a recent meta-analysis). A major open question is whether exercise influences IGF-1 levels across the lifespan, as studies of exercise and IGF-1 in age groups other than older adults are lacking. The evidence linking VEGF and exercise in humans is similarly limited [19]. An overarching limitation of assessing Level 1 mechanisms in humans is that it is notoriously difficult to assess these molecular pathways in vivo. That is, rather than measuring the relevantbiomolecules directly from the brain, as is typical in animals, indirect measures of them (i.e., circulating analytes) are often used to infer brain levels in humans. However, there are also non-neuronal sources, kinetics, and roles of these biomolecules in humans [20], which introduces an inherent source of error into inferences about their brain levels. Furthermore, these biomolecules could play different roles in childhood versus older adulthood or across health states [21], and this could potentially influence their sensitivity to exercise. For example, it is possible that older adults or patients deficient in one or more of these biomolecules may experience greater increases in response to exercise compared with groups with normal levels.
