Lifelong brain health is a lifelong challenge: from evolutionary principles to empirical evidence

Abstract

Although the human brain is exceptional in size and information processing capabilities, it is similar to other mammals with regard to the factors that promote its optimal performance. Three such factors are the challenges of physical exercise, food deprivation/fasting, and social/intellectual engagement. Because it evolved, in part, for success in seeking and acquiring food, the brain functions best when the individual is hungry and physically active, as typified by the hungry lion stalking and chasing its prey. Indeed, studies of animal models and human subjects demonstrate robust beneficial effects of regular exercise and intermittent energy restriction/fasting on cognitive function and mood, particularly in the contexts of aging and associated neurodegenerative disorders. Unfortunately, the agricultural revolution and the invention of effort-sparing technologies have resulted in a dramatic reduction or elimination of vigorous exercise and fasting, leaving only intellectual challenges to bolster brain function. In addition to disengaging beneficial adaptive responses in the brain, sedentary overindulgent lifestyles promote obesity, diabetes and cardiovascular disease, all of which may increase the risk of cognitive impairment and Alzheimer's disease. It is therefore important to embrace the reality of the requirements for exercise, intermittent fasting and critical thinking for optimal brain health throughout life, and to recognize the dire consequences for our aging population of failing to implement such brain-healthy lifestyles.

Keywords: Alzheimer's disease; Exercise; Intermittent fasting; Ketone bodies; Parkinson's disease; Synaptic plasticity.

Figure 1

Images depicting the evolutionary basis for the importance of optimal brain function under conditions of food deprivation and physical exertion. Carnivorous animals in the wild, and our human ancestors, had to expend considerable effort to catch and kill prey. Advances in cognitive capabilities were driven, in large part, by the need to develop strategies and tools that enabled consistent success in the hunt for food. The upper image shows a tiger chasing two antelope (source: Wikemedia Commons). The lower image shows an American Indian hunting a bison (source: Wikipedia). In the case of the Indian, the human brain evolved the capabilities of making tools (bow and arrow), taming and training horses, and language for communication in planning and executing the hunt.

Figure 2

Model for the impact of aging and lifelong intermittent challenges on the trajectories of processes promoting and protecting against age-related neuronal dysfunction and cognitive impairment. During aging the ability of neurons to efficiently acquire energy substrates (e.g., glucose and ketones) and process them to produce ATP (mitochondrial function) is impaired. Neurotrophic support, synaptic plasticity and neurogenesis (the production of new neurons from stem cells) also decline during aging. During aging brain cells experience increased levels of oxidative stress, inflammation, protein aggregation and DNA damage. Intermittent exercise, energy restriction and intellectual challenges (IC) during adult life forestall age-related dysfunction of and damage to neurons (dashed lines).

Figure 3

Intermittent intellectual challenges, exercise and energy restriction support optimal brain function and resistance to disease via of effects in the brain and peripheral organs. Intellectual challenges primarily affect the brain directly by increasing synaptic activity resulting in the production of neurotrophic factors such as BDNF, and by stimulating mitochondrial biogenesis, DNA repair and the production of cytoprotective protein chaperones. Cognitive stimulation may also promote enhance peripheral organ health by, for example, BDNF-mediated activation of the parasympathetic nervous system and increased insulin sensitivity of muscle and liver cells (Wan et al., 2014). Exercise and intermittent energy restriction/fasting elicit changes in brain signaling and gene expression that overlap considerably with those that occur in response to intellectual challenges. In addition, exercise and energy restriction reduce inflammation (microglial activation and pro-inflammatory cytokine production) in the brain. Energy restriction and exercise have profound effects on peripheral organs including a metabolic shift that mobilizes fatty acids (in adipose cells) which are then converted to ketone bodies (e.g., β-hydroxybutyrate) in the liver. Ketones enter the brain, are used as an energy source by neurons, and are neuroprotective. Fasting and exercise also increase insulin sensitivity and reduce inflammation in peripheral tissues. Some hormones produced in response to energy restriction and exercise are known to promote neuronal plasticity and survival, including glucagon-like peptide 1 (GLP-1) and adiponectin (Li et al., 2009, ; Qui et al., 2011). Moreover, recent findings suggest that muscle-derived factors can enter the brain and contribute to enhanced neuroplasticity and stress resistance. Altogether, the effects of intermittent challenges in the brain and periphery support optimal brain function, resistance to disease and improved recovery from injury.