Recruiting adaptive cellular stress responses for successful brain ageing

Abstract

Successful ageing is determined in part by genetic background, but also by experiential factors associated with lifestyle and culture. Dietary, behavioural and pharmacological interventions have been identified as potential means to slow brain ageing and forestall neurodegenerative disease. Many of these interventions recruit adaptive cellular stress responses to strengthen neuronal networks and enhance plasticity. In this Science and Society article, we describe several determinants of healthy and pathological brain ageing, with insights into how these processes are accelerated or prevented. We also describe the mechanisms underlying the neuroprotective actions of exercise and nutritional interventions, with the goal of recruiting these molecular targets for the treatment and prevention of neurodegenerative disease.

Figure 1. Intrinsic features of normal and pathological aging

Normal aging is accompanied by alterations in neuronal calcium handling and changes in lipid peroxidation, leading to increased generation of reactive oxygen species and damage to mitochondria. These changes are permissive or instructive for the suppression of adult neurogenesis beginning in middle age. Successful aging is characterized by implementation of alternative plasticity mechanisms to compensate for changes in the local microenvironment. Age-related pathologies such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) arise from a combination of genetic and environmental factors, but each disease shares a common feature in that age is a risk factor for disease onset. In this respect, aging sets the stage for the onset of pathology. REST, repressor element 1-silencing transcription factor; ROS, reactive oxygen species, P, phosphorylation site; Aβ, amyloid β-peptide; Ca, calcium; BDNF, brain-derived neurotrophic factor; DJ1, Parkinson protein 7.

Figure 2. Adaptive cellular stress response signaling mediates beneficial effects of environmental challenges on neuroplasticity and vulnerability to degeneration

A typical glutamatergic neuron in the hippocampus is depicted receiving excitatory inputs (red) from neurons activated in response to exercise, cognitive challenges and dietary energy restriction. In the cell body of the postsynaptic neuron are depicted a mitochondrion (top), the endoplasmic reticulum (left) and the nucleus (right). Examples of seven different adaptive stress response signaling pathways that protect neurons against degeneration and promote synaptic plasticity are shown. During exercise and cognitive challenges postsynaptic receptors for glutamate (1, 2), serotonin (3) and acetylcholine (4) are activated to engage intracellular signaling cascades and transcription factors that induce the expression of neuroprotective proteins including BDNF, mitochondrial uncoupling proteins (UCPs) and anti-apoptotic proteins (e.g., Bcl2). BDNF promotes neuronal growth, in part, by activating mTOR. Mild cellular stress resulting from reduced energy substrates (5) and reactive oxygen species (ROS) (6) engage adaptive stress response pathways including those that up-regulate antioxidant enzymes (AOE) and protein chaperones. Release of γ-aminobutyric acid (GABA) from interneurons (7), in response to activity in excitatory circuits (as occurs during exercise and cognitive challenges), hyperpolarizes the excitatory neurons which can protect them from Ca²⁺ overload and excitotoxicity. BDNF, brain-derived neurotrophic factor; CREB, cyclic AMP response element-binding protein; DAG, diacylglycerol; HO1, heme oxygenase 1; HSF1, heat shock factor 1; MnSOD, manganese superoxide dismutase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor κB; NQO1, NADH-quinone oxidoreductase 1; Nrf2, nuclear regulatory factor 2; Ph2E, phase 2 enzyme; PKC, protein kinase C; PMRS, plasma membrane redox system; SIRT, sirtuin.

Figure 3. Potential for mechanistic synergy between exercise and pharmacological treatments designed to maintain cognition in an aging population

The locus coeruleus (LC) projection to the hippocampus is essential for exercise-induced brain-derived neurotrophic factor (BDNF) expression. Exercise enhances hippocampal BDNF synthesis, leading to activation of the extracellular signal-related kinase (ERK) pathway, which converges on the transcription factor cyclic adenosine monophosphate (cAMP) response element binding protein (CREB). Treatment with drugs that block norepinephrine (NE) reuptake enhance noradrenergic neurotransmission, leading to activation of adenyl cyclase and cAMP, which also activates CREB, leading to transcription of a number of different genes associated with synaptic plasticity and neurogenesis. Concurrent exercise and norepinephrine reuptake inhibitor treatment could additively enhance hippocampal BDNF production and be neuroprotective. AMPA, {alpha}-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA, N-methyl-D-aspartate; TrkB, high-affinity BDNF receptor; CamKII, calcium calmodulin kinase II; MEK1/2, mitogen-activated protein kinase kinase 2; ERK, extracellular-signal related kinase; P, phosphorylation site.