The adaptive aging brain

Abstract

The aging brain is shaped by many structural and functional alterations. Recent cross-disciplinary efforts have uncovered powerful and integrated adaptive mechanisms that promote brain health and prevent functional decline during aging. Here, we review some of the most robust adaptive mechanisms and how they can be engaged to protect, and restore the aging brain.

Figure 1. Adaptive mechanisms of brain aging.

Physiologic adaptive mechanisms (inside white circle) and those that can be recruited by lifestyle and therapeutic interventions (outer light red ring) promote stress resistance and functional integrity of the aging brain. Physiologic adaptive mechanisms include neural network changes, increased synaptic plasticity, and reduced neural excitation, as well as broader metabolic and systemic adaptations that involve vascular function and circulating factors. Genetic factors, such as the protective APOE2 allele, may also engage adaptive mechanisms. Adaptive mechanisms can also be recruited by physiologic and pharmacologic interventions (outer ring). Examples of induced physiologic adaptations are those engaged by lifestyle choices and changes, such as diet and physical activity, caloric restriction, education, mental training, meditation, social interactions, and sleep. Pharmacologic and therapeutic interventions target metabolic, neuroprotective, and inflammatory pathways. Other approaches target senescent cells, blood pressure, and vascular health or mentally stimulate the aging brain.

Figure 2. Metabolic adaptations in the aging brain.

Several conserved metabolic regulators can be engaged physiologically or therapeutically. Fasting, exercise, downregulation of insulin/insulin-like growth factor 1 (IGF1–1) signaling, and decreased protein and amino acid levels inhibit the activity of mammalian target of rapamycin (mTOR). This results in inhibition of protein synthesis and stimulation of autophagy. Physical exercise and fasting also increase nicotinamide adenine dinucleotide (NAD⁺) production, which serves as a critical redox cofactor for metabolism and ATP generation. NAD⁺ also serves as cofactor for sirtuins. Nuclear localization of sirtuins (SIRTs) leads to deacetylation of target genes, such as Fork-head box O (FOXO) proteins, peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), and nuclear factor erythroid 2-related factor 2 (NRF2). FOXO1-dependent transcription can also be activated by REST, a transcriptional repressor that is activated in the aging brain and correlates with longevity. FOXOs, PGC-1α, and NRF2 activate the transcription of genes that promote stress resistance, autophagy, proteostasis, DNA repair, mitochondrial biogenesis, and cell survival. Increased AMP and decreased ATP during fasting activate AMP kinase (AMPK). AMPK can also be activated pharmacologically by metformin. NAD precursors such as nicotinamide mononucleotide can pharmacologically increase cellular NAD⁺ levels.

Figure 3. Neural adaptations in the aging brain.

(a) Neural network compensatory adaptations preserve neural network homeostasis during aging. Three broad age-related neural mechanisms of compensation in the aging brain have been described: (1) Some neural networks can increase activity during aging, such as the dorsolateral prefrontal cortex (DLPFC) that is involved in working memory. (2) Neural networks that are not typically involved in a task can be recruited, such as the recruitment of the rhinal cortex to augment the function of the hippocampus (HPC) in recognition memory. (3) Neural networks can be reorganized in the aging brain to improve performance. For example, the frontal cortex can become activated bilaterally in aged individuals to perform executive function tasks, in contrast to the unilateral frontal activation pattern that occurs in young individuals. (b) Reducing neural excitation may protect against hyperexcitation and also reduce the transsynaptic spread of misfolded proteins, such as Aβ and tau, which contribute to the pathogenesis of AD. (c) The molecular mechanism of reduced neural excitation in a well-adapted aging brain may involve the transcriptional repressor REST, which is activated in aging neurons. AD, Alzheimer disease.

Figure 4. Adaptation of the neuron–glia interface in the aging brain.

(a) Homeostatic microglia become phagocytic in the presence of protein aggregates and degenerating cells. Gamma entrainment can recruit and augment microglial phagocytic activity. Inhibition of the CD22 receptor and the other indicated interventions can restore beneficial microglial activity and reduce proinflammatory responses. (b) Senescent microglia and astrocytes exhibit the senescence-associated secretory phenotype (SASP) with the release of proinflammatory mediators. Senescent cells do not efficiently clear misfolded proteins, such as Aβ and tau, leading to their accumulation and spread. Strategies that eliminate senescent glial cells, such as the use of senolytics, can allow the bystander glial cells to more efficiently clear misfolded proteins, leading to decreased pathology and potentially improving cognitive function. (c) TREM2 is a microglial receptor that interacts with lipids, lipoproteins, and Aβ and activates pathways that restrict proinflammatory NF-κB signaling. NF-κB is activated by a variety of proinflammatory stimuli, including cytokines, infection, stress, and circadian disturbance. Inhibition of NF-κB signaling by anti-inflammatory drugs, blockade of immune checkpoints, or physical exercise leads to reduced inflammation and increased microglial phagocytic activity.