Novel Strategies for Healthy Brain Aging

Abstract

One of the best strategies for healthy brain aging is regular aerobic exercise. Commonly studied "anti-aging" compounds may mimic some effects of exercise on the brain, but novel approaches that target energy-sensing pathways similar to exercise probably will be more effective in this context. We review evidence in support of this hypothesis by focusing on biological hallmarks of brain aging.

Figure 1.

Aging is the primary risk factor for the development of cognitive dysfunction, mild cognitive impairment (MCI) and dementia. Numerous, established biological “hallmarks of brain aging” (shown at top) contribute to age-related reductions in cognitive function and increased neurodegeneration/dementia risk with aging.

Figure 2.

Exercise is perhaps the best strategy for inhibiting all major hallmarks of brain aging, largely because it activates key cellular energy sensing pathways. This enhanced energy metabolism/regulation with exercise is important because the proteins and cellular pathways involved (in bold) can also directly influence other hallmarks. Abbreviations: REST: RE1-silencing transcription factor; BDNF: brain-derived neurotrophic factor; IL-10: Interleukin 10; VEGF: Vascular Endothelial Growth Factor; GLUT: glucose transporters; SIRT1: Sirtuin 1; AMPK: AMP protein kinase; mTOR: mammalian target of rapamycin; PGC-1α: proliferator-activated receptor gamma coactivator-1α; Nrf2: nuclear factor erythroid 2-related factor 2; GSH: Glutathione; CREB: cyclic AMP response element-binding protein; SIRT3: Sirtuin 3.

Figure 3.

Select pharmacological “anti-aging” treatments that have been shown to increase lifespan/healthspan in the NIA Intervention Testing Program may inhibit certain hallmarks of brain aging, but some are supported by more evidence than others. To date, rapamycin and 17-α-estradiol appear to be the most effective in this context. However, more research is needed to determine how these and other compounds affect additional hallmarks of brain aging, and to fully characterize bioavailability and safety in humans.

Figure 4.

Exercise is more broadly effective than traditional anti-aging compounds for preserving cognitive function and reducing dementia risk, because it is associated with a strong bioenergetic stimulus that directly influences all hallmarks of brain aging. However, some energy-targeting pharmacological agents (e.g., AICAR, nicotinamide riboside) and lifestyle interventions (e.g., calorie restriction [CR], protein restriction, intermittent fasting) may better mimic effects of exercise on the hallmarks of brain aging. Potential synergistic effects among these interventions and compounds could hold particular promise for promoting healthy brain aging.