The practice of calorie restriction improves long-term health and slows near all aspects of aging assessed to date. In humans, the beneficial effects of calorie restriction on healthy people are larger than any enhancement technology is yet proven to supply; it remains to be seen as to how the first rejuvenation therapies such as senolytics perform in larger populations of old individuals. Here, researchers focus on the effects of calorie restriction on the function of aging brain tissue. They take a conservative viewpoint on the widespread implementation of calorie restriction, despite the comprehensive animal data, as the sort of stringent dose-response studies and other evaluations required for the approval of pharmaceutical treatments have yet to be carried out in human patients for the practice of calorie restriction in the context of brain health.
The extracellular microenvironment is critical for maintaining normal physiological functions of cells because of its role in the homeostatic regulation of various components. Various factors, such as inflammation, metabolic waste, and the blood-brain barrier, can disrupt normal brain microenvironments. Thus, the maintenance of the extracellular environment is vital for brain health. Current studies have suggested that lifestyle interventions, such as regular exercise training, a healthy diet, and sufficient sleep, protect the brain by improving the microenvironment balance under pathological conditions.
Caloric restriction effectively protects the brain microenvironment via multiple mechanisms at molecular, cellular, and tissue levels. Major benefits obtained by CR are based on recent findings in aging and neuropathological models. However, there is currently no consensus on a unified protocol for CR because the duration or starting age of CR has not been clarified in animals. Reports have shown that the initiation age and duration of CR are critical factors that influence overall efficiency. Specifically, CR started at middle-age has the most potent neuroprotective effect.
Current studies on the neuroprotective effects of CR have various weaknesses, which include the lack of a precise description of the dosage curve (i.e., the relationship between CR duration and overall efficiency of neuroprotection), the lack of systematic observations of the additive effect of CR and drugs in counteracting neurodegeneration, and the absence of a neural circuit-specific effect of dietary interventions. These factors limit the large-scale promotion of CR in aging and high-risk populations with neurodegenerative diseases. Therefore, future explorations are required to understand the neuroprotective mechanisms underlying CR to develop alternative pharmaceutical or non-drug interventions for brain aging and neurodegeneration.