Ai-Ling Lin of the Lin Brain Lab details how neuroimaging research can be used to reduce brain aging and the impact of Alzheimer’s disease
Alzheimer’s disease (AD) is one of the most common forms of dementia, accounting for 60%-80% of all dementia. The neuropathological hallmarks of AD include extracellular β-amyloid (Aβ) senile plaques and intracellular neurofibrillary tangles (tau). Neuroimaging studies in humans show that decades before the aggregation of Aβ and tau tangles, cognitively normal individuals had developed metabolic and vascular deficits. In particular, significantly reduced cerebral metabolic rates of glucose (CMRglc) and cerebral blood follow (CBF) were found in people at high risk for AD several decades before the possible onset of dementia.
Brain metabolic and vascular integrity plays an important role in determining cognitive capability and mental health. Failure to maintain CMRglc has been shown to lead to cognitive impairment and brain volume atrophy. Similarly, studies have shown that neurovascular risk is highly associated with an accelerated decline in language ability, verbal memory, attention and visuospatial abilities. Reduced CBF is linked to anxiety and depression, and impaired blood-brain barrier is associated with neuroinflammation and synaptic dysfunction. These metabolic and vascular reductions precede brain structural alteration (grey matter and white matter atrophy) and cognitive impairment. Therefore, preserving brain metabolism and hemodynamics are critical for optimising our lifespan, as well as our health span.
Caloric restriction (CR), without malnutrition, has been repeatedly shown to extend life expectancy, as well as enhance brain functions. On biochemical and molecular levels, CR shows to improve glucose homeostasis and insulin sensitivity, up-regulate brain-derived neuro-trophic factor, reduce oxidative stress, inflammation, and retention of Aβ and tau. CR also shows beneficial effects on vascular systems by decreasing blood pressure, atherogenic lipids, inflammatory cytokines and increased cellular stress resistance. In line with this, animals treated with CR had lower incidences of age-related neurodegenerative disorders and diabetes.
To study the functions in a living brain in real time, non-invasive neuroimaging methods have been developed as powerful tools for identifying in vivo metabolic and vascular biomarkers. For example, CMRglc can be measured using positron emission tomography (PET), and CBF by magnetic resonance imaging (MRI). Our group also uses magnetic resonance spectroscopy (MRS) to measure levels of various brain metabolites, mitochondrial oxidative metabolism, and neuronal activity. We have used this state-of-the-art, multimodal imaging technology to identify CR effects in brain aging.
Recent neuroimaging studies with mice
In a recent animal study, we found an age-dependent decline in CBF, neuronal activity, mitochondrial oxidative metabolism, total creatine (TCr) levle, and adenosine triphosphate (ATP) in mice fed with ad libitum (ad lib; meaning “at one’s pleasure”). However, all these physiological functions preserve with age in mice fed with a 40% CR diet. Interestingly, we found CR also has significant effects in young mice (5-6 months of age). Within 2 months taking the diet, the young mice show significantly enhanced CBF, TCr, ATP, and taurine (related to neurotransmission), compared to age-matched mice fed ad lib. In addition, CR causes a metabolic shift in the mice at a very early age. Instead of using glucose as the predominant energy source for sustaining brain functions, young CR mice shifts to use ketone bodies as the fuel. In bodies with increased ketone, their metabolism suggests increased oxidative metabolism. Utilisation of ketone bodies significantly elevates the oxygen utilisation in mitochondria through beta-oxidation of fatty acid. This is supported by evidence from isolated mitochondria and our imaging results that old animals with CR diet had preserved oxidative metabolism, mitochondrial functions, and neuronal activity compared to the age-matched ad lib animals.
The increased oxidative metabolism also plays a critical role in preventing Aβ retention. Previous neuroimaging studies showed that cognition-associated brain regions have non-oxidative glycolysis exceeding the required needs of oxidative phosphorylation, a phenomenon known as aerobic glycolysis (AG). Excessive AG (or the “Warburg effect”) is a key process that sustains T cell activation and differentiation, and is involved in inflammatory-mediated conditions. In line with this, the distribution of AG in normal young adults is spatially correlated with Aβ deposition in AD patients and cognitively normal individuals with elevated Aβ. Animal studies further demonstrated that Aβ plaque formation is an activity dependent process associated with AG. Therefore, increased oxidative metabolism in cognition-related regions may decrease AG and thus reduce the risk for AD, consistent with the literature that CR reduces AD-like symptoms in mice. Reduced AD risk was also found in rhesus monkeys, showing CR impedes age-related iron deposition in the brain, which consequently reduces the potential interaction between metal and Aβ, and thus decelerates the pathogenesis of AD.
CR has repeatedly shown to improve memory in aging, both for studies in humans and animals. We had similar observations in a recent study, showing CR had significantly protective effects on learning and spatial memory for old mice. The cognitive outcomes are correlated with CBF in hippocampus and frontal cortex, the brain areas regulating learning and memory. The findings indicate that the level of CBF in cognition-associated brain regions may play a critical role for determining performances on learning and spatial memory. We further identified that the anxiety level in the mice had significant and inverse correlations with CBF in hippocampus and in frontal cortex. These findings indicate that preservation of CBF with age is pivotal for sustaining memory and mental health. More importantly, this positive impact on cognitive functions may also be attributed to early-life changes in neurovascular and neurometabolic functions. A recent study suggested that neuroprotective mechanisms play a major role during early stages and compensatory mechanisms in later stages of neurological diseases. This is consistent with our imaging findings that CR induces early enhancements, and later preservation, on brain metabolic and vascular physiology.
In summary, CR has repeatedly shown to extend lifespan and health span in various animal models. Using neuroimaging methods, we demonstrated that CR induces early enhancements in brain metabolic and vascular functions, and preserves these functions with age; the preservation of brain functions is highly associated with cognition and mental health in aging mice fed with CR. As neuroimaging can be readily applied to humans, it has tremendous translational values to identify dietary effects to slow brain aging and prevent AD in humans.
Ai-Ling Lin, PhD
The Lin Brain Lab
Sanders-Brown Center on Aging
Department of Pharmacology and Nutritional Sciences, and Department of Biomedical Engineering
University of Kentucky
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