Diet modulates brain network stability, a biomarker for brain aging, in young adults

Don't worry, your doctor and stroke hospital will never contact anyone to get research done to see if this also works for the elderly and stroke patients.  Don't do this until such testing is done, maybe in 50 years, you'll be dead, so never mind.

Diet modulates brain network stability, a biomarker for brain aging, in young adults

Lilianne R. Mujica-Parodi, View ORCID ProfileAnar Amgalan, Syed Fahad Sultan, Botond Antal, Xiaofei Sun, Steven Skiena, Andrew Lithen, Noor Adra, Eva-Maria Ratai, Corey Weistuch, Sindhuja Tirumalai Govindarajan, Helmut H. Strey, Ken A. Dill, Steven M. Stufflebeam, Richard L. Veech, and Kieran Clarke

PNAS March 17, 2020 117 (11) 6170-6177; first published March 3, 2020 https://doi.org/10.1073/pnas.1913042117

1. Contributed by Ken A. Dill, January 9, 2020 (sent for review July 30, 2019; reviewed by Peter Crawford and Stephen C. Cunnane)

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Significance

To better understand how diet influences brain aging, we focus here on the presymptomatic period during which prevention may be most effective. Large-scale life span neuroimaging datasets show functional communication between brain regions destabilizes with age, typically starting in the late 40s, and that destabilization correlates with poorer cognition and accelerates with insulin resistance. Targeted experiments show that this biomarker for brain aging is reliably modulated with consumption of different fuel sources: Glucose decreases, and ketones increase the stability of brain networks. This effect replicated across both changes to total diet as well as fuel-specific calorie-matched bolus, producing changes in overall brain activity that suggest that network “switching” may reflect the brain’s adaptive response to conserve energy under resource constraint.

Abstract

Epidemiological studies suggest that insulin resistance accelerates progression of age-based cognitive impairment, which neuroimaging has linked to brain glucose hypometabolism. As cellular inputs, ketones increase Gibbs free energy change for ATP by 27% compared to glucose. Here we test whether dietary changes are capable of modulating sustained functional communication between brain regions (network stability) by changing their predominant dietary fuel from glucose to ketones. We first established network stability as a biomarker for brain aging using two large-scale (n = 292, ages 20 to 85 y; n = 636, ages 18 to 88 y) 3 T functional MRI (fMRI) datasets. To determine whether diet can influence brain network stability, we additionally scanned 42 adults, age < 50 y, using ultrahigh-field (7 T) ultrafast (802 ms) fMRI optimized for single-participant-level detection sensitivity. One cohort was scanned under standard diet, overnight fasting, and ketogenic diet conditions. To isolate the impact of fuel type, an independent overnight fasted cohort was scanned before and after administration of a calorie-matched glucose and exogenous ketone ester (d-β-hydroxybutyrate) bolus. Across the life span, brain network destabilization correlated with decreased brain activity and cognitive acuity. Effects emerged at 47 y, with the most rapid degeneration occurring at 60 y.(Oh shit, at 64 I'm way past this and obviously my brain stability is gone, as proven by my profane rants.) Networks were destabilized by glucose and stabilized by ketones, irrespective of whether ketosis was achieved with a ketogenic diet or exogenous ketone ester. Together, our results suggest that brain network destabilization may reflect early signs of hypometabolism, associated with dementia. Dietary interventions resulting in ketone utilization increase available energy and thus may show potential in protecting the aging brain.

Because the human brain is only 2% of the body’s volume but consumes over 20% of its energy (1, 2), it is particularly vulnerable to changes in metabolism. Dietary increase in glycemic load over the past 100 y has led to a national epidemic of insulin resistance (type 2 diabetes [T2D]) (3, 4), which has been identified by several large-scale epidemiological studies as an early risk factor for later-life dementia (5). For example, a post hoc analysis of the UK Whitehall II cohort study (n = 5,653) reported that those with diabetes showed a 45% faster decline in memory, a 29% faster decline in reasoning, and a 24% faster decline in global cognitive score and that the risk of accelerated cognitive decline in middle-aged patients with T2D is dependent on both disease duration and glycemic control (6). Similar results were reported using cohorts obtained from Israel (n = 897) (7) and the United States (n = 4,135) (8), the latter of which found the relationship between T2D and cognitive dysfunction to be evident even in younger adults. This marked association has led some researchers to propose that dementia may be the brain’s manifestation of metabolic disease (9).

This association is all the more surprising because, until quite recently, the brain was assumed to make use of purely insulin-independent transport of glucose into cells (GLUT3), utilizing neither insulin nor insulin transport (GLUT4). However, there now is rapidly accumulating evidence that insulin is directly relevant to neurons, brain aging, and associated memory deficits. For example, an early breakthrough study with radioactive insulin staining found that, contrary to the assumption that neurons did not utilize insulin, the rat brain was, in fact, densely populated with insulin receptors in both the hippocampus and cortex (10). Positron emission tomography in humans has demonstrated reduced glucose uptake in insulin-resistant participants versus healthy controls (11), suggesting that even the earliest stages of T2D induce hypometabolism of neurons, as with other cells in the body and as per brain glucose hypometabolism commonly seen in dementia. Finally, infusing insulin, without increasing glucose, has been shown to increase memory for Alzheimer’s disease patients (12). These clinical studies suggest that deleterious cognitive effects of insulin resistance may result from metabolic stress, as neurons gradually lose access to glucose. If so, it may be possible to bypass insulin resistance to refeed neurons by exploiting ketone bodies as an alternative fuel.

Endogenous ketone bodies, including d-β-hydroxybutyrate, are primarily produced in the liver from long- and medium-chain free fatty acids released from adipose tissue during hypocaloric/fasting states or food when following a low-carbohydrate/moderate-protein/high-fat diet (13). In rats, neurological and cognitive effects of glucocorticoid-induced insulin resistance in the hippocampus were reversed by ketone bodies (d-β-hydroxybutyrate) and mannose but not by either glucose or fructose (14). Likewise, in humans there is evidence that even as older brains become hypometabolic to glucose, neural uptake of ketone bodies remains unaffected, even for the most severe glucose hypometabolism endemic to Alzheimer’s disease (15, 16). Finally, lifelong hypocalorically induced ketosis preserves synaptic plasticity (17) and cognition (18) in elderly animals [chronological age equivalent to ∼87 to 93 human years (19)].

Beyond the ability to short-circuit insulin resistance, however, ketone bodies have other metabolic advantages (20⇓⇓⇓–24) that may confer neurobiological benefits even to younger healthy individuals not yet in a deficit (hypometabolic) state. Of those advantages, one of the most fundamental is that, as cellular inputs, β-hydroxybutyrate molecules increase Gibbs free energy change for ATP by 27% compared to glucose (24). While it is currently unknown how increasing available energy might impact a healthy brain, one consequence suggested by prior animal data is an increase in neurotransmitter production. Eight- to ten-month-old mice, the chronological equivalent of ∼27- to 33-y-old humans (19), showed increased synaptic efficiency, low-theta band oscillations, and learning consolidation during intermittent-fasting-induced ketosis (25). Mechanistically, this increase in synaptic efficiency was linked to increased expression of the N-methyl-d-aspartate (NMDA) receptor for glutamate.

Here we test two hypotheses. First, we investigate the time course of brain aging in humans to determine whether there is evidence for a long-term degenerative process that lays the foundation for neurometabolic stress—decades before cognitive effects become evident. This is clinically critical because it identifies a window of time during which neurodegenerative effects may still be reversible if we can increase neurons’ access to fuel. Second, to isolate the role of energy in modulating this variable, we hold age constant while testing the neurobiological impact of switching the primary fuel source of the human brain from glucose to ketone bodies. The above translational results showed that fasting increases NMDA-driven synaptic efficiency (25); neurotransmission, in turn, has been shown to drive change in cerebral blood flow (26) and thus functional communication between brain regions measured by blood oxygen level–dependent (BOLD) functional MRI (fMRI) resting-state connectivity (27). Therefore, we expected that ketone bodies might improve fMRI-derived measures of neurobiological functioning, even in healthy younger adults.

To test these hypotheses, we proceeded in two stages. First, using independent large-scale human fMRI datasets, sampling across the adult life span (ages 18 to 88), we established a whole-brain-scale biomarker (network stability, defined as the brain’s ability to sustain functional communication between its regions) that robustly associates with brain aging. Second, we conducted two targeted experiments in humans, optimized for detection sensitivity at the single-participant level, to test the impact of manipulating fuel type: glucose versus ketone bodies, using both diet and bolus, on that biomarker. Of note, while translational studies tend to employ long-term (“lifelong”) dietary modifications—equivalent to 20 to 30 y of human life span—for our targeted experiments we deliberately focused on rapid effects (after 1 wk of the ketogenic diet and half an hour for the d-βHb ketone ester). This was done for three reasons. First, it permitted a within-subject design, thereby rigorously controlling for genetic and environmental differences between subjects. Second, it narrowed down the number of potential biological mechanisms to those capable of acting over minutes or days, rather than months, years, or decades. Finally, we maximized clinical relevance by using dietary modifications that would be realistic to implement by most individuals in real-world environments.