Low carb-based diet help to reverse signs of early brain aging in middle-aged people


A study using neuroimaging led by Stony Brook University professor and lead author Lilianne R. Mujica-Parodi, PhD, and published in PNAS, reveals that neurobiological changes associated with aging can be seen at a much younger age than would be expected, in the late 40s.

However, the study also suggests that this process may be prevented or reversed based on dietary changes that involve minimizing the consumption of simple carbohydrates.

To better understand how diet influences brain aging, the research team focused on the presymptomatic period during which prevention may be most effective.

In the article titled “Diet modulates brain network stability, a biomarker for brain aging, in young adults,” they showed, using large-scale life span neuroimaging datasets, that functional communication between brain regions destabilizes with age, typically in the late 40’s, and that destabilization correlates with poorer cognition and accelerates with insulin resistance.

Targeted experiments then showed this biomarker for brain aging to be reliably modulated with consumption of different fuel sources: glucose decreases, and ketones increase, the stability of brain networks.

This effect was replicated across both changes to total diet as well as after drinking a fuel-specific calorie-matched supplement.

“What we found with these experiments involves both bad and good news,” said Mujica-Parodi, a Professor in the Department of Biomedical Engineering with joint appointments in the College of Engineering & Applied Sciences and Renaissance School of Medicine at Stony Brook University, and a faculty member in the Laufer Center for Physical and Quantitative Biology.

“The bad news is that we see the first signs of brain aging much earlier than was previously thought. However, the good news is that we may be able to prevent or reverse these effects with diet, mitigating the impact of encroaching hypometabolism by exchanging glucose for ketones as fuel for neurons.”

What the researchers discovered, using neuroimaging of the brain, is that quite early on there is breakdown of communication between brain regions (“network stability”).

“We think that, as people get older, their brains start to lose the ability to metabolize glucose efficiently, causing neurons to slowly starve, and brain networks to destabilize,” said Mujica-Parodi.

“Thus, we tested whether giving the brain a more efficient fuel source, in the form of ketones, either by following a low-carb diet or drinking ketone supplements, could provide the brain with greater energy. Even in younger individuals, this added energy further stabilized brain networks.”

To conduct their experiments, brain network stability was established as a biomarker for aging by using two large-scale brain neuroimaging (fMRI) datasets totaling nearly 1,000 individuals, ages 18 to 88.

Destabilization of brain networks was associated with impaired cognition and was accelerated with Type 2 diabetes, an illness that blocks neurons’ ability to effectively metabolize glucose.

To identify the mechanism as being specific to energy availability, the researchers then held age constant and scanned an additional 42 adults under the age of 50 years with fMRI. This allowed them to observe directly the impact of glucose and ketones on each individual’s brain.

The brain’s response to diet was tested in two ways. The first was holistic, comparing brain network stability after participants had spent one week on a standard (unrestricted) vs. low carb (for example: meat or fish with salad, but no sugar, grains, rice, starchy vegetables) diet.

In a standard diet, the primary fuel metabolized is glucose, whereas in a low-carb diet, the primary fuel metabolized is ketones.

However, there might have been other differences between diets driving the observed effects. Therefore, to isolate glucose vs. ketones as the crucial difference between the diets, an independent set of participants was scanned before and after drinking a small dose of glucose on one day, and ketones on the other, where the two fuels were individually weight-dosed and calorically matched.

The results replicated, showing that the differences between the diets could be attributed to the type of fuel they provide to the brain.

Additional findings from the study included the following: Effects of brain aging emerged at age 47, with most rapid degeneration occurring at age 60. Even in younger adults, under age 50, dietary ketosis (whether achieved after one week of dietary change or 30 minutes after drinking ketones) increased overall brain activity and stabilized functional networks.

This is thought to be due to the fact that ketones provide greater energy to cells than glucose, even when the fuels are calorically matched.

This benefit has previously been shown for the heart, but the current set of experiments provides the first evidence for equivalent effects in the brain.

This effect matters because brain aging, and especially dementia, are associated with “hypometabolism,” in which neurons gradually lose the ability to effectively use glucose as fuel.

Therefore, if we can increase the amount of energy available to the brain by using a different fuel, the hope is that we can restore the brain to more youthful functioning.

In collaboration with Dr. Eva Ratai at Massachusetts General Hospital, we’re currently addressing this question, by now extending our studies to older populations,” said Mujica-Parodi.

Targeted experiments then showed this biomarker for brain aging to be reliably modulated with consumption of different fuel sources: glucose decreases, and ketones increase, the stability of brain networks.

“Additional research with collaborators at Children’s National, under the direction of Dr. Nathan Smith, focuses on discovering the precise mechanisms by which fuel impacts signaling between neurons.

Finally, in collaboration with Dr. Ken Dill and Dr. Steven Skiena, at Stony Brook, we’re working on building a comprehensive computational model that can incorporate our understanding of the biology, from individual neurons to whole brains to cognition, as it develops.”

The research is currently funded under a new $2.5 million National Science Foundation BRAIN Initiative “Frontiers” grants (numbers (NSFECCS1533257 and NSFNCS-FR 1926781) awarded to Stony Brook, as well as by the W. M. Keck Foundation, which originally funded the team in 2017 with a $1 million seed grant designed to jump-start “pioneering discoveries in science, engineering, and medical research.”

Collaborators included Stony Brook faculty from the Laufer Center for Physical and Quantitative Biology, Departments of Biomedical Engineering, Applied Mathematics and Statistics, Physics and Astronomy, and Computer Science; and scientists at the Athinoula A. Martinos Center for Biomedical Imaging (Massachusetts General Hospital and Harvard Medical School), Children’s National, the National Institutes of Health, and Oxford University.

Type 2 diabetes (T2D), obesity, and metabolic disease impact over one billion people and present a challenge to public health and economic growth (12). In the United States, over 30 million people have diabetes and it is recognized among the leading causes of morbidity and mortality, especially through increased cardiovascular disease (CVD) (3).

The remission rate under usual care is 0.5–2% (4) while an intensive lifestyle intervention resulted in remission rates (both partial and complete) of 11.5 and 9.2% at 1 and 2 years (5). When lifestyle interventions are insufficient, medications are indicated to manage the disease and slow progression (67).

When T2D care directed at disease reversal is successful, this includes achievement of restored metabolic health, glycemic control with reduced dependence on medication, and in some cases disease remission.

Three non-pharmaceutical approaches have demonstrated high rates of at least temporary T2D diabetes reversal or remission: bariatric surgery, very low calorie diets (VLCD), and nutritional ketosis achieved through carbohydrate restriction (810).

In controlled clinical trials, each approach has demonstrated improved glycemic control and CVD risk factors, reduced pharmaceutical dependence, and weight loss.

The three approaches show a similar time-course with glycemic control preceding weight loss by weeks or months, suggesting potential overlap of mechanisms (1112).

With bariatric surgery, up to 60% of patients demonstrate T2D remission at 1 year (13). Outcomes at 2 years and beyond indicate ~50% of patients can achieve ongoing diabetes remission (1314).

The second Diabetes Surgery Summit recommended using bariatric surgery to treat T2D with support from worldwide medical and scientific societies (15), but both complications associated with surgery and cost limit its widespread use (1617).

VLCDs providing <900 kcal/day allow rapid discontinuation of most medications, improved glycemic control, and weight loss. This approach is necessarily temporary, however, with weight regain and impaired glucose control typically occurring within 3–6 months of reintroduction of substantial proportions of dietary carbohydrates (91820).

A third approach to diabetes reversal is sustained dietary carbohydrate restriction. Low-carbohydrate diets have consistently elicited improvements in T2D, metabolic disease, and obesity up to one year (2122), however, longer-term studies and studies including patients prescribed insulin are limited.

A low-carbohydrate Mediterranean diet caused remission in 14.7% of newly diagnosed diabetes patients at 1 year vs. 4.1% with a low-fat diet (23), and a small randomized trial utilizing a ketogenic diet demonstrated improved weight and diabetes control at 1 year (24).

Systematic reviews also corroborate the effectiveness of a low-carbohydrate diet for T2D (2526) and it has recently become a consensus recommended dietary option (2729). Nonetheless, sustained adherence to carbohydrate restriction is considered challenging (2728) and an LDL-C increase is sometimes observed (3033).

Given that total LDL-particles (LDL-P), small LDL-P, and ApoB tend to improve or remain unchanged, the impact of an increase in LDL-C on CVD risk in the context of this dietary pattern is unknown.

We have previously reported 1 year outcomes of an open-label, non-randomized, controlled, longitudinal study with 262 continuous care intervention (CCI), and 87 usual care (UC) participants with T2D (10).

The CCI included individualized support with telemedicine, health coaching, and guidance in nutritional ketosis using an individualized low-carbohydrate diet. Nutritional guidance encouraged sustained nutritional ketosis; patients were counseled on preparation of a low-carbohydrate diet adapted to meet their life circumstances.

Eighty-three percent of CCI participants remained enrolled at 1 year and 60% of completers achieved an HbA1c <6.5% while prescribed metformin or no diabetes medication. Weight was reduced and most CVD risk factors improved (33).

Long-term studies of low-carbohydrate dietary approaches to treat type 2 diabetes and obesity are limited, particularly among those that are delivered and supported remotely. Here we assess longer-term outcomes in CCI participants with T2D at 2 years, as well as the effects on body composition and related comorbidities.

The primary aims were to investigate the effect of the CCI on retention, glycemic control, diabetes status, and weight. Secondary aims included: (1) investigating the effect of the CCI on bone mineral density, visceral fat composition, cardiovascular risk factors, liver, kidney, thyroid and inflammatory markers, and related disease outcomes (e.g., metabolic syndrome); and (2) comparing 2-year outcomes between the CCI and UC groups.

Stony Brook University


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