The brain requires a lot of energy to function. Like muscle tissue, it is particularly vulnerable to age-related dysfunction in energy metabolism, the various pathways by which cells make use of nutrients to supply energy for the operation of vital biochemical processes. The brain primarily makes use of glucose as a nutrient, but this process of deriving energy from glucose becomes dysfunctional with age, and this dysfunction tends to be particularly pronounced in patients exhibiting neurodegenerative conditions such as Alzheimer's disease. An alternative to glucose readily used elsewhere in the body is β-oxidation of fatty acids. There are reasonable explanations as to why the brain has evolved not to favor this path, such as the greater degree of oxidative stress it generates. But at the end of the day, if the brain had more access to compensatory sources of energy, dysfunction would be slowed with aging.
So to today's research materials, in which the scientists involved show that people with higher degrees of β-oxidation of fatty acids throughout the body tend to suffer less as glucose metabolism in the brain runs awry with age. Thus one could use biomarkers of β-oxidation and call it a measure of the age of energy metabolism, as the researchers do here, but I think that to be an unhelpful framing obscures the relationships between the underlying processes and capacities. As the researchers note, the beneficial effects of present anti-amyloid immunotherapies are small enough, only a modest slowing of disease progression, that a shift in metabolism to favor β-oxidation can produce a similar outcome. What one should take away from this is not that we should all jump up and focus research efforts on upregulation of β-oxidation of fatty acids, which can be achieved to a reasonable degree by ketogenic and calorie restricted diets, but rather that there remains a great unmet need for actually effective therapies to turn back the progression of neurodegenerative conditions.
Lowering Bioenergetic Age May Help Fend Off Alzheimer's
A person's "bioenergetic age" - or how youthfully their cells generate energy - might be a key indicator of whether they're at risk of developing Alzheimer's disease, new research shows. One of the early warning signs of Alzheimer's is that brain cells start losing their ability to produce and use energy efficiently, such as metabolizing glucose. But some people don't show disease symptoms for years. This delay between abnormalities in energy pathways and the onset of symptomatic disease suggests there is a "bioenergetic capacity" that provides a buffer for these individuals. Their bodies and brains are better at keeping energy levels up even when problems start.
Researchers turned to a group of molecules called acylcarnitines, which are associated with declining cognition and breaking down or metabolizing fats and proteins for energy. To test if high acylcarnitine levels in the blood could predict who's at risk of developing Alzheimer's, the researchers used data from a large-scale study called the Alzheimer's Disease Neuroimaging Initiative. This led the researchers to define a bioenergetic clock based on acylcarnitines - how old a person's metabolism acts, compared to actual age. Higher bioenergetic age is linked to higher acylcarnitine levels, worsened Alzheimer's pathology, cognitive decline, and brain atrophy.
The researchers also quantified cognitive decline using a common test called the mini-mental state examination, on which a score below 24 out of 30 points indicates impairment. They found that people with low acylcarnitine levels to begin with declined more slowly, losing about 0.5 points less per year than people with high acylcarnitine levels. The benefit is on par with the Alzheimer's drug lecanemab. To some degree, a person's bioenergetic clock ticks forward at a rate determined by their genetics, but having a healthy lifestyle - for example, eating a plant-based diet and exercising - can help keep acylcarnitine levels low, which means a younger bioenergetic age.
Individual bioenergetic capacity as a potential source of resilience to Alzheimer's disease
Impaired glucose uptake in the brain is an early presymptomatic manifestation of Alzheimer's disease (AD), with symptom-free periods of varying duration that likely reflect individual differences in metabolic resilience. We propose a systemic "bioenergetic capacity", the individual ability to maintain energy homeostasis under pathological conditions. Using fasting serum acylcarnitine profiles from the AD Neuroimaging Initiative as a blood-based readout for this capacity, we identified subgroups with distinct clinical and biomarker presentations of AD.
Our data suggests that improving beta-oxidation efficiency can decelerate bioenergetic aging and disease progression. The estimated treatment effects of targeting the bioenergetic capacity were comparable to those of recently approved anti-amyloid therapies, particularly in individuals with specific mitochondrial genotypes linked to succinylcarnitine metabolism. Taken together, our findings provide evidence that therapeutically enhancing bioenergetic health may reduce the risk of symptomatic AD. Furthermore, monitoring the bioenergetic capacity via blood acylcarnitine measurements can be achieved using existing clinical assays.
View the full article at FightAging
