Does our brain suddenly need an alternative fuel to glucose when we hit middle age....or even sooner


An astonishing set of observations within neurological research could fundamentally change how we see nutrition and the way in which nutrition could ‘treat’ age-related illness in the future.

The research is still at a very early stage with large parts of the jigsaw puzzle still missing. These pieces could still completely negate what we think the research shows, so we must be cautious to not extrapolate the results yet or draw any fundamental conclusions at this stage.

However, the results that seem to be accumulating at this early stage are little short of astounding.

‘Neurodegeneration’ refers to the degeneration of our nervous system that is seen both in ageing and in age-related disease states, such as Alzheimer’s Disease.

All our nerve cells contain little ‘factories’ that produce energy for each nerve cell to function. These factories are called ‘mitochondria’. Nerve cells are heavily reliant on energy because every time they fire, the electrical signal uses up a lot of energy, so they are constantly working at the fringes of their energy supply.

One theory of neurodegeneration is based on the mitochondria becoming damaged over time, through ‘wear and tear’. If the mitochondria become damaged, they stop producing enough energy. Without enough energy, nerve cells cannot function and ‘die’. For most of us, ‘glucose’ is our main source of fuel. Mitochondria ‘burn’ glucose to provide energy.

Here is where the astonishing results come in. A while ago, we observed that with ageing and neurodegeneration, we see a reduction in the use of glucose by the brain. We initially dismissed this as nothing out of the ordinary because if nerve cells degenerate and die with age, then there are fewer nerve cells around to use the glucose. However, we then noticed two things.

First, if we look at the brains of people who are at high risk of Alzheimer’s disease while they are still young and their brains are still ‘healthy’, we see a reduction in glucose metabolism, compared to controls. This implies that their brain cells might be getting a reduced supply of energy. They seem to enter into a phase of reduced glucose metabolism (hence, reduced energy supply) which precedes their entry into Alzheimer's Disease. Could this reduction in energy supply play a role in triggering their Alzheimer's Disease?

Second, If we look at the brains of people with established neurodegeneration, we find that parts of the brain that show a reduction in glucose metabolism extend beyond parts of the brain that are showing obvious signs of neurodegeneration. Instead, parts that are still 'relatively' better off but will eventually descend into degeneration also seem to have reduced glucose metabolism. Again, could the phase of a reduced supply of energy be triggering the neurogeneration?

A third study published this year is even more fascinating. This was an animal study on mice that showed that at the onset of menopause and long before age-related degeneration, brain cells seem to start to prefer ‘ketone bodies’ (or ‘ketones’) rather than glucose as fuel. Ketones are breakdown products of fat and are an alternative fuel source for the brain.

This study is not isolated. There have been similar observations on humans where when comparing younger and older volunteers, we find that as we grow older, parts of our brain seem less ‘able’ to metabolise glucose whereas this change is not seen with the ability to metabolise ketones. We continue to be able to metabolise ketones just as we do when we are young. Compared to ketones, the ability to use glucose declines. Ketones bypass some steps involved with glucose processing and this might 'lighten' the load on mitochondria. Adding ketones has been shown to increase the amount of energy available to nerve cells, even when some of the mitochondrial machinery is malfunctioning.

Although we are at a very early stage, these observations have huge implications.

  • Could brain ageing be partly caused by a reduction in energy supply from an inability to process glucose as fuel?

  • Could using ketones as fuel and reducing glucose supply as soon as we grow a little older prevent our brain cells from ‘dying’?

  • Could ketones halt or prevent neurodegeneration? Could they stop ageing?

  • At what age does the decline in glucose metabolism begin in our brain? Could it begin at middle age? Could it begin even sooner?

  • Could ketones make us sharper and improve brain function from as early as our forties?

The medical world is hard at work trying to find the answers to these questions and until it does, we must watch and wait.

One way of increasing levels of ketones naturally within the body is through following a ketogenic diet. This is a high-fat diet where carbohydrates are kept very low (e.g. below 20g per day) and protein intake is kept at moderate levels. The ketogenic diet challenges existing dietary advice to limit fat consumption and increase carbohydrate consumption and a ketogenic diet must always be undertaken under medical supervision. More about this in a future post!

References:

1: Mosconi L. Glucose metabolism in normal aging and Alzheimer's disease:

Methodological and physiological considerations for PET studies. Clin Transl

Imaging. 2013 Aug;1(4).

2: Nugent S, Castellano CA, Goffaux P, Whittingstall K, Lepage M, Paquet N, Bocti C, Fulop T, Cunnane SC. Glucose hypometabolism is highly localized, but lower cortical thickness and brain atrophy are widespread in cognitively normal older adults. Am J Physiol Endocrinol Metab. 2014 Jun 1;306(11):E1315-21.

3: Yin F, Yao J, Sancheti H, Feng T, Melcangi RC, Morgan TE, Finch CE, Pike CJ, Mack WJ, Cadenas E, Brinton RD. The perimenopausal aging transition in the female rat brain: decline in bioenergetic systems and synaptic plasticity. Neurobiol Aging. 2015 Jul;36(7):2282-95.

4: Chételat G, Landeau B, Salmon E, Yakushev I, Bahri MA, Mézenge F, Perrotin A, Bastin C, Manrique A, Scheurich A, Scheckenberger M, Desgranges B, Eustache F, Fellgiebel A. Relationships between brain metabolism decrease in normal aging and changes in structural and functional connectivity. Neuroimage. 2013 Aug

1;76:167-77.

5: Samuraki M, Matsunari I, Chen WP, Shima K, Yanase D, Takeda N, Matsuda H,

Yamada M. Glucose metabolism and gray-matter concentration in apolipoprotein E ε4 positive normal subjects. Neurobiol Aging. 2012 Oct;33(10):2321-3.

6: Yao J, Rettberg JR, Klosinski LP, Cadenas E, Brinton RD. Shift in brain

metabolism in late onset Alzheimer's disease: implications for biomarkers and therapeutic interventions. Mol Aspects Med. 2011 Aug;32(4-6):247-57.

7: Yao J, Brinton RD. Targeting mitochondrial bioenergetics for Alzheimer's

prevention and treatment. Curr Pharm Des. 2011;17(31):3474-9.

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