Neuroprotective Potential of Calorie Restriction, Alternate-Day Fasting, and Carb-Concentrated Diets

A considerable amount of recent research has focused on the neuroprotective properties of intermittent fasting and chronic calorie restriction; the impacts of calorie restriction and alternate-day fasting appear to be quite parallel in this regard, although the effects of alternate-day fasting have been more dramatic in some studies, possibly because it is associated with higher levels of ketones bodies, which are themselves neuroprotective in various respects.  In rodents, these strategies increase brain levels of an array of protective factors, including Sirt1, “neurotrophic” hormones such as BDNF, and heat shock proteins (that help to prevent or correct protein mis-folding, a common cause of cellular distress.)  In aggregate, these effects are thought to be largely responsible for the wide range of neuroprotective benefits observed in rodents subjected to chronic calorie restriction or intermittent fasting: improved neuronal survival and better preservation of cognitive function in rodent models of Alzheimer’s, Parkinson’s, and Huntington’s disease; better neuronal survival and decreased loss of functional capacity following induced stroke or exposure to various neurotoxins; a retardation of the age-related deficits in learning and motor coordination, associated with relative preservation of the “long-term potentiation” mechanism that underlies learning.  As mentioned above, long-term calorie restriction in rhesus monkeys is associated with greater preservation of gray matter in some parts of the brain.  And, although relatively few epidemiological studies to date have examined the impact of total daily calorie intake on health outcomes, studies in New York City have concluded that people who keep their calorie intake relatively low are at reduced risk for both Alzheimer’s and Parkinson’s diseases.

A remarkable aspect of this neuroprotective effect is that, whereas calorie restriction or intermittent fasting tend to reduce growth factor activities (insulin/IGF-I) throughout much of the body – an effect which appears to be crucial to the anti-aging and cancer-preventive impacts of these strategies – they actually appear to increase effective growth factor activity in the brain!  Thus, calorie restriction in mice has been found to increase both the expression level and activation state of insulin receptors in the brain – even though blood levels of insulin are of course notably reduced.  This may reflect, in part, a compensatory increase in the efficiency with which insulin is transported into the brain via the blood-brain barrier.  Moreover, as noted, these food deprivation strategies also boost the expression of other growth factors that target neurons, most notably brain-derived neurotrophic factor (BDNF).  This increase in brain growth factor activity promotes reparative neurogenesis, helps neurons to survive a range of toxic insults, and aids the efficiency of learning.

An area of ongoing controversy is the impact of calorie restriction on autophagy in the brain.  As we have noted elsewhere, autophagy (or more properly, macroautophagy) is a carefully regulated process which sweeps proteins and membranes – including sub-cellular structures (organelles) such as mitochondria – residing in the cell’s cytoplasm into special vacuoles, where they are degraded to yield their constituent amino acids and fatty acids.  When this process is properly balanced with the biosynthesis of new proteins, membranes, and mitochondria (using the amino acids and fatty acids derived from autophagy as building blocks), the net effect is to insure that the proteins and organelles inside our cells are “shiny and new”, so that they function optimally.  The proteins and membranes inside our cells are under constant attack by oxidative stress, and can also spontaneously lose their proper conformation; autophagy compensates for this by clearing out the damaged cellular constituents, which can then be replaced.  Autophagy is of particular importance to the proper functions of organs such as the brain and heart whose cells are long-lived and difficult to replace.

When properly regulated, autophagy aids the proper function and survival of neurons, by disposing of toxic protein aggregates and insuring that mitochondria are structurally and functionally sound.  Indeed, a steady low level of neuronal autophagy is crucial to brain health; mice in whom the process of autophagy is genetically defective develop fatal neurodegenerative disorders.  Moreover, activation of brain autophagy by certain drugs (e.g. rapamycin) has been found to be protective in rodent models of Alzheimer’s and Parkinson’s disease; pharmaceutical companies are scrambling to develop other, safer drugs that could be used to treat neurodegenerative disorders by stimulating brain autophagy.  However, whereas the reduction in growth factor activities associated with calorie restriction tends to boost protective autophagy in most tissues, the few studies that have examined brain autophagy in short-term fasted mice (none so far have looked at this in calorie-restricted mice) have yielded conflicting conclusions.  The increase of brain growth factor activity seen during fasting or calorie restriction would be expected to inhibit autophagy; on the other hand, certain enzymes which can be activated in the brain by fasting or calorie restriction, such as sirt1 or AMPK, have the potential to boost autophagy.  Clearly, further studies are required to clarify whether calorie restriction has the potential to protect the brain via autophagy induction.  But even if such studies ultimately have a negative outcome, it is clear that the net impact of calorie restriction on the brain is neuroprotective.

As noted, the somewhat greater neuroprotection seen with intermittent fasting than with daily calorie restriction may be attributable in part to increased production of ketone bodies.  Ketogenic diets, in which the liver converts large amounts of fat to ketone bodies that can be utilized by the brain as fuel when glucose availability is reduced, have long been known to be an effective treatment for epilepsy.  Such diets have also shown neuroprotective properties in rodent studies.  This may stem, in part, from the value of ketones as alternative fuel for brain neurons when energy production from glucose is suboptimal; however, it is clear that additional factors are involved.  In particular, there are theoretical grounds for suspecting that neuronal metabolism of ketone bodies might promote activation of AMPK, an enzyme which has the potential to activate neuronal autophagy, and exert other neuroprotective effects.  As we discuss elsewhere on this website, the liver’s production of ketone bodies can be increased not only by fasting, but by ingestion of a type of oil known as medium-chain triglycerides; it would be interesting to know whether these can boost autophagy in the brain.

Evidently, CC dieting, to the extent that it can mimic the metabolic effects of intermittent fasting, and can achieve a genuine moderate reduction in daily calorie intake, has real potential for slowing the inroads of the aging process on optimal cognitive function, and for providing some measure of protection from age-related neurodegenerative disorders such as Alzheimer’s and Parkinson’s which can have such a devastating impact not only on their victims, but their loved ones as well.

← Back to Frequently Asked Questions