CompletedNCT03457870ChANgEUpdated Feb 18, 2021

Intermittent Energy Restriction and Chewing on Neural Stem Cell Ageing and Adult Hippocampal Neurogenesis Associated Cognition

An interventional study of Intermittent Energy Restriction and Chewing in Aging and Cognitive Decline, sponsored by King's College London. Completed at 1 site in United Kingdom. Open to female participants aged 60 Years and older, including healthy volunteers. Per ClinicalTrials.gov, last updated 2021-02-18.

Sponsored by King's College London · Not applicable, Interventional, and Prevention

Phase: Not applicable
Study type: Interventional
Enrollment: 123
Allocation: Randomized
Ages: 60 Years and older
Sex: Female

Study summary

Extended bouts of periodic mastication and intermittent energy restriction (IER) may improve cognitive performance in the context of adult hippocampal neurogenesis in an ageing population. A randomised controlled parallel design trial will determine the impact of a 3 month IER diet (2 consecutive days of very low calorie diet and 5 days of normal eating) and a mastication intervention (1 piece of gum chewed for 10 minutes 3 times a day) in comparison to a control on neurogenesis-associated cognitive measures and circulating levels of the anti-ageing protein Klotho.

Read the detailed description

Nutrition and human health are strongly related. Altering overabundance through fasting/calorie-restricted diets has profound effects on homeostasis, tissue regeneration, and cancer. Tissue stem cells respond to the physiological changes that occur during fasting through dynamic shifts in their metabolism. Restricting energy intake in mice or introducing mutations in nutrient-sensing pathways can extend lifespans by as much as 50%. Post-mortems reveal that tumours, heart problems, neurodegeneration and metabolic disease are generally reduced/delayed in long-lived mice. Therefore, extending lifespan by energy restriction (ER) also seems to increase 'healthspan', the time lived without chronic age-related conditions. These insights have hardly made a dent in human medicine. Molecular and cellular insights should be established in humans to validate interventions such as ER to delay ageing and associated conditions e.g. cognitive decline (Murphy et al., 2014).

Stem cells from the central nervous system also respond to ER. Recently, the Thuret lab have found that ER, in the absence of malnutrition, promotes hippocampal stem cells to proliferate and differentiate into new-born neurons. Because these new postnatal hippocampal neurons have been shown to play a role in cognition, ER also promoted enhanced cognition in rodents (Zainuddin et al., 2012; de Lucia et al., 2017; Thuret et al., 2012). This phenomenon of neurogenesis, the process by which new neurons are generated from neural stem cells, is also occurring in humans (Spalding et al., 2013). It is a tightly regulated process occurring in the mammalian hippocampus which is an environmentally responsive brain structure known to regulate learning, memory and mood. Proposed functions of adult hippocampal neurogenesis (AHN). include enhancing recognition memory, the ability to recognise previously encountered stimuli, and pattern separation, the ability to differentially encode small changes in similar inputs (Clelland et alk., 2009; Sahay et al., 2011). It has been posited that calorie restriction may increase neurogenesis as a "cellular relic" of intermittent feeding patterns during evolution as a response to alternating periods of famine and abundant food (Murphy \& Thuret, 2015). Human trials have found significant improvements in verbal recognition memory after 30% reduction in calorie intake (Witte et al., 2009). Also, intermittent fasting in humans has been associated with significant increases in brain activation volume in areas involved in brain function control and plasticity(Belaïch et al., 2016). Food texture and mastication have also been implicated in AHN and cognitive ability (Smith et al., 2016). Decreased mastication due to the removal of molars and edentulism in both humans and animals have a negative impact on AHN and associated cognition. Human populations, in particular, have shown a close association between masticatory function, cognitive status and age-related neurodegeneration in the elderly (Miura et al., 2003). The exact mechanism by which mastication affects cognition is unknown.

Research question: In older, overweight participants does IER and/or extended periods of mastication enhance performance inhippocampus-dependent memory tasks and increase anti-ageing marker Klotho?

Objectives:

A randomised controlled parallel-design trial will determine the impact of an IER diet (2 consecutive days of a very low calorie diet, 5 days of normal healthy eating for 3 months) and/or extended periods of mastication (10 minutes 3 times a day for 3 months) compared to a control group (continued habitual eating behaviour, dietary patterns) on primary outcome variables (MST and Klotho) in older, healthy participants with overweight or class I obesity.
To assess the impact of an IER diet and extended periods of mastication on secondary outcomes variables including body composition, mood and sleep.
To explore whether extended periods of mastication can be utilised as a weight loss/fasting aid.

Conditions studied

Aging
Cognitive Decline

Browse trials for

Keywords

Intermittent fasting
Adult hippocampal neurogenesis
Mastication
Pattern separation
Recognition memory
Klotho

In context

Cognitive Dysfunction

3,872 studies on the registry are indexed under Cognitive Dysfunction; 1,119 are open to participants now.

This study's enrollment of 123 is above the median of 64 across 2,794 interventional studies indexed under Cognitive Dysfunction.

Browse Cognitive Dysfunction studies →

Lead sponsor

King's College London is the lead sponsor of 520 studies on the registry; 126 are open to participants now.

Browse King's College London studies →

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 60 Years and older
Sexes eligible: Female
Accepts healthy volunteers: Yes

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

Inclusion criteria

Male and female subjects.
60+ years of age at the time of consent.
25-35.

Exclusion criteria

Exclusion Criteria:

Subject is unable to understand the participant information sheet.
Subject is unable to understand and/or completely perform the cognitive testing.
Chews more than 3 sticks of gum per month, including nicotine replacement gum.
Unable to provide written .
Impaired vision that is not corrected.
Does not agree to maintain their habitual exercise routine.
Is not in general good health on the basis of medical history.
Unwilling to chew gum for 3 times a day for 12 weeks.
Unwilling to maintain an intermittent fasting diet regime.
Unwilling to have blood taken.
History of or are currently diagnosed with a significant psychiatric disorder (e.g. schizophrenia, anxiety, PTSD).
Subject has any neurological disorder that could produce cognitive deterioration (e.g. Alzheimer's disease, Parkinson's disease, stroke).
History of traumatic brain injury, stroke or any other medical conditions causing cognitive impairment.
Has uncontrolled epilepsy or is prone to fainting.
Participated in a weight management drug trial in previous 3 months.
Has undergone bariatric surgery.
Known or suspected of alcohol abuse defined as >14 drinks per week (1 drink = 1 pint of beer, 1 large glass of wine or 50ml spirit).
Gastrointestinal or liver disease.
Subject has a sleep disorder or an occupation where sleep during the overnight hours is irregular.
Subjects taking the following prescription medications: Donepezil (Aricept), Galantamine (Reminyl), Rivastigmine (Exelon), Tacrine (Cognex), Bethanechol (Urecholine), Memantine (Namenda) Selegiline (Eldepryl) or any other medication for cognitive impairment.
Subject has a known sensitivity to the study product.
Individual has a condition the chief investigator believes would interfere with his or her ability to provide informed consent, comply with the study protocol, might confound the interpretation of study results or put the subject at undue risk.

Terms in these criteria, in plain language(2)

Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.

BMI (body mass index)

Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.

What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.

Informed consent

Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.

You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.

Study design

Phase: Not applicable
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel assignment
Masking: None (open label)
Enrollment: 123 participants (actual)

Study arms

Experimental
Intermittent Energy Restriction
Dietary intervention: Intermittent energy restriction
Behavioral: Intermittent Energy Restriction
Experimental
Chewing
Mastication intervention: chewing
Behavioral: Chewing
Experimental
Chewing + Intermittent Energy Restriction
Dietary and mastication intervention: Intermittent energy restriction and chewing
Behavioral: Chewing + Intermittent Energy Restriction
No intervention
Control
No intervention: Control

Interventions

BehavioralIntermittent Energy Restriction
Dietary advice to follow a 5:2 diet.
BehavioralChewing
Asked to chew 1 piece of gum for 10 minutes 3 times a day.
BehavioralChewing + Intermittent Energy Restriction
Dietary advice to follow a 5:2 diet. Asked to chew 1 piece of gum for 10 minutes 3 times a day.

What researchers measure

Primary outcomes

Serum Klotho concentration
Anti-ageing longevity protein
Time frame: Baseline
Serum Klotho concentration
Anti-ageing longevity protein
Time frame: Day 42
Serum Klotho concentration
Anti-ageing longevity protein
Time frame: Day 84
Mnemonic Similarity Task
Neurogenesis-associated cognition
Time frame: Baseline
Mnemonic Similarity Task
Neurogenesis-associated cognition
Time frame: Day 42

Secondary outcomes

Body weight
Time frame: Baseline
Body weight
Time frame: Day 42
Body weight
Time frame: Day 84
Body fat percentage
Time frame: Baseline
Body fat percentage
Time frame: Day 42
Body fat percentage
Time frame: Day 84
Body Mass Index
Time frame: Baseline
Body Mass Index
Time frame: Day 42
Body Mass Index
Time frame: Day 84
Waist circumference
Time frame: Baseline
Waist circumference
Time frame: Day 42
Waist circumference
Time frame: Day 84
Hip circumference
Time frame: Baseline
Hip circumference
Time frame: Day 42
Hip circumference
Time frame: Day 84
Patient Health Questionnaire
Questionnaire
Time frame: Baseline
Patient Health Questionnaire
Questionnaire
Time frame: Day 42
Patient Health Questionnaire
Questionnaire
Time frame: Day 84
Zung Self-Rating Anxiety Scale
Questionnaire - Scale can be scored from 20 (normal) to 80 (extreme anxiety levels). The total score is reported.
Time frame: Baseline
Zung Self-Rating Anxiety Scale
Questionnaire
Time frame: Day 42
Zung Self-Rating Anxiety Scale
Questionnaire
Time frame: Day 84
Pittsburgh Sleep Quality Index
Questionnaire
Time frame: Baseline
Pittsburgh Sleep Quality Index
Questionnaire
Time frame: Day 42
Pittsburgh Sleep Quality Index
Questionnaire
Time frame: Day 84
Plasma glucose concentration
Fasting
Time frame: Baseline
Plasma glucose concentration
Fasting
Time frame: Day 42
Plasma glucose concentration
Fasting
Time frame: Day 84
Cholesterol
Fasting
Time frame: Baseline
Cholesterol
Fasting
Time frame: Day 42
Cholesterol
Fasting
Time frame: Day 84
Triglycerides
Fasting
Time frame: Baseline
Triglycerides
Fasting
Time frame: Day 42
Triglycerides
Fasting
Time frame: Day 84
High Density Lipoprotein
Fasting
Time frame: Baseline
High Density Lipoprotein
Fasting
Time frame: Day 42
High Density Lipoprotein
Fasting
Time frame: Day 84
Low Density Lipoprotein
Fasting
Time frame: Baseline
Low Density Lipoprotein
Fasting
Time frame: Day 42
Low Density Lipoprotein
Fasting
Time frame: Day 84
Total/HDL Cholesterol Ratio
Fasting
Time frame: Baseline
Total/HDL Cholesterol Ratio
Fasting
Time frame: Day 42
Total/HDL Cholesterol Ratio
Fasting
Time frame: Day 84
Plasma adiponectin concentration
Fasting
Time frame: Baseline
Plasma adiponectin concentration
Fasting
Time frame: Day 42
Plasma adiponectin concentration
Fasting
Time frame: Day 84
Plasma leptin concentration
Fasting
Time frame: Baseline
Plasma leptin concentration
Fasting
Time frame: Day 42
Plasma leptin concentration
Fasting
Time frame: Day 84
Plasma beta-hydroxybutrate concentration
Fasting
Time frame: Baseline
Plasma beta-hydroxybutrate concentration
Fasting
Time frame: Day 42
Plasma beta-hydroxybutrate concentration
Fasting
Time frame: Day 84
Plasma total cholesterol concentration
Fasting
Time frame: Baseline
Plasma total cholesterol concentration
Fasting
Time frame: Day 42
Plasma total cholesterol concentration
Fasting
Time frame: Day 84
Plasma low density lipoprotein (LDL) cholesterol concentration
Fasting
Time frame: Baseline
Plasma LDL cholesterol concentration
Fasting
Time frame: Day 42
Plasma LDL cholesterol concentration
Fasting
Time frame: Day 84
Plasma high density lipoprotein (HDL) cholesterol concentration
Fasting
Time frame: Baseline
Plasma HDL cholesterol concentration
Fasting
Time frame: Day 42
Plasma HDL cholesterol concentration
Fasting
Time frame: Day 84
Plasma triglyceride concentration
Fasting
Time frame: Baseline
Plasma triglyceride concentration
Fasting
Time frame: Day 42
Plasma triglyceride concentration
Fasting
Time frame: Day 84
Plasma total cholesterol:HDL cholesterol ratio
Fasting
Time frame: Baseline
Plasma total cholesterol:HDL cholesterol ratio
Fasting
Time frame: Day 42
Plasma total cholesterol:HDL cholesterol ratio
Fasting
Time frame: Day 84

Other outcomes

Adverse events
Time frame: Baseline until endpoint: Day 84

Study locations

1 site

Diabetes & Nutritional Sciences Division, King's College London, Franklin-Wilkins Building, 150 Stamford St
London, England SE1 9NH, United Kingdom

References and documents

Publications

Murphy T, Dias GP, Thuret S. Effects of diet on brain plasticity in animal and human studies: mind the gap. Neural Plast. 2014;2014:563160. doi: 10.1155/2014/563160. Epub 2014 May 12. PubMed 24900924 ↗
Witte AV, Fobker M, Gellner R, Knecht S, Floel A. Caloric restriction improves memory in elderly humans. Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1255-60. doi: 10.1073/pnas.0808587106. Epub 2009 Jan 26. PubMed 19171901 ↗
Akazawa Y, Kitamura T, Fujihara Y, Yoshimura Y, Mitome M, Hasegawa T. Forced mastication increases survival of adult neural stem cells in the hippocampal dentate gyrus. Int J Mol Med. 2013 Feb;31(2):307-14. doi: 10.3892/ijmm.2012.1217. Epub 2012 Dec 18. PubMed 23254518 ↗
Smith, N., Miquel-Kergoat, S. & Thuret, S., 2016. The impact of mastication on cognition: Evidence for intervention and the role of adult hippocampal neurogenesis. Nutrition and Aging, 3(2-4), pp.115-123

Individual participant data

Plan to share: Undecided

Timeline

Tracking since Sep 25, 2026

ElapsedEstimatedEstimated, not yet reachedSimilar studies: half by the dot; the band is the middle halfHalf of similar studies reached it by the dot; the band is the middle half, from a quarter to three quarters

Ran from Apr 2018 to primary completion in Mar 2020, 23 months.

Of 1,442 non-industry interventional studies with no phase under Cognitive Dysfunction, half reached primary completion within 27 months of starting (the median), counting those still running; a quarter within 13 and three quarters within 51. This study's 23 months is below that.

Counting every sponsor, half of 1,511 studies reached it within 27 months; a quarter within 12 and three quarters within 50.

How these figures are worked out, and which studies are left out of them.

Registered: Feb 23, 2018
First posted: Mar 8, 2018
StartActual: Apr 18, 2018
Primary completionActual: Mar 23, 2020
CompletionActual: Mar 23, 2020
Last update: Feb 18, 2021

What these dates mean

Start.: When the first participant enrolled; while estimated, when the study expects to open to recruitment.
Primary completion.: When the last participant was examined or treated to collect data for the study's main question, its primary outcome. A study that stopped early gives the date its data collection stopped.
Completion.: When the last participant's last visit took place, for every outcome, secondary ones and side effects included: the end of the study. Often later than primary completion, sometimes the same day.
Actual and Est.: Actual means the registry says the date has happened. Est. (estimated) is a date the sponsor plans or expects. It can still move, and the sponsor is expected to change it to actual once it has passed.

No changes since tracking began. The registry record was last updated on Feb 18, 2021, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT03457870
Lead sponsor: King's College London
Collaborators: Medical Research Council, Mars, Inc.
Responsible party: Sponsor
First posted: Mar 8, 2018
Start date: Apr 18, 2018
Primary completion: Mar 23, 2020
Completion: Mar 23, 2020
Last update: Feb 18, 2021

Study contacts

Sandrine Thuret, PhD

principal investigator · King's College London

Wendy L Hall, PhD

principal investigator · King's College London

Oversight

Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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