- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03457870
Intermittent Energy Restriction and Chewing on Neural Stem Cell Ageing and Adult Hippocampal Neurogenesis Associated Cognition (ChANgE)
Investigating the Impact of Intermittent Energy Restriction and Chewing on Neural Stem Cell Ageing and Adult Hippocampal Neurogenesis: The ChANgE Study
Study Overview
Status
Conditions
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.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
-
-
England
-
London, England, United Kingdom, SE1 9NH
- Diabetes & Nutritional Sciences Division, King's College London, Franklin-Wilkins Building, 150 Stamford St
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Male and female subjects.
- 60+ years of age at the time of consent.
- BMI 25-35.
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 informed consent.
- 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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: PREVENTION
- Allocation: RANDOMIZED
- Interventional Model: PARALLEL
- Masking: NONE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
EXPERIMENTAL: Intermittent Energy Restriction
Dietary intervention: Intermittent energy restriction
|
Dietary advice to follow a 5:2 diet.
|
EXPERIMENTAL: Chewing
Mastication intervention: chewing
|
Asked to chew 1 piece of gum for 10 minutes 3 times a day.
|
EXPERIMENTAL: Chewing + Intermittent Energy Restriction
Dietary and mastication intervention: Intermittent energy restriction and chewing
|
Dietary advice to follow a 5:2 diet.
Asked to chew 1 piece of gum for 10 minutes 3 times a day.
|
NO_INTERVENTION: Control
No intervention: Control
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Serum Klotho concentration
Time Frame: Baseline
|
Anti-ageing longevity protein
|
Baseline
|
Serum Klotho concentration
Time Frame: Day 42
|
Anti-ageing longevity protein
|
Day 42
|
Serum Klotho concentration
Time Frame: Day 84
|
Anti-ageing longevity protein
|
Day 84
|
Mnemonic Similarity Task
Time Frame: Baseline
|
Neurogenesis-associated cognition
|
Baseline
|
Mnemonic Similarity Task
Time Frame: Day 42
|
Neurogenesis-associated cognition
|
Day 42
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Body weight
Time Frame: Baseline
|
Baseline
|
|
Waist circumference
Time Frame: Baseline
|
Baseline
|
|
Body weight
Time Frame: Day 42
|
Day 42
|
|
Body weight
Time Frame: Day 84
|
Day 84
|
|
Body fat percentage
Time Frame: Baseline
|
Baseline
|
|
Body fat percentage
Time Frame: Day 42
|
Day 42
|
|
Body fat percentage
Time Frame: Day 84
|
Day 84
|
|
Body Mass Index
Time Frame: Baseline
|
Baseline
|
|
Body Mass Index
Time Frame: Day 42
|
Day 42
|
|
Body Mass Index
Time Frame: Day 84
|
Day 84
|
|
Waist circumference
Time Frame: Day 42
|
Day 42
|
|
Waist circumference
Time Frame: Day 84
|
Day 84
|
|
Hip circumference
Time Frame: Baseline
|
Baseline
|
|
Hip circumference
Time Frame: Day 42
|
Day 42
|
|
Hip circumference
Time Frame: Day 84
|
Day 84
|
|
Patient Health Questionnaire
Time Frame: Baseline
|
Questionnaire
|
Baseline
|
Patient Health Questionnaire
Time Frame: Day 42
|
Questionnaire
|
Day 42
|
Patient Health Questionnaire
Time Frame: Day 84
|
Questionnaire
|
Day 84
|
Zung Self-Rating Anxiety Scale
Time Frame: Baseline
|
Questionnaire - Scale can be scored from 20 (normal) to 80 (extreme anxiety levels).
The total score is reported.
|
Baseline
|
Zung Self-Rating Anxiety Scale
Time Frame: Day 42
|
Questionnaire
|
Day 42
|
Zung Self-Rating Anxiety Scale
Time Frame: Day 84
|
Questionnaire
|
Day 84
|
Pittsburgh Sleep Quality Index
Time Frame: Baseline
|
Questionnaire
|
Baseline
|
Pittsburgh Sleep Quality Index
Time Frame: Day 42
|
Questionnaire
|
Day 42
|
Pittsburgh Sleep Quality Index
Time Frame: Day 84
|
Questionnaire
|
Day 84
|
Plasma glucose concentration
Time Frame: Baseline
|
Fasting
|
Baseline
|
Plasma glucose concentration
Time Frame: Day 42
|
Fasting
|
Day 42
|
Plasma glucose concentration
Time Frame: Day 84
|
Fasting
|
Day 84
|
Cholesterol
Time Frame: Baseline
|
Fasting
|
Baseline
|
Cholesterol
Time Frame: Day 42
|
Fasting
|
Day 42
|
Cholesterol
Time Frame: Day 84
|
Fasting
|
Day 84
|
Triglycerides
Time Frame: Baseline
|
Fasting
|
Baseline
|
Triglycerides
Time Frame: Day 42
|
Fasting
|
Day 42
|
Triglycerides
Time Frame: Day 84
|
Fasting
|
Day 84
|
High Density Lipoprotein
Time Frame: Baseline
|
Fasting
|
Baseline
|
High Density Lipoprotein
Time Frame: Day 42
|
Fasting
|
Day 42
|
High Density Lipoprotein
Time Frame: Day 84
|
Fasting
|
Day 84
|
Low Density Lipoprotein
Time Frame: Baseline
|
Fasting
|
Baseline
|
Low Density Lipoprotein
Time Frame: Day 42
|
Fasting
|
Day 42
|
Low Density Lipoprotein
Time Frame: Day 84
|
Fasting
|
Day 84
|
Total/HDL Cholesterol Ratio
Time Frame: Baseline
|
Fasting
|
Baseline
|
Total/HDL Cholesterol Ratio
Time Frame: Day 42
|
Fasting
|
Day 42
|
Total/HDL Cholesterol Ratio
Time Frame: Day 84
|
Fasting
|
Day 84
|
Plasma adiponectin concentration
Time Frame: Baseline
|
Fasting
|
Baseline
|
Plasma adiponectin concentration
Time Frame: Day 42
|
Fasting
|
Day 42
|
Plasma adiponectin concentration
Time Frame: Day 84
|
Fasting
|
Day 84
|
Plasma leptin concentration
Time Frame: Baseline
|
Fasting
|
Baseline
|
Plasma leptin concentration
Time Frame: Day 42
|
Fasting
|
Day 42
|
Plasma leptin concentration
Time Frame: Day 84
|
Fasting
|
Day 84
|
Plasma beta-hydroxybutrate concentration
Time Frame: Baseline
|
Fasting
|
Baseline
|
Plasma beta-hydroxybutrate concentration
Time Frame: Day 42
|
Fasting
|
Day 42
|
Plasma beta-hydroxybutrate concentration
Time Frame: Day 84
|
Fasting
|
Day 84
|
Plasma total cholesterol concentration
Time Frame: Baseline
|
Fasting
|
Baseline
|
Plasma total cholesterol concentration
Time Frame: Day 42
|
Fasting
|
Day 42
|
Plasma total cholesterol concentration
Time Frame: Day 84
|
Fasting
|
Day 84
|
Plasma low density lipoprotein (LDL) cholesterol concentration
Time Frame: Baseline
|
Fasting
|
Baseline
|
Plasma LDL cholesterol concentration
Time Frame: Day 42
|
Fasting
|
Day 42
|
Plasma LDL cholesterol concentration
Time Frame: Day 84
|
Fasting
|
Day 84
|
Plasma high density lipoprotein (HDL) cholesterol concentration
Time Frame: Baseline
|
Fasting
|
Baseline
|
Plasma HDL cholesterol concentration
Time Frame: Day 42
|
Fasting
|
Day 42
|
Plasma HDL cholesterol concentration
Time Frame: Day 84
|
Fasting
|
Day 84
|
Plasma triglyceride concentration
Time Frame: Baseline
|
Fasting
|
Baseline
|
Plasma triglyceride concentration
Time Frame: Day 42
|
Fasting
|
Day 42
|
Plasma triglyceride concentration
Time Frame: Day 84
|
Fasting
|
Day 84
|
Plasma total cholesterol:HDL cholesterol ratio
Time Frame: Baseline
|
Fasting
|
Baseline
|
Plasma total cholesterol:HDL cholesterol ratio
Time Frame: Day 42
|
Fasting
|
Day 42
|
Plasma total cholesterol:HDL cholesterol ratio
Time Frame: Day 84
|
Fasting
|
Day 84
|
Other Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Adverse events
Time Frame: Baseline until endpoint: Day 84
|
Baseline until endpoint: Day 84
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Sandrine Thuret, PhD, King's College London
Publications and helpful links
General 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.
- 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.
- 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.
- 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
Study record dates
Study Major Dates
Study Start (ACTUAL)
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ACTUAL)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- Change 2018
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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