Clinical trial NCT03457870: Intermittent Energy Restriction and Chewing on Neural Stem Cell Ageing and Adult Hippocampal Neurogenesis Associated Cognition
Official title: Investigating the Impact of Intermittent Energy Restriction and Chewing on Neural Stem Cell Ageing and Adult Hippocampal Neurogenesis: The ChANgE Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Aging
Cognitive Decline
Keywords: Intermittent fasting
Adult hippocampal neurogenesis
Mastication
Pattern separation
Recognition memory
Klotho
Lead sponsor: King's College London
Sponsor class: OTHER
Collaborators: name: Medical Research Council
name: Mars, Inc.
First posted: 2018-03-08
Enrollment: 123
Sex: FEMALE
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief 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.

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:

1. 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.
2. To assess the impact of an IER diet and extended periods of mastication on secondary outcomes variables including body composition, mood and sleep.
3. To explore whether extended periods of mastication can be utilised as a weight loss/fasting aid.

Eligibility criteria: 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.

Primary outcomes:
measure: Serum Klotho concentration
timeFrame: Baseline
measure: Serum Klotho concentration
timeFrame: Day 42
measure: Serum Klotho concentration
timeFrame: Day 84
measure: Mnemonic Similarity Task
timeFrame: Baseline
measure: Mnemonic Similarity Task
timeFrame: Day 42
Secondary outcomes:
measure: Body weight
timeFrame: Baseline
measure: Body weight
timeFrame: Day 42
measure: Body weight
timeFrame: Day 84
measure: Body fat percentage
timeFrame: Baseline
measure: Body fat percentage
timeFrame: Day 42
measure: Body fat percentage
timeFrame: Day 84
measure: Body Mass Index
timeFrame: Baseline
measure: Body Mass Index
timeFrame: Day 42
measure: Body Mass Index
timeFrame: Day 84
measure: Waist circumference
timeFrame: Baseline
measure: Waist circumference
timeFrame: Day 42
measure: Waist circumference
timeFrame: Day 84
measure: Hip circumference
timeFrame: Baseline
measure: Hip circumference
timeFrame: Day 42
measure: Hip circumference
timeFrame: Day 84
measure: Patient Health Questionnaire
timeFrame: Baseline
measure: Patient Health Questionnaire
timeFrame: Day 42
measure: Patient Health Questionnaire
timeFrame: Day 84
measure: Zung Self-Rating Anxiety Scale
timeFrame: Baseline
measure: Zung Self-Rating Anxiety Scale
timeFrame: Day 42
measure: Zung Self-Rating Anxiety Scale
timeFrame: Day 84
measure: Pittsburgh Sleep Quality Index
timeFrame: Baseline
measure: Pittsburgh Sleep Quality Index
timeFrame: Day 42
measure: Pittsburgh Sleep Quality Index
timeFrame: Day 84
measure: Plasma glucose concentration
timeFrame: Baseline
measure: Plasma glucose concentration
timeFrame: Day 42
measure: Plasma glucose concentration
timeFrame: Day 84
measure: Cholesterol
timeFrame: Baseline
measure: Cholesterol
timeFrame: Day 42
measure: Cholesterol
timeFrame: Day 84
measure: Triglycerides
timeFrame: Baseline
measure: Triglycerides
timeFrame: Day 42
measure: Triglycerides
timeFrame: Day 84
measure: High Density Lipoprotein
timeFrame: Baseline
measure: High Density Lipoprotein
timeFrame: Day 42
measure: High Density Lipoprotein
timeFrame: Day 84
measure: Low Density Lipoprotein
timeFrame: Baseline
measure: Low Density Lipoprotein
timeFrame: Day 42
measure: Low Density Lipoprotein
timeFrame: Day 84
measure: Total/HDL Cholesterol Ratio
timeFrame: Baseline
measure: Total/HDL Cholesterol Ratio
timeFrame: Day 42
measure: Total/HDL Cholesterol Ratio
timeFrame: Day 84
measure: Plasma adiponectin concentration
timeFrame: Baseline
measure: Plasma adiponectin concentration
timeFrame: Day 42
measure: Plasma adiponectin concentration
timeFrame: Day 84
measure: Plasma leptin concentration
timeFrame: Baseline
measure: Plasma leptin concentration
timeFrame: Day 42
measure: Plasma leptin concentration
timeFrame: Day 84
measure: Plasma beta-hydroxybutrate concentration
timeFrame: Baseline
measure: Plasma beta-hydroxybutrate concentration
timeFrame: Day 42
measure: Plasma beta-hydroxybutrate concentration
timeFrame: Day 84
measure: Plasma total cholesterol concentration
timeFrame: Baseline
measure: Plasma total cholesterol concentration
timeFrame: Day 42
measure: Plasma total cholesterol concentration
timeFrame: Day 84
measure: Plasma low density lipoprotein (LDL) cholesterol concentration
timeFrame: Baseline
measure: Plasma LDL cholesterol concentration
timeFrame: Day 42
measure: Plasma LDL cholesterol concentration
timeFrame: Day 84
measure: Plasma high density lipoprotein (HDL) cholesterol concentration
timeFrame: Baseline
measure: Plasma HDL cholesterol concentration
timeFrame: Day 42
measure: Plasma HDL cholesterol concentration
timeFrame: Day 84
measure: Plasma triglyceride concentration
timeFrame: Baseline
measure: Plasma triglyceride concentration
timeFrame: Day 42
measure: Plasma triglyceride concentration
timeFrame: Day 84
measure: Plasma total cholesterol:HDL cholesterol ratio
timeFrame: Baseline
measure: Plasma total cholesterol:HDL cholesterol ratio
timeFrame: Day 42
measure: Plasma total cholesterol:HDL cholesterol ratio
timeFrame: Day 84
Other outcomes:
measure: Adverse events
timeFrame: Baseline until endpoint: Day 84
Locations:
city: London
country: United Kingdom
facility: Diabetes & Nutritional Sciences Division, King's College London, Franklin-Wilkins Building, 150 Stamford St
state: England
Study officials:
affiliation: King's College London
name: Sandrine Thuret, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: King's College London
name: Wendy L Hall, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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