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Caloric restriction improves memory in elderly humans

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Animal studies suggest that diets low in calories and rich in unsaturated fatty acids (UFA) are beneficial for cognitive function in age. Here, we tested in a prospective interventional design whether the same effects can be induced in humans. Fifty healthy, normal- to overweight elderly subjects (29 females, mean age 60.5 years, mean body mass index 28 kg/m(2)) were stratified into 3 groups: (i) caloric restriction (30% reduction), (ii) relative increased intake of UFAs (20% increase, unchanged total fat), and (iii) control. Before and after 3 months of intervention, memory performance was assessed under standardized conditions. We found a significant increase in verbal memory scores after caloric restriction (mean increase 20%; P < 0.001), which was correlated with decreases in fasting plasma levels of insulin and high sensitive C-reactive protein, most pronounced in subjects with best adherence to the diet (all r values < -0.8; all P values <0.05). Levels of brain-derived neurotrophic factor remained unchanged. No significant memory changes were observed in the other 2 groups. This interventional trial demonstrates beneficial effects of caloric restriction on memory performance in healthy elderly subjects. Mechanisms underlying this improvement might include higher synaptic plasticity and stimulation of neurofacilitatory pathways in the brain because of improved insulin sensitivity and reduced inflammatory activity. Our study may help to generate novel prevention strategies to maintain cognitive functions into old age.
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Caloric restriction improves memory in
elderly humans
A. V. Witte
a
, M. Fobker
b
, R. Gellner
c
, S. Knecht
a
, and A. Flo
¨el
a,d,1
Departments of aNeurology and cInternal Medicine, bCenter for Laboratory Medicine, and dInterdisciplinary Center of Clinical Research, University of
Mu¨ nster, Albert-Schweitzer-Strasse 33, 48149 Mu¨ nster, Germany
Edited by Fred Gage, The Salk Institute, San Diego, CA, and approved December 19, 2008 (received for review September 4, 2008)
Animal studies suggest that diets low in calories and rich in
unsaturated fatty acids (UFA) are beneficial for cognitive function
in age. Here, we tested in a prospective interventional design
whether the same effects can be induced in humans. Fifty healthy,
normal- to overweight elderly subjects (29 females, mean age 60.5
years, mean body mass index 28 kg/m
2
) were stratified into 3
groups: (i) caloric restriction (30% reduction), (ii) relative increased
intake of UFAs (20% increase, unchanged total fat), and (iii)
control. Before and after 3 months of intervention, memory per-
formance was assessed under standardized conditions. We found
a significant increase in verbal memory scores after caloric restric-
tion (mean increase 20%; P<0.001), which was correlated with
decreases in fasting plasma levels of insulin and high sensitive
C-reactive protein, most pronounced in subjects with best adher-
ence to the diet (all rvalues <0.8; all Pvalues <0.05). Levels of
brain-derived neurotrophic factor remained unchanged. No signif-
icant memory changes were observed in the other 2 groups. This
interventional trial demonstrates beneficial effects of caloric re-
striction on memory performance in healthy elderly subjects.
Mechanisms underlying this improvement might include higher
synaptic plasticity and stimulation of neurofacilitatory pathways in
the brain because of improved insulin sensitivity and reduced
inflammatory activity. Our study may help to generate novel
prevention strategies to maintain cognitive functions into old age.
aging cognition diet unsaturated fatty acids
Because of the constant growth of the elderly population in
today’s societies worldwide (1), the search for new preven-
tion and treatment strategies to maintain higher brain functions
throughout life is of major economic and medical importance
(see for example ref. 2). In the last 3 decades, numerous studies
suggested that modifiable lifestyle factors including a low-calorie
diet (caloric restriction, CR), and specific micro- and macronu-
trients like unsaturated fatty acids (UFA), might exert beneficial
effects on the aging brain (3–7). In animal models of aging and
neurodegenerative diseases, CR protected hippocampal, striatal,
and cortical neurons, and ameliorated functional decline (8–18).
In longitudinal observations in humans, it was found that a CR
diet, as consumed by residents of the city of Okinawa, Japan,
contributed to healthy aging and longevity (19). Conversely,
obesity as a result of high energy intake has been shown to
increase the risk of age-related cognitive decline (20).
A diet rich in mono- and polyUFA has been demonstrated
to enhance cognitive performance in rats (21). It has been
further proposed by epidemiological studies in humans that
UFA, provided e.g., by olive oil and sea-fish in the traditional
mediterranean diet, exert a risk-lowering effect for AD and
cognitive impairment (22–27). Recently, 2 interventional stud-
ies reported a significant cognitive improvement in patients
suffering from mild cognitive impairment (MCI) after intake
of omega-3 polyUFA supplements vs. placebo (28, 29). How-
ever, inconclusive or negative findings from animal and ob-
servational studies have also been reported for CR (e.g., 30, 31,
32) and UFAs (33, 34).
Taken together, potential benefits of specific ‘‘brain-healthy
diets’’ have been proposed, but have not been confirmed un-
equivocally by animal experiments and human epidemiological
studies. Evidence drawn from prospective interventional trials in
humans is still missing (CR) or scarce (UFA, 28, 29). Therefore,
the aim of the present study was to elucidate cognitive effects of
a diet low in calories or high in UFAs in healthy elderly
individuals (for a f lowchart, see Fig. 1). Because memory
impairment is an early indication of AD and its precursor, MCI
(35), we considered the ability to remember and learn new
contents as our primary outcome measure, in accordance with
previous studies on lifestyle interventions (36, 37). Moreover, we
tried to identify potential mechanisms underlying the positive
effects of these dietary interventions. Metabolic factors like
insulin-resistance or low-grade inflammation might contribute
to age-related cognitive impairments (38, 39), and improvement
of metabolic state should result in acute improvement of cog-
nition, in addition to long-term deceleration of cognitive decline.
Therefore, we assessed peripheral blood levels for insulin,
glucose, and markers of inflammation. Neuronal function may
also be enhanced via neurotrophic factors (4), which are sug-
gested to be activated by moderate stressors like CR via adaptive
cellular stress response pathways (5). This possibility was tested
by assessing neurotrophic levels in peripheral blood.
Results
Dietary Compliance. Details of physiological measures and serum
levels at baseline and after intervention are shown in Table S1.
As intended by the intervention, there was a significant weight
loss (F
(2, 46)
7.25, P0.002; t
(18)
3.24, P0.005; Fig. 2;
Table S1) and body mass index (BMI) reduction (F
(2, 46)
7.24,
P0.002; t
(18)
3.33, P0.004; Fig. 2, Table S1) in the CR
group (group 1). In addition to significant weight loss and
reduction of fasting insulin levels, CR subjects’ postintervention
questionnaire on adherence to dietary guidelines demonstrated
that they followed the instructions (16 of 18 answered ‘‘definitely
yes,’’ or ‘‘predominantly yes’’). The remaining 2 subjects of the
CR group (n 18, 1 subject did not complete the questionnaire)
answered they changed their dietary habits ‘‘at least half of the
time. Asked whether they changed their physical activity during
the study, 18 of 18 answered with ’’no.‘‘ No significant changes
emerged for body fat and waist-to-hip ratio in this group, nor for
parameters of lipid metabolism (P0.05; Table S1). For the
UFA enhancement group (group 2) and for the control group no
Author contributions: S.K. and A.F. designed research; A.V.W., M.F., and A.F. performed
research; A.V.W., M.F., R.G., and A.F. analyzed data; and A.V.W., R.G., S.K., and A.F. wrote
the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
1To whom correspondence should be addressed at: Department of Neurology, University
of Mu¨ nster, Albert-Schweitzer-Strasse 33, 48129 Mu¨ nster, Germany. E-mail: floeel@
uni-muenster.de.
This article contains supporting information online at www.pnas.org/cgi/content/full/
0808587106/DCSupplemental.
© 2009 by The National Academy of Sciences of the USA
www.pnas.orgcgidoi10.1073pnas.0808587106 PNAS
January 27, 2009
vol. 106
no. 4
1255–1260
NEUROSCIENCE
significant changes emerged for weight, BMI, body fat, and waist
to-hip ratio, nor for serum levels of triglycerides, cholesterol,
HDL, LDL, or their ratio (all P0.05; Fig. 2; Table S1).
Dietary intake at baseline and after the intervention (self-
reported) is shown in Table S2. Dietary records revealed that all
groups increased the proportional intake of UFAs significantly
(F
(1,46)
92.45, P0.001; t
(48)
⫽⫺10.06, P0.001; Table S2),
yet with highest increase in the UFA enhancement group
(18%, close to the aim of 20%). The UFA-to-saturated fatty
acids ratio was significantly improved only in the UFA enhance-
ment group (F
(2, 46)
3.32, P0.045; t
(19)
⫽⫺4.58, P0.001;
Fig. 2; Table S2). Considering marine sources of omega-3 UFAs,
intake of eicosapentaenoic acid (EPA) and docosahexaeinoic
acid (DHA) was relatively low at baseline (mean 0.2 g/day; max.
1.6 g/day) and did not increase over the intervention (P0.05).
Intervention Effects. ANOVA
RM
showed a significant TIME x
GROUP interaction on memory scores (F
(2, 46)
5.42, P
0.008). Subsequent t tests revealed that this was due to significant
differences in memory scores in the CR group before and after
intervention, with higher scores after the intervention (t
(18)
4.73, P0.0002; Fig. 3). Likewise, there was a significant
difference for memory scores uncorrected for false-positive
misidentifications (t
(18)
⫽⫺2.85, P0.011) and for ‘‘number of
false-positives’’ (t
(18)
2.62, P0.018). In summary, subjects
remembered more words and made fewer mistakes after caloric
restriction. No differences were shown for memory scores in the
UFA enhancement group (all Pvalues 0.31) or in the control
group (all Pvalues 0.62).
In the CR group, inverse associations emerged between
changes in several laboratory parameters [insulin, fasting glu-
cose, hs-CRP, and tumor necrosis factor-alpha (TNF-
)] and
changes in memory score:
Increases in memory score were correlated with decreases in
insulin levels (r⫽⫺0.45, P0.06). Focusing the analysis on
those individuals with best adherence to the intervention (de-
fined as weight loss 1 SD of mean weight loss of the control
group, resulting in a weight loss of 2 kg, n9), a highly
significant inverse association emerged (Bonferroni corrected,
r⫽⫺0.78, P0.014; Fig. 4). In addition, there was a trend for
Fig. 1. Flow-chart of the study. 50 healthy elderly subjects were initially
included in the study and performed baseline measurements of physiological
parameters, fasting serum levels, and memory tests (session I). Based on age,
sex, and BMI, subjects were stratified into 3 groups to follow either a specific
diet, namely caloric restriction (n20, group 1) or unsaturated fatty acids
(UFA) enhancement (n20, group 2), or not to change previous eating habits
(control, n10). Dietary instructions were provided by clinical dieticians. One
women from group 1 was not available for posttesting. After a period of 3
months, participants again underwent measurements of physiological param-
eters, fasting serum levels, and memory tests (session II). At baseline, after 6
and after 12 weeks, subjects additionally completed nutrition diaries over 7
consecutive days.
Fig. 2. Percentage changes in weight (black bars), BMI (gray bars), and
changes in unsaturated fatty acids (UFA)-to-saturated fatty acids (SFA) ratio
(striped bars) after caloric restriction (group 1), UFA enhancement (group 2),
and control condition. Note that caloric restriction led to a significant decrease
in weight, BMI, and UFA enhancement to a significant increase in the UFA-
to-SFA-ratio. Error bars indicate standard error. ***,P0.001; **,P0.01
according to ANOVARM posthoc testings.
Fig. 3. Percentage memory scores normalized to baseline values before and
after caloric restriction (dashed line), unsaturated fatty acid (UFA) enhance-
ment (dotted line), and control (solid line). Note that after caloric restriction,
a highly significant improvement in memory scores can be seen. Baseline
memory scores were not significantly different. Dots give means, bars indicate
standard error. ***,P0.001.
Fig. 4. Inverse correlation (Spearman, r⫽⫺0.81, P0.014) between
changes in insulin levels and memory score improvements after caloric restric-
tion in those subjects with best adherence to the diet (n9). Line indicates
regression fit.
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www.pnas.orgcgidoi10.1073pnas.0808587106 Witte et al.
a significantly reduced mean value of fasting glucose serum
levels in the CR group after the intervention (t
(18)
1.82, P
0.086), yet ANOVA
RM
failed to reach significance (F
(2, 46)
1.98; P0.15).
Furthermore, increases in memory score were correlated with
decreases in hs-CRP levels (trend; r⫽⫺0,41, P0.083). Again,
if including only those subjects with best adherence to the diet,
a highly significant inverse association emerged (Bonferroni
corrected, r⫽⫺0.83, P0.005; Fig. 5). A weak correlation was
also found for increases in memory score and decreases in
TNF-
in the CR group (r⫽⫺0.39, P0.102), more obvious
in those subjects with best adherence to the diet (r⫽⫺0.59, P
0.094).
For serum levels of BDNF, IGF-1, and IL-1
, no significant
correlations with memor y scores emerged (P0.05), nor for
these or any of the other parameters in the UFA enhancement
group or in the control group (P0.05). Likewise, no significant
effects for GROUP TIME was detected by ANOVA
RM
.
Discussion
In this prospective interventional study in healthy normal to
overweight elderly individuals, we found a significant improve-
ment in memory performance after a caloric restricted diet (CR)
over a period of 3 months. Memory improvement was correlated
with decreases in fasting insulin and hs-CRP, most pronounced
in those individuals with best adherence to the CR diet. In
contrast, no significant changes in memory performance
emerged after a diet rich in UFA or after control conditions.
Caloric Restriction. The findings of this interventional trial in
humans support experimental animal studies (4) and epidemi-
ological observations in humans (19, 40) that have suggested
beneficial effects of CR on the aging brain. For example, CR has
been demonstrated to enhance spatial memory performance in
rats (17), and even CR over a period of 4 months sufficed to
reduce age-related impairments in motor- and learning tasks in
mice (9). Moreover, Fontan-Lozano and colleagues (41) re-
ported that a CR diet, using an intermittent fasting regime
enhanced learning and consolidation processes in mice, probably
via higher expression of an NMDA-receptor subunit in the
hippocampus. Interestingly, adult-onset short-term CR over 7
weeks in rats attenuated the effects of excitotoxic insults in
hippocampal slices compared with ad libitum control diet (8).
These results concur with the current study, because we found
that even moderate CR over a period of 3 months improves
cognition in healthy elderly subjects.
Unsaturated Fatty Acids. Considering UFA, observational studies
in elderly cohorts (23, 25, 42) and small clinical trials in patients
suffering from MCI or AD (43, 44) suggested that a diet high
in mono- or omega-3 UFA might postpone cognitive decline.
In rats, it has been demonstrated that a diet rich in mono- and
di-UFA enhanced spatial memory performance (21). Con-
versely, higher intake of omega 3-fatty acids did not improve
cognitive performance in epidemiological studies (for exam-
ple, see ref. 33). The latter results are consistent with our study
that failed to detect a beneficial effect of a 3-month dietary
intervention high in UFA on cognitive performance. Several
possible explanations may account for these negative findings:
First, our results could be due to low adherence to the UFA
diet, or to insufficiently high UFA dosage in the dietary
protocol, rather than to a lack of positive effects of UFA on
cognition per se. Because our dietary protocol promoted a
self-prepared diet arranged independently at home, the
present study does not allow us to distinguish between these
possibilities. According to dietar y records, however, there was
a significant increase in the UFA-to-saturated fatty acids ratio
in the UFA enhancement group, which nearly met the protocol
aim of 20% UFA increase. However, self-reported dietary
information is prone to errors (45).
Second, the amount of marine omega-3 UFA (mainly EPA,
DHA) did not increase over the intervention period according
to dietary records, mainly because there was no significant
increase in fatty seafish meals. Because these sources of omega-3
fatty acids are suggested to be most effective in delaying cog-
nitive decline (23, 28, 29), a low EPA/DHA-intake might have
contributed to our negative findings, yet the evidence is still
unequivocal (see e.g., 46 for positive results on olive oil, however,
this might also depend on other, non-UFA ingredients in olive
oil). Therefore, future studies have to further evaluate the effects
of different UFAs on cognitive functions on the aging brain in
health and disease.
Mechanisms of Diet-Induced Cognitive Changes.
Insulin.
In the
present study, we found a decrease of fasting peripheral insulin
in the CR group, in accordance with studies in healthy rats (47)
and monkeys (48–50) after CR, and with clinical data in obese
patients (e.g., 51). Reducing peripheral insulin levels should
result in increased insulin sensitivity and central insulin levels
(3), because higher levels of peripheral insulin lead to a down-
regulation of insulin transport at the bloodbrain-barrier and thus
to central hypoinsulinemia (52, 53). Importantly, improved
insulin signaling in the brain has been suggested to have neu-
roprotective effects (38, 52, 54,), whereas increased peripheral
circulating insulin may promote the development of cognitive
impairments and AD (52, 54, 55).
Furthermore, the observed correlation between decrease in
peripheral insulin and increase in memory points to a possible
role of insulin in mediating the beneficial effects of CR on
memory functions (for review, see ref. 7). Levels of insulin,
insulin receptors, and insulin-regulated pathways in the brain are
involved in glutamate- and GABA-mediated synaptic plasticity
and in gene expressions required for long-term memory consol-
idation (38, 56). For example in the hippocampus, insulin has
been shown to induce NMDA receptor phosphorylation (57),
and to increase channel activities of NMDA receptors (58),
which play an important role in learning and memory formation
(for example, see ref. 59). Thus, it has been convincingly
demonstrated that insulin signaling exerts neuroprotective and
neuromodulatory effects in the brain, although the molecular
machinery linking insulin and cognitive improvement, for ex-
ample the exact role of kinase molecules in learning and
memory, needs to be further elucidated (38).
In summary, the present study lends experimental support to
a model derived from animal studies in which reduced fasting
insulin levels due to CR led to lower insulin resistance, higher
insulin sensitivity, subsequently to improved insulin signaling in
Fig. 5. Inverse correlation (Spearman, r⫽⫺0.83, P0.005) between
changes in high sensitive C-reactive protein (hs-CRP) and memory score im-
provements after caloric restriction in those subjects with best adherence to
the diet (n9). Line indicates regression fit.
Witte et al. PNAS
January 27, 2009
vol. 106
no. 4
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NEUROSCIENCE
the brain and to increased synaptogenesis and neuronal survival
(3). Higher insulin sensitivity due to CR in our subjects, with
subsequently improved insulin signaling in the brain, would be a
plausible explanation for the observed memory improvements in
the current study.
Neurotrophic factors.
Neuronal function may also be enhanced via
neurotrophic factors (5, 38), which are suggested to be activated
by moderate stressors like exercise and CR via adaptive cellular
stress response pathways (e.g., heat shock protein 70; for details,
see refs. 4 and 60). Neurotrophic factors, such as IGF-1 and
BDNF, are widely known to be involved in neuronal growth and
neurogenesis and might also protect mature neurons from
degeneration (61). IGF-1 is also a ligand for insulin receptors
(62), thus activating insulin pathways in the brain. Both IGF-1-
(63) and BDNF-levels (64) have been suggested to be enhanced
after CR in rodents. Our results did not show a significant
difference in either IGF-1 or BDNF induced by dietary inter-
ventions. One explanation might be that we could only assess
peripheral levels of IGF-1 and BDNF. Even though both pe-
ripheral IGF-1 (65) and BDNF (66) have been shown to pass the
blood–brain barrier, these measures may not be a perfect
reflection of brain concentrations. In addition, other neurotro-
phic molecules such as glia-derived neurotrophic factor (GDNF)
and nerve growth factor (NGF) might have changed in adapta-
tion to CR (3), which were not assessed in the current study. To
clarify these issues, measurements of these factors could be
additionally assessed in future studies.
Inflammation.
CR has been shown to exert anti-inflammatory
effects (4), including down-regulation of hs-CRP levels in ro-
dents (67) and TNF-
in humans (68, 69), in line with the present
data. With regard to cognition, several studies have proposed
that ‘‘inflammatory activity,’’ as indicated by serum markers of
inflammatory responses, is negatively correlated with neuropsy-
chological performance and cognitive decline (70, 71). For
example, an observational study by Teunissen and colleagues
(72) found significant inverse correlations of serum levels of
CRP and haptoglobin with performance in a verbal learning task
(congruent to the memor y test used in the current study) in
healthy elderly individuals. The current study is the first to
confirm these findings, and to extend the proposed association
for TNF-
in an interventional design. However, anti-
inflammatory pathways linking CR and memory remain to be
further elucidated (4), e.g., by including a larger number of
subjects with elevated levels of inf lammatory markers at base-
line, and testing an extended range of markers. Interestingly,
TNF-
has been demonstrated to promote insulin resistance in
experimental animal studies (73, 74). Therefore, a reduction of
TNF-
by CR might additionally contribute to maintain cogni-
tive functions via improved insulin signaling (3).
Limitations. Several limitations should be considered when in-
terpreting our findings. First, dietary habits were self-reported
only and thus prone to over- or underestimation (45). However,
in the CR group, weight loss and BMI reduction demonstrated
adherence to the intended dietary regime. Second, individuals in
the control group did not receive the same amount of attention
by dietary counsellors, and interaction with group members, as
participants in the CR group. Better memory per formance may
thus be due to a Hawthorne (75) effect or an effect of ‘‘enhanced
environmental enrichment’’ by social interaction in the CR
group. However, the finding that individuals in the UFA en-
hancement group, receiving a similar amount of attention and
social interaction, did not show memory improvements, renders
this explanation highly unlikely.
Conclusion
To our knowledge, the current results provide first experimental
evidence in humans that caloric restriction improves memory in
the elderly. Our findings further point to increased insulin
sensitivity and reduced inf lammatory activity as mediating
mechanisms, leading to higher synaptic plasticity and stimulation
of neuroprotective pathways in the brain. Future studies incor-
porating measurements of additional neurotrophic and inflam-
matory markers, and brain imaging to assess structural changes
(for example, see ref. 36), should provide further insights into
potential mediators of improved cognition by changes in dietar y
habits.
The present findings may help to develop new prevention and
treatment strategies for maintaining cognitive health into old
age (3).
Materials and Methods
Subjects. Fifty healthy elderly subjects (age: 60.5 years 7.6 SD, BMI: 28 kg/m2
3.7 SD; 29 females) were recruited via newspaper advertisement. Inclusion
criteria were age between 50 and 80 years, a BMI 21 to exclude potential
underweight after intervention, and postmenopausal status for women. At
screening visit, participants underwent a routine medical and neurological
examination. Exclusion criteria were severe cardiac and pulmonary disease,
diabetes or other metabolic disorder, psychiatric disorders, memory impair-
ment based on a score of 26 on the MiniMental State Examination (MMSE;
76), and drug abuse, including alcohol dependence and heavy smoking.
Psychiatric comorbidity was additionally monitored using the Beck’s Depres-
sion Inventory (BDI, German version; 77) and Spielberger’s State Trait Angst
Inventar (STAI 1 and 2, German version; 78). One woman was not available for
postassessment, leaving 49 participants for final analyses. Based on age, sex,
and BMI, subjects were stratified into 3 groups: (i) Caloric restriction, (ii)
increase of the amount of UFA (‘‘UFA enhancement’’), and (iii) control group;
for details on groups see below. Demographic variables at baseline are given
in Table S3. The study was conducted at the Department of Neurology at the
University of Mu¨ nster, Germany. All subjects provided written informed con-
sent and received reimbursement for participation. The research protocol was
approved by the Ethics Committee of the University Hospital of Muenster,
Germany.
Caloric Restriction. According to previous recommendations based on studies
of rodents and rhesus monkeys (49, 60), participants (n19) were instructed
to reduce caloric intake aiming at a 30% reduction relative to previous habits,
over a period of 3 months. The intended individual caloric intake was calcu-
lated a priori based on individual dietary records, because the aim of the
caloric restriction intervention was to reduce each subject’s individual caloric
intake by 30%, compared with pretrial levels. To avoid cognitive changes due
to malnutrition (79), minimal intake was set to 1,200 kcal per day.
Unsaturated Fatty Acids Enhancement. According to previous recommenda-
tions based on studies of rodents (21), participants (n20) were instructed to
enhance intake of UFAs aiming at a 20% increase compared with previous
habits, over a period of 3 months. They were instructed to keep the amount
of total fat intake unchanged.
All subjects assigned to 1 of the 2 dietary interventions were trained on how
to follow their respective diet by experienced clinical dieticians blinded to the
underlying study hypothesis. Therefore, after completing baseline measure-
ments, participants attended a 2-h tutorial (maximum 12 persons each).
Additionally, they received dietary instructions in written forms. Group 1
additionally underwent 1-h individual schooling at baseline and a second 1-h
tutorial carried out by the clinical dieticians after a period of 6 weeks.
Moreover, subjects of the 2 intervention groups received supplementary
dietary counseling via telephone if needed, so that any problems in adhering
to the intervention could rapidly be addressed during the entire intervention
period. To provide optimal supervision, dieticians obtained information
about individual nutritional intake from the nutrition diaries and personal
interviews. Adherence to the intervention was monitored by measures of
weight, BMI, waist-to-hip ratio, amount of body fat, and fasting serum levels
of triglycerides, cholesterol, and hs-CRP, because these parameters have been
shown to decrease after caloric restriction and/or after a dietary enhancement
of UFA (80–83). In addition, information on adherence to the diet was
collected by a postintervention Questionnaire, and self-reported nutritional
records were collected in the course of the intervention period.
Control. Participants (n10) were instructed not to change previous eating
habits over a period of 3 months. No specific dietary counselling was admin-
istered to avoid self-chosen/self-administered changes in dietary patterns that
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have been reported after any dietary counselling (for example, ref. 84). For
simplicity this condition is subsequently referred to as control intervention.
Nutritional records. Supply of nutrients, caloric-, and UFA-intake were docu-
mented by nutritional records at the beginning of the study (record 1), after
6 weeks intervention (record 2), and after 12 weeks intervention (record 3).
Each record encompassed 7 days of protocol. For nutritional records, all
subjects had to plot, on a daily basis, all food and drink intake in an in-house
developed standard nutrition diary (University of Mu¨ nster, Department of
Internal Medicine) similar to records used in other studies (see e.g., 45). The
diary contained numerous nutritional items presented in standard servings,
and additional free lines to describe foods not listed in the diary. Subjects had
to mark the respective items, with the possibility to adjust for individual
servings. Nutrients, amount of calories, and amount of UFAs where quantified
using the software EBISpro (Erhardt).
Physiological Parameters and Blood Sampling. Before and after 3 months of
intervention (sessions I and II; see Fig. 1), the following variables were assessed:
Weight (in kilograms; measured), height (in meters; self-reported), waist-to-
hip ratio (in centimeters/centimeters, measured), body fat (percentage, mea-
sured), diastolic and systolic blood pressure, heart rate, fasting serum levels of
triglyceride, total-, HDL- and LDL-cholesterol, insulin, glucose, insulin-like
growth factor 1 (IGF-1), brain derived neurotrophic factor (BDNF), cat-
echolamines (85), markers of inflammation [i.e., high sensitive-C-reactive
protein (hs-CRP) and tumor necrosis factor-alpha (TNF-
)], and routine pa-
rameters (sodium, potassium, calcium, phosphate, protein, creatinine, urea;
data not shown), for details, see SI Text.
Neuropsychological Testing. Before and after 3 months of intervention, sub-
jects were tested on memory performance using the German version of the
Rey Auditory Verbal Learning Task (AVLT) (84). The test was performed by a
trained clinical neuropsychologist. Participants were asked to learn as many
words as possible out of a list of 15 words. As primary outcome measure
‘‘memory score,’’ we considered the total number of retrieved words after 30
min (delayed memory), adjusted for false positive misidentifications (86, 87),
in line with previous studies (36, 37, 88), and with signal detection theory (89).
Additionally, analysis was conducted for total number of retrieved words
without adjustment for false-positives, and for total numbers of false-positive
errors. Two different but congruent versions were presented at the 2 test
sessions to avoid test-retest effects.
To assess potential differences in attention or working memory due to the
intervention, subjects completed trail making tests (TMT) A and B (90), and
forward/backward digit span (WMS-R, 91), before and after the intervention.
No significant differences emerged between pre and post intervention test
sessions (all P0.5).
Statistical Analysis. Before data analysis, normal or near-normal distribution
and homogeneity of variances were tested by the Kolmogorov–Smirnov test
and the Levene’s Test.
To monitor dietary compliance, individual physiological parameters and
serum levels and dietary intake before and after the intervention were
compared by a repeated measures analysis of variance (ANOVARM) with TIME
(‘‘baseline,’’ ‘‘after intervention period’’), and between factor GROUP (‘‘ca-
loric restriction,’’ ‘‘UFA enhancement,’’ ‘‘control’’), followed by post hoc
paired ttests (2-tailed) as appropriate.
To assess intervention effects, an ANOVARM on the outcome variable
‘‘memory scores’’ was conducted, with TIME and between factor GROUP.
Depending on significance, post hoc paired ttests (two-tailed) were per-
formed as appropriate.
Correlations between changes in memory score and changes in physiolog-
ical parameters and serum levels from baseline to post intervention assess-
ment were assessed using Spearman’s correlation coefficient.
Significance was set at P0.05, all data are presented as mean with
standard error of the mean, unless indicated otherwise.
ACKNOWLEDGMENTS. We thank N. Ro¨ sser and C. Willemer for help with
subject recruitment. This work was supported by Deutsche Forschungsge-
meinschaft Grant Fl 379 –4/1 (to A. F.), Interdisziplina¨ res Zentrum fu¨ r Klinische
Forschung Grant Floe/3/004/08 (to A.F.), Bundesministerium fu¨ r Forschung
und Bildung Grant 01GW0520 (to A.F. and S.K.), and Innovative Medizinische
Forschung Mu¨ nster Grant FL110605 (to A. F.).
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www.pnas.orgcgidoi10.1073pnas.0808587106 Witte et al.
... Subsequent studies demonstrated that CR promotes the metabolism of fats and ketones, activates cellular repair mechanisms, and optimizes energy utilization in the body (Di Francesco et al., 2018). These findings later spurred investigations into other effects of CR on cognition, for example on increasing hyperphagia, improving reward learning (Cameron et al., 2008;Moyse et al., 2012;Witte et al., 2009), and attenuating the pathology of age-related disease like dementias (Cardoso et al., 2016;Lin et al., 2014;Maswood et al., 2004;Wang et al., 2005;Witte et al., 2009). CR affects plasticity and cognition. ...
... Subsequent studies demonstrated that CR promotes the metabolism of fats and ketones, activates cellular repair mechanisms, and optimizes energy utilization in the body (Di Francesco et al., 2018). These findings later spurred investigations into other effects of CR on cognition, for example on increasing hyperphagia, improving reward learning (Cameron et al., 2008;Moyse et al., 2012;Witte et al., 2009), and attenuating the pathology of age-related disease like dementias (Cardoso et al., 2016;Lin et al., 2014;Maswood et al., 2004;Wang et al., 2005;Witte et al., 2009). CR affects plasticity and cognition. ...
... In appetitive conditioning paradigms in laboratory rodents, CR can enhance the learning of associations between novel environments, cues, and responses that lead to a food reward, for example in spatial learning tasks like those in operant conditioning chambers (Fulton et al., 2004, Ingram et al., 1987Lee et al., 2002aLee et al., , 2002b. CR or intermittent fastinglimiting food intake during certain times of the day, week, or month (Baik et al., 2020;Singh et al., 2011) induces a mild adaptive cellular stress response, which promotes neuronal resilience to injury and pathology in rodents (Bruce-Keller et al., 1999;Duan et al., 2001;Maswood et al., 2004;Stranahan and Mattson, 2012;Wang et al., 2005;Youssef et al., 2008;Zhu et al., 1999) and improves memory in humans (Witte et al., 2009). As a result, restricted food intake may be beneficial in promoting resistance to ageing-associated cognitive decline (Arslan-Ergul et al., 2013;Lin et al., 2014;Witte et al., 2009). ...
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Objectives: This study aimed to determine the relationship between oxidative stress, DNA damage, inflammation, and metabolic biomarkers as the mediating factor between Islamic Sunnah intermittent fasting (IF) practice and cognitive function among older adults with mild cognitive impairment (MCI). Design: This study was a 36 months prospective cohort study. Setting: Community-dwelling older participants recruited through a stratified random sampling method from four states representing Malaysia's central, north-west, northeast and southern regions. Participants: Ninety-nine Malay Muslim older adults (n= 99) aged 60 and above with MCI and no known critical illnesses were included in the current analysis. The participants were divided into regularly practicing IF (r-IF), irregularly practicing IF (i-IF) and not practicing IF (n-IF) groups. Measurements: Fasting venous blood was collected and used to determine the levels of oxidative stress, DNA damage, inflammatory and metabolic biomarkers. Mini-Mental State Examination, Montreal Cognitive Assessment, Rey Auditory Verbal Learning Test, Digit Span and Digit symbol were used to evaluate the cognitive function. Then, the mediation analysis was conducted using a multistep regression model to determine the mediating role of various biomarkers between IF practice and cognitive function. Results: When comparing the r-IF and n-IF groups, higher SOD activity, lower DNA damage (percentage of DNA in tail), lower CRP levels and higher HDL-cholesterol levels established partial mediation while lower insulin levels established complete mediation between IF practice and better cognitive function. Meanwhile, when comparing the r-IF and i-IF groups, higher SOD activity and lower CRP levels completely mediated the effects of IF practice on better cognitive function. Conclusion: It can be concluded that changes in antioxidant function, DNA damage, inflammation and a limited set of metabolic biomarkers (insulin and HDL cholesterol) may mediate improvements in cognitive function among older participants with MCI who practice Islamic Sunnah IF.
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Parkinson's disease (PD) is an age-related disorder characterized by progressive degeneration of dopaminergic neurons in the substantia nigra (SN) and corresponding motor deficits. Oxidative stress and mitochondrial dysfunction are implicated in the neurodegenerative process in PD. Although dietary restriction (DR) extends lifespan and reduces levels of cellular oxidative stress in several different organ systems, the impact of DR on age-related neurodegenerative disorders is unknown. We report that DR in adult mice results in resistance of dopaminergic neurons in the SN to the toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP-induced loss of dopaminergic neurons and deficits in motor function were ameliorated in DR rats. To mimic the beneficial effect of DR on dopaminergic neurons, we administered 2-deoxy-D-glucose (2-DG; a nonmetabolizable analogue of glucose) to mice fed ad libitum. Mice receiving 2-DG exhibited reduced damage to dopaminergic neurons in the SN and improved behavioral outcome following MPTP treatment. The 2-DG treatment suppressed oxidative stress, preserved mitochondrial function, and attenuated cell death in cultured dopaminergic cells exposed to the complex I inhibitor rotenone or Fe2+. 2-DG and DR induced expression of the stress proteins heat-shock protein 70 and glucose-regulated protein 78 in dopaminergic cells, suggesting involvement of these cytoprotective proteins in the neuroprotective actions of 2-DG and DR. The striking beneficial effects of DR and 2-DG in models of PD, when considered in light of recent epidemiological data, suggest that DR may prove beneficial in reducing the incidence of PD in humans. J. Neurosci. Res. 57:195–206, 1999. © 1999 Wiley-Liss, Inc.
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The methodology of signal detection theory is a preferred technique for assessing an S's ability to discriminate the occurrence of discrete binary events. A compact table is presented which will permit precise calculation of signal detection parameters, d' (discrimination index) and BETA (response bias), for hit and false alarm rate combinations in the range from .01-.99. (PsycINFO Database Record (c) 2012 APA, all rights reserved)