I will present the topic "Metabolic transformation: ketosis during long-term fasting". Humans had to survive situations of food   shortage during their evolutionary history. Thereby 
the metabolic switch ensures a constant energy   supply. It is thus an elementary ability to live 
from the body's own reserves in the times of food   shortage. In the eating state the body burns mainly 
glucose for energy production. During fasting   the metabolism switches from glucose burning to 
ketosis thereby using mainly fat and ketone bodies.   The reintroduction of food leads to the 
switchback of the metabolism. This is   followed by a regeneration phase.

This 
change to switching back and forth of   the metabolism is called metabolic 
flexibility. Today's lifestyle limits   our metabolic flexibility due to overeating, 
missing meal breaks and too little exercise. In the post absorptive phase after the cessation 
of food intake energy is industrially provided   by glucose from the glycogen stores in the 
muscle and liver. However these energy stores   are depleted relatively quickly. Blood glucose 
and insulin levels drop while lipolysis starts.   Now the fat tissue releases more free fatty acids 
and glycerol. Free fatty acids can be used directly   as energy substrate or are converted to the ketone 
bodies in the liver. Rapidly available proteins are   transitionally used for gluconeogenesis. The 
metabolic switch takes about 12 to 36 hours   and depends on glycogen stores and individual 
energy expenditure, for example through exercise.   Several signaling pathways are affected by the 
metabolic switch. Nutrient deficiency leads to down   regulation of the mTOR pathway. The energy deficit 
activates MP Kinesis and citrines. This causes   multiple systemic effects such as improving cell 
survival, increasing stress resistance, autophagy,   mitophagy, mitochondrial function, antioxidant 
capacity and DNA repair. The synthesis of ketone   bodies, known as ketogenesis, occurs from Acetoacetate 
in the mitochondrial matrix of the liver.   In this process the ketone bodies Acetoacetate 
and β-Hydroxybutyrate are formed.

Spontaneous   Decarboxylation of Acetoacetate produces the 
volatile Acetone, which is responsible for the   typical fruity smell of the breath in fasting 
patients. Acetoacetate and β-Hydroxybutyrate   are water soluble and pass the blood-brain barrier 
by faciliated diffusion. In peripheral tissues they   are degraded in mitochondria via the citric acid 
cycle. Under normal conditions the concentration of   ketone bodies in the blood is very low. With β-Hydroxybutyrate predominating at about 85 percent.   During fasting ketone body levels rise to 
values of up to seven to nine millimolar. β-Hydroxybutyrate rate is not 
only an energy supplier.

It has   been shown to have numerous positive 
effects in cell and animal models.   It leads to satiety. Improves cognitive abilities 
such as learning and memory. It protects   neurons, promotes plasticity and decreases 
narrow inflammation and neurodegeneration.   In addition, β-Hydroxybutyrate modifies 
gene expression through β-Hydroxybutylation   and reduction of Histonedeacetylation, 
so that the protection against oxidative   stress is increased. Inflammation is inhibited 
and mitochondrial biogenesis is increased.   Overall β-Hydroxybutyrate leads to anti-aging 
effects and positively influences longevity. For everyday clinical practice there are two 
measurement methods that can be easily performed.   First ketonuria can be tested using urine 
test stripes.

The nitro proceed reaction   is a semi-quantitative detection for Acetoacetate 
in urine. Statements about the level of ketosis are   limited because the color change only indicates 
different categories from traces to high levels.   The second feasible method is the measurement of ketonemia   in capillary blood. For this purpose β-Hydroxybutyrate is detected qualitatively. We use the two measurement methods within 
the scope of a clinical trial. 16 men and 16   women between the age of 20 and 70 years 
fasted for 12 days. The left graph shows   the increase in ketonuria and the right graph 
shows the increase in ketonemia. We then performed   the correlation analysis to see if there was a 
relationship between ketonuria and ketonemia.   A significant medium-strong, positive, 
linear correlation was demonstrated.   This means that a certain comparability 
between the two measurement methods is given.   As shown at the beginning we were able to 
demonstrate the metabolic switch to fasting   metabolism. Parallel to the increase of ketone 
bodies in the blood, we found a decrease of glucose   levels to the lower norm range and the decrease 
of insulin levels. Furthermore triglycerides and   cholesterol levels decreased. In this slide you 
see the changes in ketonuria in a large cohort   of 1610 subjects.

The subjects fasted for up to 
21 days. It is noticeable that the intensity of   ketonuria is very individual. On the one hand there 
are persons who excrete hardly any ketone bodies.   This is represented by the light red shades. On the 
other hand there are persons who excrete very high   amounts of ketone bodies, these are shown in the 
heat map in dark red. Black means that no measured   values were available due to the different fasting 
lengths of the participants. The subjects can be   clustered in two groups by means of hierarchical 
clustering. One group of persons who have low   ketonuria and the other group of persons who have 
high ketonuria. In the group of low ketonuria   predominantly traces of ketone bodies are detected 
in the urine during the fasting process, which   are shown here in yellow.

In addition there is a 
rather slow transition to higher excretion rates.   In contrast a rapid increase in ketonuria 
is observed in the high ketonuria group. The   majority of this group excretes large amounts of 
ketone bodies during fasting, shown here in purple.   We also see in this graph the switchback of 
ketosis excretion along with the   reintroduction of food. One question now arises. Why 
do these two groups exist? Therefore we have tested   the influence of the fasting supplements. Buchinger Wilhelmi offers fasting supplements during long-term fasting.   These include 250 milliliters of fruit juice, 250 
milliliter of soup and about 20 gram of honey.   It is possible to replace the juice with a second soup and omit the honey.

We have   now analyzed the effect of taking the fasting 
supplements on ketonuria the following day.   This is shown here for the second, third and fourth fasting days.   In the contingency tables you can find the 
number of subjects depending on the level   of ketonuria from small traces to large amounts 
and better the fasting supplement was taken or not.   We found that ketonuria was lower the following 
day in subjects who consumed honey and juice.   However ketosis was still detectable.
Consumption of soup had no effect on ketonuria. Next we tested the influence of physiological factors on ketonuria.   For this purpose a machine learning method was used.   The strongest factor that influenced ketonuria 
was age. This was followed by baseline levels of   urea, c. reactive protein and HDL cholesterol. 
In conclusion individuals with high ketonuria   were found to be younger and to have lower 
urea and HDL levels and higher CRP levels.

The question now is whether long-term fasting 
has different effects in the two groups?   We have indeed found differences between 
the groups. A greater reduction in abdominal,   circumference and weight was observed with high 
ketonuria. Uric acid increased more, whereas urea   was reduced less. In addition glucose and glycated 
hemoglobin levels were reduced to a greater extent.   Overall the metabolic effects of fasting appear 
to be more pronounced in the high ketonuria group   independent of fasting length and age. I would 
like to share a final observation with you. Uric   acid is known to increase during fasting as can 
be seen here impressively in the 32 subjects.   In addition we had just seen that a stronger 
increase was detected in the group with high   ketonuria.

In a correlation analysis we were able 
to demonstrate a high positive correlation between   uric acid and ketonemia. This is due to the fact 
that uric acid and ketone bodies are excreted by   the same transporters in the kidney. The ketone 
bodies are preferentially excreted residing in   a competitive inhibition of uric acid excretion 
and thus an increase in uric acid in the blood.   Dr. Wilhelmi will now explain why uric acid 
and ketosis are important for our sleep..