The Bottom of Liebig's Barrel : What Determines Our Life or Death?

The German chemist, Justus von Liebig (1803-1873), is known as the Father
of Agricultural Chemistry. For he was the first scientist who established
what are the major nutrients essential for the growth of plants: nitrogen
(N), phosphate (P), and potassium (K), by growing a plant in water. Based
on this finding, he made the first chemical fertilizer containing these
three elements. Of course two additional things are essential for the growth
of green plants, air (oxygen) and sun light. He then asked, supposed these
three environmental factors (water, air, and light) are plenty, what would
limit the growth of a plant? He found that the amount of each element would
limit the growth even if two other elements are more than sufficient. In
other words, these three elements are not inter-exchangeable. Based on this
observation, he concluded the law of the minimum, the minimum element limits
the growth, which is now called "Liebig's Barrel".

Like plants, we, human beings, need air, water, and sun light, as well as
so many nutrients including C-sources, N-sources, essential amino acids,
vitamins and minerals. In addition, unlike insects and other invertebrates,
we need special cardiovascular organs such as lung, heart and blood vessels
for taking oxygen from air, and pumping and delivering oxygen through blood
vessels to each tissues. When one of these cardiovascular systems stop working,
and in particular brain suffers from oxygen shortage, we have to die almost suddenly.
So in our Liebig's Barrel, this cardiovascular system plays the most crucial
role for our life line. The failure of cardiovascular system means a big hole
at the bottom of Liebig's Barrel. That is the major reason why cardio-
vascular diseases are among the major cause of our death, along with
cancers. In other words our life span is mainly determined by our cardio-
vascular conditions and whether we have a cancer or not. Having a cancer
also implies another big hole at the bottom of our own "Barrel".

How can we maintain our cardiovascular system healthy during our aging?
First of all, don't smoke! Otherwise, you will get lung, pancreatic or
liver cancers, soon or later. How about nutrients/diet and exercise?

The major disorders of cardiovascular system among aging people are hypertension
(high blood pressure) and arteriosclerosis (AS, hardening of arteries).
Hypertension is caused by abnormal contraction of arterial smooth muscles.
Thus, hypertension can be reduced by relaxation of this smooth muscle,
that is blocking smooth muscle actomyosin ATPase by either anti-Rock (Rho
kinase) or anti-PAK1 products. As previously mentioned, natural anti-PAK1
products such as propolis, Chinese (Sichuan) pepper called Hua Jiao, curcumin
in Indian Curry, vitamin K2 (menaquinone-7) in "Natto", a Japanese fermented
sticky soy bean product, resveratrol (trans R3) in red wine or red grapes
would be useful for the treatment of hypertension.

The AS is caused by accumulation of cholesterol along the wall of blood
vessels. Statins that block the biosynthesis of cholesterol would solve
this AS problem. Alternatively, natural approaches such as cutting calories
by 30%, IF (intermittent fast) and exercise also would prevent the accumulation
of excess fatty acids including cholesterol.

Interestingly, these natural anti-PAK1 products, CR (calorie restriction)
and exercise that prevent cardiovascular disorders are also known to suppress
or prevent cancerous growth. In other words, these natural approaches would
fill both of the two major potential holes at the bottom of our aging "Barrel",
to prolong our life span in good health, perhaps by upto 50%, as have been shown
in nematodes, Penguins and mice/rats so far.


Two Kinds of Barrels, Growing and Aging

The original Liebig's barrel for the growth of plants has a solid bottom,
and their growth solely depends on the minimum stave, either N-sources,
P-sources or K-sources as well as either water, air or sunlight. In Germany
and Japan, water is not the minimum stave, but in Australia, Sahara Desert
or other dry countries where rain falls rarely, the precious water is definitely
the No. 1 minimum stave, in particular when the global warming continues
taking place.

Likewise, during our last war (WWII) and shortly after the end of this bloody
war, the majority of children in both Far East including Japan, Korea, and
China and the whole Europe including Germany and UK where battles actually
took place, used to suffer from starvation or malnutrition, due to the serious
food shortage. Their growing barrel did depend on the food supply (mainly
wheat and skim milk) from US under the Marshall Plan. These children had
no time to worry about the bottom of their barrel. My own generation was
among these children.

More than a half century later, these "lucky" children have fully grown
up and many of them have reached even their retirement age (over 65 or so).
Now, they have a plenty of time to worry about the "fragile" bottom of their
aging barrel, instead of the minimum staves, mainly due to overweight, hypertension,
AS and even cancers. They gradually realized that unnecessary (extra)
food intake does definitely harm the health of their aging body, by generating
extra fats and feeding their benign or malignant tumors inside. To limit
their food intake to the minimum level by CR or IF and daily exercise appear
to be the best (simplest and effective) strategy for maintain the bottom
of their aging barrel "intact". Besides this same strategy also improves
their fading memory or learning ability, delaying the onset of Alzheimer's
symptom.


Excess of Phenylalanine (PKU) Causes Mental Retardation

Of 20 natural amino acids, only 8 amino acids are generally regarded as
essential for humans: phenylalanine (Phe), valine, threonine, tryptophan,
isoleucine, methionine, leucine, and lysine. Cysteine, tyrosine (Tyr), histidine
and arginine are additionally required by infants and growing children.
Essential amino acids are so called because our body cannot synthesize them,
making it essential to include them in our diet in order to obtain them.
In addition, the amino acids arginine, cysteine, glycine, glutamine, histidine,
proline, serine and tyrosine are considered conditionally essential, meaning
they are not normally required in the diet, but must be supplied exogenously
to specific populations that do not synthesize it in adequate amounts. An
example would be with the disease phenylketonuria (PKU). PKU is caused by
deficiency of an enzyme called Phe hydroxylase, which converts Phe to Tyr
by oxidation. Individuals living with PKU must keep their intake of Phe
extremely low to prevent mental retardation and other metabolic complications.
However, Phe is the precursor for Tyr synthesis. Without Phe, Tyr cannot
be made and so Tyr becomes essential in the diet of PKU patients.

Pearl Buck (1892-1973), the first American woman Nobel laureate in literature,
and the author of the best-selling book "The Good Earth" (1931) has a daughter
called Carol. Carol was born in 1920 when Pearl and her husband stayed in China
for four decades. Carol was a perfectly healthy child, but it became evident that
she was severely (permanently) mentally retarded when Carol reached around
10. Later she was found to suffer from PKU, but it was too late to treat
her PKU by a low Phe and Tyr-rich diet, because the excess of Phe had already
poisoned her brain completely. PKU was first discovered in association with
mental retardation by the Norwegian physician Ivar Asbjorn Folling in 1934.
Since then Carol was taken care by a special school in US for the rest of
her life (six decades), and her mother, Pearl Buck, then a simple house
wife, started writing a novel in order to cover the high cost of her life-time
special care. That novel turned out to be the famous "The Good Earth",
a unique story about Chinese poor peasants, which was awarded a Pulitzer Prize
in 1932, and Nobel Prize in 1938.

It is of great interest to note that in these old days the majority of
farmers in China and other Far East countries were poor, and used/recycled
only our human waste as the natural fertilizer, instead of modern chemical
fertilizers that were invented by Liebig and other western scientists. So
their soil or earth remained very fertile, certainly rich in all three major
elements, for thousands years. The earth was the most precious treasure
for these poor farmers.

In 1950, Pearl Buck published a non-fiction book "The Child Who Never Grew",
a moving life-story about her own daughter Carol. So many mothers or parents
who have similar hidden children were both wept and encouraged by this book.
Among them were Rose Kennedy (the mother of John F. Kennedy) and Madam De
Gaulle (the wife of Charles De Gaulle).

PKU as an example clearly shows that not only the "minimum" stave, but also
the "excess" stave of our barrel could limit badly the growth of our body,
in particular the development of very sensitive and sophisticated organs
such as our brain.


Homeostasis for Health: "Too Little" or "Too Much" Causes Illness

To keep the normal function of any organs in our body, all essential elements
have to be kept at a certain "minimum" level (homeostasis). When this homeostasis
is broken by either too little or too much synthesis of given elements such
as Phe and PAK, the sensitive organs such as brain start suffering from
disorder or dysfunction, leading to a number of illnesses such as cancers
and mental retardation. Our body normally has a very sophisticated mechanism
to keep this delicate balance (homeostasis) of each essential element for
a good health. However, a certain genetic disorder or environmental stress
breaks this delicate balance, leading to either deficiency or overproduction
of a certain element, resulting in a severe illness.

Here I shall give you a more familiar example: PAK is an enzyme belonging
to a kinase family which is essential for a number of physiological functions
such as cell proliferation (growth) and migration, blood vessel formation
and memory/learning. If you knock out (delete) this PAK gene completely
in mice for an example, embryo fails to develop fully, and it causes the
death of this embryo in womb or mental retardation after the birth, depending
on the timing of gene deletion (and conditions of a few related genes).
If the same PAK gene is over-expressed/ over-activated, the excess of PAK
activity causes a number of severe illnesses, including more than 70% of
all cancers such as formidable pancreatic cancer, melanoma and gliomas,
NF (neurofibromatosis) tumors, mental retardation or learning deficit (LD)
often associated with NF1 and fragile X syndrome (autism), inflammation
(asthma and arthritis), epilepsy, hyper-tension, AD (Alzheimer's disease)
and HD (Huntington's diseases). To cure or treat these illness, the PAK
level has to be reduced to the basic "minimum" level by one of natural or
synthetic anti-PAK1 products. Besides CR, IF and daily exercise also would
help/boost these therapeutics synergestically, because they eventually
activate the longevity/anti-cancer protein FOXO by activating another enzyme
called AMPK (AMP-dependent kinase), as do these anti-PAK1 drugs.

In other words, fattening or overweight significantly would hamper or reduce
the therapeutic efficacy of these anti-PAK products, because the extra calorie
(=sugar) and fat continue inactivateing the FOXO, while these therapeutics
are trying to activate the FOXO. There is the international standard formula
telling you whether you are pleasantly slender/slim or over-weighted, in
order to judge the potential efficacy of these therapeutics by yourself:

S (slimness) = H (height in cm) minus W (weight in kg).

For instance, if you are 173 cm tall and weigh 63 kg, your "S" value would
be 110. If your "S" value is around 110 or higher, you are considered "slim",
clearly a splendid candidate for the "effective" therapy (if you have any
PAK-related illness such as NF). However, your "S" value is significantly
lower than 110, for instance 100 or even 90, you would definitely need to make
an extra effort to reduce your weight by 10 or even 20 kg (if you are grown-up,
and cannot increase your height any more), by CR (diet), IF (fast) or
vigorous exercise (or all of them), to make the therapeutics work more
efficiently. Clear?

Of course the recommended dose of each therapeutic is roughly proportional
of your weight, but if you are taller (or slimmer), you would get much more
benefit from the same dose!

Even in this 21st century, the Liebig's Barrel still serves as a valid model
for children suffering from starvation or malnutrition in poor African or Asian
countries. However, what the majority of people in western industrial countries
or Japan should concern more seriously would be the bottom of their own
barrel which is badly damaged by either cancers or cadio-vascular diseases,
and the belt (waist line) of their over-fed barrel, instead of the 'minimum'
stave. In the latter case, the slimmer its barrel, the longer it lasts (if not
ultra-thin cat-walk models on world fashion stages).