Solution to the Puzzle of Human Evolution.
Matthias Rath M.D.
Journal of Orthomolecular Medicine 7: 73-80.
light will be thrown on the origin of man and his history."
Charles Darwin "On the Origin of Species"
Until now human evolution has remained one of the greatest puzzles of
mankind. Neither paleoanthropology nor behavioral or genetic approaches
are able to explain the dramatic development that let to the evolution
of modern man and made him the dominant species on earth. This explanation
is provided by a fascinating combination of genetic, metabolic, environmental,
and dietary elements. Several of my recent discoveries turned out to
be important to solve the puzzle of human evolution.
After the loss of endogenous ascorbate synthesis in the ancestor of
man, scurvy became the greatest threat to the evolutionary survival of
our ancestors.¹ Apo(a) and Lp(a) became important metabolic constituents
in man and subhuman primates after they had lost the ability for endogenous
ascorbate synthesis.² Apo(a) functions as an adhesive protein and
was a metabolic key in the development of intelligence and fertility
during human evolution.³ These discoveries, together with the fact
that the evolution of man was greatly accelerated during the Ice Ages
starting about 2.5 million years ago,4 led me to the solution of the
puzzle of human evolution, which will be presented in the following paragraphs.
The Loss of Endogenous Ascorbate Production –
Genetic Precondition For Human Evolution
About 40 million years ago the ancestor of man lost the ability to synthesize
ascorbate endogenously. This was the result of the mutation of the gene
encoding for the enzyme L-gulono-?-lactone oxidase, a key enzyme in the
conversion of glucose to ascorbate. This genetic mutation left all descendants,
including all human beings living today, dependent on sufficient exogenous
ascorbate supply in the diet.
The precondition for this genetic mutation was a sufficient dietary
supply of ascorbate. The precondition was met by the fact that at the
time of the mutation our ancestors lived in the central regions of Africa
and their diet consisted mainly of fruits and other nutrition rich in
ascorbate and other vitamins. Nevertheless, as a result of this mutation
the availability of ascorbate in the body of our ancestors dropped from
between 10,000 to 20,000 milligrams synthesized endogenously every day,
to several hundred milligrams taken up in the diet of the African habitat.
More than 30 million years later this genetic defect was completely unmasked
by environmental conditions triggering the evolution of man.
Ice Ages – The Environmental Trigger
For the Evolution of Man
The evolution of man was greatly accelerated during the Ice Ages, which
started about 2.5 million years ago. During this relatively short time
the size of the human brain quadrupled and man became the dominant species
on earth. Since that time the glaciation periods occurred periodically
about every 100,000 years, lasting for several tens of thousands of years.
During the short warm interglacial periods, lasting about 10,000 years,
our ancestors expanded their habitat and migrated to other hemispheres.
Until now evolutionary theories postulate that the dramatic leap in
human evolution is the result of natural selection processes that occurred
during the recent 2.5 million years. It was hypothesized that only the
fittest and most intelligent among our ancestors would have survived
these harsh conditions and would have been able to propagate. This hypothesis,
however, cannot explain why the increase in brain size and other significant
changes were limited to the ancestor of man and did not occur in other
mammalian species. The concept presented in the following paragraphs
can explain this phenomenon.
The dramatic drop in temperature during the Ice Ages affected the vegetation
on a global level. Scarce nutrition and frequent deficiency in vitamin
and other essential nutrients affected all species equally. The ancestor
of man shared with most other mammals genetic defects that rendered them
susceptible to pellagra, pernicious anemia, beri-beri, and other diseases
caused by nutritional deficiencies. Human metabolism, however, was set
apart from the metabolism of other species by the inability for endogenous
ascorbate production. While other species continued to manufacture ascorbate
endogenously, generally at a rate of several grams per day compared to
the human body weight, our ancestors’ body ascorbate concentration
was limited by the low ascorbate intake in their diet. During the tens
of thousands of years each glaciation period lasted ascorbate intake
approximated zero and scurvy became the greatest threat to the evolutionary
survival of man.
Scurvy – The Greatest Challenge
For The Evolutionary Survival of Man
Scurvy is the result of total ascorbate depletion of the body and of
a gross impairment of collagen and elastin synthesis. Scurvy is a fatal
disease characterized by a virtual dissolution of the connective tissue
throughout the body including the walls of the blood vessels. He sailors
of earlier centuries died from scurvy, particularly from blood loss through
the scorbutic vascular walls, within a few months. During the millennia
of glaciation, billions of our ancestors died from scurvy particularly
during the most recent Ice Ages, when they had migrated to climatically
exposed hemispheres of the earth.
The death toll from scurvy was so enormous that our ancestors in many
regions were virtually rendered to extinction. One example are the Neanderthals.
These highly developed hominids living in many parts of Europe had became
extinct during the last glaciation period. Which lasted from about 120,000
years ago to about 15,000 years ago. Neanderthal fossils reveal obvious
signs of scurvy: frequent fractures of bones and disrupted growth of
Since scurvy was the greatest threat, the greatest pressure for the survival
and the evolution of man was the need for genetic features able to counteract
the fatal consequences of scurvy.
The Vascular Wall – the Focus of Genetic Adaptation
The focus of these countermeasures and of the associated genetic adaptation
process was the vascular wall and the paramount need to counteract blood-loss
through the scorbutic vascular wall. This adaptation process was characterized
by a selective advantage of inherited features that rendered compensatory
stability to the ascorbate-deficient vascular wall.¹
These genetic features comprise a multitude inherited metabolic disorders
that can lead to the deposition of plasma constituents in the vascular
wall, to proliferative responses of cellular systems in the vascular
wall or by other mechanism resulting in a compensatory stabilization
of the ascorbate-deficient vascular wall. By favoring these genetic features
nature decided for the lesser of two evils: death from cardiovascular
disease during adulthood rather than death from scurvy during infancy.
Ascorbate deficiency favored this genetic adaptation process against
the fatal consequences of scurvy also in another way. Ascorbate is the
strongest antioxidant in the body. Low ascorbate concentrations decrease
the protection against oxidative damage of DAN and thereby increase the
rate of genetic mutations.5 Ascorbate intake approximating zero during
the millennia of glaciation initiated a form of ‘genetic roulette’ in
our ancestors. The significantly increased genetic mutation rate greatly
accelerated the genetic adaptation that favored not only countermeasures
against scurvy but at the same time promoted human evolution. The more
effective a genetic feature stabilizes the vascular wall during ascorbate
deficiency the more important became this genetic feature as a metabolic
promoter for the development of man.
Ascorbate Deficiency and Metabolic Promoters of Human Evolution
In general, all metabolic changes induced by ascorbate deficiency have,
to a variable degree, affected organ development and differentiation
during the evolution of man. Those metabolic factors that become available
at increasing concentrations during ascorbate deficiency were metabolic
promoters of evolution. Many of the metabolic changes induced by ascorbate
deficiency are enhanced by a simultaneous deficiency in other essential
nutrients such as niacin and riboflavin, which frequently interact synergistically
with ascorbate. A deficiency of ascorbate, however, the strongest hydroxylating
and reducing agent in the body, is the most important among them. In
the following paragraphs I will focus on some metabolic interactions
of ascorbate, which are important in the context of this publication.
An effective and therefore frequent mechanism counteracting scorbutic
blood loss and therefore an important metabolic promoter of evolution
was the elevation of plasma levels of lipid-rich ‘atherogenic’ lipoproteins.
Low density lipoprotein (LDL), very low density lipoprotein (VLDL), and
particularly lipoprotein(a) (Lp(a)) are found to be significantly elevated
in humans compared to other species with endogenous ascorbate synthesis.
Even more pronounced is the difference between man and ascorbate producing
animals for the ratio between these ‘atherogenic’ lipoproteins
and the ‘anti-atherogenic’ high-density lipoprotein (HDL).
Atherogenic lipoproteins are characterized by a high content of lipids,
e.g. cholesterol and fatty acids, and their elevated plasma concentration
reflects an improved substrate supply for organ development and growth.
Ascorbate deficiency also leads to an increased availability of glucose.
The increased availability of lipids and carbohydrates may in part be
mediated by an increased corticotropin and cortisol release during ascorbate
deficiency.6 Other mechanisms leading to an increased substrate supply
in ascorbate-deficient conditions are reviewed elsewhere.1,6,7
However, improved metabolic substrate supply alone cannot explain the
complex organ changes during evolution such as the development and differentiation
of the human brain. These changes require an increased availability of
metabolic factors involved in organ morphogenesis. Such metabolic factors
are represented by a group of proteins called adhesive proteins. These
proteins share a characteristic tripeptide sequence, arginine-glycine-aspartate
(RGD), and they mediate the interaction between cellular systems and
the extracellular matrix in a multitude of conditions such as organ differentiation,
repair and growth (review in 8).
While ascorbate deficiency decreases the rate of synthesis for certain
adhesive proteins such as collagen and fibronectin the production of
certain other adhesive proteins such as fibrinogen and apo(a) is increased
at low ascorbate concentrations. Of particular importance for organ development
and differentiation during the evolution of man was apo(a).
Apoprotein(a) and Lipoprotein(a) – Decisive Metabolic Promoters
of Human Evolution
Apo(a) and Lp(a) became major constituents in the metabolism of our
ancestors after they had lost the ability to synthesize ascorbate. Lp(a),
a unique combination of the adhesive protein apo(a) with an LDL particle,
and apo(a) are quite likely the single most important metabolic promoters
of evolution. One of the reasons for the selective evolutionary advantage
of apo(a) and Lp(a) was their extraordinary effectiveness in counteracting
scorbutic blood loss by their extracellular deposition in the ascorbate
deficient vascular wall.9
The other reason for the selective advantage of the adhesive protein
apo(a) is its contribution to the development of the human body during
evolution. Beside the liver, where apo(a) is secreted as Lp(a), only
two other organs were reported to have the ability for autonomous apo(a)
production: the brain and the testes.¹º These two organs have
determined critical evolutionary advantages: intelligence and fertility.
Apo(a) and Brain Development
A dramatic increase in brain size and differentiation during the evolution
of man determined his dominant role today. Acquisition of language and ‘toolmaking’ have
been proposed as factors responsible for the rapid encephalication. However,
these factors are rather the result than the cause of increased brain
size and intelligence. Moreover, these hypotheses leave open the decisive
question of why a similar development did not occur in other mammals,
which were exposed, to the same environmental conditions.
Apo(a) was an important metabolic factor in the development and the
differentiation of the human brain during evolution. Like other adhesive
proteins apo(a) contains an RGD tripeptide. RGD sequences are critically
involved in the morphogenesis and differentiation of the central and
peripheral nervous system (review in 8). During human evolution apo(a)
synthesis rate in the brain continuously increased as the result of the
genetic adaptation to counteract scurvy. Moreover, dietary deficiencies
particularly of ascorbate and niacin during the millennia of glaciation
let to a metabolic upregulation and a high apo(a) synthesis rate. It
is therefore concluded that apo(a) has been a metabolic clue to the development
of the human brain and the increase of intelligence during human evolution.
During this development apo(a) has been interacting with other adhesive
proteins such as fibronectin and collagen. These adhesive proteins, however,
cannot offer a clue to human evolution – they are present throughout
the animal world and are not preferential features of human metabolism.
Apo(a) and Increased Fertility
Another decisive advantage during evolution was the improvement of fertility.
This is even more remarkable since during evolution female reproductive
physiology has lot an important signal, the estrus, and developed a concealed
form of ovulation. Improved fertility was an important precondition for
the development of concealed ovulation. Adhesive proteins are known to
improve fertility by facilitating the interaction of sperm cells with
egg cells as well as by mediating egg penetration (review in 8). Apo(a)
was recently detected in human sperm ³ and increased apo(a) concentrations
in the seminal fluid of our ancestors must have led to improved fertility.
In conclusion, apo(a) was a metabolic clue in determining decisive advantages
during the evolution of man: intelligence and fertility.
The role of apo(a) for the development of the body during human evolution
was not confined to the brain and the testes. Elevated plasma levels
of Lp(a) in newborns today¹¹ indicate an important role of
apo(a) in development, differentiation and growth of the human body as
Plasma constituents reacting with antibodies against human apo(a) are
also found in lower mammals, particularly in those with permanent or seasonal
susceptibility to ascorbate deficiency such as the guinea pig and the
hedgehog. These findings do not contradict the conclusions presented here.
They rather underline human evolution as a multifactorial process with
apo(a) and Lp(a) being of particular importance.
The Evolution of Man and Human Health Today
The mutation of a single gene encoding for a key enzyme in the conversion
of glucose to ascorbate 40 million years ago in the ancestor of man became
a two-sided sword. On one side this genetic mutation became the precondition
for human evolution and was the decisive precondition why within the
last 2.5 million years one species, man, became the dominant species
on earth. On the other side this very same mutation left all descendants
including over four billion people living today susceptible to scurvy
and other characteristic diseases that are essentially unknown in animals
with endogenous ascorbate production.
While scurvy is essentially unknown today, chronic insufficient dietary
intake of ascorbate is widespread. Chronic ascorbate deficiency is the
underlying cause for the most frequent diseases, diabetes, and other
diseases. Millions of people die every year and millions more become
disabled from these preventable diseases. Optimum dietary intake of ascorbate,
particularly in combination with niacin, riboflavin, and other essential
nutrients, should compensate for the genetic defect that lead to a cessation
of endogenous ascorbate synthesis. The discoveries presented in this
publication open the opportunity to greatly improve human health in this
generation and future generations of mankind.
The Determining Principles of Human Evolution
The dramatic acceleration of human evolution during the recent 2.5 million
years and the dominant role of humans on earth today are not the result
of random selection during this period. Human evolution is the result
of a unique combination of genetic, metabolic, environmental and dietary
The underlying genetic precondition for the evolution of man was a
genetic mutation that occurred 40 million years ago in our ancestors:
of endogenous ascorbate production. This genetic mutation left all
descendants dependent on dietary ascorbate intake and set their metabolism
from other species which continued endogenous ascorbate production
at an average daily rate of several thousand milligrams per day compared
to the human bodyweight. The loss of endogenous ascorbate production
resulted in a significant drop of body ascorbate concentrations in
ancestors. This fact may have triggered a first leap towards the evolution
of man which occurred about 40 million years ago.
The Ice Ages, starting about 2.5 million years ago, became the environmental
trigger condition for the evolution of man. Human evolution was particularly
accelerated during the most recent Ice Ages, when our ancestors had
migrated to the Northern Hemisphere and other parts of the world directly
to harsh climatic conditions. The cooling of the earth led to a decreased
vegetation and to a limited availability of essential nutrients.
The dietary trigger condition for the evolution of man was an insufficient
intake of vitamin C. During glaciation the ancestor of man shared with
other mammals a limited food supply and a deficiency in most essential
nutrients. Ascorbate deficiency, however, became a characteristic condition
in the metabolism of our ancestors.
Scurvy was the greatest threat to the evolutionary survival of our
ancestors particularly during the millennia of glaciation. While other
were protected during the Ice Ages from scurvy by their endogenous
ascorbate synthesis, billions of our ancestors died from this disease.
The greatest evolutionary pressure during the evolution of man was
the need for genetic and metabolic countermeasures to limit the fatal
of scurvy. These genetic countermeasures against scurvy had a selective
evolutionary advantage over millions of generations.
In ascorbate deficiency the weakest sites of the body are the blood
vessels, and hemorrhagic blood loss through the scorbutic vascular wall
is a frequent
cause of death in scurvy. The vascular wall became the focus of genetic
countermeasures that protect the ascorbate-deficient walls against
fatal blood loss.
Advantageous genetic features counteracting scurvy became the genetic
and metabolic base for the evolution of man. The more effective a genetic
or metabolic feature protected the vascular walls against scorbutic
blood loss, the greater was its contribution to the development and differentiation
of the human body during the evolution of man.
The single most important metabolic feature for the evolution of man
was aporotein(a). In association with LDL, apo(a) became the most effective
mechanism to stabilize the ascorbate-deficient vascular wall. As an
adhesive protein expressed in the brain and the testes, apo(a) was involved
determining decisive evolutionary advantages: intelligence and fertility.
In general, all metabolic factors that become available at increased
concentrations during ascorbate deficiency have to be considered a
metabolic promoters of evolution. These metabolic factors include lipid
(cholesterol, triglycerides), and lipoproteins (Lp(a), LDL, VLDL).
The genetic adaptation was accelerated by the fact that ascorbate deficiency
greatly favored the rate of genetic mutations. This increased mutation
rate favored the selective evolutionary advantage of genetic and metabolic
features counteracting scurvy an simultaneously promoting evolution.
The genetic mutation that resulted in the loss of endogenous ascorbate
synthesis in the ancestor of man became a two-sided sword. On one side
it let to a great death toll from scurvy and other diseases in the
descendants; on the other side this mutation was a decisive genetic precondition
man to become the dominant species on earth.
The critical role of ascorbate deficiency during human evolution has
immediate implications for the health of human beings today. While
scurvy is essentially unknown today, chronically insufficient dietary
is widespread. Ascorbate deficiency is a precondition for the most
frequent human diseases today, including cardiovascular diseases, diabetes,
many other diseases. These diseases are essentially unknown in animals
producing high amounts of ascorbate endogenously and they can be prevented
in humans by optimum dietary ascorbate supplementation.
In this paper I presented decisive missing pieces in the puzzle of human
evolution. The remaining questions may largely be answered by a new scientific
discipline: metabolic anthropology. The solution to the puzzle of human
evolution and its direct implications for human health today is a modest
contribution by an individual scientists, but it may turn out to be a
major step for mankind.
Rath, M., Pauling, L. A unified theory of human cardiovascular disease
leading the way to the abolition of this disease as a cause for human
mortality. Journal of Orthomolecular Medicine 1992; 7: 5-15
Rath M, Pauling L, Hypothesis: Lipoprotein (a) is a surrogate for ascorbate.
Proceedings of the National Academy of Sciences USA 1990; 87: 6204-6207
Rath M, Pauling L. Apoprotein(a) is an adhesive protein. Journal of
Orthomolecular Medicine 1991; 6:139-143.
Calvin W. The ascent of mind, Ice Age climates and the evolution of
intelligence. Bantam Books, New York, Toronto London, Sydney, Auckland
Fraga CG, Motchnik PS, Shigenaga MK, Helbock HJ. Jacob RA, Ames BN.
Ascorbic acid protects against endogenous oxidative DANN damage in human
sperm. Proceedings of the National Academy of Sciences USA 1991; 88:
Clementson CAB: Vitamin C, Volume I-III. Florida: CRC Press, Inc. 1989.
Burns JJ, Rivers JM, Machlin LJ, eds. Third Conference on Vitamin C,
Annals of the New York Academy of Sciences 1987, 498.
Hynes R.O.: Fibronectins. Springer-Verlag Series in Molecular Biology,
Springer-Verlag, New York 1990.
Rath, M., Pauling, L. Solution to the puzzle of human cardiovascular
disease: its primary cause is ascorbate deficiency leading to the deposition
of lipoprotein (a) and fibrinogen/fibrin in the vascular wall. Journal
of Orthomolecular Medicine 1991; 6:125-134.
Tomlinson J.E., McLean J.W., Lawn R.M.: Rhesus monkey apolipoprotein(a).
Sequence, evolution and sites of synthesis. Journal of Biological Chemistry
1989; 26664: 5957-5965.
Van Biervliet JP, Labeur C, MNichiels G, Usher DC, Rosseneu M. Lipoprotein(a)
profiles and evolution in newborns. Atherosclerosis 1991, 86: 173-181.
Eccles JC. The human mystery. Routledge & Kegan Paul,
London, Boston, Melbourne and Henley 1984.