|
THE
Oxygen MODEL OF AGING
The
Dysox State
Majid Ali, M.D.
My grandfather forgot to die on
time. We do not know how long he lived
— 101 years, 102 years, or
more. My grandmother was also a centenarian. With
that genetic pool, I sometimes wonder about my own
life span. Then I realize that my grandparents lived
free of pesticides, refrigerators, and CNN. A large
proportion of people of Hunza Valley and Okinawa
Islands live for 110 or more years. When their
children travel down to polluted plains of Pakistan
or toxic cities of Japan in search of employment,
they begin to fall prey to degenerative disorders
within a decade or two. Their life span plummets.
There is more to be learned about healthful aging
there — in my view
— than in all the hopes and
claims of enthusiasts of gene and 'longevity
hormone' therapies. In this column, I look at old
and new theories of aging through the prism of
oxygen metabolism, and marshall evidence for my view
that healthful human aging is, first and foremost, a
matter of compromised oxygen homeostasis.
Is aging necessary?
— The Science of Longevity.
That was the title of the cover story of Harvard
Magazine of September 2005. That article
included the following: "The experimental evidence
that suggests that aging is under genetic control,
rather than a consequence of normal wear and tear,
is compelling.1 I do not share the
author's excitement about that discovery. The
language of genes is far too complex to accomodate
that view of genomics. The issue is not that life
can be extended by genetic modifications, but that
the longer-living mutants show other serious effects
— reduced fertility,
developmental deformities, and others
— a trade-off of uncertain values that is not
likely to be acceptable to humans. Even when limited
longevity advantage are realized through genetic
modifications, I predict that those benefits will be
drawn only to the degree that oxygen homeostasis of
the subjects can be optimised. I return to this
crucial subject later.
Some mechanically-oriented
writers in the field of aging assert that what is
required is a simple business plan for some grand
spare parts relacement industry. One of them
recently proclaimed: 'It is only a matter of years —
decades at most — until futuristic technologies will
entirely reverse-engineer the human machine.'2
He went on to prophesize 'a radical life extension
is close at hand.' Such individuals seem
not to see any differences between the precisely
definable chemistry of inanimate materials and the
ever-changing energetic-molecular kaleidoscopic
mosaics of living beings. Some of them have
pronounced aging to be disease curable by
nutritional and herbal products they sell. I do not
share their enthusiasm either. The
inter-relationships of ligands, receptors,
biomemebrane channels, protein pumps, and mediators
of inflammation are far too intricate and labile to
sustain those claims. Again, when limited longevity
advantage are acheived through such 'reverse
engineering,' I predict that those benefits will not
last unless oxygen homeostasis can be preserved.
During 1930s, Clive McKay
established that caloric restriction extends life
span in many species.3 He implied that
that is the only way of increasing the lifespan of
mammals. Since that classic work, an enormous body
of literature has accumulated validating the direct
relationship between caloric restriction and
longevity.4-9 This linkage has been
documented in yeast, mosquitoes, flies, and rats. To
cite a specific example, the life span of
Saccharomyces cerevisiae increases by 25% when
the glucose level in the culture is reduced from 2%
to 0.5%.10 Similarly mosquitoes on
caloric restrictions live longer than those with
ad-lib (unrestricted) feeding.
In 1955, Johan Bjorksten proposed
his cross-linking theory of aging.11
According to this theory, the basic aging process
involves accumulation of disfigured and insoluble
(cross-linked) proteins, DNA, fats, and other
large-sized molecules, such as vitamin A. Simply
stated, cross-linked molecules are two molecules
wrapped around each other in such a way that neither
can function normally. Such molecules cause aging by
impeding or blocking the actions of redox-restorative
and oxystatic substances — enzymes, antioxidants,
and other nutrients. The process of cross-linking
may be illustrated as follows: The structure of many
healthy proteins resembles long threads of different
sizes. Under heat or chemical stresses, individual
molecules are bent, turned and twisted into many
different shapes. Such misshapen molecules quickly
regain their original shapes when the stresses
subside. The term cross-linking means that such
turned and twisted molecules get permanently
disfigured because of excessive stress. Thus, such
molecules are torn apart and, when the ends unite,
they get tangled with each other and form crooked
protein molecules.
In 1956, Denham Harmon proposed
his free radical theory of aging.12
According to this theory, the aging process involves
molecular and cellular injury caused by free
radicals. Free radicals are highly unstable,
extremely reactive atoms or molecules that form
during normal metabolism, as well as during cellular
injury caused by chemicals, microbes, radiation, and
other types of injury. Since its introduction, the
basic tenet of this theory was supported by an
ever-growing body of data. Indeed, until
recently, the case for this theory seemed iron-clad.
In 1962, Roy Walford put forth an
immune theory of aging.13,14 He proposed
that the aging process involves injury to the immune
system of the body so that the immune system of a
person becomes confused and turns against that
person's tissues. Specifically, immune injury
results in the production of abnormal antibodies
that injure the body's own tissues rather than
fighting microbes. Such antibodies are called
autoantibodies.
Aging and Rates of Auto-Oxidation
and DNA Repair
The rates of spontaneous tissue
generally correlate inversely with the species life
spans — the animal species with the highest rates of
auto-oxidation have the shortest life spans, while
those with the lowest rates of auto-oxidation have
the longest life spans.15 Man—with the
lowest rate of tissue breakdown — has the highest
longevity, while the mouse (which has the highest
oxidation rate among the species listed in Table 1)
has the lowest longevity. However, there are
exceptions to that rule. For instance, mice and bats
have similar metabolic rates, yet bats live nearly
ten times longer than mice. It is also noteworthy in
this context that antioxidant supplementation, in
general, does not allow various species to live
longer.
|
Table 1. Rates of
Auto-Oxidation and Life Spans of Mammalian
Species |
|
Species |
Oxidation Rate |
Life Span (yrs) |
|
Man |
24 |
90 |
|
Orangutan |
25 |
50 |
|
Baboon |
35 |
37 |
|
Green monkey |
41 |
34 |
|
Squirrel monkey |
74 |
18 |
|
Rat |
104 |
4 |
|
Mouse |
182 |
3.5 |
Deoxyribonucleic acid in cells is
under unrelenting assault from disruptive
influences. Fidelity in its structure and during its
duplication is evidently crucial to cellular
structural and functional integrity. That is assured
by a stunning array of cellular enzymes that detect
and repair deletions, additions, and translocations
in DNA threads. Such enzymes not only remove damaged
segments, but also rapidly reconstitute the DNA
threads in areas of gaps left by the damaging
agents. The functionalities of such enzymes diminish
with age. The efficiency of DNA repair enzymes can
be assessed by measuring the rate of consumption of
such enzymes added to DNA damaged under control
conditions (in which nucleotides are exposed to
various DNA-damaging agents).
In 1973, Hart and Setlow measured
rates of DNA repair in fibroblasts from a number of
species and plotted it as a function of the maximum
life span of the species.16 Table 2 shows
data for humans, Indian elephant, cow, golden
hamster, Norwegian rat, field mouse, and long-tailed
shrew. The numbers have been rounded to simplify the
presentation of data.
In 1983, I put forth my
spontaneity of oxidation (SO) model of aging.17
This model holds that aging involves loss of energy
triggered, perpetuated, and completed by the ongoing
and spontaneous loss of electrons in the body. Even
a cursory look at the cross-linkage, free radical,
and immune theories makes it clear that the SO model
is fully consistent with all three. Indeed, my model
then represented an extension of those theories in
the sense that it provides a clear underlying
mechanism for all three. A large body of data is
summarized in Tables 1 and 2 to validate the various
aspects of the SO model of aging.
|
Table 2. DNA Repair as a
Function of Life Span* |
|
Species |
DNA Repair
(relative) |
Life Span**
(logarithm) |
|
Man |
5 |
2 |
|
Indian elephant |
4.3 |
1.9 |
|
Cow |
4 |
1.5 |
|
Golden hamster |
2 |
0.6 |
|
Norwegian rat |
1.8 |
0.5 |
|
Field mouse |
0.8 |
0.38 |
|
Long-tailed shrew |
0.5 |
0.2 |
* All values are included as close approximations
for the sake of simplicity.
** Life span is given as logarithmic value of the
maximum species life span.
In 1996, Cynthia Kenyon
demonstrated that C. elegans round worm
missing one copy of daf-2 gene 'stop the
clock' by becoming dauers — assume a spore-like
state akin to hibernatiion — and can live for long
periods of time.18-20 She deduced from
her observations that the program that controls
longevity in that worm can be uncoupled from other
physiological processes. In that year, Guy Ruvkun
extended Kenyon's observations by showing that
daf-2 and age-1 genes were were part of
the same genetic/molecular pathway, and that
daf-2 encodes an insulin receptor, thus linking
aging to insulin signalling and to McKay's
observations concerning the extension of life span
with caloric restriction.21,22
During the late 1990s, Leonard
Guarente and David Sinclair examined the mechanisms
of aging in yeast cells that divide an average of 20
times — 40 times at
most — and showed that the life span of yeast can be
extended when its DNA is stabilized (rearrangements
are prevented).21-23
Specifically, the yeast
live about thirty percent when an extra copy of Sir2
gene is inserted in it to stabilize its DNA. The
Sir2 gene is considered to be the founding member of
the family of genes that encode sirtuins, proteins
that evolved about a billion years ago to preserve
the life span of various species during periods of
stress. PNC1 is another gene — designated as the
'master regulator' that regulates Sir2 — of
importance in this context. It has also been shown
that the levels of SIRT1 (the mammalian equivalent
of Sir2 in yeast) rise when the levels of insulin
and IGF-1 fall during caloric restriction.
Sinclair then claimed he had
identified certain plant molecules that can activate
the Sir2 protein — designated sirtuin activating
compounds, or STACs — with life extension benefits.
Resveratrol — of no proven value for human life
extension so far — is one such STAC that excites the
practitioners the anti-aging industry most. Sirtuins
are considered to be controlled by insulin and
insulin-like growth factor-1 (IGF-1).
The Sir2 family of regulatory
proteins with important regulatory roles in aging.24-33
Specifically, this family links chromatin
silencing, metabolism, and aging.24 In
yeast aging—and most likely in aging of many other
species—the chromatin silencing functions are
critical to life extension. Caloric extension
increases the activity of Sir2.25 Some
members of this family function as longevity
proteins with transcriptional silencing ability.26
The silencing protein Sir2 and its homologs are NAD-dependent
protein deacetylases.27 Sir2 protein and
its homologs contain a phylogenetically conserved
NAD+-dependent protein deacetylase activity.28
The Sir2/3/4 complex and Sir2 alone promote
longevity in Saccharomyces cerevisiae by two
different mechanisms. Sir2 proteins also has a
well-delineated role in life extension by calorie
restriction in Saccharomyces cerevisiae. The
effect of caloric restriction in this context also
requires a role of nicotinamide adenine dinucleotide
(NAD).
Genetic
Modifications and Aging
During the last two decades,
remarkable advances in the genetics of aging
occurred. Most notable among, in addition to the
Sir2 family of genes, are genes of Hap4
Transcription Factor, HXK2, daf-2, age-1, and
cytochrome c1 (CYT1) groups. 34-36
HXK2 is another gene of
importance. It encodes one of the three hexokinases
that introduce glucose into glycolysis.34
It was expected to mimic the effects of growth in
low-glucose medium, which it did. HXK2 deletion is
known to extend life. Interestingly, that deletion
was found to also increase respiration.
Transcriptional profiling of S. cerevisiae
genome disclosed a highly significant overlap in the
transcriptional changes induced by low glucose
(0.5%) growth and that seen with HXK2 deletion. Hap4
transcription factor activates many genes involved
with mitochondrial respiration.35
Transcriptional profiling reveals that many of those
genes, upregulated more than two-fold by Hap4, are
involved in the metabolic switch from fermentation
to respiration. In S. cerevisiae life
extension studies, overexpression of Hap4 redirects
the respiro-fermentative flux distribution,
resulting in a switch of metabolism from
fermentation toward respiration, and provides
further direct evidence for the pivotal role of
oxygen in aging. Cytochrome C1 is the protein
involved with electron transport in S. cerevisiae.
The life span of some yeast strains can be extended
under certain conditions. Deletion of the gene
encoding cytochrome c1 (CYT1) abrogates life
extension under those conditions,
supporting the view that metabolic shift to
respiratory ATP production is a pre-requisite for
life extension under the experimental conditions.
Respiratory-to-Fermentative Shift and Aging
In 1998, I introduced the term
dysoxygenosis for a state of partial or complete
failure of oxygen utilization in cells.36-38
I put forth the hypothesis that dysoxygenosis
is caused by impaired function of enzymes involved
in oxygen homeostasis ("oxyenzymes") and leads to
altered expressions of genes induced by hypoxic
environment ("oxygenes"). The webs of oxyenzymes are
vast, with each entity linked to every other through
multiple pathways. The webs of oxygenes are
seemingly far more complex. All such webs are
exquisitely 'aware' of changes in oxygen
availability in their microenvironment and
vigorously respond to them. When one thing changes
in those webs in one way, everything changes in some
way. Dysoxygenosis, then, is discerned as a state
caused by a rich diversity of elements but one that
creates the same cellular oxygen dysfunction. In
1998, I also introduced the terms dysfunctional
oxygen metabolism and oxygen disorder for
readers without medical or biochemical background.39
In 2000 in Oxygen and Aging,
I presented my oxidative-dysoxygenative model of
aging,40 as an extension of the earlier
SO model of aging. Simply stated, that theory holds
that within the confines of genetic limits, the
primary aging process involves dysoxygenosis. In
that state, the cells, tissues, and body organs age
because they cannot maintain oxygen homeostasis. The
essential difference between the 1983 and 2000
models is this: In the former, the focus was
essentially on the primal oxidative drive provided
by spontaneity of oxidation in nature—and the
degradative consequences of free radical generation
triggered, amplified, and perpetuated by the
phenomenon; by contrast, the emphasis in the
oxidative-dysoxygenative model is on both the
regenerative and degradative aspects of oxygen
homeostasis and of oxygen-related factors.
During the early years of this
century, Llyod Demetrius put forth his metabolic
stability hypothesis of aging hold that the length
of life span is determined by the stability of free
radical activity.41 The proposed
mechanism in this model is based on the hypothesis
that metabolic stability — the
capacity of an organism to maintain steady state
values of redox couples — is a
prime determinant of longevity. It integrates a
molecular model of metabolic activity (quantum
metabolism) with an entropic theory of evolutionary
change (directionality theory) to propose a
proximate mechanism and an evolutionary rationale
for aging. The mechanistic aspects of this model are
used to predict that caloric restriction extends
life span by increasing metabolic stability. The
evolutionary aspect is used to predict that the
observed increased longevity with caloric
restriction in rats will not hold for primates. That
is because rats show early sexual maturity, a narrow
reproductive span and a large litter size, all three
features indicating low entropy. This model then
holds that Darwinian fitness in the mouse derives
from its metabolic flexibility, whereas such fitness
in humans relates to their physical robustness, and
dashes the hopes of those who undertake severe
caloric restriction in order to live longer.
Insulin
Signalling and Aging
In 1997, Gary Ruvkin showed that
daf-2 encodes an insulin receptor.41,42
His landmark studies firmly established the link
between aging to caloric restriction in roundworms.
That also raised some important questions. Could an
experimental model be generated in which the animal
eats more, weighs less, and lives longer? Since
insulin signalling is clearly involved with the
current epidemic of obesity 43
— and presumably
reduced life span —
could such animal model be produced by genetic
modification of insulin signalling? In fruit flies
and roundworms, the same protein serves as the
receptor for insulin and growth hormone. Could that
knowledge be of value in constructing the desired
animal model? To pursue those questions, C. Ronald
Kahn generated mutant mice with genetically knocked
out insulin signalling. 44 Specifically,
he generated fat cell insulin receptor to knockout
mice (FIRKO mice), the muscle cell insulin receptor
knockout (MIRKO) mice, the liver cell insulin
receptor knockout (LIRKO) mice, and the neuron
insulin receptor knockout (NIRKO) mice). FIRKO,
MIRKO, anmd LIRKO mice are metabolically
inefficient. The FIRKO mice turned out to eat more,
weigh less, and live longer. Interestingly, these
mice showed no change in the level of sirtuin
proteins in their fat. I might point here that there
is decreased expression of several genes involved
with mitochondrial oxidative phosphorylation, as
well as changes in the levels and ratio (NAD/NADH)
of crucial metabolites. The observations with FIRKO,
MIRKO, and LIRKO mice have so far not provided clear
answers as to the essential nature of the aging
process; however, those findings do shed some light
on the dysox model of aging as discussed below.
In human biology, mitochondrial
respiration energetics produce ATP from ADP
phosphorylation, and the electron transport in that
process accounts for most reactive oxygen species (ROS)
production.46 ROS generation begins with
molecular oxygen picking up electrons to produce
superoxide at complex I and III.47
Located at the inner mitochondrial membrane are
anion transporters called uncoupling proteins
(UCP-1, UCP-2, and UCP-3), which permit proton
leakage back into the mitochondrial matrix, two
consequences of which are a decrease in the
potential energy available for ADP phosphorylation
and a reduction in ROS generation. UCPs also
increase respiration, which accelerates superoxide
production in the setting of low protonmotive force.48
Superoxide, in turn, activates uncoupling protein.
Thus, is established a valuable contrariety in free
radical homeostasis at one of the most fundamental
levels of molecular energetics of human biology.
In the vascular wall, smooth
muscle cells are the principal source of ROS.46
For studying the effects of uncoupling respiration
and oxidative phosphorylation, mice with doxycycline-inducible
expression of UCP1 restricted to aortic smooth
muscle cells were generated. In mice given
doxycycline (2 mg/ ml in sucrose-containing drinking
water), aortic UCP-1 messenger RNA expression was
induced by nearly 12-fold compared with mice
drinking sucrose-containing water alone.49
Doxycycline induction of aortic UCP-1 expression
significantly increases both systolic and diastolic
blood pressure. That hypertensive effect was
abrogated 10 days after removing doxycycline from
the drinking water. Plasma renin activity also
increases significantly — up to three-fold — in
doxycycline-treated mice. Concomitantly, urinary
sodium excretion decreases in the presence of
doxycycline, suggesting activation of the
renin-angiotensin-aldosterone system. By contrast,
urinary excretion of norepinephrine, a marker of
sympathetic activation, is not altered by UCP1
induction.
The Dysox
Model of Aging
Models in
medicine are proposed for two primary reasons: (1)
for their power to bring together seemingly
disparate findings to make a meaningful whole; and
(2) to provide scientific rationale and/or basis for
designing strategies for meaningful interventions.
The dysox model of aging — my view — has enormous
explanatory power for nearly all, if not all,
clinical, epidemiologic, and experimental
observations concerning the aging processes in
humans as well animal aging models. McKay's caloric
intake extends life span because it reduces the
total burden on oxygen homeostatic mechanisms. The
same holds for Björksten's cross-linking, Harmon's
free radicals, and Demetrius's metabolic stabilities
theories. The dysox model also provides the thread
that binds Kenyon's observations with C. elegans,
Ruvkin's linking of daf-2 with insulin signaling,
Guarente and Sinclair's findings with Sir2, and
works of others with HXK2, Hap4, cyctochronme C1,
superoxidase genes. Finally, and most importantly,
the dysox model of aging is supported by the recent
work that established that atherosclerosis results
from uncoupling of respiratory chain complexes from
oxidative phosphorylation. Clearly, one cannot
separate the aging process among humans without
considering the clinical consequences of common
degenerative disorders, such as cardiovascular
lesions, obesity, diabetes, and neurodegenerative
disorders.
As for designing intelligent
interventional strategies, the dysox model of aging
clearly shifts the focus from the dynamics of
individual genes to a holistic view of the three
primary regulatory mechanisms of the body: oxygen
homeostasis, redox equilibrium, and acid-base
balance. For addressing those issues, I employ the
Sun-Soil Model of the health/dis-ease/disease
continuum. The Sun in that model symbolizes a
person's spiritual belief in the healing dynamics,
whereas the soil is represented by ecologic dynamics
and inter-relationships among the bowel, blood, and
liver ecosystems. The Sun-Soil Model of health and
healing has been described at length in Integrative
Nutritional Medicine, the fifth volume of The
Principles and Practice of Integrative Medicine.50
The various aspects of that model are addressed at
length by other contributors to this special
Townsend issue on aging.
k
Dr. Ali's Course on Aging
k
The Oxygen Model of
Aging
k
Premature Aging and
Early Dying
k
Oxygen
Model of Premature Aging
k
The Oxygen Model of Disease
k
Oxygen
Kaleidoscope
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