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Free Radical Theory of Aging:

An Update
Increasing the Functional Life Span
DENHAM HARMAN
Department of Medicine, University of Nebraska College of Medicine,
984635 Nebraska Medical Center, Omaha, Nebraska, 68198-4635, USA

ABSTRACT: Aging is the progressive accumulation of diverse, deleteri-


ous changes with time that increase the chance of disease and death.
The basic chemical process underlying aging was first advanced by the
free radical theory of aging (FRTA) in 1954: the reaction of active free
radicals, normally produced in the organisms, with cellular constituents
initiates the changes associated with aging. The involvement of free radi-
cals in aging is related to their key role in the origin and evolution of life.
Aging changes are commonly attributed to development, genetic defects,
the environment, disease, and an inborn aging process (IAP). The latter
produces aging changes at an exponentially increasing rate with age, be-
coming the major risk factor for disease and death for humans after
the age of 28 years in the developed countries. In them the IAP limits
human average life expectancy at birth (ALE-B)a rough measure of
the healthy life spanto about 85 years; few reach 100 years and only
one is known to have lived to 122 years. In these countries, improvements
in living conditions (ILC) have gradually raised ALE-Bs to 7679 years,
69 years less than the limit imposed by aging, with no change in the
maximum life span (MLS). The extensive studies based on the FRTA
hold promise that ALE-B and the MLS can be extended, the ALE-B
possibly by a few years, and the MLS somewhat less.

KEYWORDS: aging; mitochondria; mutations; free radicals; longevity;


origin of life; evolution

INTRODUCTION

Aging is the progressive, more-or-less random, accumulation of diverse,


deleterious changes1,2,3 first in the male and female gametes, then in the

Address for correspondence: Denham Harman, M.D., Ph.D., Department of Medicine, University
of Nebraska College of Medicine, 984635 Nebraska Medical Center, Omaha, Nebraska, 68198-4635,
USA. Voice: 402-559-4416; fax: 402-559-7330.
e-mail: vcerino@unmc.edu

Ann. N.Y. Acad. Sci. 1067: 1021 (2006). 


C 2006 New York Academy of Sciences.

doi: 10.1196/annals.1354.003

10
HARMAN: SLOWING THE INHERENT AGING PROCESS 11

developing zygote formed from them, and finally throughout the cells and
tissues of the resulting individualthat increase the chance of disease and
death with advancing age. Aging changes are commonly attributed to devel-
opment, genetic defects, environment, disease, and an inborn aging process
(IAP). These changes limit the human life expectancy at birth (ALE-B)a
rough measure of the healthy life spanto a maximum of about 85 years.
The human ALE-B is increased by improvements in general living conditions
(ILC), e.g., better nutrition, housing, medical care. These efforts are becom-
ing increasingly less effective;4,5 this is illustrated in FIGURE 1 by the curves
of the logarithm of the chance of death versus age for Swedish females for
various periods from 1751 to 1992, and in FIGURE 2 by the increases in the
ALE-B of the population of the United States from 1900 to 1996.3 The chances
for death in the developed countries are now near limiting values.
Thus, as living conditions in a population approach the optimum, the curve
of the chance of death versus age shifts toward a limit determined by the sum
of the irreducible contributions to the chance of death by aging changes that
can be prevented to varying degrees by ILC (e.g., those due to nutrition or
disease) and contributions that can be influenced little, if at all, by ILC (e.g.,
due to the IAP).

The Inborn Aging Process

Aging changes produced by the IAP are few early on in life but increase
rapidly with age, as illustrated in FIGURE 3 by a plot of the chances for death
in 1985 for the U. S. population as a function of age.6 IAP changes are largely
responsible for the now almost exponential rise in the limiting chances for
death after about the age of 28 years in the developed countries. Only 12%
of a cohort die before this age.3 The IAP limits ALE-B to about 85 years,
permits a growing few to live to 100 years, and maintains the maximum life
span (MLS) at around 122 years.

Free Radical Theory of Aging

The basic chemical process underlying aging was advanced in 1954 by the
free radical theory of aging (FRTA):7,8 the reaction of active free radicals,
normally produced in the organism, with cellular constituents. The FRTA, and
the simultaneous discovery of the important, ubiquitous involvement of free
radicals in endogenous metabolic reactions, arose9 from a consideration of
aging phenomena (in the light of chemical knowledge, including free radical
chemistry), from the premise that a single common process, modifiable by
genetic and environmental factors, was responsible for the aging and death of
all living things.
12 ANNALS NEW YORK ACADEMY OF SCIENCES

FIGURE 1. Age-specific death rates of Swedish females in various periods from 1751
to 1992. (Adapted from Jones and the Sveriges Officiella Statistik.5 )

FRTAAn Update

1. 1972. The FRTA was first extended in 197210 with the suggestion that
(1) most FRRs stemmed from superoxide radicals (SO) formed by the
mitochondria in the course of normal metabolism and (2) the life span is
determined primarily by the rate of free radical damage to mitochondria,
apparently largely to mitochondrial DNA.
2. 1983. Consequences of mitochondrial aging11 were discussed in 1983.
HARMAN: SLOWING THE INHERENT AGING PROCESS 13

FIGURE 2. Average life expectancy at birth: United States, 19001996.

FIGURE 3. The chance of dying in 1985 as a function of age for the total population
of the United States.
14 ANNALS NEW YORK ACADEMY OF SCIENCES

3. 1998. Later it became clear12,13 that ILC increased ALE-B by decreas-


ing the free radical reactions (FRRs) associated with suboptimal living
conditions. The latter includes exposure of tissue to air.
During surgery or trauma in the absence of measures to maintain nor-
mal tissue O 2 levels, antioxidant levels, such as that of serum ascorbic
acid,14 are depressed by tissue-derived FRRs. Thus limiting tissue ex-
posure to air may have beneficial effects (e.g., on rate of recovery and
the incidence of sepsis),15 minimizing the expected shortening of the life
spans. In accord with the foregoing are the beneficial effects of mini-
mal access procedures in surgery16 and those expected from antioxidant
therapy.17 In addition, the long-term postoperative cognitive dysfunction
in older individuals18 may reflect, in part, the exposure of the brain to
lower-than-normal levels of antioxidants, such as ascorbic acid, during
surgery.
4. 2002. Finally, it also became clear19 that aging is the sum of the free
radical damage associated with suboptimal living conditions plus that
produced by the IAP.

Further support for the FRTA includes: (a) Genetically engineered mice that
develop a 35-fold increase in the level of point mutations in mitochondrial
DNA and increased amounts of deleted mtDNA have reduced life spans and
premature onset of aging-related phenotypes.20 (b) Transgenic mice that over-
express human catalase lived longer than controls.21 (c) Comparing birds with
mammals with similar metabolic rates, the much longer life spans of birds
are related to a smaller diversion of O 2 to SO by the bird mitochondria.22,23
Similarly, there is the difference in life spans between two closely related ro-
dents.24 (d ) Life spans of different mammalian species are related to the rate of
mitochondrial SO formation.25 (e) The frequency of mitochondrial genotype,
Mt5178A, in Japan is higher in centenarians than in healthy blood donors.26
Since mitochondria are of maternal origin, siblings of centenarians live longer
than normal.27 ( f ) Mice genetically manipulated to accumulate high levels of
mtDNA mutations had a significantly reduced life span and signs of premature
aging.28
The FRTA suggests that measures to decrease (a) the rate of initiation of
FRRs (e.g., by minimizing the presence of copper, iron, and other oxidant
catalysts), and/or (b) the chain lengths of FRRs (e.g., with antioxidants such as
vitamin E) can lower the rate of formation of aging changes, even under optimal
living conditions, and in turn decrease the rate of aging and pathogenesis. Many
studies now support this possibility.2,29,30
However, because the IAP increases exponentially with age it will progres-
sively lower the rate of these decreases toward zero as the ALE-Bs approach
the potential maximum of about 85 years.2,3
Nutrition has played a significant role in increasing ALE-B while having
little or no effect on the MLS.31 Future nutritional attempts to raise ALE-B
HARMAN: SLOWING THE INHERENT AGING PROCESS 15

further should be more effective using diets carefully selected to minimize free
radical damage.32

Origin and Evolution of Life

The FRTA helped to focus interest on why free radical reactions are ubiq-
uitous in living things. A reasonable explanation, as well as insight into the
nature of the IAP, is provided by studies on the origin and evolution of life:33
an overview is summarized in TABLE 1.
Life apparently arose spontaneously 3.54.0 billion years ago from amino
acids, nucleotides, and other basic chemicals of living things. These building
blocks were produced from simple reduced components (methane, hydrogen,
ammonia, and water) of the primitive oxygen-free atmosphere by free radical
reactions,3436 initiated mainly by ionizing radiation from the sun. The steady-
state products, including the first protocells with simple self-replicating pro-
genitors of DNA, reflected the innate chemical properties of the atoms and
molecules from which they had been formed, as well as the environment in
which they had been produced. The environment became warmer, and O 2
appeared in the atmosphere after the advent of blue-green algae, decreasing
the intensity of ionizing radiation on Eartheventually forming the ozone
shield. Precursors of life were the steady-state products of protocells that
had been subjected to a long constant reiterative process. As the precursors

TABLE 1. Overview of the origin and evolution of life


Years ago Main Events
3.5 billion Basic chemicals of life formed by free radical reactions, largely
initiated by ionizing radiation from the sun
Life begins
Excision repair and
Recombinational repair
Ferredoxin
RH or H 2 S + CO 2 (h ) CH
2.6 billion Blue-green algae
H 2 O(h ) 2H + O 2
1.3 billion Atmospheric O 2 reaches 1% of present value
Anaerobic prokaryotes disappear
Eukaryotes become dominant cells
Eukaryotes + blue-green algae the green leaf plants
Eukaryotes + a prokaryote able to reduce O 2 to H 2 O animal
kingdom
Emergence of multicellular organisms and plants
Meiosis
500 million Atmospheric O 2 reaches 10% of present value
Ozone screen allows emergence of life from sea
56 million Primates appear
5 million Man
16 ANNALS NEW YORK ACADEMY OF SCIENCES

evolved and became more complex, one or more of them somehow acquired
the characteristics of life, including the ability to internalize the initiation of
free radical reactions.
Approximately 1.3 billion years ago the progenitor of the green plants ac-
quired blue-green algae to assist with its energy needs, whereas that of the
animal kingdom took in a prokaryote able to reduce O 2 to water. Subsequently,
colonies of cells appeared that evolved into multicellular organisms and plants.
About 500 million years ago absorption of UV radiation by atmospheric
oxygen reduced radiation reaching the surface to a level compatible with exis-
tence on land. Evolution then accelerated. Primates appeared about 65 million
years ago, and man some 45 million years ago.

The Inborn Aging ProcessContinued

The prokaryote acquired by the progenitor of the animal kingdom evolved


into the mitochondrion.37 Collectively, they are the IAP,38,39 the major source
of: (1) energy for metabolic needs and the activities of life, by using the conver-
sion of ADP to ATP to capture energy released by the 4-electron reduction of
O 2 to water during oxidative phosphorylation, and (2) superoxide radicals
largely responsible for the free radical reactions involved in mutations, dis-
ease, and deathby the one-electron reduction of O 2 , using about 13% of
the amount of O 2 consumed by oxidative phosphorylation. In addition, the
mitochondria play a major role in apoptotic cell death.40
Further, all, or almost all, mitochondria are maternally inherited.38 An in-
dividuals mitochondria in post-mitotic cells undergo free radicalinduced
changes with age;11 only minor changes occur with age in the mitochondria of
dividing cells.
Formation of SO in the course of normal metabolism apparently does not
increase significantly with age,39 while that of ATP declines on account of
free radical damage. The latter may be largely responsible for the exponential
nature of the mortality curve in a manner analogous to the autoxidation of a lipid
containing an antioxidant:41,42 the rate of oxidative change in the lipid is slow
at first, becoming progressively faster as the antioxidant is consumed through
the inhibition of free radical reactions. In living organisms the antioxidant
level seemingly also decreases with age, as production of ATP for reductive
synthesis (e.g., of glutathione and NADPH) declines as mitochondria age.
The relatively low free radical activity in early life permits growth and
development of new offspring. These processes are slowed with age by the
widespread continuous accumulation of IAP-associated free radical damage,
including mutations, plus similar damage from ionizing radiation43,45,46 and
oxygen exposure,44 as well as that produced by suboptimal living conditions.19
This damage, incompletely repaired by processes dependent on ATP, is at-
tributed to Aging, and causes the transition into childhood, adolescence,
HARMAN: SLOWING THE INHERENT AGING PROCESS 17

adulthood, old age, and death. The transition rates determine longevity; evo-
lution limits ALE-B of humans to about 85 years and the MLS to around
122 years. Efforts to decrease these rates will eventually be thwarted by the
exponential nature of the IAP.
Thus, the IAP, a magnificent product of evolution, provides with the aid of
the growing accumulation of free radical damage with age, for the development
and birth of new individuals, mutations, activities during life and their eventual
death. Aging is a growing expression with time of free radical damage from
both endogenous and exogenous sources, incompletely repaired by processes
dependant on ATP.

Slowing the IAP

Measures that can, or may, slow the rate of formation of aging changes with
age, without significantly lowering normal ATP levels, include:
1. Caloric restriction. Increases in human longevity will be small with a tol-
erable level of restriction.12 A recent study with Drosophila melanogaster
concluded47 : Caloric restriction extends life span by slowing down the
rate of normal aging.
2. Compounds that compete with O 2 for access to electron-rich areas
of the mitochondria. Nitroxides compete with O 2 for electrons from the
mitochondrial respiratory chain to form hydroxylamines48 instead of su-
peroxide radicals.
3. Compounds that may decrease loss of mtDNA function with age. (a) Lev-
els of coenzyme Q 10 decrease with age; dietary supplementation sig-
nificantly increases them.49 (b) Increased oxidative damage to mtDNA
also decreases mitochondrial glutathione (GSH) content; reversed by oral
antioxidants,50 such as thiazolidine carboxylate, a Ginkgo biloba extract,
and targeted antioxidants.51 (c) Other measures directed at increasing
mitochondrial GSH include supplementing the diet with GSH esters.52
(d) The life span of Drosophila melanogaster was increased about 18%
when maintained on a diet supplemented with either sodium or magne-
sium thiazolidine carboxylate.53 (e) Increases in mitochondrial damage
with age are decreased by supplementing the diet with a combination of
acetyl-L-carnitine plus lipoic acid.54,55
4. Genetic change. (a) Efforts to determine the cause(s) for differences in
O 2 diversion to SO (see above) may suggest measures to do so in hu-
mans. (b) In mice a homozygous mutation of p66shc increased life span
by about 30%around the same increase achievable by caloric restriction
in the absence of any obvious defective phenotype.56 (c) Similarly, in-
creases in longevity demonstrated in the numerous and steadily increasing
studies of mice and other model aging systems, e.g., yeast, C. elegans,
18 ANNALS NEW YORK ACADEMY OF SCIENCES

and Drosophila are compatible in most cases, if not all, with the possi-
bility57 that they are caused by lower levels of free radical reactions. (d)
Genetic studies of premature aging syndromes are now also under way
in an effort to increase longevity.5860 (e) Genetic changes that take place
in early life may predispose to premature death. Some of these changes
can be prevented, thus extending the normal life span.12
Engineered negligible senescenceThis term has been suggested61 for
measures that may serve to remove or prevent the normal accumulation of
aging changes.

COMMENT

Studies based on the FRTA have helped to increase the ALE-B; the exponen-
tial nature of the IAP blocks increases in MLS. However, growing knowledge
of the IAP suggested potentially practical measures to increase the MLS dis-
cussed above; those directed at minimizing changes in early life and decreasing
diversion of O 2 to SO might be the most productive. These efforts should also
serve to focus further attention on the problems of old age62,63 and how best
to ameliorate them. The desire to live long but not be old is gradually being
fulfilled.
Finally, the creation of life and its evolution on earth during the past 3.5 bil-
lion years is a truly remarkable example of what can be accomplished by chance
through the continued interplay over time of energy, suitable molecules, sim-
ple chemical reactions, and environmental modulations. Energy sources on
the earth initiated free radical reactions to create life from inert chemicals,
starting with molecules of the primitive atmosphere. Then, by means of the
same chemical reactions life evolved into chemically diverse complex forms.
The growing knowledge of evolution and aging permits modulation to some
extent of the duration of life and its quality, as well as acceptance with equa-
nimity, of the inevitable death mandated by evolution.

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