Free Radical Research, December 2006; 40(12): 1230–1238
Theories of biological aging: Genes, proteins, and free radicals
Laboratory of Cellular Ageing, Department of Molecular Biology, Danish Centre for Molecular Gerontology, University ofAarhus, Aarhus-C, Denmark
AbstractTraditional categorization of theories of aging into programmed and stochastic ones is outdated and obsolete. Biological agingis considered to occur mainly during the period of survival beyond the natural or essential lifespan (ELS) in Darwinian terms. Organisms survive to achieve ELS by virtue of genetically determined longevity assuring maintenance and repair systems(MRS). Aging at the molecular level is characterized by the progressive accumulation of molecular damage caused byenvironmental and metabolically generated free radicals, by spontaneous errors in biochemical reactions, and by nutritionalcomponents. Damages in the MRS and other pathways lead to age-related failure of MRS, molecular heterogeneity, cellulardysfunctioning, reduced stress tolerance, diseases and ultimate death. A unified theory of biological aging in terms of failure ofhomeodynamics comprising of MRS, and involving genes, milieu and chance, is acquiring a definitive shape and wideracceptance. Such a theory also establishes the basis for testing and developing effective means of intervention, prevention andmodulation of aging.
Keywords: Biogerontology, gerontogenes, molecular damage, stress, homeostasis, homeodynamics, hormesis, anti-aging
Abbreviations: FR, free radicals; ROS, reactive oxygen species; ELS, essential lifespan
highly variable in different species, in organismswithin a species, in organs and tissues within an
In a frequently cited paper from 1990, Zhores
organism, in cell types within a tissue, in sub-cellular
Medvedev had attempted to make a rational classifi-
compartments within a cell type, and in macromol-
cation of theories of aging . He counted more than
ecules within a cell. These observations necessarily
300 theories, none of which could qualify as being the
lead to the conclusion that aging has no universal
theory of aging, and all of them could be, at best,
cause, phenotype, and consequence, except death.
labeled as “hypotheses” or “aspect theories”. Over the
However, the above conclusion does not imply that
years, gerontologists have become resigned to the
there cannot be any satisfactory, rational and scientific
futility of formulating a unified theory of aging which
explanations for the origin, occurrence, progression
can encompass its evolutionary, biological, and
and consequences of aging, and that aging is an
sociological aspects. The main reason for the
unsolved or unsolvable problem in biology. To the
emergence of this pessimistic view is that the large
contrary, as reasserted by Robin Holliday in his
body of descriptive data in gerontology underlines the
recently published article titled “Aging is No Longer
multifaceted, diverse and complex nature of aging.
an Unsolved Problem in Biology” , the biological
Most significantly, it has been clearly shown that the
basis of aging are well understood, and important
phenotype and the rate of progression of aging are
general principles of aging and longevity can be
Correspondence: S. Rattan, Department of Molecular Biology, University of Aarhus, Gustav Wieds Vej 10C, DK8000 Aarhus-C, Denmark. Tel: 45 8942 5034. Fax: 45 8612 3178. E-mail: [email protected]
ISSN 1071-5762 print/ISSN 1029-2470 online q 2006 Informa UK Ltd. DOI: 10.1080/10715760600911303
derived, which can be the basis for future research
systems, tissues, cells, organelles and macromolecules.
and intervention towards achieving a healthy old age
Therefore, a major challenge for any theory of
biological aging is to provide mechanistic explanationsfor the origin and occurrence of both “universal” and“specific” age-related changes, also termed “public”
and “private” mechanisms, respectively 
The evolutionary “life history principle” describes
Since the biological bases of all aging systems reside
aging as an emergent phenomenon that takes place
in the optimal functioning of molecules within a cell, it
primarily in protected environments which allow
is useful to recapitulate what molecular changes
survival beyond the natural lifespan in the wild. The
happen during aging. Observational and descriptive
natural lifespan of a species, termed “essential
studies performed on a large variety of aging systems
lifespan” (ELS) [4,7], or the “warranty period” ,
have demonstrated that the main molecular charac-
is the time required to fulfill the Darwinian purpose of
teristic of aging is the progressive accumulation of
life in terms of successful reproduction for the
damages in macromolecules. Although different types
continuation of generations. Species that undergo
of molecular damage accumulate at different rates and
fast maturation and have an early onset of reproduc-
to different extents in different cells, the fact remains
tion with large reproductive potential generally have a
that there is a progressive increase in molecular
short ELS, whereas slow maturation, late onset of
heterogeneity with age. Table I gives a list of major
reproduction, and small reproductive potential of a
categories of age-related damage in macromolecules,
species is concurrent with its long ELS. For example,
which have been observed during various cells, tissues
the ELS of Drosophila is less than a week as compared
with that of about 50 years of Homo sapiens, even
It is obvious that all small and big molecules are
though in protected environments (laboratories and
prone to damage, but the source and biological
modern societies, respectively), a large proportion of
consequences of various molecular damage may vary
populations of both species can and do live for much
widely, thus increasingly creating molecular hetero-
longer than that. Therefore, from an evolutionary
geneity. Furthermore, although the action of a
point of view, ELS is the canvas against which the
damaging agent is essentially stochastic, the vulner-
genetic selection and functional optimization unfold.
ability of a macromolecule to the damaging agent may
(The biochemical and physiological basis of ELS will be
be dependent on its chemical sequence, structure and
accessibility in the presence of several other interactive
While detailed arguments about evolutionary
macromolecules. It is not simple to relate any
explanations for the origin and occurrence of aging
particular kind of damage and its levels in the cells
can be accessed in extensive writings of several authors
to a specific biological consequence, especially aging,
(for example, see [9 – 12]), here it may be sufficient to
point out that from evolutionary, biological and lifehistory points of view, aging is considered to set in and
manifest mainly during the period of extended survivalbeyond ELS.
There are three major sources of damage within a cell:(1) reactive oxygen species (ROS) and free radicals(FR) formed due to external inducers of damage (for
example ultra-violet rays), and as a consequence of
Biogerontologists and geriatric pathologists have
cellular metabolism involving oxygen, metals and other
gleaned a wealth of information regarding age-related
metabolites; (2) nutritional glucose and its metabolites,
changes at all levels of biological organization. While
and their biochemical interactions with ROS; and
several of these age-related normal and pathological
(3) spontaneous errors in biochemical processes, such
changes may be widely observed across species, other
as DNA duplication, transcription, post-transcrip-
changes are specific to specific species, organs,
tional processing, translation, and post-translational
Main categories of molecular damage occurring during cellular aging.
Mutations, epimutations, base modifications,
Base modifications, miscoding, missplicing
Amino acid modifications, misincorporation,
Carbohydrates, lipids, and molecular conjugates
modifications. The so-called mechanistic theories of
Further evidence in support of PETA comes from
biological aging have often focused on a single category
experiments which showed that an induction and
of inducers of molecular damage as an explanation for
increase in protein errors can accelerate aging in
possible mechanisms of aging. Of these, two theories
human cells and bacteria [19,38,39,43,44]. Similarly,
which have been the basis of most of the experimental
an increase in the accuracy of protein synthesis can
biogerontology research are the free radical- and the
slow aging and increase the lifespan in fungi [45 – 47].
protein error-theories of aging. Although neither of
Therefore, it is not ruled out that several kinds of
them can be considered to be the complete theory of
errors in various components of protein synthetic
biological aging, their contributions in providing a solid
machinery, including tRNA charging, and in mito-
scientific footing to experimental aging research and
chondria do have long term effects on cellular stability
anti-aging interventions cannot be overestimated.
and survival [48 – 51]. However, almost all thesemethods have relied on indirect in vitro assays, and sofar direct, realistic and accurate estimates of age-
related changes in errors in cytoplasmic and mito-
FRTA, proposed in 1956, arose from a consideration
chondrial proteins, and their biological relevance,
of the aging phenomenon from the premise that a
have not been made. Similarly, applying methods such
single common biochemical process may be respon-
as two-dimensional gel electrophoresis, which can
sible for the aging and death of all living beings (for an
resolve only some kinds of mis-incorporations, have so
update, see ). There is abundant evidence to show
far remained insensitive and inconclusive [19,38,39].
that a variety of ROS and other FR are indeed involved
It will be necessary to combine several methods, such
in the occurrence of molecular damage which can lead
as electrophoresis, mass-spectrometry, protein-pro-
to structural and functional disorders, diseases and
tein interactions and antibody-based detection of
death. The chemistry and biochemistry of FR is very
molecular heterogeneity to find out the extent of
well worked out, and the cellular and organismic
protein errors and their biological role in aging.
consequences are well documented . However,the main criticisms raised against this theory are with
From FRTA and PETA to higher order theories
respect to its lack of incorporation of the essential andbeneficial role of FR in the normal functioning and
survival of biological systems [33,34]. Additionally,
mechanisms for the occurrence of molecular damage.
FRTA presents FR as the universal cause of damage
Additionally, nutritional components, specially the
without taking into account the differences in the wide
sugars and metal-based micronutrients can induce,
range of FR-counteracting mechanisms in different
enhance and amplify the molecular damage either
species. Furthermore, a large body of data showing the
independently or in combination with other inducers
contrary and/or lack of predictable and expected
of damage. The biological consequences of increased
beneficial results of anti-oxidant and FR-scavenging
levels of molecular damage are wide ranging and
therapies have restricted the FRTA to being only a
include altered gene expression, genomic instability,
partial explanation of some of the observed changes
mutations, molecular heterogeneity, loss of cell
division potential, cell death, impaired intercellularcommunication, tissue disorganization, organ dys-functions, and increased vulnerability to stress and
other sources of disturbance. Historically, each of
The history of PETA, also known as the error
these biological consequences has been used as the
catastrophe theory, is full of controversy and
basis of putting forward other theories of aging, such
premature declaration of its demise [19,38,39].
as replicative senescence theory, neuroendocrine
Since the spontaneous error frequency in protein
theory, pineal gland theory, immunological theory
translation is generally several orders of magnitude
higher than that in DNA replication and RNAtranscription, the role of protein errors and their
Genetics, post-genetics and epigenetics of aging
feedback in biochemical pathways has been con-sidered to be a crucial one with respect to aging.
Since all molecular processes in a living system are
Several attempts have been made to determine the
based in and regulated by genes, an attractive research
accuracy of translation in cell-free extracts, and most
strategy has been to discover genes for aging, termed
of the studies show that there is an age-related increase
gerontogenes [53 – 55]. However, the evolutionary
in the mis-incorporation of nucleotides and amino
explanation for the origin of aging and limited lifespan
acids [19,38,39]. It has also been shown that there is
discussed above have generally ruled out the notion of
an age-related accumulation of aberrant DNA
any specific genetic programme involving specific
polymerases and other components of the transcrip-
gerontogenes. But a lack of specific gerontogenes with
tional and translational machinery [19,38 – 42].
the sole purpose of causing aging and terminating the
lifespan of an individual does not imply that genes do
for life to exist. “Epigenetics” is the most commonly used
not or cannot influence survival, longevity and the rate
term to account for and to explain the consequences of
the intracellular and extracellular milieu which establish
There is ample evidence from studies performed on
and influence the structural and functional stability of
yeast and other fungi, nematodes, insects, rodents and
genes [2,70]. These epigenetic effects and alterations
humans that mutations in various genes can either
generally remain uninherited from one generation to the
prolong or shorten the lifespan, and some of these are
next, but have strong deterministic effects on the health,
also the cause of premature aging syndromes in
survival and aging of the individual.
human beings [56 – 58]. Additionally, genetic linkage
So far, there is only scanty information available
studies for longevity in mice have identified major
about the involvement in aging of various intracellular
histocompatibility complex regions , and quanti-
epigenetic markers such as methylated cytosines,
tative trait loci on several chromosomes [60,61] as
oxidatively modified nucleotides, alternatively spliced
putative genes for aging. In gene association studies
RNAs, and post-translationally modified proteins,
with human centenarians, certain alleles of HLA locus
including protein folding . The full spectrum of
on chromosome 6 , regions of chromosome 4
epigenetics of aging is yet to be unraveled and at
, different alleles of APO-E and APO-B, and DD
present is one of the most attractive and challenging
genotype of angiotensin converting enzyme (ACE)
areas of research in biogerontology [72,73]. A major
have been linked to exceptional longevity. Similarly,
reason for apparent difficulties in fully understanding
several other studies have reported an association
the epigenetics of aging is the existence of several
between human longevity and single nucleotide
orders of higher complexity and diversity of the
polymorphisms (SNP) in a variety of genes in various
constituting components, such as physical, chemical,
biological pathways, including heat shock response,
biological and environmental factors, including
mitochondrial functions, immune response, choles-
psychological factors in human beings. Furthermore,
terol metabolism and others [58,63 – 67].
in order to understand how various conditions
An analysis of the various functions of the genes
influence, regulate and modulate the actions, inter-
associated with aging and longevity shows that these
actions and networks of gene products during aging
genes cover a wide range of biochemical pathways,
will require new intellectual and technical tools, such
such as energy metabolism, kinases, kinase receptors,
as systems analysis, bioinformatics, and functional
transcription factors, DNA helicases, membrane
genomics involving simultaneous multiple analyses.
glucosidases, GTP-binding protein coupled receptors,chaperones, and cell cycle check point pathways [56 –
58]. What is clear from the identification of the genesinfluencing aging and longevity is that whatever their
Another approach in developing a unified theory of
normal function and mechanism of action may be,
aging is based in the basic characteristic of biological
these gerontogenes did not evolve to cause and
systems called homeostasis or homeodynamics. All
accumulate molecular damage, to cause functional
living systems, have the intrinsic ability to respond, to
disorders, and to terminate the life of the organism.
counteract and to adapt to the external and internal
Most of these genes have well defined roles in
sources of disturbance. The traditional conceptual
normal metabolism, in intra- and inter-cellular
model to describe this property is homeostasis, which
signaling, and in maintenance and repair functions
has dominated biology, physiology and medicine since
including stress response. It is the damage-induced
the 1930s. However, advances made in our under-
changes in the regulation, structure and/or activity of
standing of the processes of biological growth, develop-
their gene products which result in their altered
ment, maturation, reproduction, and finally, of aging,
biological role with age. Therefore, such genes have
senescence and death have led to the realization that the
been termed “virtual gerontogenes” [54,68]. Further-
homeostasis model as an explanation is seriously
more, a lack of evolutionary selection of virtual
incomplete. The main reason for the incompleteness
gerontogenes has given rise to the notion of post-
of the homeostasis model is its defining principle of
genetics or “post-reproductive genetics” as an
“stability through constancy”, which does not take into
explanation for different biological roles played at
account the new themes, such as cybernetics, control
different ages by the same genetic variants .
theory, catastrophe theory, chaos theory, informationand interaction networks, that comprise and underlinethe modern biology of complexity. Since the 1990s, the
term homeodynamics , is being increasingly used.
Although genes are the foundation of life, genes in
The concept of homeodynamics accounts for the fact
themselves are non functional entities. It is the wide
that the internal milieu of complex biological systems is
variety of gene products, including coding and non-
not permanently fixed, is not at equilibrium, and
coding RNAs, proteins and other macromolecules,
is a dynamic regulation and interaction among various
which constitute the biochemical and biophysical milieu
In parallel with the development of the concept of
between three fundamental features of life: (1) the
homeodynamics, another term allostasis has also been
basic metabolism, which includes biochemical syn-
gaining recognition and use . According to this
thesis, respiration, cell turnover, movement, feeding,
model, “stability through change” is the most realistic
digestion and excretion; (2) the reproduction; and (3)
situation for living systems. Allostasis model also takes
the maintenance through homeodynamic machinery
into account the characteristics such as reciprocal
trade-offs between various cells, tissues and organs,
Whereas the basic metabolism is essential for all
accommodative sensing and prediction with respect to
animals, the extent of investment in reproduction and
the severity of a potential stressor, and the final cost of
maintenance can vary between species. This is the
making a response and readjustment to bring about
trade-off, which is the basis of the disposable soma
the necessary change. Aging, senescence and death
theory of aging, between investment in maintenance
are the final manifestations of unsuccessful home-
and investment in reproduction, which are related
odynamics or failure of allostasis [2,76].
inversely [9,34]. The evolved balance between the two
Table II gives a list of the key biochemical and
depends on the life history strategy and ecological
physiological pathways and processes operating
niche of the species. Several comparative studies have
in cells, tissues and organ systems, and which are
reported positive correlations between lifespan and
quintessential components of the homeodynamic
the ability to repair DNA, to detoxify reactive oxygen
molecules, to respond and counteract stress, and to
Of course, all these processes involve genes whose
replace worn-out cells . In addition, negative
products and their interactions give rise to a “home-
correlation has been demonstrated between longevity
odynamic space” or the “buffering capacity”, which is
and the rate of damage accumulation, including
the ultimate determinant of an individual’s chance and
mutations, epimutations, macromolecular oxidation
ability to survive and maintain a healthy state . At
and aggregation of metabolic byproducts [9,34].
present, our knowledge about the number of genes
The evolved nature of the homeodynamic machin-
and their variants, their multiple interactions and
ery, in accordance with the life history traits of
consequences is too meagre to identify, define and
different species, sets an intrinsic genetic limit on the
manipulate the homeodynamic machinery in any
ELS, as described above. Therefore, the main cause of
age-related accumulation of molecular damage is the
Theoretically, it may be possible to design or
inefficiency and failure of maintenance, repair and
engineer much better protected and better performing
turnover pathways. Several theoretical and mathemat-
homeodynamic processes, and thus make organismic
ical models are being developed in order to under-
survival extended indefinitely. However, arguments
stand the interactive nature of the biological networks
based on the allocation of energy and metabolic
and trade-offs [103,104]. Similarly, the reliability
resources (EMR) as the determinants of an organism’s
theory of aging and longevity discusses the inevitable
longevity and survival potential rule out such
failure of complex systems such as cells and organisms
simplistic interventions [9,34]. According to these
, and reiterates the principle that no process can
arguments, available EMR must be partitioned
be one-hundred-percent accurate one-hundred-per-cent of the time; and it is the interactive nature ofgenes, milieu and chance that effectively determines
Main pathways of maintenance and repair homeo-
how long homeodynamic ability can keep a biological
Implications for aging intervention, prevention
According to the homeodynamics-based explanations
for aging and longevity described above, occurrence of
aging in the period beyond ELS, and the onset of one
or more diseases before eventual death, appear to be
the evolutionary “default” setting. This viewpoint
makes interventions in aging different from the
treatment of one or more specific diseases. Also,
although single or serial replacement of non-func-
tional or dysfunctional body parts with natural or
synthetic parts made of more durable material may
provide a temporary solution to the problems of age-
related impairments, it does not modulate the
underlying complex aging process as such .
Scientific and rational anti-aging strategies have the
temperature shock, irradiation, heavy metals, pro-
aim to slow down aging, to prevent and/or delay the
oxidants, acetaldehyde, alcohols, hypergravity, exer-
physiological decline, and to regain lost functional
cise and food restriction [6,110]. Hormesis-like
abilities. Strengthening, improving or enlarging the
beneficial effects of episodic and chronic, but mild,
homeodynamic space or the buffer capacity at the
undernutrition have been reported for human beings.
level of all genes comprising the homeodynamic
Intermittent fasting has been reported to have
machinery of an individual may be the ideal anti-aging
beneficial effects on glucose metabolism and neuronal
remedy. However, such a gene-therapy approach for
resistance to injury. Although at present there are only
gerontomodulation requires redesigning the blueprint
a few studies performed which utilize mild stress as a
for structural and functional units of the body at the
modulator of aging and longevity, hormesis can be a
level of genes, gene products, macromolecular
useful experimental approach in biogerontology.
interactions, molecular-milieu interactions, and soon. Considering how little information and knowledgewe have at present about all those interacting variants
of genes, molecules, milieu and chance, it is not clear
Living systems survive by virtue of a set of defensive
what this approach really means in practical and
maintenance and repair systems which comprise their
homeodynamic ability. A large number of interacting
Improving the milieu in which the homeodynamic
genes and genetic networks constitute this machinery,
machinery operates is the other strategy that is being
the exact details of which are yet to be unravelled.
followed by the majority of the practitioners of the so-
Successful homeodynamics is crucial for the growth,
called anti-aging medicine. Some of the main
development and maturation of an organism until the
approaches are supplementation with hormones
reproduction and continuation of generations is
including growth hormone, dehydroepiandrosterone,
assured. Homeodynamics is thus a longevity assur-
melatonin and estrogen, and nutritional supplemen-
ance mechanism, whose strength, efficiency and range
tation with synthetic and natural antioxidants in
have evolved in accordance with the evolutionary
purified form or in extracts prepared from plant and
history of the species. Survival beyond the ELS of a
animal sources . Although some of these
species is necessarily accompanied by the progressive
approaches have been shown to have some clinical
accumulation of random molecular damage. The
benefits in the treatment of some diseases in the
progressive failure of homeodynamics leads to the
elderly, none of these really modulate the aging
physiological malfunctioning manifested as a general
process itself. Furthermore, claims for the benefits of
functional decline, diseases and ultimate death. A
intake of high doses of vitamins and various
unified theory of biological aging involving genes,
antioxidants and their supposed anti-aging and life-
milieu and chance is emerging, maturing and
prolonging effects have very little scientific evidence to
acquiring a definitive shape, and can be the basis of
back them [6,106]. In contrast to this, nutritional
aging intervention, prevention and modulation.
modulation through caloric restriction (CR) has beenshown to be an effective anti-aging and longevityextending approach in rodents and monkeys, with
possible applications to human beings. But, this is ahighly debatable issue at present both in terms of the
Laboratory of Cellular Ageing (LCA) is supported by
practicalities of defining CR and of applying CR in
grants from the Danish Research Councils (FNU and
human beings in physiological and evolutionary
FSS), EU-Biomed programme “Proteomage”, and
A more realistic and promising approach in aging
intervention and prevention is based in making use ofan organism’s intrinsic homeodynamic property of self
maintenance and repair. It has been suggested that if
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