I am posting an article about the nature of genes involved in ageing. This
article has already been published in the FASEB Journal, vol. 9, pp.
284-286, 1995 (February issue) under the category of "Hypothesis". I
thought it might be of interest to a wider readership:
________________________________________
Gerontogenes: real or virtual ?
Suresh I. S. Rattan
Laboratory of Cellular Ageing, Department of Chemistry, Aarhus University,
DK-8000 Aarhus-C, Denmark.
Summary:
The view that lifespan of an organism is intrinsically limited and is
largely species-specific necessarily involves certain notions of genetic
elements of regulation. The term gerontogenes refers to any such genetic
elements that are involved in the regulation of aging and lifespan. The
existence of genes for programmed aging is generally discounted on the
basis of evolutionary arguments against the notion of adaptive nature of
aging. It is suggested here that the concept of gerontogenes be linked with
the idea of genes involved in homeostasis and longevity assurance, which is
not contradictory to the non-adaptive nature of aging. Since these genes
were not originally selected as real genes for aging, their involvement in
aging is an emergent property making them virtual gerontogenes. Some
experimental evidence is available that suggests that sets of genes
involved in the maintenance and repair of various cellular functions are
the primary candidates qualifying as virtual gerontogenes.
Key Words: Aging * lifespan * homeostasis * virtual genes
Sooner or later, all individuals die. There may or may not be any genetic
program that determines the exact time of death, but there appears to be an
evolutionary constraint in terms of maximum achievable lifespan within a
species. The view that lifespan of an organism is intrinsically limited and
lies largely within a species-specific range involves necessarily certain
notions of genetic elements of regulation. In this context, the term
gerontogenes (1) refers to any such genetic elements that are involved in
aging.
The idea of gerontogenes does not contradict the non-adaptive
nature of aging. Rather, it reasserts the importance of the genetic
mechanisms of somatic maintenance in assuring germ line continuity, as
envisaged by both antagonistic pleiotropy theory and disposable-soma theory
of the evolution of aging and lifespan (2, 3). Since the existence of
gerontogenes as genes for programmed self-destruction is on the whole
discounted on the basis of evolutionary arguments against the notion of
adaptive nature of aging (4, 5), the concept of gerontogenes is intimately
linked with the idea of genes involved in homeostasis and longevity
assurance, instead of certain special genes for aging.
the nature of gerontogenes
The term "gerontogenes" does not refer to a tangible physical reality of
real genes for aging but to an emergent functional property of a number of
genes which may influence aging. For this purpose, the term "virtual"
gerontogenes has been suggested (6, 7) in which "virtual" is defined, as in
the Shorter Oxford Dictionary, as something that "is so in essence or
effect although not formally or actually; admitting of being called by the
name so far as the effect or result is concerned". In science, the term
"virtual" is used for entities that it is helpful to regard as being
present although they have no physical existence. The paradigm of such an
entity is the virtual image of optics. Another example is the currently
fashionable "virtual reality", which fulfills the same definition.
The concept of virtual genes therefore refers to the emergent
property of several genes whose functions are tightly coupled and whose
combined action and interaction resembled the effect of one gene. Treating
such a group as a virtual gene is a useful conceptual tool while the search
continues for the genetic elements of regulation of complex biological
processes, such as aging. Although differentiation and development are good
examples of highly complicated and complex systems involving a large number
of genes, the concept of virtual genes may be inappropriate to apply to
them because these processes are under direct genetic control and have
evolved as a result of natural selection. This situation is unlike aging
where no natural selection for any specific genes is envisaged. Therefore,
the concept of virtual genes is appropriate only for phenomena such as
aging where a genetic involvement is expected without direct genetic
control open to natural selection.
The idea of gerontogenes as being virtual implies that every time a
gene is discovered which appears to have a role in the process of aging, it
will, on sequencing and identification, turn out to be a familiar normal
gene with a defined function. Its role as a gerontogene can only be
realised in the context of its emergent property in relation to several
other genes which influence its activity and interactivity. Such genes
cannot be hidden, because their identities can in principle become well
known. Individually, the functions of such genes can in principle be
clearly established. Yet, as a result of concerted action and interaction,
the combined effect of these genes resembles that of a "gene for aging"
although these were not specially designed or naturally selected for
causing aging. This idea of virtual gerontogenes is in line with the
evloutionary explanation of the process of aging as being an emergent
phenomenon owing to the lack of eternal maintenance and repair instead of
it being an active and adaptive process.
EVIDENCE for candidate gerontogenes
Obviously, not every gene is potentially a virtual gerontogene. However,
potentially every gene can affect the survival of an organism. Therefore, a
distinction must be made between the immediate survival or death and the
process of aging. Knocking out any essential gene will result in the death
of an organism without having anything to do with the process of aging.
For virtual gerontogenes, one could narrow down the possibilities
to sets of genes involved in the maintenance and repair of the cellular and
sub-cellular components as the primary candidates for qualification as
virtual gerontogenes. This is because almost all theories of aging imply
directly or indirectly that the progressive failure of homeostatic
mechanisms is crucial for the process of aging. For example, theories
emphasising the accumulation of somatic mutations, the build-up of
oxidative damage in macromolecules, the accumulation of abnormal, erroneous
and defective proteins, deficiency of the signal transduction pathways,
deficiency of the immune system and several other similar hypotheses all
point to the failure of maintenance at all levels of organization as a
crucial determinant of aging and lifespan (8-10).
Evidence for the hypothesis that candidate virtual gerontogenes
operate through one or more of the mechanisms of somatic maintenance and
repair comes from experiments performed to slow down aging and to increase
the lifespan of organisms. For example, anti-aging and life-prolonging
effects of calorie restriction are seen to stimulate various maintenance
mechanisms. These include increased efficiency in DNA repair (11),
increased fidelity of genetic information transfer (12, 13), more efficient
protein synthesis (14-16), more efficient protein degradation (17), more
effective cell replacement and regeneration, improved cellular
responsiveness (18), fortification of the immune system and enhanced
protection from free-radical- and oxidation-induced damage (19-21). Genetic
selection of Drosophila for longer lifespan also appears to work mainly
through an increase in the efficiency of maintenance mechanisms, such as
antioxidation potential (2, 22-24). An increase in lifespan of transgenic
Drosophila containing extra copies of Cu-Zn superoxide dismutase (SOD) and
catalase genes is primarily due to enhanced defences against oxidative
damage (25). Similarly, anti-aging effects of a dipeptide, carnosine (26)
and a cytokinin, kinetin (27) on human diploid fibroblasts also appear to
be due to the effect of these chemicals on maintaining the efficiency of
defence mechanisms, including efficient protein synthesis and turnover and
the removal of oxidative damage.
Attempts at identifying determinants of longevity by finding a
correlation between maximum lifespan of a species and certain biological
characteristics have also shown that it is the efficiency of various
defence mechanisms that correlates best with longevity (28). Some of the
well-known maintenance mechanisms whose activity levels and efficiencies
are directly correlated with species lifespan include DNA repair (29-31),
cell proliferative capacity (32, 33) and antioxidative potential (34-37).
Further experimental evidence in favour of the concept of virtual
gerontogenes comes from several studies to identify senescence-specific
genes in old cells and tissues. Almost all such studies have resulted in
the identification of genes, such as those of the components of the
extracellular matrix, which are known to have other functions in cell
metabolism and physiology (38-41). Studies on the extension of lifespan and
slowing-down of various age-related biochemical and functional alterations
of D. melanogaster by simultaneous overexpression of Cu-Zn-SOD and catalase
(25) indicate that these free-radical-scavenging and antioxidant genes are
part of the gerontogene family by virtue of their role in influencing aging
and lifespan.
The identification of the long-lived mutants of the nematode
Caenorhabditis elegans, involving the age-1 (38, 42-44), dauer-constitutive
daf-2 (45) and spermatogenesis defective spe-26 (46) genes may provide
other examples of virtual gerontogenes. Although the exact nature of the
final protein products of these genes is at present unknown,
characterization of the age-1 mutant strain of C. elegans has shown
increased resistance to hydrogen peroxide-induced oxidative damage and an
increase in the activities of SOD and catalase enzymes in the mutants (47).
Other possibilities may be found in the complex regulatory mechanisms known
to exist in connection with the end-replication problem of telomeres (48)
and the post-replicative processing of DNA, such as methylation (49).
Molecular studies using a comparative approach, including the use of
transgenic organisms, will be useful to identify most important genes in
this respect and can form the basis of developing appropriate strategies
for future gerontological research.
Implications for aging research
The objective of this article is to develop the concept of virtual genes in
aging as an emergent property of several functionally-coupled genes which
were not naturally selected to cause aging, but whose combined action and
interaction reveals their role as gerontogenes. Therefore, in order to
unravel the genetic elements regulating the aging process, studies should
be directed towards understanding the mechanisms of interaction and
inter-dependence of various genes involved in maintenance and repair.
The phenomenology of aging is rich in empirical data showing that
individually no tissue, organ or system becomes functionally exhausted even
in very old organisms, yet it is their combined interaction and
inter-dependence that determines the survival of the whole. The same logic
needs to be applied for studies on the molecular and genetic levels.
Searching for an all-encompassing aging gene(s) is unlikely to be
successful. Estimates of the number of genes which could influence aging
and lifespan run up to a few hundred out of about one hundred thousand
genes, and their allelic variants, in mammalian systems (50). A search for
universal biomarkers of aging is likely to remain unsuccessful because of
the astronomical number of ways in which such interactive units or networks
can manifest stochastic alterations.
Therefore, manipulating any single gene or a few genes that show
some effects on aging and lifespan will help to identify genes that might
qualify as being a part of the virtual gerontogene family. Of course, such
studies will be valuable to find ways to "fine-tune" the network and to
prevent the onset of various age-related diseases and impairments by
maintaing the efficiency of homeostatic processes. In the short term, such
studies will also result in developing a variety of so-called anti-aging
products by concentrating on the individual members of the gerontogene
family. In contrast, direct gene therapy of the total aging process seems
to hold little promise. In order to unravel the molecular basis of aging
and modulate the process, the most promising research strategies will
incorporate an analysis of the formation and functioning of maintenance and
repair networks. The concept of virtual gerontogenes can be useful to
design new experiments and help to search for the genetic "hand of cards"
that provides the best possible combination to prevent succumbing to
perturbations from internal and external sources.
Acknowledgement: I am grateful to Dr. Paul Woolley for several discussions
and critical reading of the manuscript.
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Suresh I.S. Rattan
Laboratory of Cellular Ageing
Department of Chemistry
Aarhus University
DK-8000 Aarhus-C, Denmark. Phone: +45 8942 3956; Fax: +45 8619 6199
