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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Aarhus-C, Denmark AbstractTraditional categorization of theories of aging into programmed and stochastic ones is outdated and obsolete.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 [1]. 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” [2], 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: rattan@mb.au.dk 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 [13] 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” [8], 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 [31]). 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 [32]. 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 [59], 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 [71]. The full spectrum of on chromosome 6 [59], regions of chromosome 4 epigenetics of aging is yet to be unraveled and at [62], 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 [69].
theory, catastrophe theory, chaos theory, informationand interaction networks, that comprise and underlinethe modern biology of complexity. Since the 1990s, the term homeodynamics [74], 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 [75]. 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 [7]. 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 [76]. 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 [105], 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 [6].
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 [5]. 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.
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