Cellular Theory of Aging
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Cellular theories explain the aging process as originating in individual cells, either at the level of the genetic information or through changes in metabolism.
The quest for understanding the process of aging is probably as long as human history, and its resolution is still far from clear or even assured. A major factor for this state of affairs is that aging is a complex, multifactorial process that develops during ontogeny gradually, at multiple levels, involving a certain degree of stochastic randomness. At a certain time (early 1990s), more than 300 various hypotheses were circulating for explaining aging, and, responding to a need for organizing such a vast catalogue, these hypotheses were classified as cellular theories that explain the aging process as originating in individual cells, either at the level of the genetic information or through changes in metabolism; system theories, that propose that aging, while expressed at the level of individual cells, results from dysfunction in one or another of the general system that maintain overall body homeostasis (e.g., the neuroendocrine theory of aging); and evolutionary theories, that address the fundamental biological puzzle that aging, as a fundamentally deleterious process, should have been gradually eliminated during evolution since evolution aims to improve the adaptation of individuals and species to their environment.
Within the group of cellular theories, the various hypotheses can be further separated into those that invoke (a) changes in the genetic makeup (genome) of cells or (b) alterations and dysfunction in various metabolic pathways (overall, the “wear and tear” theories).
The genome-related theories of aging start from the fundamental fact that the whole of the genetic information that controls the identity, development, and status of a cell is contained within the DNA. Like anything else in nature, this molecule can be damaged either by random, stochastic agents or by specific factors or processes. Amongst other features, one of the unique properties of the DNA is that it is the only biological molecule that relies for maintenance on the repair of the same existing molecule, without the possibility of remanufacture. Apart from the implications for the importance and reliability of the DNA repair mechanisms, this fact also leads to the conclusion that DNA molecules accumulate damage over a lifetime since an error in DNA sequence information, once made during replication or recombination, becomes irreversible, due to the loss of the reference template. DNA integrity can be affected by several mechanisms. One is endogenous, represented by the cellular metabolism; activity in all cells will generate continuously reactive oxygen and nitrogen species (free radicals) that either directly, or secondarily, through generation of lipid peroxidation products, alkylating agents or protein carbonyl species, will damage DNA by inducing single-strand breaks and oxidation of various bases. The other category of damaging agents is exogenous, represented by chemical or physical (e.g., UV and other types of ionizing radiations) factors. It has been shown that DNA mutations/alterations and chromosomal abnormalities increase with age both in animals (e.g., rodents) and humans. In addition, the role of genetic mutation in inducing the aging phenotype is demonstrated by a number of syndromes of accelerated aging (progeria). Amongst them, the best known is the Werner’s syndrome which is determined by an autosomal recessive mutation in a gene, WRN, that encodes for a protein with structural similarities with a DNA helicase (enzyme catalyzing DNA unwinding). Loss of WRN function results in a syndrome displaying the typical features of aging, but starting as early as the second decade of life: bilateral cataracts, graying of hair and alopecia, type 2 diabetes, atherosclerosis and hyperlipidemia, osteoporosis, etc. Another progeric manifestation is the Hutchinson-Gilford’s syndrome, with a rather similar clinical manifestation but resulting from a point mutation in the gene encoding for a nuclear protein: lamin A/C (LMNA). Although the exact function of either protein is not fully established, recent experimental evidence point to the fact that they are involved in the process of DNA repair. The importance of maintaining a robust genomic stability led to the evolutionary development of powerful and flexible DNA repair systems that include mechanisms for dealing with both single-stand breaks (e.g., base excision repair and nucleotide excision repair) and double-strand breaks (e.g., homologous recombination or nonhomologous end joining). Although there are many reports of correlations between stability of DNA repair mechanisms and rate of aging in various animals (mammals) and, also, of an age-dependent functional decline in one or another DNA repair mechanism, other studies found no clear evidence for a drastic decline in DNA repair during aging, an observation taken simply to reflect the central role of genome stability for cell viability. In addition, accumulation of damage with age does not necessarily imply a decline in DNA repair – as any biological process, genome maintenance systems are imperfect, and alterations can accumulate over time, particularly in animals with longer life spans.
A more recent line of investigation of the relationships between DNA damage and aging stems from the fact that genome maintenance involves not only the DNA repair systems but also the cellular responses triggered directly by the DNA damage. These responses include apoptosis, cellular senescence, and cell cycle arrest, known to cause age-related impairments in various tissues. Thus, one of the most ubiquitous response to unrepaired or improper repair double-strand breaks involves the ataxia-telangiectasia-mutated (ATM) kinase. Activated ATM, in addition to modulation of several cell cycle proteins DNA repair factors, targets p53, a central protein at the crossroad of several cell viability pathways. While p53 suppresses the onset of malignancy, having an indirect positive on lifespan, it also triggers cellular senescence and apoptosis. A strong theoretical argument for the involvement of such a universal and general cellular response in mediating the pro-aging effects of DNA damage is that the phenotype of aging is relatively constant from species to species and also, in general lines, from individual to individual whereas, with few exceptions, the exo- or endogenous induction of DNA damage is stochastic and should result in highly variable functional outcomes.
An important cellular theory of aging is the cell senescence/telomere theory. The idea of cell senescence was formulated in 1965, describing the fact that normal cells can undergo only a limited number of cell divisions (Hayflick’s limit), after which the cells enter replicative senescence, remain quiescent, and then, after a period of time, die. Since the number of cell divisions varies from species to species (e.g., mouse cells divide roughly 15 times, while the cells for Galapagos tortoise divide 110 times), it has been proposed that this process of replicative senescence is an important regulator of life span and thus a contributor to aging (NB this senescence process, dependent on the cell replication, is different from the metabolic cellular senescence, that results from the accumulation with time of metabolic dysfunction, that result in functional impairment of various cellular activities, see below). It has been proposed that replicative senescence ultimately results from the loss of telomeres, which are specific chains of a repeating DNA sequences located at the ends of each linear chromosome. With each cell division, a small amount of DNA is necessarily lost on each chromosome end, resulting in ever-shorter telomeres, altered telomere structure, and, when the telomere is under a critical length, a stop of replication and eventual replicative senescence. Activation of the telomerase enzyme will regenerate telomeres, prevent replicative senescence, and immortalize human primary cell cultures. Importantly, in all cancer cells, there is an activation of telomerase or of an alternate pathway of telomere extension that avoids replicative senescence.
Although there is a wealth of correlative data (e.g., shorter telomeres in aged people or, more specifically, in individuals with neurodegenerative diseases, including Alzheimer’s; induction of telomere shortening in condition of increased metabolic stress), a causal involvement of telomere reduction in aging is doubtful as telomerase-deficient mice do not age more rapidly. Instead, as with the other genetic theories of aging discussed above, it is more likely that replicative senescence influences aging through the various cellular responses it triggers. It has been described that senescent cells produce and secrete various degradative enzymes and inflammatory factors that alter the microenvironment and lead to disturbed tissue structure and function. Also, replicative senescence degrades and ultimately limits the regenerative potential of stem cell. The intracellular mechanism triggered by telomere shortening is the activation of the same tumor suppressor p53 protein. The type of p53-dependent cellular response (cell arrest, apoptosis, or senescence) is often cell type dependent and varies with the type of stimulus that triggers it and severity of stress that the cells are exposed to. Being a tumor suppressor protein, it is not surprising that mice mutated for p53 with loss of function have a dramatically increased incidence of cancer, while p53 signaling is altered in the majority of human cancers. However, if cellular senescence, linked with p53 activation, acts to suppress tumor formation, how can it be explained that cancer is more prevalent with age when senescence is also increased? There is currently no generally accepted explanation, and it is likely that it results from subtle changes in the balance between several processes and factors, such that, due to its ample homeostatic and functional reserve, in the adult organisms, the functional and structural deleterious effects that senescent cells might cause to the tissues can be efficiently repaired by the normal tissue renewal processes. Thus, in the main, in the mature organisms, the main role of the p53-dependent senescence is to provide cancer protection. In contrast, in the aged organisms, the time-dependent accumulation of mutations (i.e., DNA damage), together with the unfavorable metabolic environment, and the decrease in the renewing capacity generate conditions suitable for cancer growth.
One of the most widely acknowledged theories of aging is the Mitochondrial Free Radical Theory of Aging (MFRTA), which has been presented in various guises, either as metabolic or as “wear and tear” theories, and linked to other hypotheses, such as the “rate of living” theory. The latter probably has the longest history, originating at the beginning of last century with the empirical observation of a relationship between metabolic rate, body size, and longevity, such that long-lived animals are, on average, larger. Further metabolic studies led to the proposal that the faster the metabolic rate of an animal, a standby for biochemical activity and for the effect of temperature, the faster the organism will age. In the mid-1950s, the mechanisms causing cell damage and death in response to ionizing radiation were becoming clearer: the production of free radicals, a highly reactive species of molecules characterized by the existence of a single unpaired electron in the outer layers of the atom. Due to their chemical properties, oxygen and nitrogen are the molecules most prone to become free radicals, and the instability of such a molecule renders them very reactive, generating chain redox reactions of sequential oxidation (loss of electrons) and reduction (gain of electrons) of a variety of cellular substrates. In many instances, such redox changes result in a modification of function of the target proteins, leading to loss of metabolic homeostasis and ensuing damage. If the free radicals attack is of limited intensity or duration, the cellular damage can be contained and either accumulate slowly over time or be repaired; more intense level of injury would result in cell death. The original form of the Free Radical Theory of Aging (FRTA) envisaged aging as resulting from the long-term accumulation of free radical-induced damage, affecting mainly nuclear DNA, which is very sensitive to the action of free radicals. An important development of this hypothesis came with the discovery that the free radicals can result not only from the effects of exogenous factors, such as irradiation, but are also a natural output of normal physiology. One of the reasons why this hypothesis of aging became so paradigmatic is that it linked with several previous views, such that a higher rate of metabolism would generate higher free radical loads and consequent damage, and lead to a higher rate of aging. In the mid-1980s, the FRTA was complemented with the mitochondrial perspective, with several observations contributing to this development. (1) The mitochondria are the major source of free radicals since two of the protein complexes that form the mitochondrial respiratory chain (aka, electron transport chain) generate stochastically, in an unregulated fashion, reactive oxygen species (i.e., oxygen free radicals). (2) Mitochondria possess specific mitochondrial DNA, that is, spatially located very near to the source of free radicals, in the mitochondrial matrix. (3) Mitochondrial DNA has limited repair capacity. (4) Mitochondrial DNA codes for some of the proteins in the respiratory complex, and DNA mutation could generate dysfunctional proteins, initiating a time (age)-dependent vicious circle of increased free radical producing. Thus, the strong formulation of the complete MFRTA flows along the following functional axis: (a) oxygen free radicals generated (mainly from mitochondria) as a function of metabolic rate cause cumulative oxidative damage, resulting in structural degeneration, functional decline, and age-related diseases, leading to (b) oxidative stress that is the predominant cause of age-associated degenerative change, and thus (c) the mitochondrial free radicals are the cause of aging.
In the last few decades, a huge amount of experimental evidence accumulated to show that with age there is indeed an accumulation of mitochondrial oxidative damage and a progressive decline in mitochondrial function and performance. In many tissues, including the brain (which has a special position since the neurons are the only cell types in the body that are maintained in a postmitotic state, i.e., they do not divide), there is an age-dependent accumulation of global oxidative damage to proteins, DNA, and lipids. However, in the last few years, the availability of very powerful experimental models that allow genetic manipulations (full or conditional knock-in of proteins or knockdown of proteins, use of interference RNA as silencers of specific protein synthesis, etc.) led to the expression of serious reservations about the full validity of MFRTA. Thus, decreasing free radical levels with dietary antioxidants or by genetically induced overexpression of protein antioxidants, such as superoxide dismutase (SOD), that metabolizes the oxygen superoxide (a free radical) to hydrogen peroxide, or catalase, that metabolizes hydrogen peroxide to water and regenerates the gaseous oxygen, did not induce the expected significant increase in lifespan of the test animals. In contrast, inactivation of antioxidant activity while increasing the free radical levels did not determine a significant reduction of lifespan and even increased, in some instances, the lifespan.
It is worth assessing for a moment the reasons of the discrepancy between the two sets of data. The important point about most of earlier studies mentioned is that they were correlative, reporting that with age there is an increase in oxidative damage. However, correlation is not necessarily causation and implies the possibility that both aging and increased oxidation can be caused, at the same time, by another process(es), and, indeed, aging is viewed now as a multifactorial process. It also can be that oxidative stress might be the consequence of aging, with aging having some discrete cause, or causes, distinct from oxidative stress. Alternatively, oxidative stress might result from the failure of one particular maintenance system of the organism and thus participate in causing aging, but only as a factor amongst others. This perspective on the role of oxidative stress in actually causing aging has also practical implications, as it is still possible to advocate antioxidant therapies as being beneficial to health in counteracting the effects of free radicals, but not as a magic, blanket coverage anti-aging cure. In addition, each intervention should be critically evaluated, both because some antioxidant supplementation trials provided surprising results and because of an increasing number of studies showing the crucial roles of ROS in cellular signaling, and thus advocating against a too strong suppression of free radicals production.