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The Ageing Theory
12.32 | 
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Forsema 95
Hipothesis regulasi gene menyatakan bahwa gen-gen berperan penting di dalam siklus hidup organisme. Menurut hipothesis telomere, proses penuaan terjadi karena pemendekan telomere selama proses pembelahan sel. Hipothesis stres oksidatif menyatakan bahwa akumulasi berbagai spesies reaktif, termasuk radikal-radikal bebas, menyebabkan kerusakan-kerusakan pada sel-sel, yang pada akhirnya menyebabkan penuaan. Banyak teori penuaan yang tergolong kelompok hipothesis neuroendokrin maupun neuroendokrin-imun berbagai gagasan bahwa aksis hipothalamus-hipophysis-kelenjar adrenal terlibat di dalam proses penuaan.
The term “ageing” is usually understood in its wide meaning. However, it seems so far that no single formal definition has been universally agreed, although attempts have been made to make an exact definition of ageing. One definition describes ageing as “the progressive accumulation of changes with time associated with or responsible for the ever increasing susceptibility to disease and death which accompany age”. These changes can be due to development, genetic abnormality, the environment, or disease. Ageing is also delineated as a decreasing ability to respond to stress concomitant with the increasing homeostatic imbalance and incidence of disorders.
In 1990, Medvedev reported that at that time there were more than 300 hypotheses of ageing, and the number was still increasing. However, no single hypothesis has been able to satisfactorily explain the whole phenomena of ageing. It is believed that the processes of ageing involve incredibly complex and multifactorial mechanisms. Hence a single, unifying hypothesis, becomes less plausible, and may not even be realistic since the processes of ageing can take different forms and variations. For example, ageing changes, such as collagen cross-linking, may appear strikingly similar across species in mammals. However, the lifespan differences between these species varied by approximately 30 fold. Therefore, although ageing phenomenon may look similar, the ageing changes appear at very different rates. In addition, different tissue in a given individual undergoes different rates and characteristics of ageing. Thus, the ageing process of neurons may appear differently from that of blood cells, epithelial cells of intestine, skin, eye, liver, thymus, artery, or connective tissue.
It seems that the hypotheses of ageing fall into two major categories, namely those that involve some pre-programmed changes and those that suggest that ageing comes about due to increases in the number of “errors” introduced in cellular structures with increasing “wear and tear” or cell division. Hypotheses that advocated preprogrammed changes as an explanation of ageing argue that ageing is ruled intrinsically by biological clocks, which depend on genes. These genes successively turn various metabolic pathways on and off during the lifespan of organisms. “Error” (or stochastic) related hypotheses contend that various extrinsic events lead to progressive and random damage on cells (e.g. molecular cross-linking, oxidative damage, lipofuscin accumulations). Knight (2000) has argued that ageing may be better explained by adopting several of the current hypotheses from both categories. This essay aims at outlining several prominent hypotheses of ageing, namely “evolutionary” hypotheses, gene regulation hypothesis, the telomere hypothesis, oxidative stress hypothesis, neuroendocrine hypotheses, and neuroendocrine-immuno hypotheses.
“Evolutionary” Hypotheses"
There are three main “evolutionary” hypotheses of ageing, namely “mutation-accumulation hypothesis”, “disposable soma hypothesis”, and “antagonistic pleiotrophy hypothesis”. Evolutionary hypotheses postulate that ageing is a non-adaptive product of the progressive weakening of the natural selection with age. In a natural environment, aged animals are rarely observed due to the high mortality rate at younger ages. The mortality is mainly caused by extrinsic threats such as diseases, predation, starvation, or other environmental stresses such as cold. It is assumed that as a result of this high rate of extrinsic mortality, the force of natural selection declines with age. This is in spite of the detrimental effects of ageing, which evolutionary force should select against. In addition, most reproduction occurs early in young adult life. Young adults are the largest producers of offspring, and thus they are the greatest sources of gene propagation in the population. It is at these young ages that the maximum intensity of selection occurs. Genes that manifest later in life are less important to be selected against, since many organisms die due to extrinsic mortality before reaching old age. The weakening of natural selection with age then allows the accumulation of mutations with late-manifesting detrimental effects, and hence, ageing process appears. This is the idea proposed by the mutation-accumulation hypothesis. However, studies in Drosophilia showed little evidence is in favour of this hypothesis. Studies on transgenic and knockout mice demonstrated that mutations do accumulate with age. However, whether or not this accumulation causes deleterious effects on the mice, as suggested by the mutation hypothesis, remains to be determined.
Evolutionary force aims at maximizing reproductive success of species. A longevity trait is selected by this force only if beneficial for this objective. This idea leads to the disposable soma hypothesis of ageing. This states that the soma (body) of a given organism is maintained as long as it still fit for reproduction. The underlying tenet of this hypothesis is that there is a trade-off in the distribution of energy resources available for organisms.
The energy resources available for organisms have to be divided into three important activities, namely basic metabolism, maintenance of the body (soma), and reproduction. The basic metabolism includes biochemical synthesis, respiration, cells turnover, movement, digestion, and excretion. The maintenance of the body includes DNA repair, anti-oxidant defence, protein removal and repair, immune response, proof reading mechanisms for macromolecule synthesis, detoxification of harmful agents, wound healing, homeostasis, epigenetic stability of differentiated cells, apoptosis, fat deposition, grooming of fur or feathers. All of this maintenance consumes a considerable energy.
While the energy for the basic metabolism cannot be compromised for the life of organisms, a trade-off occurs between the maintenance of soma and reproduction. The increased investment of energy on reproduction will result in a decreased investment on the maintenance of soma, and thus decrease the lifespan of organisms. On the other hand, the extension of lifespan often sacrifices the fecundity of organisms.
This has been demonstrated in Drosophilia flies and Caenorhabditis elegans worms. The destruction of germ line cells of these animals can extend their lifespan.
The concept of evolutionary trade-off also applies to another evolutionary hypothesis, namely the antagonistic pleiotropy hypothesis. Some traits may be beneficial early in the life of organism, but they become detrimental later in life. The pleiotropy hypothesis argues that evolutionary force selects the genes with beneficial effects early in life, albeit small effects, and in spite of their deleterious effects later in life resulting in ageing and death. An example is androgens, which are important for the function of the prostate gland. Later in life, these same hormones may induce prostate cancer.
This hypothesis also acquires support from studies in Drosophilia. Furthermore, evolutionary hypotheses predict that genes promoting senescence are unlikely to be selected, since such genes are disadvantageous for the animals. Ageing is not programmed, but occurs as a result of the lack of investments of energy resource on the maintenance of the soma. As predicted by the disposable soma hypothesis, longevity is influenced by genes regulating the maintenance of soma, such as antioxidant defence, and not by genes promoting ageing. In support to this hypothesis are some studies showing the inverse correlation between mitochondrial reactive oxygen species (ROS) production and lifespan in animals.
Gene Regulation Hypothesis
The gene regulation hypothesis of ageing suggests that senescence occurs under genetic controls. It has been thought that genes send specific signals that regulate growth, maturation, decline, and death during the life of organisms. However, in view of the evolutionary hypothesis as described above, it is unlikely that evolutionary force selects genes that promote senescence. Rather, the force selects genes that promote longevity.
Some studies have reported that mutations of several genes, such as daf-2, age-1, eat-2, FIRKO, mth, and p66 cause the extension of lifespan in different organisms (flies, worms, and mice). Lifespan-extending effects also occurred as a result of the over-expression of some genes, such as Sir2, old-1, and hsp-70F. In contrast, mutations of several other genes, such as XPD and p53 seem to accelerate ageing in mice.
One might question whether the extension of lifespan following gene manipulation corresponds to the retardation or delay of ageing. Some studies on the mutations of genes such as pit-1, indy, daf-2, and age-1, have indeed demonstrated the slowing of ageing biomarkers (e.g. collagen cross-linking, decreased fecundity, tissue deterioration) beside the extension of lifespan of the animals examined. The manipulations of several genes, such as daf-2, mth,2 p66, or sod1, enhanced the anti-oxidant defence system. It has been considered that the effects on these anti-oxidant defence mechanisms may contribute to the lifespan extension.
The above-mentioned genes are involved in diverse biochemical pathways and physiological functions, such as insulin metabolism, kinase activities, heat shock protein production, anti-oxidant defence, or protein deacetylase. It is unlikely that these genes function to cause senescence and eventually lead to the death of organisms. Rather, they may play a role in maintenance and repair mechanisms, and hence, warrant the “essential lifespan” of organisms. “Essential lifespan” is defined as “the time required for successful reproduction and continuation of generations”. Senescence starts with the malfunction of maintenance and repair mechanisms.
The Telomere/Cellular Senescence Hypothesis
The “telomere hypothesis of ageing” pays attention on the role of telomere in cellular ageing process. Telomeres consist of noncoding genomic DNA located at the termini of linear eukaryotic chromosomes. They are thought to play a role in maintaining the stability of chromosomal end structures; suppressing abnormal fusions or rearrangements that appear in the damaged parts of chromosomes; and allowing the complete duplication of the terminal bases of the 5’-end. During cellular division, this end of telomeres is lost in every round of DNA replication, and hence shortens the length of the telomeres. The lost sequence is normally replaced by new sequence by an enzyme termed telomerase.
The “cellular senescence hypothesis” describes cell senescence as the process that limits the number of cell proliferations in culture. This limit (“Hayflick’s limit”) appears following a number of cellular proliferations. It hinders subsequent divisions, and finally allows the arrest of the cells at the M1 stage. The telomere hypothesis argues that the shortening of telomeres is responsible in the cellular divisions limitation. Oxidative stress may also contribute to the shortening of telomeres. It has been reported that mild oxidative stress accelerated the shortening of telomeres, whereas low oxidative stress allowed the maintenance of the length of telomeres.
The senescence occurring in the cells that undergo active divisions is termed replicative senescence. While the telomere hypothesis may be more suitable to elucidate the ageing of actively mitotic cells, it might also be relevant to post-mitotic cells, such as neurons. It has been suggested that telomeres may play a role in maintaining genomic stability and influencing gene expression. These functions might apply equally to non-dividing cells, although this notion awaits further investigation.
Telomere shortening, and thus replicative senescence, seems not to affect the ageing of mice, whereas it may influence the normal ageing process of humans. Telomere shortening might not contribute to the ageing of mice, due to the excessively long telomeres in mice. Furthermore, it has been contended that another type of cellular senescence, termed stress-induced senescence (SIS) may play a more pivotal role in the ageing process, especially in mice.
SIS appears as a response to various stresses, such as DNA damage or alterations in heterochromatin structure. It has been suggested that the senescence in mice is due to SIS, which is caused by oxidative damage.
Oxidative Stress Hypothesis
The “oxidative stress hypothesis of ageing” is also known as the “free radical hypothesis of ageing”. The original free radical hypothesis of ageing suggests that the process of ageing is largely determined by the accumulating destruction of cells with age by
free radicals, such as O2.
-(superoxide anion) or OH.
- (hydroxyl radical). Free radicals are defined as “molecules that have an unpaired electron in the outer orbit”. Together with H2O2 (oxygen derived non-radical molecule which also causes deleterious effects on cells), O2.
- and OH.
- belong to a group termed “reactive oxygen species” (ROS). Later in the development of the free radical hypothesis, it was found that the progressive and irreversible cellular destruction can also be brought about by other reactive species, such as reactive nitrogen species (RNS) and reactive aldehydic species. Hence, these findings lend credence to the name oxidative stress hypothesis of ageing as an alternative of free radical hypothesis of ageing. Thus far, the oxidative stress hypothesis of ageing seems to be the most popular hypothesis of ageing, albeit not proven up to date.
ROS production occurs in various organelles in the cells through multiple enzymatic reactions, such as fatty acid metabolism in the peroxisomes, cytochrome P450 reactions, cyclooxigenases activities, NADPH oxidation, or mitochondrial electron transport.
However, approximately 90% of ROS are generated in mitochondria. It is well known that the inner membrane of mitochondria of cells produces ATP (adenosine triphosphate) through molecular processes involving nutrients and oxygen. Complexes I and II of the inner membrane of mitochondria take electrons from nutrients. These electrons are relayed down the respiratory chains to complex IV, where they react with oxygen and hydrogen to make up water. This electron flow induces ATP-synthase to compose ATP from ADP (adenosine diphosphate) and phosphate, using energy from protons (H+). However, leakage of electrons occurs during the transport of electrons. These electrons interact with the nearby oxygen to form O2.
-,which then yield H2O2 by dismutation. It is believed that ROS are manufactured mostly in complexes I and III (57). The accumulation of ROS subsequently destroy proteins, lipids, and DNA components of cells. Among all other components of the cells, mitochondrial components responsible for producing ATP are believed to be the most susceptible to free radicals attack. The damage of few mitochondria in cells, which results in the mutations of mitochondrial DNA (mtDNA), may not necessarily cause cellular dysfunction.
This is because each mitochondrion has many genomic copies of itself, and each cell has many mitochondria. However, the damage accumulates with time, and eventually disrupts cellular functions. The damage on mitochondria results in the exponential increase of the production of ROS and the decrease of the efficiency of ATP production. More impairment of the mitochondria occurs as a result of this increase of ROS production. This eventually leads to vicious cycle of the destruction of cells. This notion is termed the “vicious cycle accumulation hypothesis of ageing”. A recent work in Barja’s laboratory, however, demonstrated that although there was an increase of ROS production in mitochondria, it was unlikely that the production increased exponentially. Yet, the production of ROS may still contribute to the increase of oxidative stress.
Another hypothesis related to the role of mitochondria in ageing is the “survival of the slowest hypothesis”. This hypothesis suggests that mutant mtDNA accumulates in cells due to their slower degradation compared to normal or less damaged mtDNA.
The “mitochondrial-lysosomal axis hypothesis of ageing” furthermore proposes that the slow degradation of defective mitochondria is due to the increasing inability of lysosomes to remove them. In aged post-mitotic cells, many mitochondria are enlarged and structurally disorganized. These mitochondria cannot be efficiently auto-phagocytosed by lysosomes. Gradually the number of non-autophagocytosed, enlarged, and dysfunctional mitochondria increase, predominantly occupy the cellular space, and inhibit the replication of normal mitochondria. Macromolecules of defective mitochondria inside lysosomes undergo further oxidative alteration and turn into lipofuscin, an undegradable molecule. Later, significant accumulation of lipofuscin in the cell inhibits the auto-phagocytotic ability of the cells even further. All these processes lead to the death of the cells.
The reactive species are normally removed from the cells by antioxidant defence mechanisms, which include enzymatic and non-enzymatic pathways. Oxidative stress occurs as a result of the imbalance between prooxidant and anti-oxidant defence system in favour of the pro-oxidant conditions.
The oxidative stress hypothesis of ageing seems to obtain support mainly from studies on flies and worms. It has been shown that the accumulation of oxidative damage brought about the ageing process, which finally limits the lifespan of these animals. The lifespan of birds also seems to be inversely correlated with the production rate of H2O2. Studies on the correlation between oxidative stress and ageing in mammals, in contrast, show less compelling evidence.
Neuroendocrine Hypotheses
The neuroendocrine system performs various essential functions, including communication, integration, and control of various other systems in the body, in order to maintain homeostasis. The neuroendocrine system coordinates physiological responses of various soma systems towards environmental stimuli. It also maintains all other systems in the body in the most optimal condition for reproduction and survival. The “neuroendocrine hypotheses of ageing” propose that ageing occurs as a result of the failure or the decline of these functions.
Declines of various neurotransmitter systems in the hypothalamus, including dopaminergic, monoamine oxidase, noradrenergic, serotonergic, amino acid, and cholinergic systems have been observed in studies on both humans and animals. Similarly, deterioration of various hormones produced by the hypothalamic-pituitary axis, including growth hormone (GH), GH-releasing hormone, adrenocorticotropic hormone (ACTH), thyroid stimulating hormone (TSH), and oxytocin, have been reported in many studies.
Such decline has also been found in other hormones produced by other endocrine glands, such as thyroid hormones, calcitonin, DHEA (dehydroepiandrosterone), aldosterone, estrogens, and testosterone. All of these findings have led to the proposal of various neuroendocrine hypotheses of ageing, including “the ageing clock hypothesis”,“the hypothalamic disregulation hypothesis”,“the hypothalamic elevation hypothesis”,“the neuroendocrine deficiency hypothesis”,“the neurotransmitter hypothesis”,“the hypopituitary hypothesis”,“the hypothyroid hypothesis”,“the neuroendocrine over stimulation hypothesis”,“the pituitary hypothesis”, and “the stress hypothesis”. Many of these hypotheses share an emphasis on the role of hypothalamic-pituitary axis on senescence.
Recent studies on insulin/insulin-like growth factor 1 (IGF-1) signalling pathway sheds light on the role of GH, one of the hormones produced by the anterior pituitary gland, on ageing processes. One of the functions of GH is stimulating liver to secrete IGF-1, which plays a role in the development of cartilage. It has been suggested that the downstream pathways of IGF-1 include the suppressions of anti-oxidant defence systems (superoxide dis mutase and catalase enzymes), heat shock proteins, and fat deposition; and the increase of growth and mortality. Studies on mice with homozygous mutations in the pit-1 and prop-1 genes demonstrated a considerably longer lifespan of these mice compared to wild-type mice. The mutations of these genes caused low levels of GH, IGF-1, and TSH.
Although GH and IGF-1 may seem to modulate ageing, the exact relationship between GH/ IGF-1 and ageing remains unclear. Studies on rodents and humans have shown that ageing is associated with the decline of GH and IGF-1 levels, and yet GH- and IGF-1-deficient mice have shown delayed ageing. In humans, chronic and excessive secretion of GH may bring about the shortening of lifespan due to cardiovascular diseases, diabetes, or tumours. Conversely, GH deficiency may also cause the shortening of lifespan due to premature atherosclerosis, insulin resistance, or other disorders. Such paradoxical effects also apply to IGF-1.
Neuroendocrine-immuno Hypothesis
The “neuroendocrine-immuno hypothesis of ageing” suggests that senescence occurs due to the deterioration of both the neuroendocrine and the immunes. The immune system interacts with the neuroendocrine system via several agents, namely neuropeptides, cytokines, and hormones produced by the pituitary gland. In humans, the decline of the immune system with age, termed as “immuno-senescence”, is characterized by the increased susceptibility to autoimmune diseases and age-related disorders, such as atherosclerosis, cancer, or Alzheimer’s disease. Immuno-senescence is primarily associated with the progressive involution of the thymus with age, the decline of T lymphocytes proliferation, and the low counts of naïve T cells. B lymphocytes are also affected by ageing, although not as markedly as T cells. Other alterations of the immune system include the reduction of interleukin-2 (IL-2) production, T cell response to IL-2, response to mitogen induction, antibody response to antigens; and the increase of autoantibody production and various pro-inflammatory agents, such as IL-6, NF-kB, IL-b, TNFa, cyclooxygenase-2, and inducible NO synthase.
The atrophy of the thymus and the decline of T cell production might be related to the alterations of the glucocorticoid (cortisol) and DHEA levels. Ageing is characterized by the increased activity of HPA (hypothalamic-pituitary-adrenal) axis due to the accumulation of various psychological stressors and stress hormones.
The increased activity of HPA axis in turn increases the cortisol and decreases the DHEA production from the adrenal cortex. The alterations in the levels of these two hormones cause the involution of the thymus and suppress the production of T-cells. In addition, they also directly affect the levels of the peripheral T-cells. The increase of cortisol level causes more neuronal damage in the hypothalamus.
It also reduces the hypothalamic sensitivity towards the cortisol feedback mechanism. This further leads to the increased activity of HPA axis, which in turn causes more production of cortisol and less production of DHEA hormones. This vicious cycle of HPA axis – cortisol/ DHEA might be over-simplistic to explain the ageing process. However, it might offer another piece for a more comprehensive explanation on ageing.
Conclusions
Several important hypotheses of ageing have been described, including “evolutionary” hypotheses, gene regulation hypothesis, the telomere hypothesis, oxidative stress hypothesis, neuroendocrine hypotheses, and neuroendocrine-immuno hypotheses. Among these theories, it seems that up to present the oxidative stress hypothesis of ageing garners support the most amongst all other hypotheses of ageing. Notably, this is not to say that the remaining of more than 300 hypotheses of ageing is not as significant as these hypotheses, since our understanding on the phenomenon of ageing is still developing.
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