I was hoping that one with a little background knowledge of biology could explain what function in all living things causes aging, especially to the point of natural death.
What causes aging?
What causes us to die?
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I was hoping that one with a little background knowledge of biology could explain what function in all living things causes aging, especially to the point of natural death.
What causes aging?
What causes us to die?
Damage-Based Theories of Aging
One class of theories of aging is based on the concept that damage, either due to normal toxic by-products of metabolism or inefficient repair/defensive systems, accumulates throughout the entire lifespan and causes aging. In this essay, I present and review the most important of these theories.
Keywords: ageing, anti-oxidants, biogerontology, geriatrics, hypotheses, life span
Orgel's Hypothesis
Aging has long been seen as a result of errors of many kinds. An early attempt to build a theory engulfing the genetic and protein machineries was Orgel's hypothesis (Orgel, 1963). His argument was that errors in transcription led to errors in the DNA creating an amplifying loop that eventually kills the cell and leads to aging. Indeed, damaged proteins accumulate with age, and enzymes lose catalytic activity with age (Gershon and Gershon, 1970). This can lead to cellular dysfunctions and accumulation of other forms of damage and senescence. Proteasome is a protein that degrades other proteins; its expression decreases with age (Lee et al., 1999) and this has been implicated as a factor contributing to aging (Friguet et al., 2000). Also, the half-life of proteins is longer in older animals (Friguet et al., 2000). On the other hand, this theory has been regarded as unlikely: feeding abnormal amino acids to animals does not result in a shorter lifespan (Strehler, 1999, p. 293); errors in macromolecular synthesis also does not appear to increase with age (Rabinovitch and Martin, 1982); cultured fibroblasts do not have increased protein errors (Harley et al., 1980); and cellular senescence appears to derive from the telomeres. Presently, Orgel's hypothesis is largely discarded. It is useful to point out, however, that some authors (e.g., Olson, 1987; Holliday, 2004; Kirkwood, 2005) defend that aging is a result of many forms of damage accumulation, and hence that aging is due to an overlap of the mechanistic theories of aging described next.
Energy Metabolism and Aging
In 1908, physiologist Max Rubner discovered a relationship between metabolic rate, body size, and longevity. In brief, long-lived animal species are on average bigger--as detailed before--and spend fewer calories per gram of body mass than smaller, short-lived species. The energy consumption hypothesis states that animals are born with a limited amount of some substance, potential energy, or physiological capacity and the faster they use it, the faster they will die (Hayflick, 1994). Later, this hypothesis evolved into the rate of living theory: the faster the metabolic rate, the faster the biochemical activity, the faster an organism will age. In other words, aging results from the pace at which life is lived (Pearl, 1928). This hypothesis is in accordance with the life history traits of mammals in which a long lifespan is associated with delayed development and slow reproductive rates (reviewed in Austad, 1997a & 1997b).
As previously mentioned, caloric restriction (CR) is one of the most important discoveries in aging research. Although the mechanisms behind CR remain a subject of discussion (see below), since it involves a decrease in calories, one obvious hypothesis is that maybe CR works by delaying metabolic rates, in accordance with the energy consumption hypothesis (reviewed in Masoro, 2005). Body temperature is crucial to determine metabolic rate since the rate of chemical reactions rises with temperature. One common feature of animals, such as mice, rats, and monkeys, under CR is a lower body temperature (Weindruch and Walford, 1988; Ramsey et al., 2000), which is consistent with the energy consumption hypothesis. On the other hand, some evidence indicates that mice under CR burn the same amount of energy as controls, suggesting they have similar metabolic rates. These studies, however, remain controversial in the way metabolic rate is normalized to metabolic mass (McCarter and Palmer, 1992). One hypothesis is that CR shifts metabolic pathways (Duffy et al., 1990). More recent results suggest that previous studies used unreliable estimates of metabolic mass in their calculations and indeed CR changes metabolic rates, supporting the rate of living hypothesis (Greenberg and Boozer, 2000), but the debate has not been settled.
Several experiments, however, have cast doubts on the energy consumption hypothesis. For instance, mice kept at lower temperatures eat 44% more than control mice and yet do not age faster (Holloszy and Smith, 1986). In fact, mice with higher metabolic rates may live slightly longer (Speakman et al., 2004). Mutations in the tau protein in hamsters increase metabolic rates and extends lifespan (Oklejewicz and Daan, 2002). Lastly, as detailed before, metabolic rates, when correctly normalized for body size, do not correlate with maximum lifespan in mammals. Despite its intuitive concept, the rate of living is practically dead. Based on CR, it is likely that energy metabolism plays a role in aging but, as described below, it is not clear how this process occurs. One hypothesis is that energy metabolism is linked to insulin-signaling, as mentioned ahead.
Free Radical Theory of Aging
Free radicals and oxidants--such as singlet oxygen that is not a free radical--are commonly called reactive oxygen species (ROS) and are such highly reactive molecules that they can damage all sorts of cellular components (Fig. 1). ROS can originate from exogenous sources such as ultraviolet (UV) and ionizing radiations or from several intracellular sources. The idea that free radicals are toxic agents was first suggested by Rebeca Gerschman and colleagues (Gerschman et al., 1954). In 1956, Denham Harman developed the free radical theory of aging (Harman, 1956; Harman, 1981). Since oxidative damage of many types accumulate with age, the free radical theory of aging simply argues that aging results from the damage generated by ROS (reviewed in Beckman and Ames, 1998).
ROS and aging
Figure 1: ROS or reactive oxygen species can be formed by different processes including normal cell metabolic processes. Due to their high reactivity, ROS can damage other molecules and cell structures. The free radical theory of aging argues that oxidative damage accumulates with age and drives the aging process.
To protect against oxidation there are many different types of antioxidants, from vitamins C and E to enzymes such as superoxide dismutase (SOD), catalase, and glutathione peroxidase. Briefly, antioxidant enzymes are capable of degrading ROS into inert compounds through a series of chemical reactions (Ames et al., 1981). The simple existence of enzymes to prevent damage by ROS is a strong indicator that ROS are biologically important, dangerous molecules (de Magalhaes and Church, 2006).
Most experimental evidence in favor of the free radical theory of aging comes from invertebrates. Transgenic fruit flies, Drosophila melanogaster, overexpressing the cytoplasmic form of SOD, called Cu/ZnSOD or SOD1, and catalase have a 34% increase in average longevity and a delayed aging process (Orr and Sohal, 1994). Recent findings, however, suggest that the influence of SOD1 and catalase in Drosophila aging may had been overestimated because the authors only took into account short-lived strains (Orr et al., 2003). Overexpressing bovine SOD2, the mitochondrial form of SOD, also called MnSOD, in Drosophila slightly extends average longevity but does not delay aging (Fleming et al., 1992). Also in Drosophila, expression of SOD1 in motor neurons increases longevity by 40% (Parkes et al., 1998). Finally, certain long-lived strains of both Drosophila (Rose, 1989; Hari et al., 1998) and the nematode worm Caenorhabditis elegans (Larsen, 1993) have increased levels of antioxidant enzymes.
In addition to antioxidants, some enzymes catalyze the repair caused by ROS. One of such enzymes is methionine sulfoxide reductase A (MSRA), which catalyzes the repair of protein-bound methionine residues oxidized by ROS. Overexpression of MSRA in the nervous system of Drosophila increases longevity (Ruan et al., 2002) while mice without MSRA have a decreased longevity of about 40% (Moskovitz et al., 2001). Whether the aging process is affected remains to be seen (de Magalhaes et al., 2005a), although the results from Drosophila suggest that age-related decline is also delayed by MSRA overexpression. Another enzyme that repairs oxidative damage is 8-oxo-dGTPase, which repairs 8-oxo-7,8-dihydroguanine, an abundant and mutagenic form of oxidative DNA damage. But contrary to the results involving MSRA, when researchers knocked out the gene responsible for 8-oxo-dGTPase, although the mutated mice had an increased cancer incidence, their aging phenotype did not appear altered (Tsuzuki et al., 2001).
Targeted mutation of p66shc in mice has been reported to increase longevity by about 30%, inducing resistance to oxidative damage, and maybe delaying aging (Migliaccio et al., 1999). Although the exact function of p66shc remains unclear, some evidence suggests it may be related to intracellular oxidants and apoptosis (Nemoto and Finkel, 2002; Trinei et al., 2002; Napoli et al., 2003). Also, transgenic mice overexpressing the human thioredoxin gene featured an increased resistance to oxidative stress and an extended longevity of 35% (Mitsui et al., 2002). Like p66shc, thioredoxin regulates the redox content of cells and is thought to have anti-apoptotic effects (Saitoh et al., 1998; Kwon et al., 2003). Neither p66shc nor thioredoxin are antioxidants, so these findings could be unrelated to the free radical theory of aging but rather, for instance, tissue homeostasis. Mice with extra catalase in their mitochondria lived 18% more than controls and were less likely to develop cataracts, but they did not appear to age slower and their extended lifespan appeared to derive from a decrease in cardiac diseases throughout the entire lifespan (Schriner et al., 2005). Lastly, the phenotype witnessed in a strain called senescence-accelerated mice may be related to free radical damage (Edamatsu et al., 1995; Mori et al., 1998).
Several attempts have been made to overexpress or knock-out antioxidants in mice, but the results have been largely disappointing (Sohal et al., 2002; de Magalhaes, 2005a; de Magalhaes and Church, 2006). In some cases animals do not show any differences in their aging phenotype when compared to controls (Reaume et al., 1996; Ho et al., 1997; Schriner et al., 2000). Experiments in feeding mice antioxidants--either a single compound or a combination of compounds--were able to decrease oxidative damage and increase average longevity but none of them delayed aging (Harman, 1968; Comfort et al., 1971; Heidrick et al., 1984; Saito et al., 1998; Holloszy, 1998), while other studies did not conclude that feeding mice antioxidants increases longevity (Lipman et al., 1998). Ubiquitous overexpression of SOD1 in mice also failed to increase longevity (Huang et al., 2000). These results suggest that antioxidant proteins are already optimized in mammals. Indeed, correlations between rate of aging and antioxidant levels in mammals are, if they exist, very weak (reviewed in Finch, 1990; Sohal and Weindruch, 1996; and see Andziak et al., 2005). Some studies found correlations between the levels of certain antioxidants and longevity in mammals, but failed to find any consensus (Tolmasoff et al., 1980; Ames et al., 1981; Cutler, 1985; Sohal et al., 1990). The way antioxidants can increase longevity but do not affect rate of aging suggests that antioxidants may be healthy but do not affect the aging process, as debated elsewhere. Finally, another experiment raised doubts regarding the free radical theory of aging: knockout mice heterozygous for SOD2 showed increased oxidative damage at a cellular and molecular level but did not show significant changes in longevity or rate of aging (Van Remmen et al., 2003).
Although ROS can have several sources, some argue that ROS originating in the cellular metabolism which takes place in the cell's energy source, the mitochondrion, are the source of damage that results in aging. Since ROS are a result of cellular metabolism, the free radical theory of aging has been associated with the rate of living theory (Harman, 1981). One mechanism proposed for CR is that animals under CR produce less ROS and therefore age slower (Weindruch, 1996; Masoro, 2005), but since the rate of living theory seems out-of-favor this perspective will not be further discussed here. An alternative hypothesis is that the rate of mitochondrial ROS generation, independently of metabolic rates or antioxidant levels, may act as a longevity determinant (Sohal and Brunk, 1992; Barja, 2002). Some results suggest that the rate of ROS generated in the mitochondria of post-mitotic tissues helps explain the differences in lifespan among some animals, particularly among mammals (Ku et al., 1993; Barja and Herrero, 2000; Sohal et al., 2002) and between birds and mammals (reviewed in Barja, 2002). One pitfall of these studies is that technical limitations exist in measuring ROS production in isolated mitochondria. For example, none of these studies measures the levels of hydroxyl radical, the most reactive and destructive of the ROS; often, hydrogen peroxide and superoxide anion are measured since they can react to give the hydroxyl radical. Even so, such studies may not be representative of what actually occurs. Moreover, two studies in Drosophila found that lowering ROS leakage from the mitochondria either did not result in a longer lifespan (Miwa et al., 2004) or even resulted in a shorter lifespan (Bayne et al., 2005).
Several pathologies exist in mice and humans derived from mutations affecting the mitochondrion, which often involve an increase in ROS leakage from the mitochondrion (Pitkanen and Robinson, 1996; Wallace, 1999; DiMauro and Schon, 2003). Yet these pathologies do not result in an accelerated aging phenotype, but frequently result in diseases of the central nervous system (Martin, 1978). One example is Friedreich's ataxia which appears to result from increased oxidative stress in the mitochondria and does not resemble accelerated aging (Rotig et al., 1997; Wong et al., 1999). Deficiency of the mitochondrial complex I has been reported in a variety of pathologies such as neurodegenerative disorders (reviewed in Robinson, 1998). Cytochrome c deficiency has also been associated with neurodegenerative disorders (reviewed in DiMauro and Schon, 2003) as has selective vitamin E deficiency (Burck et al., 1981). Perhaps ROS are involved in some pathologies involving post-mitotic cells, such as neurons; another alternative is that mitochondrial diseases affect mainly the central nervous system due to its high energy usage (Parker, 1990 for arguments). There is some evidence of a mitochondrial optimization in the human lineage to delay degenerative diseases, but not aging (de Magalhaes, 2005b). Interestingly, both Drosophila and C. elegans are mostly composed of post-mitotic cells, which can explain why results from these invertebrates are much more supportive of the free radical theory of aging than results from mice.
Although it is undeniable that ROS play a role in several pathologies, including age-related pathologies like cataracts (Wolf et al., 2005), the exact influence of ROS in mammalian aging is undetermined. In conclusion, there is very little direct evidence that ROS influence mammalian aging.
DNA Damage Theory
The DNA, due to its central role in life, was bound to be implicated in aging. One hypothesis then is that damage accumulation to the DNA causes aging, as first proposed by physicist Leo Szilard (Szilard, 1959). The theory has changed a bit over the years as new forms of DNA damage and mutation are discovered, and several theories of aging argue that DNA damage or mutation accumulation causes aging (Gensler and Bernstein, 1981 for arguments).
As briefly mentioned before, progeroid syndromes are rare genetic diseases that appear as accelerated aging. Interestingly, the most impressive progeroid syndromes, Werner's, Hutchinson-Gilford's, and Cockayne syndrome originate in genes that are related to DNA repair/metabolism (Martin and Oshima, 2000). Werner's syndrome (WS) originates in a recessive mutation in a gene, WRN, encoding a RecQ helicase (Yu et al., 1996; Gray et al., 1997). Since WRN is unique among its family in also possessing an exonuclease activity (Huang et al., 1998), it may be involved in DNA repair. Although the exact functions of WRN remain a mystery, it is undeniable that WRN plays a role in DNA biology, particularly in solving unusual DNA structures (reviewed in Shen and Loeb, 2000; Bohr et al., 2002; Fry, 2002). In fact, cells taken from patients with WS have increased genomic instability (Fukuchi et al., 1989). Topoisomerases are enzymes that regulate the supercoiling in duplex DNA. WS cells are hypersensitive to topoisomerase inhibitors (Pichierri et al., 2000). As such, WS is an indicator that alterations in the DNA over time play a role in aging.
As with WRN, the protein whose mutation causes Hutchinson-Gilford's syndrome is also a nuclear protein: lamin A/C (Eriksson et al., 2003). Recent results also suggest that some atypical cases of WS may be derived from mutations in lamin A/C (Chen et al., 2003). The exact functions of lamin A/C remain unknown, but it appears to be involved in the biology of the inner nuclear membrane. Further evidence suggests that the DNA machinery is impaired in Hutchinson-Gilford's syndrome (Wang et al., 1991; Sugita et al., 1995), again suggesting that changes in the DNA are important in these diseases and, maybe, in normal aging. The protein involved in Cockayne Syndrome Type I participates in transcription and DNA metabolism (Henning et al., 1995).
Other progeroid syndromes exist, though the classification is subjective. For example, Nijmegen breakage syndrome, which derives from a mutated DNA double-strand break repair protein (Carney et al., 1998; Matsuura et al., 1998; Varon et al., 1998), has been considered as progeroid (Martin and Oshima, 2000). Mouse accelerated aging syndromes have also been implicated in DNA repair such as the mouse homologues of xeroderma pigmentosum, group D (de Boer et al., 2002), ataxia telangiectasia mutated or ATM (Wong et al., 2003), p53 (Donehower et al., 1992; Donehower, 2002; Tyner et al., 2002; Cao et al., 2003), and Ercc1 (Weeda et al., 1997). Thus many progeroid syndromes of mice involve the DNA machinery (Hasty et al., 2003). Please take a look at the list of genes that can modulate the aging phenotype present in GenAge.
It appears well-established that DNA mutations and chromosomal abnormalities increase with age in mice (Martin et al., 1985; Dolle et al., 1997; Vijg, 2000; Dolle and Vijg, 2002) and humans (e.g., Esposito et al., 1989). It is impossible, however, to tell whether these changes are effects or causes of aging. In addition, there is no consensus as to what type, if any, of DNA changes are crucial in aging. Correlations have been found between DNA repair mechanisms and rate of aging in some mammalian species (Hart and Setlow, 1974; Grube and Burkle, 1992; Cortopassi and Wang, 1996), though this may be an artifact of long-lived species being on average bigger (Promislow, 1994). On the other hand, mice overexpressing a DNA repair gene called MGMT had a lower cancer incidence but did not age slower (Zhou et al., 2001). Mice deficient in Pms2, another DNA repair protein, had elevated levels of mutations in multiple tissues and yet did not appear to age faster than controls (Narayanan et al., 1997). Embryos of mice and flies irradiated with x-rays do not age faster (reviewed in Cosgrove et al., 1993; Strehler, 1999), though one report argued that Chernobyl victims do (Polyukhov et al., 2000). Certain mutations in DNA repair proteins, such as p53 in humans (Varley et al., 1997), despite affecting longevity and increasing cancer incidence, fail to accelerate aging.
One possibility is that ROS damage to DNA plays a role in aging, and some circumstantial evidence exists in favor of such hypothesis (Hamilton et al., 2001). Damage from free radicals to nuclear DNA remains an unproven cause of aging but since ROS originate in the mitochondria, and since mitochondria possess their own genome, many advocates of the free radical theory of aging consider that oxidative damage to mitochondria and the mitochondrial DNA (mtDNA) is more important (Harman, 1972; Linnane et al., 1989; de Grey, 1997; Barja, 2002). Indeed, some evidence exists that under CR oxidative damage to mtDNA is more important than oxidative damage to nuclear DNA (reviewed in Barja, 2002). At present, and despite contradictory evidence in favor (Khaidakov et al., 2003 for arguments) and against the theory (Rasmussen et al., 2003 for arguments), current technology does not appear capable of assessing the true relevance of damage to mtDNA in aging (Lightowlers et al., 1999; DiMauro et al., 2002). Interestingly, disruption of the mitochondrial DNA polymerase resulted in an accelerated aging phenotype, for the first time directly implicating the mtDNA in aging (Trifunovic et al., 2004). This appears to be unrelated to oxidative damage but instead result from increased apoptosis and accumulated mtDNA damage (Kujoth et al., 2005). As such, mtDNA may play a role in age-related diseases and aging, though much research remains to confirm such hypothesis and elucidate the exact mechanisms involved.
Animal cloning involving somatic cells to create new organisms is an interesting technique for gerontologists (e.g., Lanza et al., 2000; Yang and Tian, 2000). Clones from adult frogs do not show signs that differentiation affects the genome (Gurdon et al., 1975). Dolly was "created" by transferring the DNA-containing nucleus of a post-mitotic mammary cell into an egg and from there a whole new organism was formed. We know Dolly had some genetic (Shiels et al., 1999) and epigenetic defects (Young et al., 2001), so maybe her arthritis and the pathologies leading to her death are a result of damage present in the DNA, perhaps in the telomeres. Nonetheless, she was remarkably "normal," having endured a complete developmental process and being fertile (Wilmut et al., 1997). Moreover, mice have been cloned for six generations without apparent harm (Wakayama et al., 2000). Perhaps the highly proliferative nature of the embryo can, by recombination, dilute the errors present in the DNA, but results from cloning experiments suggest that at least some cells in the body do not accumulate great amounts of DNA damage. It will be interesting to see the longevity of more cloned animals.
If progeroid syndromes represent a phenotype of accelerated aging then changes in DNA over time likely play a role in aging. Nevertheless, the essence of those changes remains to be determined. Since many genetic perturbations affecting DNA repair do not influence aging, it is doubtful overall DNA repair is related to aging or that DNA damage accumulation alone drives aging. Understanding which aspects, if any, of DNA biology play a role in aging remains a great challenge in gerontology. The next step to give strength to this theory would be to delay aging in mice based on enhanced DNA repair systems, but that has so far eluded researchers. In conclusion, changes in DNA over time might play some kind a role in aging, but the essence of those changes and the exact mechanisms involved remain to be determined.
Thank you for the in depth reply, Kurosaki, I very much enjoyed reading it. Did you type this for a college course?
My first presumtion with aging was that it had to somehow be directly controlled by the genetic code. The DNA would be coded in such a ways as to force a physiological reaction of the body to time. That would suggest that our genetic code is somehow time-conscious, in a sense.
Is there an actual link between aging and longevity then? If longevity can be increased or decreased without effecting aging, should it not be possible to stall death for some hundred years while the aging process continues (I can imagine that aging over such a period of time wouldn't be aesthetically pleasing, but it's beside the point)?
Moreover, if we were able to stop the aging process, would it favorably effect longevity at all? I could remain my age physically whilst my body would still suffer the damage that would cause the inevitable death over what the average lifespan is today. I could, say, look 22, but die at 80 years of age.
I suppose that's the prime question then, which i'll reiterate: Is aging and longevity linked? (I always USED to think that aging was one cause of natural death, which i'm rethinking as of now).
A man who is doing a lot of work on the subject:
http://www.ted.com/index.php/talks/v...FR-YWAodh3xl9g
If you are religious, you likely are going to support death, or even have no fear of it.
Is aging a disease?
Not in my opinion.
I was thinking... what would happen if everyone could live as long as they like...
Suicide would be so prominent. At 300 years old, even if you could possibly retain a youthful image, would you want to continue living?
There would come a point that you would just stop.
Stop wanting things.
Death would no longer be an obstacle.
It would be embraced.
Eventually,there would be no materialism, there would be no attachment.
Is dying such a bad thing?
No.
The fear that is generated from it is a barrier, though.
Submit to your nature and die.