Everything about Premature Aging totally explained
Senescence refers to the biological processes of a living
organism approaching an advanced age (for example, the combination of processes of deterioration which follow the period of development of an organism). The word
senescence is derived from the Latin word
senex, meaning "old man" or "old age" or "advanced in age".
Cellular senescence
Cellular senescence is the phenomenon where normal diploid differentiated
cells lose the ability to divide after about 50 cell divisions. This phenomenon is also known as "replicative senescence", the "Hayflick phenomenon", or the
Hayflick limit in honour of
Dr. Leonard Hayflick who was the first to publish this information in 1965. In response to
DNA damage (including shortened
telomeres) cells either age or self-destruct (
apoptosis,
programmed cell death) if the damage can't be repaired. In this 'cellular suicide', the death of one, or more, cells may benefit the organism as a whole. For example, in plants the death of the water-conducting
xylem cells (
tracheids and
vessel elements) allows the cells to function more efficiently and so deliver water to the upper parts of a plant.
Aging of the whole organism
Organismal senescence is the aging of whole organisms. The term
aging has become so commonly equated with
senescence that the terms will be used interchangeably in this article.
Aging is generally characterized by the declining ability to respond to stress, increasing
homeostatic imbalance and increased risk of
aging-associated diseases. Because of this,
death is the ultimate consequence of aging. Differences in
maximum life span between species correspond to different "rates of aging". For example,
inherited differences in the rate of aging make a
mouse elderly at 3 years and a
human elderly at 90 years. These genetic differences affect a variety of physiological processes, including the efficiency of
DNA repair,
antioxidant enzymes, and rates of
free radical production.
Senescence of the organism gives rise to the
Gompertz-Makeham law of mortality, which says that
mortality rate rises rapidly with age.
Some animals, such as some reptiles and fish, age slowly. Some even exhibit "negative senescence", in which mortality falls with age, in disagreement with the Gompertz-Makeham "law".
Theories of aging
The process of senescence is complex, and may derive from a variety of different mechanisms and exist for a variety of different reasons. However, senescence isn't universal, and scientific evidence suggests that cellular senescence evolved in certain
species as a mechanism to prevent the onset of
cancer. In a few simple species, senescence is negligible and can't be detected. All such species have no "post-
mitotic" cells; they reduce the effect of damaging
free radicals by cell division and dilution. Such species are not immortal, however, as that'll eventually fall prey to
trauma or
disease. Moreover, average lifespans can vary greatly within and between
species. This suggests that both
genetic and environmental factors contribute to aging.
Traditionally, theories that explain senescence have generally been divided between the programmed and
stochastic theories of aging. Programmed theories imply that aging is regulated by biological clocks operating throughout the life span. This regulation would depend on changes in
gene expression that affect the systems responsible for maintenance, repair and defense responses. Stochastic theories blame environmental impacts on living organisms that induce cumulative damage at various levels as the cause of aging, examples which range from damage to
DNA, damage to tissues and cells by oxygen
radicals (widely known as
free radicals countered by the even more well known
antioxidants), and
cross-linking.
Conversely, aging is seen as a progressive failure of
homeodynamics (homeostasis) involving genes for the maintenance and repair, stochastic events leading to molecular damage and molecular heterogeneity, and chance events determining the probability of death. Since complex and interacting systems of maintenance and repair comprise the homeodynamic (old term, homeostasis) space of a biological system, aging is considered to be a progressive shrinkage of homeodynamic space mainly due to increased molecular heterogeneity.
Evolutionary theories
Aging is believed to have evolved because of the increasingly smaller probability of an organism still being alive at older age, due to predation and accidents, both of which may be random and age-invariant. It is thought that strategies which result in a higher reproductive rate at a young age, but shorter overall lifespan, result in a higher lifetime reproductive success and are therefore favoured by
natural selection. Essentially, aging is therefore the result of investing resources in reproduction, rather than maintenance of the body (the "Disposable Soma" theory), in light of the fact that accidents, predation and disease will eventually kill the organism no matter how much energy is devoted to repair of the body. Various other, or more specific, theories of ageing exist, and are not necessarily mutually exclusive.
The geneticist
J. B. S. Haldane wondered why the dominant mutation which causes
Huntington's disease remained in the population, why natural selection hadn't eliminated it. The onset of this neurological disease is (on average) at age 45 and is invariably fatal within 10-20 years. Haldane assumed, probably reasonably, that in human prehistory, few survived until age 45. Since few were alive at older ages and their contribution to the next generation was therefore small relative to the large cohorts of younger age groups, the force of selection against such late-acting deleterious mutations was correspondingly small. However if a mutation affected younger individuals, selection against it would be strong. Therefore, late-acting deleterious mutations could accumulate in populations over evolutionary time through
genetic drift. This principle has been demonstrated experimentally. And it's these later-acting deleterious mutations which are believed to cause, or perhaps more correctly allow, age-related mortality.
Peter Medawar formalised this observation in his
mutation accumulation theory of ageing . "The force of natural selection weakens with increasing age — even in a theoretically immortal population, provided only that it's exposed to real hazards of mortality. If a genetic disaster... happens late enough in individual life, its consequences may be completely unimportant". The 'real hazards of mortality' are typically predation, disease and accidents. So, even an immortal population, whose fertility doesn't decline with time, will have fewer individuals alive in older age groups. This is called '
extrinsic mortality.' Young cohorts, not depleted in numbers yet by
extrinsic mortality, contribute far more to the next generation than the few remaining older cohorts, so the force of selection against late-acting deleterious mutations, which only affect these few older individuals, is very weak. The mutations may not be selected against, therefore, and may spread over evolutionary time into the population.
The major testable prediction made by this model is that species which have high
extrinsic mortality in nature will age more quickly and have shorter
intrinsic lifespans. This is borne out among mammals, the most well studied in terms of life history. There is a correlation among mammals between body size and
lifespan, such that larger species live longer than smaller species in controlled/optimum conditions, but there are notable exceptions. For instance, many bats and rodents are similarly sized, yet bats live much, much longer. For instance, the
little brown bat, half the size of a
mouse, can live 30 years in the wild. A mouse will live 2–3 years even with optimum conditions. The explanation is that bats have fewer predators, so therefore low
extrinsic mortality. Thus more individuals survive to later ages so the force of selection against late-acting deleterious mutations is stronger. Fewer late-acting deleterious mutations = slower ageing = longer lifespan. Birds are also warm-blooded and similarly sized to many small mammals, yet live often 5–10 times as long. They clearly have fewer predation pressures compared with ground-dwelling mammals. And
seabirds, which generally have the fewest predators of all birds, live longest.
Also, when examining the body-size vs. lifespan relationship, predator mammals tend to have longer lifespans than prey animals in a controlled environment such as a zoo or nature reserve. The explanation for the long lifespans of primates (such as humans, monkeys and apes) relative to body size is that their intelligence and often sociality helps them avoid becoming prey. Being a predator, being smart and working together all reduce
extrinsic mortality.
Another evolutionary theory of ageing was proposed by
George C. Williams (Williams 1957) and involves antagonistic
pleiotropy. A single gene may affect multiple traits. Some traits that increase fitness early in life may also have negative effects later in life. But because many more individuals are alive at young ages than at old ages, even small positive effects early can be strongly selected for, and large negative effects later may be very weakly selected against. Williams suggested the following example: perhaps a gene codes for calcium deposition in bones which promotes juvenile survival and will therefore be favored by natural selection; however this same gene promotes calcium deposition in the arteries, causing negative effects in old age. Therefore negative effects in old age may reflect the result of natural selection for
pleiotropic genes which are beneficial early in life. In this case, fitness is relatively high when
Fisher's reproductive value is high and relatively low when
Fisher's reproductive value is low.
Gene regulation
A number of genetic components of aging have been identified using model organisms, ranging from the simple budding
yeast Saccharomyces cerevisiae to worms such as
Caenorhabditis elegans and
fruit flies (
Drosophila melanogaster). Study of these organisms has revealed the presence of at least two conserved aging pathways.
One of these pathways involves the gene
Sir2, a
NAD+-dependent histone deacetylase. In yeast, Sir2 is required for genomic silencing at three loci: the yeast mating
loci, the
telomeres and the
ribosomal DNA (rDNA). In some species of yeast replicative aging may be partially caused by
homologous recombination between rDNA repeats;
excision of rDNA repeats results in the formation of extrachromosomal rDNA circles (ERCs). These ERCs replicate and preferentially segregate to the mother cell during cell division, and are believed to result in cellular senescence by
titrating away (competing for) essential
nuclear factors. ERCs have not been observed in other species of yeast (which also display replicative senescence), and ERCs are not believed to contribute to aging in higher organisms such as humans. Extrachromosomal circular DNA (eccDNA) has been found in worms, flies and humans. The role of eccDNA in aging, if any, is unknown.
Despite the lack of a connection between circular DNA and
aging in higher organisms, extra copies of Sir2 are capable of extending the lifespan of both worms and flies. The mechanisms by which Sir2 homologues in higher organisms regulate lifespan is unclear, but the human SIRT1 protein has been demonstrated to
deacetylate p53, Ku70, and the
forkhead family of
transcription factors. SIRT1 can also regulate acetylates such as
CBP/p300, and has been shown to deacetylate specific
histone residues.
RAS1 and RAS2 also affect aging in yeast and have a human homologue. RAS2 overexpression has been shown to extend lifespan in yeast.
Other genes regulate aging in yeast by increasing the resistance to
oxidative stress.
Superoxide dismutase, a
protein that protects against the effects of
mitochondrial free
radicals, can extend yeast lifespan in stationary phase when overexpressed.
In higher organisms, aging is likely to be regulated in part through the insulin/IGF-1 pathway. Mutations that affect
insulin-like signaling in worms, flies and mice are associated with extended lifespan. In yeast, Sir2 activity is regulated by the nicotinamidase PNC1. PNC1 is transcriptionally
upregulated under stressful conditions such as
caloric restriction,
heat shock, and
osmotic shock. By converting
nicotinamide to
niacin, it removes nicotinamide, which inhibits the activity of Sir2. A
nicotinamidase found in humans, known as
PBEF, may serve a similar function, and a secreted form of PBEF known as
visfatin may help to regulate serum
insulin levels. It isn't known, however, whether these mechanisms also exist in humans since there are obvious differences in biology between humans and model organisms.
Sir2 activity has been shown to increase under calorie restriction. Due to the lack of available glucose in the cells more NAD+ is available and can activate Sir2.
Resveratrol, a
polyphenol found in the skin of red
grapes, was reported to extend the lifespan of yeast, worms, and flies. It has been shown to activate Sir2 activity and therefore mimics the effects of calorie restriction.
Gene expression is imperfectly controlled, and it's possible that random fluctuations in the expression levels of many genes contribute to the aging process (Ryley, J. 2006). Individual cells, which are genetically identical, none-the-less can have substantially different responses to outside stimuli, and markedly different lifespans, indicating the epigenetic factors play an important role in gene expression and aging as well as genetic factors.
This is a list of
confirmed longevity genes from
model animals.
The major genetic model organisms used in aging research are the filamentous fungus (
Podospora anserina), bakers' yeast (
Saccharomyces cerevisiae), the soil roundworm (
Caenorhabditis elegans), the fruit fly (
Drosophila melanogaster), and the mouse (
Mus musculus).
Cellular senescence
As noted above, senescence isn't universal, and senescence isn't observed in single-celled organisms that reproduce through the process of cellular
mitosis . Moreover, cellular senescence isn't observed in many organisms, including
perennial plants,
sponges,
corals, and
lobsters. In those species where cellular senescence is observed, cells eventually become post-
mitotic when they can no longer replicate themselves through the process of
cellular mitosis -- for example, cells experience
replicative senescence. How and why some cells become post-mitotic in some species has been the subject of much research and speculation, but (as noted above) it's widely believed that cellular senescence evolved as a way to prevent the onset and spread of
cancer.
Somatic cells that have divided many times will have accumulated
DNA mutations and would therefore be in danger of becoming
cancerous if cell division continued.
Lately the role of
telomeres in cellular senescence has aroused general interest, especially with a view to the possible genetically adverse effects of
cloning. The successive shortening of the
chromosomal telomeres with each
cell cycle is also believed to limit the number of divisions of the cell, thus contributing to aging. There have, on the other hand, also been reports that cloning could alter the shortening of telomeres. Some cells don't age and are therefore described as being "
biologically immortal." It is theorized by some that when it's discovered exactly what allows these cells, whether it be the result of telomere lengthening or not, to divide without limit that it'll be possible to genetically alter other cells to have the same capability. It is further theorized that it'll eventually be possible to
genetically engineer all cells in the human body to have this capability by employing
gene therapy and thereby stop or reverse aging, effectively making the entire organism potentially immortal.
Cancer cells are usually immortal. This evasion of cellular senescence is the result, in about 85% of tumors, of up-activation of their
telomerase genes . This simple observation suggests that reactivation of telomerases in healthy individuals could greatly increase their cancer risk.
Chemical damage
The earliest aging theory was the
Rate of Living Hypothesis described by
Raymond Pearl in 1928, based on the idea that fast
basal metabolic rate corresponds to short
maximum life span (much as a rapidly running machine will experience more damage from wear). (The idea had been posited earlier by
Max Rubner).
While there's likely some validity to this theory, in the form of various types of specific damage detailed below which, all other things being equal may reduce lifespan, in general this theory doesn't adequately explain the differences in lifespan either within, or between, species. Calorically-restricted animals process as much, or more, calories per gram of body mass, as their
ad libitum fed counterparts, yet exhibit substantially longer lifespans. Similarly, metabolic rate is a poor predictor of lifespan for birds, bats and other species which presumably have reduced mortality from predation, and therefore have evolved long lifespans even in the presence of very high metabolic rates.
With respect to specific types of chemical damage caused by metabolism, it's suggested that damage to long-lived
biopolymers, such as structural
proteins or
DNA, caused by ubiquitous chemical agents in the body such as
oxygen and
sugars, are in part responsible for aging. The damage can include breakage of biopolymer chains,
cross-linking of biopolymers, or chemical attachment of unnatural substituents (
haptens) to biopolymers.
Under normal
aerobic conditions, approximately 4% of the
oxygen metabolized by
mitochondria is converted to
superoxide ion which can subsequently be converted to
hydrogen peroxide,
hydroxyl radical and eventually other reactive species including other
peroxides and
singlet oxygen, which can in turn generate
free radicals capable of damaging structural proteins and DNA. Certain metal
ions found in the body, such as
copper and
iron, may participate in the process. (In
Wilson's disease, a
hereditary defect which causes the body to retain copper, some of the symptoms resemble accelerated senescence.) These processes are termed
oxidative damage and are linked to the benefits of nutritionally derived
polyphenol antioxidants .
Sugars such as
glucose and
fructose can react with certain
amino acids such as
lysine and
arginine and certain DNA bases such as
guanine to produce sugar adducts, in a process called
glycation. These adducts can further rearrange to form reactive species which can then cross-link the structural proteins or DNA to similar biopolymers or other biomolecules such as non-structural proteins. People with
diabetes, who have elevated
blood sugar, develop senescence-associated disorders much earlier than the general population, but can delay such disorders by rigorous control of their blood sugar levels. There is evidence that sugar damage is linked to oxidant damage in a process termed
glycoxidation.
Free radicals can damage
proteins,
lipids or
DNA.
Glycation mainly damages proteins. Damaged proteins and lipids accumulate in
lysosomes as
lipofuscin. Chemical damage to structural proteins can lead to loss of function; for example, damage to
collagen of
blood vessel walls can lead to vessel-wall stiffness and thus
hypertension, and vessel wall thickening and reactive tissue formation (
atherosclerosis); similar processes in the
kidney can lead to
renal failure. Damage to
enzymes reduces cellular functionality.
Lipid peroxidation of the inner
mitochondrial membrane reduces the
electric potential and the ability to generate energy. It is probably no accident that nearly all of the so-called "
accelerated aging diseases" are due to defective
DNA repair enzymes.
It is believed that the
impact of alcohol on aging can be partly explained by alcohol's activation of the
HPA axis, which stimulates
glucocorticoid secretion; long-term exposure to which produces symptoms of aging.
Reliability theory
Reliability theory suggests that biological systems start their adult life with a high load of initial damage. Reliability theory is a general theory about systems failure. It allows researchers to predict the age-related failure kinetics for a system of given architecture (
reliability structure) and given reliability of its components. Reliability theory predicts that even those systems that are entirely composed of non-aging elements (with a constant
failure rate) will nevertheless deteriorate (fail more often) with age, if these systems are redundant in irreplaceable elements. Aging, therefore, is a direct consequence of systems
redundancy.
Reliability theory also predicts the
late-life mortality deceleration with subsequent leveling-off, as well as the late-life mortality plateaus, as an inevitable consequence of
redundancy exhaustion at extreme old ages. The theory explains why mortality rates increase exponentially with age (the
Gompertz law) in many species, by taking into account the initial flaws (defects) in newly formed systems. It also explains why organisms "prefer" to die according to the
Gompertz law, while technical devices usually fail according to the
Weibull (power) law. Reliability theory allows to specify conditions when organisms die according to the
Weibull law: organisms should be relatively free of initial flaws and defects. The theory makes it possible to find a general failure law applicable to all adult and extreme old ages, where the Gompertz and the Weibull laws are just special cases of this more general failure law. The theory explains why relative differences in mortality rates of compared populations (within a given species) vanish with age (
compensation law of mortality), and mortality convergence is observed due to the exhaustion of initial differences in redundancy levels.
Neuro-endocrine-immunological theories
Senescence may also simply be a result of wear and tear overwhelming repair mechanisms. It is also possible that senescence is a mechanism to control the development and spread of
cancer; if cells have built-in limits to how many times they can replicate, they must somehow overcome this before they can spread indefinitely.
Miscellaneous
Recently, early senescence has been alleged to be a possible unintended outcome of early
cloning experiments. Most notably, the issue was raised in the case of
Dolly the sheep, following her death from a contagious lung disease. The claim that Dolly's early death involved premature senescence has been vigorously contested (for example by
Kerry Lynn Macintosh in her book,
Illegal Beings: Human Clones and the Law), and Dolly's creator,
Dr. Ian Wilmut has expressed the view that her illness and death were probably unrelated to the fact that she was a clone.
A set of rare hereditary (
genetic) disorders, each called
progeria, has been known for some time. Sufferers exhibit symptoms resembling
accelerated aging, including wrinkled skin. The cause of
Hutchinson–Gilford progeria syndrome was reported in the journal
Nature in May 2003. This report suggests that
DNA damage, not
oxidative stress, is the cause of this form of accelerated aging.
Further Information
Get more info on 'Premature Aging'.
|
External Link Exchanges
Do you know how hard it is to get a link from a large encyclopaedia? Well we're different and will prove it. To get a link from us just add the following HTML to your site on a relevant page:
<a href="http://senescence.totallyexplained.com">Senescence Totally Explained</a>
Then simply click through this link from your web page. Our crawlers will verify your link, extract the title of your web page and instantly add a link back to it. If you like you can remove the words Totally Explained and embed the link in article text.
As long as your link remains in place, we'll keep our link to you right here. Please play fair - our crawlers are watching. Your site must be closely related to this one's topic. Any kind of spamming, dubious practises or removing the link will result in your link from us being dropped and, potentially, your whole site being banned. |
