Senescence
Encyclopedia
Senescence or biological aging is the change in the biology of an organism
as it ages after its maturity. Such changes range from those affecting its cells and their function to those affecting the whole organism. There are a number of theories as to why senescence occurs; for example, some posit it is programmed by gene expression changes, others that it is the cumulative damage caused by biological processes.
Senescence is not the inevitable fate of all organisms. A variety of organisms, including some cold-blooded
animals, have negligible senescence
. This fact, and recent scientific successes in rejuvenation and extending the lifespan of
model animals
(mice, 2.5 times; yeast, 15 times; nematodes, 10 times) have inspired hope that aging may similarly be canceled, reversed or at least significantly delayed in humans.
The word senescence is derived from the Latin word senex, meaning old man, old age, or advanced in age.
Cellular senescence is the phenomenon by which normal diploid cells
lose the ability to divide
, normally after about 50 cell divisions in vitro
. Some cells become senescent after fewer replications cycles as a result of DNA double strand breaks, toxins, etc. This phenomenon is also known as "replicative senescence", the "Hayflick phenomenon", or the Hayflick limit
in honour of Dr. Leonard Hayflick
, co-author with Paul Moorhead, of the first paper describing it in 1961.. In response to DNA
damage (including shortened telomere
s), cells either age or self-destruct (apoptosis
, programmed cell death
) if the damage cannot be easily repaired. In this 'cellular suicide', the death of one cell, or more, may benefit the organism as a whole. For example, in plants the death of the water-conducting xylem
cells (tracheid
s and vessel element
s) allows the cells to function more efficiently and so deliver water to the upper parts of a plant. The ones that do not self-destruct remain until destroyed by outside forces.
In general, aging is characterized by the declining ability to respond to stress, increased homeostatic
imbalance, and increased risk of aging-associated diseases
. Death
is the ultimate consequence of aging, though "old age" is not a scientifically recognized cause of death
because there is always a specific proximal cause, such as cancer
, heart disease
, or liver failure
. Aging of whole organisms is therefore a complex process that can be defined as "a progressive deterioration of physiological function, an intrinsic age-related process of loss of viability and increase in vulnerability".
Differences in maximum life span
among 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 80 years. These genetic differences affect a variety of physiological processes, including the efficiency of DNA repair
, antioxidant
enzyme
s, 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 (negligible senescence
) and exhibit very long lifespans. Some even exhibit "negative senescence", in which mortality falls with age, in disagreement with the Gompertz–Makeham "law".
Whether replicative senescence (Hayflick limit) plays a causative role in organismal aging is at present an active area of investigation.
because it prevents the onset of cancer
. In a few simple species, such as Hydra
, senescence is negligible
and cannot 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 they will 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.
In general, theories that explain senescence have been divided between the programmed and stochastic
theories of aging. Programmed theories imply that aging is regulated by biological clocks operating throughout the lifespan. This regulation would depend on changes in gene expression
that affect the systems responsible for maintenance, repair, and defense responses. The Reproductive-Cell Cycle Theory
suggests that aging is caused by changes in hormonal signaling over the lifespan. Stochastic theories blame environmental impacts on living organisms that induce cumulative damage at various levels as the cause of aging, examples of which ranging 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.
However, 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.
. In essence, 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 theories of aging exist, and are not necessarily mutually exclusive.
The geneticist J. B. S. Haldane
wondered why the dominant mutation that causes Huntington's disease
remained in the population, and why natural selection had not eliminated it. The onset of this neurological disease is (on average) at age 45 and is invariably fatal within 10–20 years. Haldane assumed 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 is these later-acting deleterious mutations that are believed to allow—even cause—age-related mortality.
Peter Medawar
formalised this observation in his mutation accumulation theory of aging. "The force of natural selection weakens with increasing age—even in a theoretically immortal population, provided only that it is 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, in typical circumstances, predation, disease, and accidents. So, even an immortal population, whose fertility does not 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 affect only 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 that have high extrinsic mortality in nature will age more quickly and have shorter intrinsic lifespans. This is borne out among mammals, the best-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 under controlled/optimum conditions, but there are notable exceptions. For instance, many bats and rodents are of similar size, yet bats live much longer. For instance, the little brown bat
, half the size of a mouse
, can live 30 years in the wild. A mouse will only live 2–3 years even under optimum conditions. The explanation is that bats have fewer predators, and therefore low extrinsic mortality. More individuals survive to later ages, so the force of selection against late-acting deleterious mutations is stronger. Fewer late-acting deleterious mutations equates to slower aging and therefore a longer lifespan. Birds are also warm-blooded and are similar in size to many small mammals, yet often live 5–10 times as long. They have less predation pressure than ground-dwelling mammals. Seabird
s, which, in general, have the fewest predators of all birds, live longest.
When examining the body-size vs. lifespan relationship, one also observes that predatory mammals tend to live longer than prey mammals 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 their sociality, help them avoid becoming prey. Being a predator, being smart, and working together all reduce extrinsic mortality.
Another evolutionary theory of aging was proposed by George C. Williams
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. Thus, harmful biological changes in old age may result from selection for pleiotropic
genes that are beneficial early in life but harmful later on. In this case, fitness is relatively high when Fisher's reproductive value
is high and relatively low when Fisher's reproductive value
is low.
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 telomere
s 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 circle
s (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 (nor even all strains of the same yeast species) of yeast (which also display replicative senescence), and ERCs are not believed to contribute to aging in higher organisms such as humans (they have not been shown to accumulate in mammals in a similar manner to yeast). Extrachromosomal circular DNA (eccDNA) has been found in worms, flies, and humans. The origin and 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 (though, in flies, this finding has not been replicated by other investigators, and the activator of Sir2 resveratrol
does not reproducibly increase lifespan in either species). Whether the Sir2 homologues in higher organisms have any role in lifespan is unclear, but the human SIRT1 protein has been demonstrated to deacetylate p53
, Ku70, and the forkhead family of transcription factor
s. 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 the growth hormone/IGF1 axis in 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
, nicotinamide is removed, inhibiting 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 is not 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 stilbenoid found in the skin of red grape
s, was reported to extend the lifespan of yeast, worms, and flies (the lifespan extension in flies and worms have proved irreproducible by independent investigators). It has been shown to activate Sir2 and therefore mimics the effects of calorie restriction, if one accepts that caloric restriction is indeed dependent on Sir2.
Gene expression is imperfectly controlled, and it is possible that random fluctuations in the expression levels of many genes contribute to the aging process as suggested by a study of such genes in yeast. 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.
According to the GenAge database of aging-related genes there are over 700 genes associated with aging in model organisms: 555 in the soil roundworm (Caenorhabditis elegans
), 87 in the bakers' yeast (Saccharomyces cerevisiae
), 75 in the fruit fly (Drosophila melanogaster
) and 68 in the mouse (Mus musculus).
The following is a list of genes connected to longevity through research on model organisms:
. Moreover, cellular senescence is not observed in several organisms, including perennial plants, sponge
s, coral
s, and lobster
s. 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
; i.e., 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 is 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
mutation
s and would therefore be in danger of becoming cancer
ous if cell division continued.
Lately, the role of telomere
s 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 do not age and are, therefore, described as being "biologically immortal
". It is theorized by some that when it is discovered exactly what allows these cells, whether it be the result of telomere lengthening or not, to divide without limit that it will be possible to genetically alter other cells to have the same capability. It is further theorized that it will eventually be possible to genetically engineer
all cells in the human body to have this capability by employing gene therapy
and, therefore, stop or reverse aging, effectively making the entire organism potentially immortal.
The length of the telomere strand has senescence effects, telomere shortening activate extensive alterations in alternative RNA splicing that produce senescence toxins such as progerin
that degrades the tissue and makes it more susceptible to failure.
Cancer
cells are usually immortal. In about 85% of tumors, this evasion of cellular senescence is the result of up-activation of their telomerase
genes. This simple observation suggests that reactivation of telomerase in healthy individuals could greatly increase their cancer risk.
Whether cell senescence plays any role in organismal aging is at present unknown, and is an active area of investigation. Mouse mutants lacking telomerase do not immediately show accelerated aging.
One of the earliest aging theories was the Rate of Living Hypothesis described by Raymond Pearl
in 1928(based on earlier work by Max Rubner
), which states that fast basal metabolic rate
corresponds to short maximum life span
.
While there may be some validity to the idea that for various types of specific damage detailed below that are by-products of metabolism, all other things being equal, a fast metabolism may reduce lifespan, in general this theory does not 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 that, it is presumed, have reduced mortality from predation, and therefore have evolved long lifespans even in the presence of very high metabolic rates. More recently, it was shown that, when modern statistical methods for correcting for the effects of body size and phylogeny are employed, metabolic rate does not correlate with longevity in mammals or birds. (For a critique of the Rate of Living Hypothesis see Living fast, dying when?)
With respect to specific types of chemical damage caused by metabolism, it is suggested that damage to long-lived biopolymer
s, such as structural protein
s or DNA
, caused by ubiquitous chemical agents in the body such as oxygen
and sugar
s, are in part responsible for aging. The damage can include breakage of biopolymer chains, cross-linking of biopolymers, or chemical attachment of unnatural substituents (hapten
s) 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 peroxide
s and singlet oxygen
, which can, in turn, generate free radical
s capable of damaging structural proteins and DNA. Certain metal ion
s found in the body, such as copper
and iron
, may participate in the process. (In Wilson's disease
, a hereditary defect
that 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 antioxidant
s .
Sugar
s such as glucose
and fructose
can react with certain amino acid
s 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 protein
s, lipids or DNA
. Glycation
mainly damages proteins. Damaged proteins and lipids accumulate in lysosome
s 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 enzyme
s 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 disease
s" 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.
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 composed entirely 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.
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 distribution: 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.
experiments. 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, 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.
Organism
In biology, an organism is any contiguous living system . In at least some form, all organisms are capable of response to stimuli, reproduction, growth and development, and maintenance of homoeostasis as a stable whole.An organism may either be unicellular or, as in the case of humans, comprise...
as it ages after its maturity. Such changes range from those affecting its cells and their function to those affecting the whole organism. There are a number of theories as to why senescence occurs; for example, some posit it is programmed by gene expression changes, others that it is the cumulative damage caused by biological processes.
Senescence is not the inevitable fate of all organisms. A variety of organisms, including some cold-blooded
Poikilotherm
A poikilotherm is an organism whose internal temperature varies considerably. It is the opposite of a homeotherm, an organism which maintains thermal homeostasis. Usually the variation is a consequence of variation in the ambient environmental temperature...
animals, have negligible senescence
Negligible senescence
Negligible senescence refers to the failure of a few select animals to display symptoms of aging. More specifically, negligibly senescent animals do not have measurable reductions in their reproductive capability with age, or measurable functional decline with age. Death rates in negligibly...
. This fact, and recent scientific successes in rejuvenation and extending the lifespan of
model animals
Model organism
A model organism is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the organism model will provide insight into the workings of other organisms. Model organisms are in vivo models and are widely used to...
(mice, 2.5 times; yeast, 15 times; nematodes, 10 times) have inspired hope that aging may similarly be canceled, reversed or at least significantly delayed in humans.
The word senescence is derived from the Latin word senex, meaning old man, old age, or advanced in age.
Cellular senescence
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
lose the ability to divide
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
, normally after about 50 cell divisions in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
. Some cells become senescent after fewer replications cycles as a result of DNA double strand breaks, toxins, etc. This phenomenon is also known as "replicative senescence", the "Hayflick phenomenon", or the Hayflick limit
Hayflick limit
The Hayflick limit is the number of times a normal cell population will divide before it stops, presumably because the telomeres reach a critical length....
in honour of Dr. Leonard Hayflick
Leonard Hayflick
Leonard Hayflick , Ph.D., is Professor of Anatomy at the University of California, San Francisco, School of Medicine, and was Professor of Medical Microbiology at Stanford University School of Medicine. He is a past president of the Gerontological Society of America and was a founding member of the...
, co-author with Paul Moorhead, of the first paper describing it in 1961.. In response to DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
damage (including shortened telomere
Telomere
A telomere is a region of repetitive DNA sequences at the end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Its name is derived from the Greek nouns telos "end" and merοs "part"...
s), cells either age or self-destruct (apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, programmed cell death
Programmed cell death
Programmed cell-death is death of a cell in any form, mediated by an intracellular program. PCD is carried out in a regulated process which generally confers advantage during an organism's life-cycle...
) if the damage cannot be easily repaired. In this 'cellular suicide', the death of one cell, or more, may benefit the organism as a whole. For example, in plants the death of the water-conducting xylem
Xylem
Xylem is one of the two types of transport tissue in vascular plants. . The word xylem is derived from the Classical Greek word ξυλον , meaning "wood"; the best-known xylem tissue is wood, though it is found throughout the plant...
cells (tracheid
Tracheid
Tracheids are elongated cells in the xylem of vascular plants that serve in the transport of water and mineral salts. Tracheids are one of two types of tracheary elements, vessel elements being the other. All tracheary elements develop a thick lignified cell wall, and at maturity the protoplast...
s and vessel element
Vessel element
A vessel element is one of the cell types found in xylem, the water conducting tissue of plants. Vessel elements are typically found in the angiosperms but absent from most gymnosperms such as the conifers....
s) allows the cells to function more efficiently and so deliver water to the upper parts of a plant. The ones that do not self-destruct remain until destroyed by outside forces.
Aging of the whole organism
Organismal senescence is the aging of whole organisms.In general, aging is characterized by the declining ability to respond to stress, increased homeostatic
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
imbalance, and increased risk of aging-associated diseases
Aging-associated diseases
An aging-associated disease is a disease that is seen with increasing frequency with increasing senescence. Age-associated diseases are to be distinguished from the aging process itself because all adult animals age, but not all adult animals experience all age-associated diseases...
. Death
Death
Death is the permanent termination of the biological functions that sustain a living organism. Phenomena which commonly bring about death include old age, predation, malnutrition, disease, and accidents or trauma resulting in terminal injury....
is the ultimate consequence of aging, though "old age" is not a scientifically recognized cause of death
Cause of Death
Cause of Death is a 1990 album by American death metal band Obituary. Cause of Death is considered a classic album in the history of death metal. The artwork was done by artist Michael Whelan...
because there is always a specific proximal cause, such as cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
, heart disease
Heart disease
Heart disease, cardiac disease or cardiopathy is an umbrella term for a variety of diseases affecting the heart. , it is the leading cause of death in the United States, England, Canada and Wales, accounting for 25.4% of the total deaths in the United States.-Types:-Coronary heart disease:Coronary...
, or liver failure
Liver failure
Acute liver failure is the appearance of severe complications rapidly after the first signs of liver disease , and indicates that the liver has sustained severe damage . The complications are hepatic encephalopathy and impaired protein synthesis...
. Aging of whole organisms is therefore a complex process that can be defined as "a progressive deterioration of physiological function, an intrinsic age-related process of loss of viability and increase in vulnerability".
Differences in maximum life span
Maximum life span
Maximum life span is a measure of the maximum amount of time one or more members of a population has been observed to survive between birth and death.Most living species have at least one upper limit on the number of times cells can divide...
among species correspond to different "rates of aging". For example, inherited differences in the rate of aging make a mouse
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...
elderly at 3 years and a human
Human
Humans are the only living species in the Homo genus...
elderly at 80 years. These genetic differences affect a variety of physiological processes, including the efficiency of DNA repair
DNA repair
DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
, antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...
enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s, and rates of free radical
Free-radical theory
The free-radical theory of aging states that organisms age because cells accumulate free radical damage over time. A free radical is any atom or molecule that has a single unpaired electron in an outer shell. While a few free radicals such as melanin are not chemically reactive, most...
production.
Mortality rate
Mortality rate is a measure of the number of deaths in a population, scaled to the size of that population, per unit time...
rises rapidly with age.
Some animals, such as some reptiles and fish, age slowly (negligible senescence
Negligible senescence
Negligible senescence refers to the failure of a few select animals to display symptoms of aging. More specifically, negligibly senescent animals do not have measurable reductions in their reproductive capability with age, or measurable functional decline with age. Death rates in negligibly...
) and exhibit very long lifespans. Some even exhibit "negative senescence", in which mortality falls with age, in disagreement with the Gompertz–Makeham "law".
Whether replicative senescence (Hayflick limit) plays a causative role in organismal aging is at present an active area of investigation.
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 is not universal, and scientific evidence suggests that cellular senescence evolved in certain speciesSpecies
In biology, a species is one of the basic units of biological classification and a taxonomic rank. A species is often defined as a group of organisms capable of interbreeding and producing fertile offspring. While in many cases this definition is adequate, more precise or differing measures are...
because it prevents the onset of cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
. In a few simple species, such as Hydra
Hydra (genus)
Hydra is a genus of simple fresh-water animal possessing radial symmetry. Hydras are predatory animals belonging to the phylum Cnidaria and the class Hydrozoa. They can be found in most unpolluted fresh-water ponds, lakes, and streams in the temperate and tropical regions and can be found by...
, senescence is negligible
Negligible
Negligible refers to the quantities so small that they can be ignored when studying the larger effect. Although related to the more mathematical concepts of infinitesimal, the idea of negligibility is particularly useful in practical disciplines like physics, chemistry, mechanical and electronic...
and cannot be detected. All such species have no "post-mitotic
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
" cells; they reduce the effect of damaging free radicals
Free-radical theory
The free-radical theory of aging states that organisms age because cells accumulate free radical damage over time. A free radical is any atom or molecule that has a single unpaired electron in an outer shell. While a few free radicals such as melanin are not chemically reactive, most...
by cell division and dilution. Such species are not immortal, however, as they will eventually fall prey to trauma
Physical trauma
Trauma refers to "a body wound or shock produced by sudden physical injury, as from violence or accident." It can also be described as "a physical wound or injury, such as a fracture or blow." Major trauma can result in secondary complications such as circulatory shock, respiratory failure and death...
or disease
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
. Moreover, average lifespans can vary greatly within and between species
Species
In biology, a species is one of the basic units of biological classification and a taxonomic rank. A species is often defined as a group of organisms capable of interbreeding and producing fertile offspring. While in many cases this definition is adequate, more precise or differing measures are...
. This suggests that both genetic and environmental factors
Nature versus nurture
The nature versus nurture debate concerns the relative importance of an individual's innate qualities versus personal experiences The nature versus nurture debate concerns the relative importance of an individual's innate qualities ("nature," i.e. nativism, or innatism) versus personal experiences...
contribute to aging.
In general, theories that explain senescence have been divided between the programmed and stochastic
Stochastic
Stochastic refers to systems whose behaviour is intrinsically non-deterministic. A stochastic process is one whose behavior is non-deterministic, in that a system's subsequent state is determined both by the process's predictable actions and by a random element. However, according to M. Kac and E...
theories of aging. Programmed theories imply that aging is regulated by biological clocks operating throughout the lifespan. This regulation would depend on changes in gene expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
that affect the systems responsible for maintenance, repair, and defense responses. The Reproductive-Cell Cycle Theory
Reproductive-cell cycle theory
Rather than seeing aging as a loss of functionality as we get older, this theory defines aging as any change in an organism over time, as evidenced by the fact that if all chemical reactions in the body were stopped, no change, and thus no aging, would occur...
suggests that aging is caused by changes in hormonal signaling over the lifespan. Stochastic theories blame environmental impacts on living organisms that induce cumulative damage at various levels as the cause of aging, examples of which ranging from damage to DNA
DNA damage theory of aging
The DNA damage theory of aging proposes that aging is a consequence of unrepaired DNA damage accumulation. Damage in this context includes chemical reactions that mutate DNA and/or interfere with DNA replication. Although both mitochondrial and nuclear DNA damage can contribute to aging, nuclear...
, damage to tissues and cells by oxygen radicals
Radical (chemistry)
Radicals are atoms, molecules, or ions with unpaired electrons on an open shell configuration. Free radicals may have positive, negative, or zero charge...
(widely known as free radicals countered by the even more well-known antioxidants), and cross-linking.
However, aging is seen as a progressive failure of homeodynamics
Homeodynamics
Homeodynamics is a living systems theory, one of many that have emerged in recent years - which promise to open up new ways of thinking about and understanding our world and ourselves...
(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
A gene can be expressed at various stages of life. Therefore, natural selection can support lethal and harmful alleles, if their expression occurs after reproduction. Senescence may be the product of such selection. In addition, 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 that 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 selectionNatural selection
Natural selection is the nonrandom process by which biologic traits become either more or less common in a population as a function of differential reproduction of their bearers. It is a key mechanism of evolution....
. In essence, 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 theories of aging exist, and are not necessarily mutually exclusive.
The geneticist J. B. S. Haldane
J. B. S. Haldane
John Burdon Sanderson Haldane FRS , known as Jack , was a British-born geneticist and evolutionary biologist. A staunch Marxist, he was critical of Britain's role in the Suez Crisis, and chose to leave Oxford and moved to India and became an Indian citizen...
wondered why the dominant mutation that causes Huntington's disease
Huntington's disease
Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...
remained in the population, and why natural selection had not eliminated it. The onset of this neurological disease is (on average) at age 45 and is invariably fatal within 10–20 years. Haldane assumed 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
Genetic drift
Genetic drift or allelic drift is the change in the frequency of a gene variant in a population due to random sampling.The alleles in the offspring are a sample of those in the parents, and chance has a role in determining whether a given individual survives and reproduces...
. This principle has been demonstrated experimentally. And it is these later-acting deleterious mutations that are believed to allow—even cause—age-related mortality.
Peter Medawar
Peter Medawar
Sir Peter Brian Medawar OM CBE FRS was a British biologist, whose work on graft rejection and the discovery of acquired immune tolerance was fundamental to the practice of tissue and organ transplants...
formalised this observation in his mutation accumulation theory of aging. "The force of natural selection weakens with increasing age—even in a theoretically immortal population, provided only that it is 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, in typical circumstances, predation, disease, and accidents. So, even an immortal population, whose fertility does not 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 affect only 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 that have high extrinsic mortality in nature will age more quickly and have shorter intrinsic lifespans. This is borne out among mammals, the best-studied in terms of life history. There is a correlation among mammals between body size and lifespan
Life expectancy
Life expectancy is the expected number of years of life remaining at a given age. It is denoted by ex, which means the average number of subsequent years of life for someone now aged x, according to a particular mortality experience...
, such that larger species live longer than smaller species under controlled/optimum conditions, but there are notable exceptions. For instance, many bats and rodents are of similar size, yet bats live much longer. For instance, the little brown bat
Little brown bat
The little brown bat is a species of the genus Myotis , one of the most common bats of North America...
, half the size of a mouse
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...
, can live 30 years in the wild. A mouse will only live 2–3 years even under optimum conditions. The explanation is that bats have fewer predators, and therefore low extrinsic mortality. More individuals survive to later ages, so the force of selection against late-acting deleterious mutations is stronger. Fewer late-acting deleterious mutations equates to slower aging and therefore a longer lifespan. Birds are also warm-blooded and are similar in size to many small mammals, yet often live 5–10 times as long. They have less predation pressure than ground-dwelling mammals. Seabird
Seabird
Seabirds are birds that have adapted to life within the marine environment. While seabirds vary greatly in lifestyle, behaviour and physiology, they often exhibit striking convergent evolution, as the same environmental problems and feeding niches have resulted in similar adaptations...
s, which, in general, have the fewest predators of all birds, live longest.
When examining the body-size vs. lifespan relationship, one also observes that predatory mammals tend to live longer than prey mammals 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 their sociality, help them avoid becoming prey. Being a predator, being smart, and working together all reduce extrinsic mortality.
Another evolutionary theory of aging was proposed by George C. Williams
George C. Williams
Professor George Christopher Williams was an American evolutionary biologist.Williams was a professor emeritus of biology at the State University of New York at Stony Brook. He was best known for his vigorous critique of group selection. The work of Williams in this area, along with W. D...
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. Thus, harmful biological changes in old age may result from selection for pleiotropic
Pleiotropy
Pleiotropy occurs when one gene influences multiple phenotypic traits. Consequently, a mutation in a pleiotropic gene may have an effect on some or all traits simultaneously...
genes that are beneficial early in life but harmful later on. In this case, fitness is relatively high when Fisher's reproductive value
Fisher's reproductive value
Fisher's reproductive value was defined by R. A. Fisher in his 1930 book The Genetical Theory of Natural Selection as the expected reproduction of an individual from their current age onward, given that they have survived to their current age...
is high and relatively low when Fisher's reproductive value
Fisher's reproductive value
Fisher's reproductive value was defined by R. A. Fisher in his 1930 book The Genetical Theory of Natural Selection as the expected reproduction of an individual from their current age onward, given that they have survived to their current age...
is low.
Gene regulation
A number of genetic components of aging have been identified using model organisms, ranging from the simple budding yeastYeast
Yeasts are eukaryotic micro-organisms classified in the kingdom Fungi, with 1,500 species currently described estimated to be only 1% of all fungal species. Most reproduce asexually by mitosis, and many do so by an asymmetric division process called budding...
Saccharomyces cerevisiae
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
to worms such as Caenorhabditis elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
and fruit flies
Drosophilidae
Drosophilidae is a diverse, cosmopolitan family of flies, which includes fruit flies. Another family of flies called Tephritidae also includes fruit flies. The best known species of Drosophilidae is Drosophila melanogaster, within the genus Drosophila, and this species Is used extensively for...
(Drosophila melanogaster
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
). Study of these organisms has revealed the presence of at least two conserved aging pathways.
One of these pathways involves the gene Sir2
Sir2
Sir2 was the first gene of the sirtuin genes to be found. It was found in budding yeast, and, since then, members of this highly conserved family have been found in nearly all organisms studied...
, a NAD
Nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide, abbreviated NAD, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide.In metabolism, NAD is involved...
+-dependent histone deacetylase. In yeast, Sir2 is required for genomic silencing at three loci: The yeast mating loci
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
, the telomere
Telomere
A telomere is a region of repetitive DNA sequences at the end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Its name is derived from the Greek nouns telos "end" and merοs "part"...
s and the ribosomal DNA
Ribosomal DNA
Ribosomal DNA codes for ribosomal RNA. The ribosome is an intracellular macromolecule that produces proteins or polypeptide chains. The ribosome itself consists of a composite of proteins and RNA. As shown in the figure, rDNA consists of a tandem repeat of a unit segment, an operon, composed of...
(rDNA). In some species of yeast, replicative aging may be partially caused by homologous recombination
Homologous recombination
Homologous recombination is a type of genetic recombination in which nucleotide sequences are exchanged between two similar or identical molecules of DNA. It is most widely used by cells to accurately repair harmful breaks that occur on both strands of DNA, known as double-strand breaks...
between rDNA repeats; excision of rDNA repeats results in the formation of extrachromosomal rDNA circle
Extrachromosomal rDNA circle
Extrachromosomal rDNA circles are self replicating circles of ribosomal DNA found in some strains of yeast and thought to contribute to their aging.The ERC accumulate in the mother cell during the budding process....
s (ERCs). These ERCs replicate and preferentially segregate to the mother cell during cell division, and are believed to result in cellular senescence by titrating
Titration
Titration, also known as titrimetry, is a common laboratory method of quantitative chemical analysis that is used to determine the unknown concentration of an identified analyte. Because volume measurements play a key role in titration, it is also known as volumetric analysis. A reagent, called the...
away (competing for) essential nuclear factors
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
. ERCs have not been observed in other species (nor even all strains of the same yeast species) of yeast (which also display replicative senescence), and ERCs are not believed to contribute to aging in higher organisms such as humans (they have not been shown to accumulate in mammals in a similar manner to yeast). Extrachromosomal circular DNA (eccDNA) has been found in worms, flies, and humans. The origin and 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 (though, in flies, this finding has not been replicated by other investigators, and the activator of Sir2 resveratrol
Resveratrol
Resveratrol is a stilbenoid, a type of natural phenol, and a phytoalexin produced naturally by several plants when under attack by pathogens such as bacteria or fungi....
does not reproducibly increase lifespan in either species). Whether the Sir2 homologues in higher organisms have any role in lifespan is unclear, but the human SIRT1 protein has been demonstrated to deacetylate p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
, Ku70, and the forkhead family of transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s. SIRT1 can also regulate acetylates such as CBP/p300, and has been shown to deacetylate specific histone
Histone
In biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation...
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
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
. Superoxide dismutase
Superoxide dismutase
Superoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen...
, a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that protects against the effects of mitochondrial free radicals
Radical (chemistry)
Radicals are atoms, molecules, or ions with unpaired electrons on an open shell configuration. Free radicals may have positive, negative, or zero charge...
, 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
Insulin-like growth factor
The insulin-like growth factors are proteins with high sequence similarity to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment...
in worms, flies, and the growth hormone/IGF1 axis in 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
Heat shock
In biochemistry, heat shock is the effect of subjecting a cell to a higher temperature than that of the ideal body temperature of the organism from which the cell line was derived.-Heat shock response:...
, and osmotic shock
Osmotic shock
Osmotic shock or osmotic stress is a sudden change in the solute concentration around a cell, causing a rapid change in the movement of water across its cell membrane. Under conditions of high concentrations of either salts, substrates or any solute in the supernatant, water is drawn out of the...
. By converting nicotinamide
Nicotinamide
Nicotinamide, also known as niacinamide and nicotinic acid amide, is the amide of nicotinic acid . Nicotinamide is a water-soluble vitamin and is part of the vitamin B group...
to niacin
Niacin
"Niacin" redirects here. For the neo-fusion band, see Niacin .Niacin is an organic compound with the formula and, depending on the definition used, one of the forty to eighty essential human nutrients.Niacin is one of five vitamins associated with a pandemic deficiency disease: niacin deficiency...
, nicotinamide is removed, inhibiting the activity of Sir2. A nicotinamidase
Nicotinamidase
In enzymology, a nicotinamidase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are nicotinamide and H2O, whereas its two products are nicotinate and NH3....
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
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
levels. It is not 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
Resveratrol
Resveratrol is a stilbenoid, a type of natural phenol, and a phytoalexin produced naturally by several plants when under attack by pathogens such as bacteria or fungi....
, a stilbenoid found in the skin of red grape
Grape
A grape is a non-climacteric fruit, specifically a berry, that grows on the perennial and deciduous woody vines of the genus Vitis. Grapes can be eaten raw or they can be used for making jam, juice, jelly, vinegar, wine, grape seed extracts, raisins, molasses and grape seed oil. Grapes are also...
s, was reported to extend the lifespan of yeast, worms, and flies (the lifespan extension in flies and worms have proved irreproducible by independent investigators). It has been shown to activate Sir2 and therefore mimics the effects of calorie restriction, if one accepts that caloric restriction is indeed dependent on Sir2.
Gene expression is imperfectly controlled, and it is possible that random fluctuations in the expression levels of many genes contribute to the aging process as suggested by a study of such genes in yeast. 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.
According to the GenAge database of aging-related genes there are over 700 genes associated with aging in model organisms: 555 in the soil roundworm (Caenorhabditis elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
), 87 in the bakers' yeast (Saccharomyces cerevisiae
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
), 75 in the fruit fly (Drosophila melanogaster
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
) and 68 in the mouse (Mus musculus).
The following is a list of genes connected to longevity through research on model organisms:
| Podospora | Saccharomyces | Caenorhabditis | Drosophila | Mus |
|---|---|---|---|---|
| grisea | LAG1 | daf-2 Daf-2 The daf-2 gene encodes an insulin-like receptor in the worm C. elegans. Mutations in daf-2 have been shown by Cynthia Kenyon to double the lifespan of the worms... |
sod1 SOD1 Superoxide dismutase [Cu-Zn] also known as superoxide dismutase 1 or SOD1 is an enzyme that in humans is encoded by the SOD1 gene. SOD1 is one of three human superoxide dismutases.- Function :... |
Prop-1 |
| LAC1 | age-1/daf-23 | cat1 | p66shc (Not independently verified) | |
| pit-1 | Ghr GHR GHR may stand for:* Goover Howthe Ratings, a system, which involves an interview process.* Growth hormone receptor, a protein.* Gustav Heinrich Ralph von Koenigswald, a German paleontologist and geologist... |
|||
| RAS1 | daf-18 | mth MTH MTH is an initialism or abbreviation standing for:*memory translator hub*Mount Hebron High School*Mount Hood National Forest*MTH Electric Trains*MTH Racing engines*Melbourne Town Hall, Melbourne Australia*Maximum the Hormone*Mors-Thy Håndbold... |
mclk1 | |
| RAS2 | akt-1/akt-2 | |||
| PHB1 | daf-16 Daf-16 DAF-16 is part of a group of genes that drive the biological processes involved in ageing, immunity and responses to physical or environmental stresses... |
|||
| PHB2 PHB2 Prohibitin-2 is a protein that in humans is encoded by the PHB2 gene.-Further reading:... |
daf-12 | |||
| CDC7 | ctl-1 | |||
| BUD1 | old-1 | |||
| RTG2 | spe-26 | |||
| RPD3 | clk-1 Clk-1 The clk-1 gene encodes an enzyme that is necessary for ubiquinone biosynthesis in the worm C. elegans and other eukaryotes... |
|||
| HDA1 | mev-1 | |||
| SIR2 Sir2 Sir2 was the first gene of the sirtuin genes to be found. It was found in budding yeast, and, since then, members of this highly conserved family have been found in nearly all organisms studied... |
||||
| aak-2 | ||||
| SIR4-42 | ||||
| UTH4 | ||||
| YGL023 | ||||
| SGS1 | ||||
| RAD52 RAD52 RAD52 homolog , also known as RAD52, is a protein which in humans is encoded by the RAD52 gene.- Function :The protein encoded by this gene shares similarity with Saccharomyces cerevisiae Rad52, a protein important for DNA double-strand break repair and homologous recombination... |
||||
| FOB1 |
Cellular senescence
As noted above, senescence is not universal, and senescence is not observed in single-celled organisms that reproduce through the process of cellular mitosisMitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
. Moreover, cellular senescence is not observed in several organisms, including perennial plants, sponge
Sea sponge
Sponges are animals of the phylum Porifera . Their bodies consist of jelly-like mesohyl sandwiched between two thin layers of cells. While all animals have unspecialized cells that can transform into specialized cells, sponges are unique in having some specialized cells, but can also have...
s, coral
Coral
Corals are marine animals in class Anthozoa of phylum Cnidaria typically living in compact colonies of many identical individual "polyps". The group includes the important reef builders that inhabit tropical oceans and secrete calcium carbonate to form a hard skeleton.A coral "head" is a colony of...
s, and lobster
Lobster
Clawed lobsters comprise a family of large marine crustaceans. Highly prized as seafood, lobsters are economically important, and are often one of the most profitable commodities in coastal areas they populate.Though several groups of crustaceans are known as lobsters, the clawed lobsters are most...
s. 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
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
; i.e., 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 is widely believed that cellular senescence evolved as a way to prevent the onset and spread of cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
. Somatic
Somatic
The term somatic means 'of the body',, relating to the body. In medicine, somatic illness is bodily, not mental, illness. The term is often used in biology to refer to the cells of the body in contrast to the germ line cells which usually give rise to the gametes...
cells that have divided many times will have accumulated DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s and would therefore be in danger of becoming cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
ous if cell division continued.
Lately, the role of telomere
Telomere
A telomere is a region of repetitive DNA sequences at the end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Its name is derived from the Greek nouns telos "end" and merοs "part"...
s in cellular senescence has aroused general interest, especially with a view to the possible genetically adverse effects of cloning
Cloning
Cloning in biology is the process of producing similar populations of genetically identical individuals that occurs in nature when organisms such as bacteria, insects or plants reproduce asexually. Cloning in biotechnology refers to processes used to create copies of DNA fragments , cells , or...
. The successive shortening of the chromosomal
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
telomeres with each cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
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 do not age and are, therefore, described as being "biologically immortal
Biological immortality
Biological immortality refers to a stable rate of mortality as a function of chronological age. Some individual cells and entire organisms in some species achieve this state either throughout their existence or after living long enough. This requires that death occur from injury or disease rather...
". It is theorized by some that when it is discovered exactly what allows these cells, whether it be the result of telomere lengthening or not, to divide without limit that it will be possible to genetically alter other cells to have the same capability. It is further theorized that it will eventually be possible to genetically engineer
Genetic engineering
Genetic engineering, also called genetic modification, is the direct human manipulation of an organism's genome using modern DNA technology. It involves the introduction of foreign DNA or synthetic genes into the organism of interest...
all cells in the human body to have this capability by employing gene therapy
Gene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
and, therefore, stop or reverse aging, effectively making the entire organism potentially immortal.
The length of the telomere strand has senescence effects, telomere shortening activate extensive alterations in alternative RNA splicing that produce senescence toxins such as progerin
Progerin
Progerin is a truncated version of lamin A protein involved in Hutchinson-Gilford progeria syndrome. Progerin is most often generated by a silent point mutation in the lamin A gene, LMNA. This mutation activates a cryptic splice site and gives rise to a form of lamin A with a deletion of 50 amino...
that degrades the tissue and makes it more susceptible to failure.
Cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
cells are usually immortal. In about 85% of tumors, this evasion of cellular senescence is the result of up-activation of their telomerase
Telomerase
Telomerase is an enzyme that adds DNA sequence repeats to the 3' end of DNA strands in the telomere regions, which are found at the ends of eukaryotic chromosomes. This region of repeated nucleotide called telomeres contains non-coding DNA material and prevents constant loss of important DNA from...
genes. This simple observation suggests that reactivation of telomerase in healthy individuals could greatly increase their cancer risk.
Whether cell senescence plays any role in organismal aging is at present unknown, and is an active area of investigation. Mouse mutants lacking telomerase do not immediately show accelerated aging.
Chemical damage
Raymond Pearl
Raymond Pearl was an American biologist, regarded as one of the founders of biogerontology. He spent most of his career at Johns Hopkins University in Baltimore....
in 1928(based on earlier work by Max Rubner
Max Rubner
Max Rubner [ru:bner] was a German physiologist and hygienist.He studied at the University of Munich under Adolf von Baeyer and Carl von Voit . Afterwards he taught as a professor at the University of Marburg and the Robert Koch Institute of Hygiene at the University of Berlin...
), which states that fast basal metabolic rate
Basal metabolic rate
Basal Metabolic Rate , and the closely related resting metabolic rate , is the amount of daily energy expended by humans and other animals at rest. Rest is defined as existing in a neutrally temperate environment while in the post-absorptive state...
corresponds to short maximum life span
Maximum life span
Maximum life span is a measure of the maximum amount of time one or more members of a population has been observed to survive between birth and death.Most living species have at least one upper limit on the number of times cells can divide...
.
While there may be some validity to the idea that for various types of specific damage detailed below that are by-products of metabolism, all other things being equal, a fast metabolism may reduce lifespan, in general this theory does not 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 that, it is presumed, have reduced mortality from predation, and therefore have evolved long lifespans even in the presence of very high metabolic rates. More recently, it was shown that, when modern statistical methods for correcting for the effects of body size and phylogeny are employed, metabolic rate does not correlate with longevity in mammals or birds. (For a critique of the Rate of Living Hypothesis see Living fast, dying when?)
With respect to specific types of chemical damage caused by metabolism, it is suggested that damage to long-lived biopolymer
Biopolymer
Biopolymers are polymers produced by living organisms. Since they are polymers, Biopolymers contain monomeric units that are covalently bonded to form larger structures. There are three main classes of biopolymers based on the differing monomeric units used and the structure of the biopolymer formed...
s, such as structural protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s or DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
, caused by ubiquitous chemical agents in the body such as oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
and sugar
Sugar
Sugar is a class of edible crystalline carbohydrates, mainly sucrose, lactose, and fructose, characterized by a sweet flavor.Sucrose in its refined form primarily comes from sugar cane and sugar beet...
s, are in part responsible for aging. The damage can include breakage of biopolymer chains, cross-linking of biopolymers, or chemical attachment of unnatural substituents (hapten
Hapten
A hapten is a small molecule that can elicit an immune response only when attached to a large carrier such as a protein; the carrier may be one that also does not elicit an immune response by itself...
s) to biopolymers.
Under normal aerobic conditions, approximately 4% of the oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
metabolized by mitochondria is converted to superoxide
Superoxide
A superoxide, also known by the obsolete name hyperoxide, is a compound that possesses the superoxide anion with the chemical formula O2−. The systematic name of the anion is dioxide. It is important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature...
ion, which can subsequently be converted to hydrogen peroxide
Hydrogen peroxide
Hydrogen peroxide is the simplest peroxide and an oxidizer. Hydrogen peroxide is a clear liquid, slightly more viscous than water. In dilute solution, it appears colorless. With its oxidizing properties, hydrogen peroxide is often used as a bleach or cleaning agent...
, hydroxyl
Hydroxyl
A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...
radical
Radical (chemistry)
Radicals are atoms, molecules, or ions with unpaired electrons on an open shell configuration. Free radicals may have positive, negative, or zero charge...
and eventually other reactive species including other peroxide
Peroxide
A peroxide is a compound containing an oxygen–oxygen single bond or the peroxide anion .The O−O group is called the peroxide group or peroxo group. In contrast to oxide ions, the oxygen atoms in the peroxide ion have an oxidation state of −1.The simplest stable peroxide is hydrogen peroxide...
s and singlet oxygen
Singlet oxygen
Singlet oxygen is the common name used for the diamagnetic form of molecular oxygen , which is less stable than the normal triplet oxygen. Because of its unusual properties, singlet oxygen can persist for over an hour at room temperature, depending on the environment...
, which can, in turn, generate free radical
Radical (chemistry)
Radicals are atoms, molecules, or ions with unpaired electrons on an open shell configuration. Free radicals may have positive, negative, or zero charge...
s capable of damaging structural proteins and DNA. Certain metal ion
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
s found in the body, such as copper
Copper
Copper is a chemical element with the symbol Cu and atomic number 29. It is a ductile metal with very high thermal and electrical conductivity. Pure copper is soft and malleable; an exposed surface has a reddish-orange tarnish...
and iron
Iron
Iron is a chemical element with the symbol Fe and atomic number 26. It is a metal in the first transition series. It is the most common element forming the planet Earth as a whole, forming much of Earth's outer and inner core. It is the fourth most common element in the Earth's crust...
, may participate in the process. (In Wilson's disease
Wilson's disease
Wilson's disease or hepatolenticular degeneration is an autosomal recessive genetic disorder in which copper accumulates in tissues; this manifests as neurological or psychiatric symptoms and liver disease...
, a hereditary defect
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
that 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 antioxidant
Polyphenol antioxidant
A polyphenol antioxidant is a type of antioxidant containing a polyphenolic substructure. Numbering over 4,000 distinct species, many of these compounds have antioxidant activity in vitro but are unlikely to have antioxidant roles in vivo...
s .
Sugar
Sugar
Sugar is a class of edible crystalline carbohydrates, mainly sucrose, lactose, and fructose, characterized by a sweet flavor.Sucrose in its refined form primarily comes from sugar cane and sugar beet...
s such as glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
and fructose
Fructose
Fructose, or fruit sugar, is a simple monosaccharide found in many plants. It is one of the three dietary monosaccharides, along with glucose and galactose, that are absorbed directly into the bloodstream during digestion. Fructose was discovered by French chemist Augustin-Pierre Dubrunfaut in 1847...
can react with certain amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s such as lysine
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
and arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
and certain DNA bases such as guanine
Guanine
Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine . In DNA, guanine is paired with cytosine. With the formula C5H5N5O, guanine is a derivative of purine, consisting of a fused pyrimidine-imidazole ring system with...
to produce sugar adducts, in a process called glycation
Glycation
Glycation is the result of the bonding of a protein or lipid molecule with a sugar molecule, such as fructose or glucose, without the controlling action of an enzyme. All blood sugars are reducing molecules. Glycation may occur either inside the body or outside the body...
. 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
Blood sugar
The blood sugar concentration or blood glucose level is the amount of glucose present in the blood of a human or animal. Normally in mammals, the body maintains the blood glucose level at a reference range between about 3.6 and 5.8 mM , or 64.8 and 104.4 mg/dL...
, 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
Advanced glycation endproduct
An advanced glycation end-product is the result of a chain of chemical reactions after an initial glycation reaction. The intermediate products are known, variously, as Amadori, Schiff base and Maillard products, named after the researchers who first described them. An advanced glycation...
.
Free radicals
Radical (chemistry)
Radicals are atoms, molecules, or ions with unpaired electrons on an open shell configuration. Free radicals may have positive, negative, or zero charge...
can damage protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s, lipids or DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
. Glycation
Glycation
Glycation is the result of the bonding of a protein or lipid molecule with a sugar molecule, such as fructose or glucose, without the controlling action of an enzyme. All blood sugars are reducing molecules. Glycation may occur either inside the body or outside the body...
mainly damages proteins. Damaged proteins and lipids accumulate in lysosome
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
s as lipofuscin
Lipofuscin
Lipofuscin is the name given to finely granular yellow-brown pigment granules composed of lipid-containing residues of lysosomal digestion. It is considered one of the aging or "wear-and-tear" pigments, found in the liver, kidney, heart muscle, adrenals, nerve cells, and ganglion cells...
. Chemical damage to structural proteins can lead to loss of function; for example, damage to collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
of blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...
walls can lead to vessel-wall stiffness and, thus, hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
, and vessel wall thickening and reactive tissue formation (atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
); similar processes in the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
can lead to renal failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
. Damage to enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s reduces cellular functionality. Lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
peroxidation
Redox
Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....
of the inner mitochondrial membrane reduces the electric potential
Electric potential
In classical electromagnetism, the electric potential at a point within a defined space is equal to the electric potential energy at that location divided by the charge there...
and the ability to generate energy. It is probably no accident that nearly all of the so-called "accelerated aging disease
Accelerated aging disease
A DNA repair-deficiency disorder is a medical condition due to reduced functionality of DNA repair.DNA repair defects are seen in nearly all of the diseases described as accelerated aging disease, in which various tissues, organs or systems of the human body age prematurely...
s" are due to defective DNA repair
DNA repair
DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
enzymes.
It is believed that the impact of alcohol on aging
Impact of alcohol on aging
The impact of alcohol on aging is multifaceted. Evidence shows that alcoholism or chronic alcohol consumption can cause both accelerated aging – in which symptoms of aging appear earlier than normal – and exaggerated aging, in which the symptoms appear at the appropriate time but in a...
can be partly explained by alcohol's activation of the HPA axis, which stimulates glucocorticoid
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
secretion, long-term exposure to which produces symptoms of aging.
Reliability theory
Reliability theoryReliability theory
Reliability theory describes the probability of a system completing its expected function during an interval of time. It is the basis of reliability engineering, which is an area of study focused on optimizing the reliability, or probability of successful functioning, of systems, such as airplanes,...
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 composed entirely of non-aging elements (with a constant failure rate
Failure rate
Failure rate is the frequency with which an engineered system or component fails, expressed for example in failures per hour. It is often denoted by the Greek letter λ and is important in reliability engineering....
) will nevertheless deteriorate (fail more often) with age, if these systems are redundant in irreplaceable elements. Aging, therefore, is a direct consequence of systems.
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 distribution: 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
Compensation law of mortality
The compensation law of mortality states that the relative differences in death rates between different populations of the same biological species decrease with age, because the higher initial death rates in disadvantaged populations are compensated by lower pace of mortality increase with age...
), and mortality convergence is observed due to the exhaustion of initial differences in redundancy levels.
Miscellaneous
Recently, a kind of early senescence has been alleged to be a possible unintended outcome of early cloningCloning
Cloning in biology is the process of producing similar populations of genetically identical individuals that occurs in nature when organisms such as bacteria, insects or plants reproduce asexually. Cloning in biotechnology refers to processes used to create copies of DNA fragments , cells , or...
experiments. The issue was raised in the case of Dolly the sheep
Dolly the Sheep
Dolly was a female domestic sheep, and the first mammal to be cloned from an adult somatic cell, using the process of nuclear transfer. She was cloned by Ian Wilmut, Keith Campbell and colleagues at the Roslin Institute near Edinburgh in Scotland...
, following her death from a contagious lung disease. The claim that Dolly's early death involved premature senescence has been vigorously contested, and Dolly's creator, Dr. Ian Wilmut
Ian Wilmut
Sir Ian Wilmut, OBE FRS FMedSci FRSE is an English embryologist and is currently Director of the Medical Research Council Centre for Regenerative Medicine at the University of Edinburgh. He is best known as the leader of the research group that in 1996 first cloned a mammal from an adult somatic...
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
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
) disorders, each called progeria
Progeria
Progeria is an extremely rare genetic condition wherein symptoms resembling aspects of aging are manifested at an early age. The word progeria comes from the Greek words "pro" , meaning "before", and "géras" , meaning "old age"...
, has been known for some time. Sufferers exhibit symptoms resembling accelerated aging
Accelerated aging disease
A DNA repair-deficiency disorder is a medical condition due to reduced functionality of DNA repair.DNA repair defects are seen in nearly all of the diseases described as accelerated aging disease, in which various tissues, organs or systems of the human body age prematurely...
, including wrinkled skin. The cause of Hutchinson–Gilford progeria syndrome
Progeria
Progeria is an extremely rare genetic condition wherein symptoms resembling aspects of aging are manifested at an early age. The word progeria comes from the Greek words "pro" , meaning "before", and "géras" , meaning "old age"...
was reported in the journal Nature
Nature (journal)
Nature, first published on 4 November 1869, is ranked the world's most cited interdisciplinary scientific journal by the Science Edition of the 2010 Journal Citation Reports...
in May 2003. This report suggests that DNA damage, not oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
, is the cause of this form of accelerated aging.
See also
- Accelerated aging diseaseAccelerated aging diseaseA DNA repair-deficiency disorder is a medical condition due to reduced functionality of DNA repair.DNA repair defects are seen in nearly all of the diseases described as accelerated aging disease, in which various tissues, organs or systems of the human body age prematurely...
s (DNA repair-deficiency disorders) - Advanced adult
- AgeingAgeingAgeing or aging is the accumulation of changes in a person over time. Ageing in humans refers to a multidimensional process of physical, psychological, and social change. Some dimensions of ageing grow and expand over time, while others decline...
- Ageing brain
- Calorie restrictionCalorie restrictionCaloric restriction , or calorie restriction, is a dietary regimen that restricts calorie intake, where the baseline for the restriction varies, usually being the previous, unrestricted, intake of the subjects...
- DNA damage theory of agingDNA damage theory of agingThe DNA damage theory of aging proposes that aging is a consequence of unrepaired DNA damage accumulation. Damage in this context includes chemical reactions that mutate DNA and/or interfere with DNA replication. Although both mitochondrial and nuclear DNA damage can contribute to aging, nuclear...
- Evolution of ageingEvolution of ageingEnquiry into the evolution of ageing aims to explain why almost all living things weaken and die with age. There is not yet agreement in the scientific community on a single answer...
- Fisher's reproductive valueFisher's reproductive valueFisher's reproductive value was defined by R. A. Fisher in his 1930 book The Genetical Theory of Natural Selection as the expected reproduction of an individual from their current age onward, given that they have survived to their current age...
- ImmortalityImmortalityImmortality is the ability to live forever. It is unknown whether human physical immortality is an achievable condition. Biological forms have inherent limitations which may or may not be able to be overcome through medical interventions or engineering...
- Life extensionLife extensionLife extension science, also known as anti-aging medicine, experimental gerontology, and biomedical gerontology, is the study of slowing down or reversing the processes of aging to extend both the maximum and average lifespan...
- List of life extension-related topics
- Maximum life spanMaximum life spanMaximum life span is a measure of the maximum amount of time one or more members of a population has been observed to survive between birth and death.Most living species have at least one upper limit on the number of times cells can divide...
- Mitohormesis
- Plant senescencePlant senescencePlant senescence is the study of aging in plants. It is a heavily studied subject just as it is in the other kingdoms of life. Plants, just like other forms of organisms, seem to have both unintended and programmed aging...
- ProgeriaProgeriaProgeria is an extremely rare genetic condition wherein symptoms resembling aspects of aging are manifested at an early age. The word progeria comes from the Greek words "pro" , meaning "before", and "géras" , meaning "old age"...
, a disease in which symptoms resembling aspects of aging are manifested in childhood - Reliability theory of aging and longevityReliability theory of aging and longevityReliability theory of aging and longevity is a scientific approach aimed to gain theoretical insights into mechanisms of biological aging and species survival patterns by applying a general theory of systems failure, known as reliability theory.-Overview:...
- SAGE KESAGE KEThe Science of Aging Knowledge Environment was an online scientific resource provided by the American Association for the Advancement of Science .-History and Organization:...
- Strategies for Engineered Negligible Senescence (SENS)
- Sub-lethal damageSub-lethal damageCell damage is damage to any of the components of the cell.-Sub-lethal damage:If damage to a cell is minimal, the cell can recover following removal of the damaging stimulus. Damaged proteins and organelles are removed by a cell stress response and autophagy with new structural components being...
- TelomereTelomereA telomere is a region of repetitive DNA sequences at the end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Its name is derived from the Greek nouns telos "end" and merοs "part"...
- Stem cell theory of agingStem cell theory of agingThe stem cell theory of aging is a new theory which was recently formulated by several scientists and which postulates that the aging process is the result of the inability of various types of stem cells to continue to replenish the tissues of an organism with functional differentiated cells...
External links
- AgeLab (Massachusetts Institute of TechnologyMassachusetts Institute of TechnologyThe Massachusetts Institute of Technology is a private research university located in Cambridge, Massachusetts. MIT has five schools and one college, containing a total of 32 academic departments, with a strong emphasis on scientific and technological education and research.Founded in 1861 in...
)
- Aging CellCategory:Gerontology