Amyloid

From Wikipedia, the free encyclopedia

Micrograph showing amyloid deposits (pink) in small bowel. H&E stain.

Amyloids are aggregates of proteins that become folded into a shape that allows many copies of that protein to stick together forming fibrils. In the human body, amyloids have been linked to the development of various diseases. Pathogenic amyloids form when previously healthy proteins lose their normal physiological functions and form fibrous deposits in plaques around cells which can disrupt the healthy function of tissues and organs.

Such amyloids have been associated with (but not necessarily as the cause of) more than 50^[1] human diseases, known as amyloidosis, and may play a role in some neurodegenerative disorders.^[2] Some amyloid proteins are infectious; these are called prions in which the infectious form can act as a template to convert other non-infectious proteins into infectious form.^[3] Amyloids may also have normal biological functions; for example, in the formation of fimbriae in some genera of bacteria, transmission of epigenetic traits in fungi, as well as pigment deposition and hormone release in humans.^[4]

Amyloids have been known to arise from many different proteins and polypeptides.^[5] These polypeptide chains generally form β-sheet structures that aggregate into long fibers; however, identical polypeptides can fold into multiple distinct amyloid conformations. The diversity of the conformations may have led to different forms of the prion diseases.^[4]

Definition

The name amyloid comes from the early mistaken identification by Rudolf Virchow of the substance as starch (amylum in Latin, from Greek ἄμυλον amylon), based on crude iodine-staining techniques. For a period, the scientific community debated whether or not amyloid deposits are fatty deposits or carbohydrate deposits until it was finally found (in 1859) that they are, in fact, deposits of albumoid proteinaceous material.^[6]

Micrograph showing amyloid deposition in small bowel. Congo red stain.

• The classical, histopathological definition of amyloid is an extracellular, proteinaceous deposit exhibiting beta sheet structure. Common to most cross-beta-type structures, in general, they are identified by apple-green birefringence when stained with congo red and seen under polarized light. These deposits often recruit various sugars and other components such as Serum Amyloid P component, resulting in complex, and sometimes inhomogeneous structures.^[7] Recently this definition has come into question as some classic, amyloid species have been observed in distinctly intracellular locations.^[8]
• A more recent, biophysical definition is broader, including any polypeptide that polymerizes to form a cross-beta structure, in vivo or in vitro. Some of these, although demonstrably cross-beta sheet, do not show some classic histopathological characteristics such as the Congo-red birefringence. Microbiologists and biophysicists have largely adopted this definition,^[9][10] leading to some conflict in the biological community over an issue of language.

The remainder of this article will use the biophysical context.

Diseases featuring amyloids

Disease	Protein featured	Official abbreviation
Alzheimer's disease	Beta amyloid from Amyloid precursor protein[11][12][13][14]	Aβ, APP
Diabetes mellitus type 2	IAPP (Amylin)[15][16]	AIAPP
Parkinson's disease	Alpha-synuclein[12]	none
Transmissible spongiform encephalopathy (e.g. bovine spongiform encephalopathy)	PrPSc[17]	APrP
Fatal familial insomnia	PrPSc	APrP
Huntington's disease	Huntingtin[18][19]	none
Medullary carcinoma of the thyroid	Calcitonin[20]	ACal
Cardiac arrhythmias, isolated atrial amyloidosis	Atrial natriuretic factor	AANF
Atherosclerosis	Apolipoprotein AI	AApoA1
Rheumatoid arthritis	Serum amyloid A	AA
Aortic medial amyloid	Medin	AMed
Prolactinomas	Prolactin	APro
Familial amyloid polyneuropathy	Transthyretin	ATTR
Hereditary non-neuropathic systemic amyloidosis	Lysozyme	ALys
Dialysis related amyloidosis	Beta-2 microglobulin	Aβ2M
Finnish amyloidosis	Gelsolin	AGel
Lattice corneal dystrophy	Keratoepithelin	AKer
Cerebral amyloid angiopathy	Beta amyloid[21]	Aβ
Cerebral amyloid angiopathy (Icelandic type)	Cystatin	ACys
Systemic AL amyloidosis	Immunoglobulin light chain AL[20]	AL
Sporadic Inclusion body myositis	S-IBM	none

The International Society of Amyloidosis classifies amyloid fibrils based upon associated proteins.^[22]

Non-disease and functional amyloids

• Native amyloids in organisms^[23]
  • Curli fibrils produced by E. coli, Salmonella, and a few other members of the Enterobacteriales (Csg). The genetic elements (operons) encoding the curli system are phylogenetic widespread and can be found in at least four bacterial phyla.^[24] This suggest that many more bacteria may express curli fibrils.
  • Gas vesicles, the buoyancy organelles of aquatic archaea and eubacteria^[25]
  • Functional amyloids in Pseudomonas (Fap)^[26][27]
  • Chaplins from Streptomyces coelicolor
  • Podospora anserina prion het-s
  • Malarial coat protein
  • Spider silk (some but not all spiders)
  • Mammalian melanosomes (PMEL)
  • Tissue-type plasminogen activator (tPA), a hemodynamic factor
  • ApCPEB protein and its homologues with a glutamine-rich domain
  • Peptide/protein hormones stored as amyloids within endocrine secretory granules^[28]
  • Proteins and peptides engineered to make amyloid that display specific properties, such as ligands that target cell surface receptors^[29]
  • Several yeast prions are based on an infectious amyloid, e.g. [PSI+] (Sup35p); [URE3] (Ure2p); [PIN+] (Rnq1p); [SWI1+] (Swi1p) and [OCT8+] (Cyc8p)
  • Functional amyloids are abundant in most environmental biofilms according to staining with amyloid specific dyes and antibodies^[30]
  • Fungal cell adhesion proteins aggregate on the surface of the fungi to form cell surface amyloid regions with greatly increased binding strength ^[31][32]
  • The tubular sheaths encasing Methanosaeta thermophila filaments are the first functional amyloids to be reported from archeal domain of life ^[33]

Amyloid deposits occur in the pancreas of patients with diabetes mellitus, although it is not known if this is functionally important. The major component of pancreatic amyloid is a 37-amino acid residue peptide known as islet amyloid polypeptide or amylin. This is stored with insulin in secretory granules in B cells and is co secreted with insulin" (Rang and Dale's Pharmacology, 2015).

ATTR amyloid deposits from transthyretin occur not only in Transthyretin-related hereditary amyloidosis, but also in advanced cases of aging in many tissues, in many mammalian species. They are a common result in supercentenarian autopsies. A proposal is that they may mediate some tissue pathologies seen in advanced aging, and pose a limit to human life span.^[34]

Amyloid biophysics

Structure

Amyloids are formed of long unbranched fibers that are characterized by a cross-beta sheet quaternary structure in which antiparallel chains of β-stranded peptides are arranged in an orientation perpendicular to the axis of the fiber. Each individual fiber may be 5–15 nanometres in width and a few micrometres in length.^[4] While amyloid is usually identified using fluorescent dyes, stain polarimetry, circular dichroism, or FTIR (all indirect measurements), the "gold-standard" test to see whether a structure contains cross-β fibres is by placing a sample in an X-ray diffraction beam. The term "cross-β" was based on the observation of two sets of diffraction lines, one longitudinal and one transverse, that form a characteristic "cross" pattern.^[35] There are two characteristic scattering diffraction signals produced at 4.7 and 10 Ångstroms (0.47 nm and 1.0 nm), corresponding to the interstrand and stacking distances in beta sheets.^[36] The "stacks" of beta sheet are short and traverse the breadth of the amyloid fibril; the length of the amyloid fibril is built by aligned strands. The cross-beta pattern is considered a diagnostic hallmark of amyloid structure.^[4]

For a long time our knowledge of the atomic-level structure of amyloid fibrils was limited by the fact that they are unsuitable for the most traditional methods for studying protein structures. Recent years have seen progress in experimental methods that now enable direct data on the internal structure of different types of amyloid fibrils. Two prominent methods include the use of solid-state NMR spectroscopy and (cryo) electron microscopy. Combined, these methods have provided 3D atomic structures of amyloid fibrils formed by amyloid β peptides, α-synuclein, tau, and the FUS protein, associated with various neurodegenerative diseases.^[37][38]

X-ray diffraction studies of microcrystals revealed atomistic details of core region of amyloid.^[39][40] The crystallographic structures show that short stretches from amyloid-prone regions of amyloidogenic proteins run perpendicular to the filament axis, consistent with the "cross-β" feature of amyloid structure. They also reveal a number of characteristics of amyloid structures – neighboring β-sheets are tightly packed together via an interface devoid of water (therefore referred to as dry interface), with the opposing β-strands slightly offset from each other such that their side-chains interdigitate. This compact dehydrated interface created was termed a steric-zipper interface.^[4] There are eight theoretical classes of steric-zipper interfaces, dictated by the directionality of the β-sheets (parallel and anti-parallel) and symmetry between adjacent β-sheets.

A variety of tertiary structures have been observed in amyloid. The β-sheets may form a β-sandwich, or a β-solenoid which may be either β-helix or β-roll. Identical polypeptides can fold into multiple distinct amyloid conformations.^[4]

Formation

Amyloid is formed through the polymerization of hundreds to thousands of monomeric peptides into long fibers. In general, amyloid polymerization (aggregation or non-covalent polymerization) is sequence-sensitive, that is, causing mutations in the sequence can prevent self-assembly, especially if the mutation is a beta-sheet breaker, such as proline or non-coded alpha-aminoisobutyric acid.^[41] For example, humans produce amylin, an amyloidogenic peptide associated with type II diabetes, but in rats and mice prolines are substituted in critical locations and amyloidogenesis does not occur. Studies comparing synthetic to recombinant Amyloid beta 1-42 in assays measuring rate of fibrillation, fibril homogeneity, and cellular toxicity showed that recombinant Amyloid beta 1-42 has a faster fibrillation rate and greater toxicity than synthetic Amyloid beta 1-42 peptide.^[42] This observation combined with the irreproducibility of certain Amyloid beta 1-42 experimental studies has been suggested to be responsible for the lack of progress in Alzheimer's research.^[43] Consequently, there have been renewed efforts to manufacture Amyloid beta 1-42 and other amyloid peptides at unprecedented (>99%) purity.^[44]

There are multiple classes of amyloid-forming polypeptide sequences. Glutamine-rich polypeptides are important in the amyloidogenesis of Yeast and mammalian prions, as well as Trinucleotide repeat disorders including Huntington's disease. When glutamine-rich polypeptides are in a β-sheet conformation, glutamines can brace the structure by forming inter-strand hydrogen bonding between its amide carbonyls and nitrogens of both the backbone and side chains. The onset age for Huntington's disease shows an inverse correlation with the length of the polyglutamine sequence, with analogous findings in a C. elegans model system with engineered polyglutamine peptides.^[45]

Other polypeptides and proteins such as amylin and the Alzheimer's beta protein do not have a simple consensus sequence and are thought to operate by hydrophobic association.^{[citation needed]} Among the hydrophobic residues, aromatic amino-acids are found to have the highest amyloidogenic propensity.

For these peptides, cross-polymerization (fibrils of one polypeptide sequence causing other fibrils of another sequence to form) is observed in vitro and possibly in vivo.^{[citation needed]} This phenomenon is important, since it would explain interspecies prion propagation and differential rates of prion propagation, as well as a statistical link between Alzheimer's and type 2 diabetes.^[48] In general, the more similar the peptide sequence the more efficient cross-polymerization is, though entirely dissimilar sequences can cross-polymerize and highly similar sequences can even be "blockers" that prevent polymerization.^{[citation needed]} Polypeptides will not cross-polymerize their mirror-image counterparts, indicating that the phenomenon involves specific binding and recognition events.

The fast aggregation process, rapid conformational changes as well as solvent effects provide challenges in measuring monomeric and oligomeric amyloid peptide structures in solution. Theoretical and computational studies complement experiments and provide insights that are otherwise difficult to obtain using conventional experimental tools. Several groups have successfully studied the disordered structures of amyloid and reported random coil structures with specific structuring of monomeric and oligomeric amyloid as well as how genetics and oxidative stress impact the flexible structures of amyloid in solution.^[49]

Oligomeric intermediates of insulin during fibrillation (more toxic than other intermediates: native, protofibril, and fibril) decreased the surface tension of solution which indicated to detergent-like properties of oligomers and significant role of hydrophobic forces in cytotoxicity of oligomers.^[50]

Amyloid pathology

The reasons for amyloid association disease are unclear. In some cases, the deposits physically disrupt tissue architecture, suggesting disruption of function by some bulk process. An emerging consensus implicates prefibrillar intermediates rather than mature amyloid fibers in causing cell death.^[13][51]

Calcium dysregulation has been observed in cells exposed to amyloid oligomers. These small aggregates can form ion channels planar lipid bilayer membranes. Channel formation has been hypothesized to account for calcium dysregulation and mitochondrial dysfunction by allowing indiscriminate leakage of ions across cell membranes.^[52]

Studies have shown that amyloid deposition is associated with mitochondrial dysfunction and a resulting generation of reactive oxygen species (ROS), which can initiate a signalling pathway leading to apoptosis.^[53]

There are reports that indicate amyloid polymers (such as those of huntingtin, associated with Huntington's disease) can induce the polymerization of essential amyloidogenic proteins, which should be deleterious to cells. Also, interaction partners of these essential proteins can also be sequestered.^[54]

Histological staining

In the clinical setting, amyloid diseases are typically identified by a change in the fluorescence intensity of planar aromatic dyes such as thioflavin T, congo red or NIAD-4.^[55] In general, this is attributed to the environmental change, as these dyes intercalate between beta-strands to confine their structure.^[56] Congo Red positivity remains the gold standard for diagnosis of amyloidosis. In general, binding of Congo Red to amyloid plaques produces a typical apple-green birefringence when viewed under cross-polarized light. Recently, significant enhancement of fluorescence quantum yield of NIAD-4 was exploited to super-resolution fluorescence imaging of amyloid fibrils^[57] and oligomers.^[58] To avoid nonspecific staining, other histology stains, such as the hematoxylin and eosin stain, are used to quench the dyes' activity in other places such as the nucleus, where the dye might bind. Modern antibody technology and immunohistochemistry has made specific staining easier, but often this can cause trouble because epitopes can be concealed in the amyloid fold; in general, an amyloid protein structure is a different conformation from the one that the antibody recognizes.

Evolution of ageing

From Wikipedia, the free encyclopedia

Old man at a nursing home in Norway.

Enquiry into the evolution of ageing aims to explain why survival, reproductive success, and functioning of almost all living organisms decline at old age. Leading hypotheses suggest that a combination of limited resources, and an increasing risk of death by environmental causes determine an "optimal" level of self-maintenance, i.e. the repair of molecular and cellular level damage that accumulates over time. Allocation of limited resources into such damage repair is traded-off with investment into reproduction, which determines the individual's Darwinian fitness. In consequence, traits that improve an individual's performance in early life are favored by selection, even if the same traits have negative effects late in life, when the individual has already passed on their genes to the next generation.

History

August Weismann was responsible for interpreting and formalizing the mechanisms of Darwinian evolution in a modern theoretical framework. In 1889, he theorized that ageing was part of life's program because the old need to remove themselves from the theatre to make room for the next generation, sustaining the turnover that is necessary for evolution.^[3] This theory again has much intuitive appeal, but it suffers from having a teleological or goal-driven explanation. In other words, a purpose for ageing has been identified, but not a mechanism by which that purpose could be achieved. Ageing may have this advantage for the long-term health of the community; but that doesn't explain how individuals would acquire the genes that make them get old and die, or why individuals that had ageing genes would be more successful than other individuals lacking such genes. (In fact, there is every reason to think that the opposite is true: ageing decreases individual fitness.) Weismann later abandoned his theory.

Theories suggesting that deterioration and death due to ageing are a purposeful result of an organism's evolved design (such as Weismann's "programmed death" theory) are referred to as theories of programmed ageing or adaptive ageing. The idea that the ageing characteristic was selected (an adaptation) because of its deleterious effect was largely discounted for much of the 20th century, but a theoretical model suggests that altruistic ageing could evolve if there is little migration among populations.^[4]

Mutation accumulation

The first modern theory of mammal ageing was formulated by Peter Medawar in 1952. It formed from discussions in the previous decade with J. B. S. Haldane and the selection shadow concept. Their idea was that ageing was a matter of neglect. Nature is a highly competitive place, and almost all animals in nature die before they attain old age. Therefore, there is not much reason why the body should remain fit for the long haul – not much selection pressure for traits that would maintain viability past the time when most animals would be dead anyway, killed by predators, disease, or accident.^[5]

Medawar's theory is referred to as Mutation Accumulation. The mechanism of action involves random, detrimental germline mutations of a kind that happen to show their effect only late in life. Unlike most detrimental mutations, these would not be efficiently weeded out by natural selection. On the grand scale, senescence would just be the summation of deleterious genes that only present in older individuals.^[6] Hence they would 'accumulate' and, perhaps, cause all the decline and damage that we associate with ageing.^[7][8]

Modern genetics science has disclosed a possible problem with the mutation accumulation concept in that it is now known that genes are typically expressed in specific tissues at specific times (see regulation of gene expression). Expression is controlled by some genetic "program" that activates different genes at different times in the normal growth, development, and day-to-day life of the organism. Defects in genes cause problems (genetic diseases) when they are not properly expressed when required. A problem late in life suggests that the genetic program called for expression of a gene only in late life and the mutational defect prevented proper expression. This implies existence of a program that called for different gene expression at that point in life. Why, given Medawar's concept, would there exist genes only needed in late life or a program that called for different expression only in late life? The maintenance mechanism theory (discussed below) avoids this problem.

Medawar's concept suggested that the evolution process was affected by the age at which an organism was capable of reproducing. Characteristics that adversely affected an organism prior to that age would severely limit the organism's ability to propagate its characteristics and thus would be highly "selected against" by natural selection. Characteristics that caused the same adverse effects that only appeared well after that age would have relatively little effect on the organism's ability to propagate and therefore might be allowed by natural selection. This concept fits well with the observed multiplicity of mammal life spans (and differing ages of sexual maturity) and is important to all of the subsequent theories of ageing discussed below.

Antagonistic pleiotropy

Medawar's theory was further developed by George C. Williams in 1957, who noted that senescence may be causing many deaths,^{[citation needed]} even if animals are not 'dying of old age.' In the earliest stages of senescence, an animal may lose a bit of its speed, and then predators will seize it first, while younger animals flee successfully. Or its immune system may decline, and it becomes the first to die of a new infection. Nature is such a competitive place, said Williams, (turning Medawar's argument back at him), that even a little bit of senescence can be fatal; hence natural selection does indeed care; ageing isn't cost-free.

Williams's objection has turned out to be valid: Modern studies of demography in natural environments demonstrate that senescence does indeed make a substantial contribution to the death rate in nature. These observations cast doubt on Medawar's theory. Another problem with Medawar's theory became apparent in the late 1990s, when genomic analysis became widely available. It turns out that the genes that cause ageing are not random mutations; rather, these genes form tight-knit families that have been around as long as eukaryotic life. Baker's yeast, worms, fruit flies, and mice all share some of the same ageing genes.^[9]

Williams (1957) proposed his own theory, called antagonistic pleiotropy. Pleiotropy means one gene that has two or more effects on the phenotype. In antagonistic pleiotropy, one of these effects is beneficial and another is detrimental. In essence, this refers to genes that offer benefits early in life, but exact a cost later on. If evolution is a race to have the most offspring the fastest, then enhanced early fertility could be selected even if it came with a price tag that included decline and death later on.^[1] Because ageing was a side effect of necessary functions, Williams considered any alteration of the ageing process to be "impossible."

Antagonistic pleiotropy is a prevailing theory today, but this is largely by default, and not because the theory has been well verified. In fact, experimental biologists have looked for the genes that cause ageing, and since about 1990 the technology has been available to find them efficiently. Of the many ageing genes that have been reported, some seem to enhance fertility early in life, or to carry other benefits. But there are other ageing genes for which no such corresponding benefit has been identified. This is not what Williams predicted. This may be thought of as partial validation of the theory, but logically it cuts to the core premise: that genetic trade-offs are the root cause of ageing.

Another difficulty with antagonistic pleiotropy and other theories that suppose that ageing is an adverse side effect of some beneficial function is that the linkage between adverse and beneficial effects would need to be rigid in the sense that the evolution process would not be able to evolve a way to accomplish the benefit without incurring the adverse effect even over a very long time span. Such a rigid relationship has not been experimentally demonstrated and, in general, evolution is able to independently and individually adjust myriad organism characteristics.

In breeding experiments, Michael R. Rose selected fruit flies for long lifespan. Based on antagonistic pleiotropy, Rose expected that this would surely reduce their fertility. His team found that they were able to breed flies that lived more than twice as long as the flies they started with, but to their surprise, the long-lived, inbred flies actually laid more eggs than the short-lived flies. This was another setback for pleiotropy theory, though Rose maintains it may be an experimental artefact.^[10]

Disposable soma theory

A third mainstream theory of ageing, the ''Disposable soma theory, proposed in 1977 by Thomas Kirkwood, presumes that the body must budget the amount of energy available to it. The body uses food energy for metabolism, for reproduction, and for repair and maintenance. With a finite supply of food, the body must compromise, and do none of these things quite as well as it would like. It is the compromise in allocating energy to the repair function that causes the body gradually to deteriorate with age.^[11] A caveat to the disposable soma theory suggests that time, rather than energy, is a limiting resource that may be critical to an organism. The concept is that each organism must reproduce in an optimal period in order to ensure the greatest chance of success for the offspring. This optimal period is dictated by the ecological niche of the organism but in essence, it limits the time that any given organism can devote to growth and development prior to bearing offspring. Thus, developmental rate and gestational rate are subject to evolutionary pressure. The need to accelerate gestation limits the time allocated to damage repair at the cellular level, resulting in an accumulation of damage and a decreased lifespan relative to organisms with longer gestation. This concept stems from a comparative analysis of genomic stability in mammalian cells.^[12]

There are arguments against the disposable soma theory. The theory clearly predicts that a shortage of food should make the compromise more severe all around; but in many experiments, ongoing since 1930, it has been demonstrated that animals live longer when fed substantially less than controls. This is the caloric restriction (CR) effect,^[13][14][15] and it cannot be easily reconciled with the Disposable Soma theory. Though by decreasing energy expenditure the damage generated (by free radicals, for instance) is expected to be reduced and the total energy budget might indeed be reduced, but the investment in repair function might still be relatively the same. But dietary restriction has not been shown to increase lifetime reproductive success (fitness), because when food availability is lower, reproductive output is also lower. So CR does thus not completely dismiss disposable soma theory.

With respect to such limitations Kriete^[16] proposed consideration of systems-level properties like robustness to characterize ageing as a robustness tradeoff. According to this concept living systems evolve into a state of highly optimized tolerance promoting traits beneficial for survival and fitness at the cost of fragilities driving the ageing phenotype. The view is compatible with aspects of the antagonistic pleiotropy and the disposable soma theory, but offers additional mechanisms rooted in complex systems theory.

Other problems with the classical ageing theories

A raised criticism for all three mainstream theories based on classical evolutionary process concepts is the potential existence of 'deliberate' metabolic mechanisms that work to promote death.

One is apoptosis, or programmed cell death. Apoptosis is responsible for killing infected cells, cancerous cells, and cells that are simply in the wrong place during development. There are clear benefits to apoptosis, so the existence of apoptosis isn't a problem for evolutionary theory. The problem is that apoptosis seems to ramp up late in life and kill healthy cells, causing weakness and degeneration^{[citation needed]}. And, paradoxically, apoptosis has been observed as a kind of 'altruistic suicide' in colonies of yeast under stress.^[17] This seems to be a direct hint that senescence arose because it conferred a direct evolutionary advantage, rather than some kind of side effect of genes that have other evolutionary advantages (pleiotropy).

A second 'deliberate' mechanism is called replicative senescence or cellular senescence. Metaphorically, a cell may be said to 'count' (with its telomeres) the number of times that it has divided, and after a set number of replications, it languishes and dies. It has been proposed that this mechanism evolved to suppress cancer.^[18][19] Many invertebrates experience replicative senescence, though they never die of cancer.^{[citation needed]} Even one-celled organisms count replications, and will die if they don't replenish their telomeres with conjugation (sex).^[20]

More strictly, cells cannot 'count' the number of times they have divided^{[citation needed]}. Telomeres are not a counting mechanism^{[citation needed]}, though they may be used to indicate the number of times a particular chromosome has been replicated. Cellular processes for genetic material replication occur in both directions along DNA, 5' to 3' and on the other strand, 3' to 5'. As the 3' or 5' end is impossible for DNA polymerase to grab at the 1 base pair mark, a handful of basepairs (10-15) are cut off each replication. Over time, this cutting short of the DNA results in no telomeres, and the cell is unable to replicate that chromosome without cutting into genes.

The dilemma is that classical evolutionary theory says that what is maintained in a lineage is that which ensures the viability of an organism and its offspring. Ageing can only cut off an individual's capacity to reproduce. So, according to classical theory, ageing could only evolve as a side effect, or epiphenomenon of selection. The disposable soma theory and antagonistic pleiotropy theory are examples in which a compensating individual benefit, compatible with classical evolution theory (See neo-Darwinism) is proposed. Nevertheless, there is accumulated evidence that ageing looks like an adaptation in its own right, selected for its own sake.^[21][22]

Semelparous organisms and others that die suddenly following reproduction (e.g. salmon, octopus, marsupial mouse (brown antechinus), etc.) also represent instances of organisms who incorporate a lifespan-limiting feature. Sudden death is more obviously an instance of programmed death or a purposeful adaptation than gradual ageing. Biological elements clearly associated with evolved mechanisms such as hormone signalling have been identified in the death mechanisms of organisms such as the octopus.^[23]

Impact of new evolution concepts on ageing theories

At the time most of the non-programmed ageing theories were developed, there was very little scientific disagreement with classical theories (i.e. Neo-Darwinism) regarding the process of evolution. However, in addition to suicidal behaviour of semelparous species (not handled by the classical ageing theories) other apparently individually adverse organism characteristics such as altruism and sexual reproduction were observed. In response to these other conflicts, adjustments to classical theory were proposed:

• Various group selection theories (beginning in 1962) propose that benefit to a group could offset the individually adverse nature of a characteristic such as altruism. The same principle could be applied to characteristics that limited life span and theories proposing group benefits for limited lifespans appeared.
• Evolvability theories (beginning in 1995) suggest that a characteristic that increased an organism's ability to evolve could also offset an individual disadvantage and thus be evolved and retained. Multiple evolvability benefits of a limited lifespan were subsequently proposed in addition to those originally proposed by Weismann.

Ageing theories based on group selection

Group selection is often criticized to be too slow to happen in real biology. However, Jiang-Nan Yang^[4] recently showed with an individual-based model that the evolution of altruistic ageing occurs under fairly general conditions by kin/group selection. Group selection can be based on population viscosity (limited offspring dispersal, first proposed by Hamilton (1964) for kin selection) that is widely present in natural populations. This population structure builds a continuum between individual selection, kin selection, kin group selection and group selection without a clear boundary for each level. Although early theoretical models by D.S. Wilson et al. (1992)^[24] and Taylor (1992)^[25] showed that pure population viscosity cannot lead to cooperation/altruism because of the exact cancelling out of the benefit of kin cooperation and the cost of kin competition, this exact cancelling out also suggests that any additional benefit of local cooperation would be sufficient for the evolution of cooperation.^[4] Mitteldorf and D.S. Wilson (2000) later showed that if the population is allowed to fluctuate, then local populations can temporarily store the benefit of local cooperation and promote the evolution of altruism.^[26] By assuming individual differences in adaptations, Yang (2013) further showed that the benefit of local altruism can be stored in the form of offspring quality and thus promote the evolution of altruistic ageing even if the population does not fluctuate, this is because local competition among the young will result in an increased average local inherited fitness of survived progenies after the elimination of the less adapted by natural selection, since the young do not have strong age-associated abilities and have to depend more on inherited abilities to compete.^[4] In Yang (2013)'s model, altruistic ageing is stabilized by higher-level selection instead of just kin selection.^[4]

Mitteldorf^[27] proposed a group benefit of a limited lifespan involving regulation of population dynamics. Populations in nature are subject to boom and bust cycles. Often overpopulation can be punished by famine or by epidemic. Either one could wipe out an entire population. Senescence is a means by which a species can 'take control' of its own death rate, and level out the boom-bust cycles. This story may be more plausible than the Weismann hypothesis as a mechanistic explanation, because it addresses the question of how group selection can be rapid enough to compete with individual selection.

Libertini^[28] also suggests benefits for adaptive ageing.

Inversely, within a Negative Senescence Theory R.D. Lee (similarly J.W. Vaupel) considered positive group effects performing a selection force directed to survival beyond the age of fertility.^[29] Often also postreproductive individuals make intergenerational transfers: bottlenose dolphins and pilot whales guard their grandchildren; there is cooperative breeding in some mammals, many insects and about 200 species of birds; sex differences in the survival of anthropoid primates tend to correlate with the care to offspring; or an Efe infant is often attended by more than 10 people. Lee developed a formal theory integrating selection due to transfers (at all ages) with selection due to fertility.^[30]

Ageing theories based on evolvability

Goldsmith^[31] proposed that in addition to increasing the generation rate, and thereby evolution rate, a limited lifespan improves the evolution process by limiting the ability of older individuals to dominate the gene pool. Further, the evolution of characteristics such as intelligence and immunity may specially require a limited lifespan because otherwise acquired characteristics such as experience or exposure to pathogens would tend to override the selection of the beneficial inheritable characteristic. An older and more experienced, but less intelligent animal would have a fitness advantage over a younger, more intelligent animal except for the effects of ageing.

Skulachev^[32] has suggested that programmed ageing assists the evolution process by providing a gradually increasing challenge or obstacle to survival and reproduction, and therefore enhancing the selection of beneficial characteristics. In this sense, ageing would act in a manner similar to that of mating rituals that take the form of contests or trials that must be overcome in order to mate (another individually adverse observation). This suggests an advantage of gradual ageing over sudden death as a means of lifespan regulation.

Weissmann's 1889 ageing theory was essentially an evolvability theory. Ageing or otherwise purposely limited lifespan helps evolution by freeing resources for younger, and therefore, presumably better-adapted individuals.

Yang (2013)'s model^[4] is also based on mechanisms of evolvability. Ageing accelerates the accumulation of novel adaptive genes in local populations. However, Yang changed the terminology of "evolvability" into "genetic creativity" throughout his paper to facilitate the understanding of how ageing can have a shorter-term benefit than the word "evolvability" would imply.

Lenart and Vašku (2016) ^[33] have also invoked evolvability as the main mechanism driving evolution of aging. However, they proposed that even though the actual rate of aging can be an adaptation the aging itself is inevitable. In other words, evolution can change speed of aging but some aging no matter how slow will always occur.

Mechanism

If organisms purposely limit their lifespans via ageing or semelparous behaviour, the associated evolved mechanisms could be very complex, just as mechanisms that provide for mentation, vision, digestion, or other biological function are typically very complex. Such a mechanism could involve hormones, signalling, sensing of external conditions, and other complex functions typical of evolved mechanisms. Such complex mechanisms could explain all of the observations of ageing and semelparous behaviours as described below.

It is typical for a given biological function to be controlled by a single mechanism that is capable of sensing the germane conditions and then executing the necessary function^{[citation needed]}. The mechanism signals all the systems and tissues that need to respond to that function by means of organism-wide signals (hormones). If ageing is indeed a biological function, we would expect all or most manifestations of ageing to be similarly controlled by a common mechanism. Various observations (listed below) indeed suggest the existence of a common control mechanism.

It is also typical for biological functions to be modulated by or synchronized to external events or conditions. The circadian rhythm and synchronization of mating behaviour to planetary cues are examples. In the case of ageing seen as a biological function, the caloric restriction effect may well be an example of the ageing function being modulated in order to optimize organism lifespan in response to external conditions. Temporary extension of lifespan under famine conditions would aid in group survival because extending lifespan, combined with less-frequent reproduction, would reduce the resources required to maintain a given population.

Theories to the effect that ageing results by default (mutation accumulation) or is an adverse side effect of some other function are logically much more limited and suffer when compared to empirical evidence of complex mechanisms. The choice of ageing theory therefore is logically essentially determined by one's position regarding evolutionary processes, and some theorists reject programmed ageing based entirely on evolutionary process considerations.^[34]

Maintenance theories

It is generally accepted that deteriorative processes (wear, other molecular damage) exist and that living organisms have mechanisms to counter deterioration. Wounds heal; dead cells are replaced; claws regrow.

A non-programmed theory of mammal ageing^[35] that fits with classical evolution theory and Medawar's concept is that different mammal species possess different capabilities for maintenance and repair. Longer-lived species possess many mechanisms for offsetting damage due to causes such as oxidation, telomere shortening, and other deteriorative processes that are each more effective than those of shorter-lived species. Shorter-lived species, having earlier ages of sexual maturity, had less need for longevity and thus did not evolve or retain the more-effective repair mechanisms. Damage therefore accumulates more rapidly, resulting in earlier manifestations and shorter lifespan. Since there are a wide variety of ageing manifestations that appear to have very different causes, it is likely that there are many different maintenance and repair functions.

A corresponding programmed maintenance theory based on evolvability^[36] suggests that the repair mechanisms are in turn controlled by a common control mechanism capable of sensing conditions, such as caloric restriction, and also capable of producing the specific lifespan needed by the particular species. In this view, the differences between short- and long-lived species are in the control mechanisms, as opposed to each individual maintenance mechanism.

DNA damage theory

The DNA damage theory of aging is a prominent explanation for aging at the molecular level. This theory postulates that DNA damage is ubiquitous in the biological world and is the primary cause of aging.^[37] Consistent with this theory, genetic elements that regulate repair of DNA damage in somatic cells were proposed to have pleiotropic effects that are beneficial during early development but allow deleterious consequences later in life.^[37][38][39] As an example, studies of mammalian brain and muscle have shown that DNA repair capability is relatively high during early development when cells are dividing mitotically, but declines substantially as cells enter the post-mitotic state. The reduction in DNA repair capability presumably reflects an evolutionary adaptation for diverting resources from cell duplication and repair to more essential neuronal and muscular functions.^[37] The effect of reducing expression of DNA repair capability is to allow increased accumulation of DNA damage. This then impairs gene transcription and causes the progressive loss of cellular and tissue functions that define aging.

Evidence

• Complex programmed death mechanisms exist in semelparous species (e.g. octopus), including hormone signalling, nervous system involvement, etc. If a limited lifespan is generally useful as predicted by the programmed ageing theories, it would be unusual for an octopus to possess a more complex mechanism for accomplishing that function than a mammal.
• "Ageing genes" with no other apparent function. However to date no evidence that such genes exist has been found.
• Caloric restriction effect: reduction of available resources increases lifespan. This behavior has a plausible group benefit in enhancing the survival of a group under famine conditions and also suggests common control.
• Progeria and Werner syndrome are both single-gene genetic diseases that cause acceleration of many or most symptoms of ageing. The fact that a single gene malfunction can cause similar effects on many different manifestations of ageing suggests a common mechanism. However, both genes affected influence DNA stability and so can be explained by stochastic theories of ageing that attribute ageing to accumulation of DNA damage.
• Although mammal lifespans vary over an approximately 100:1 range, manifestations of ageing (cancer, arthritis, weakness, sensory deficit, etc.) are similar in different species. This suggests that the deterioration mechanisms and corresponding maintenance mechanisms operate over a short period (less than the lifespan of a short-lived mammal). All the mammals therefore need all the maintenance mechanisms. This suggests that the difference between mammals is in a control mechanism or repair efficiency.
• Lifespan varies greatly among otherwise very similar species (e.g. different varieties of salmon 3:1, different fish 600:1) suggesting that relatively few genes control lifespan and that relatively minor changes to genotype could cause major differences in lifespan. This could be consistent with a common control mechanism for lifespan but note that this does not in itself provide evidence for programmed aging but is equally consistent with traditional theories.

Problems with programmed ageing theories

Contrary to the theory of programmed death by ageing, individuals from a single species usually live much longer in a protected (laboratory, domestic, civilized) environment than in their wild (natural) environment, reaching ages that would be otherwise practically impossible. Also, in majority of species, there doesn't exist any critical age after which death rates change dramatically, as intended by the programmed death by ageing^{[citation needed]}, but the age-dependence of death rates is very smooth and monotonic. However, as mentioned above, V.P. Skulachev^[43] explained that a process of gradual ageing has the advantage of facilitating selection for useful traits by allowing old individuals with a useful trait to live longer. It is also easy to imagine that animals with gradual ageing will live longer in a protected environment.

The death rates at extreme old ages start to slow down, which is the opposite of what would be expected if death by ageing was programmed. From an individual-selection point of view, having genes that would not result in a programmed death by ageing would displace genes that cause programmed death by ageing, as individuals would produce more offspring in their longer lifespan and they could increase the survival of their offspring by providing longer parental support.^[44]

Biogerontology considerations

Theories of ageing affect efforts to understand and find treatments for age-related conditions (see biogerontology):

• Those who believe in the idea that ageing is an unavoidable side effect of some necessary function (antagonistic pleiotropy or disposable soma theories) logically tend to believe that attempts to delay ageing would result in unacceptable side effects to the necessary functions. Altering ageing is therefore "impossible",^[1] and study of ageing mechanisms is of only academic interest.
• Those believing in default theories of multiple maintenance mechanisms tend to believe that ways might be found to enhance the operation of some of those mechanisms. Perhaps they can be assisted by anti-oxidants or other agents.
• Those who believe in programmed ageing suppose that ways might be found to interfere with the operation of the part of the ageing mechanism that appears to be common to multiple symptoms, essentially "slowing down the clock" and delaying multiple manifestations. Such effect might be obtained by fooling a sense function. One such effort is an attempt to find a "mimetic" that would "mime" the anti-ageing effect of calorie restriction without having to actually radically restrict diet.

Gerontology

From Wikipedia, the free encyclopedia

Gerontology is the study of the social, cultural, psychological, cognitive, and biological aspects of ageing. The word was coined by Ilya Ilyich Mechnikov in 1903, from the Greek γέρων, geron, "old man" and -λογία, -logia, "study of". The field is distinguished from geriatrics, which is the branch of medicine that specializes in the treatment of existing disease in older adults. Gerontologists include researchers and practitioners in the fields of biology, nursing, medicine, criminology, dentistry, social work, physical and occupational therapy, psychology, psychiatry, sociology, economics, political science, architecture, geography, pharmacy, public health, housing, and anthropology.

The multidisciplinary nature of gerontology means that there are a number of sub-fields which overlap with gerontology. There are policy issues, for example, involved in government planning and the operation of nursing homes, investigating the effects of an ageing population on society, and the design of residential spaces for older people that facilitate the development of a sense of place or home. Dr. Lawton, a behavioral psychologist at the Philadelphia Geriatric Center, was among the first to recognize the need for living spaces designed to accommodate the elderly, especially those with Alzheimer's disease. As an academic discipline the field is relatively new. The USC Leonard Davis School created the first PhD, master's and bachelor's degree programs in gerontology in 1975.

History

In the medieval Islamic world, several physicians wrote on issues related to Gerontology. Avicenna's The Canon of Medicine (1025) offered instruction for the care of the aged, including diet and remedies for problems including constipation.^[3] Arabic physician Ibn Al-Jazzar Al-Qayrawani (Algizar, c. 898–980) wrote on the aches and conditions of the elderly (Ammar 1998, p. 4).^[4] His scholarly work covers sleep disorders, forgetfulness, how to strengthen memory,^[5][6] and causes of mortality^[7] Ishaq ibn Hunayn (died 910) also wrote works on the treatments for forgetfulness (U.S. National Library of Medicine, 1994).^[8]

While the number of aged humans, and the life expectancy, tended to increase in every century since the 14th, society tended to consider caring for an elderly relative as a family issue. It was not until the coming of the Industrial Revolution that ideas shifted in favor of a societal care-system. Some early pioneers, such as Michel Eugène Chevreul, who himself lived to be 102, believed that aging itself should be a science to be studied. Élie Metchnikoff coined the term "gerontology" c. 1903.^[9]

Modern pioneers like James Birren began organizing gerontology as its own field in the 1940s, later being involved in starting a US government agency on aging – the National Institute on Aging^[10] – programs in gerontology at the University of Southern California and University of California, Los Angeles, and as past president of the Gerontological Society of America (founded in 1945).^[11]

With the population of people over 60 years old expected to be some 22% of the world's population by 2050, assessment and treatment methods for age-related disease burden – a multidisciplinary field called geroscience that emerged in the early 21st century – are a frontier for modern medical research on relationships between aging and chronic diseases.^[12][13][14]

Aging demographics

The world is forecast to undergo rapid population aging in the next several decades. In 1900, there were 3.1 million people aged 65 years and older living in the United States. However, this population continued to grow throughout the 20th century and reached 31.2, 35, and 40.3 million people in 1990, 2000, and 2010, respectively. Notably, in the United States and across the world, the "baby boomer" generation began to turn 65 in 2011. Recently, the population aged 65 years and older has grown at a faster rate than the total population in the United States. The total population increased by 9.7%, from 281.4 million to 308.7 million, between 2000 and 2010. However, the population aged 65 years and older increased by 15.1% during the same period.^[15] It has been estimated that 25% of the population in the United States and Canada will be aged 65 years and older by 2025. Moreover, by 2050, it is predicted that, for the first time in United States history, the number of individuals aged 60 years and older will be greater than the number of children aged 0 to 14 years.^[16] Those aged 85 years and older (oldest-old) are projected to increase from 5.3 million to 21 million by 2050.^[17] Adults aged 85–89 years constituted the greatest segment of the oldest-old in 1990, 2000, and 2010. However, the largest percentage point increase among the oldest-old occurred in the 90- to 94-year-old age group, which increased from 25.0% in 1990 to 26.4% in 2010.^[15]

With the rapid growth of the aging population, social work education and training specialized in older adults and practitioners interested in working with older adults are increasingly in demand.^[18][19]

Gender differences with age

There has been a considerable disparity between the number of men and women in the older population in the United States. In both 2000 and 2010, women outnumbered men in the older population at every single year of age (e.g., 65 to 100 years and over). The sex ratio, which is a measure used to indicate the balance of males to females in a population, is calculated by taking the number of males divided by the number of females, and multiplying by 100. Therefore, the sex ratio is the number of males per 100 females. In 2010, there were 90.5 males per 100 females in the 65-year-old population. However, this represented an increase from 1990 when there were 82.7 males per 100 females, and from 2000 when the sex ratio was 88.1. Although the gender gap between men and women has narrowed, women continue to have a greater life expectancy and lower mortality rates at older ages relative to men. For example, the Census 2010 reported that there were approximately twice as many women as men living in the United States at 89 years of age (361,309 versus 176,689, respectively).^[15]

Geographic distribution of older adults

The number and percentage of older adults living in the United States vary across the four different regions (Northeast, Midwest, West, and South) defined by the United States census. In 2010, the South contained the greatest number of people aged 65 years and older and 85 years and older. However, proportionately, the Northeast contains the largest percentage of adults aged 65 years and older (14.1%), followed by the Midwest (13.5%), the South (13.0%), and the West (11.9%). Relative to the Census 2000, all geographic regions demonstrated positive growth in the population of adults aged 65 years and older and 85 years and older. The most rapid growth in the population of adults aged 65 years and older was evident in the West (23.5%), which showed an increase from 6.9 million in 2000 to 8.5 million in 2010. Likewise, in the population aged 85 years and older, the West (42.8%) also showed the fastest growth and increased from 806,000 in 2000 to 1.2 million in 2010. It is worth highlighting that Rhode Island was the only state that experienced a reduction in the number of people aged 65 years and older, and declined from 152,402 in 2000 to 151,881 in 2010. Conversely, all states exhibited an increase in the population of adults aged 85 years and older from 2000 to 2010.^[15]

Biogerontology

The hand of an older adult

Biogerontology is the sub-field of gerontology concerned with the biological aging process, its evolutionary origins, and potential means to intervene in the process. It involves interdisciplinary research on biological aging's causes, effects, and mechanisms. Conservative biogerontologists such as Leonard Hayflick have predicted that the human life expectancy will peak at about 92 years old,^[20] while others such as James Vaupel have predicted that in industrialized countries, life expectancies will reach 100 for children born after the year 2000.^[21] and some surveyed biogerontologists have predicted life expectancies of two or more centuries.^[22] with Aubrey de Grey offering the "tentative timeframe" that with adequate funding of research to develop interventions in aging such as Strategies for Engineered Negligible Senescence, "we have a 50/50 chance of developing technology within about 25 to 30 years from now that will, under reasonable assumptions about the rate of subsequent improvements in that technology, allow us to stop people from dying of aging at any age", leading to life expectancies of 1,000 years.^[23]

Biomedical gerontology, also known as experimental gerontology and life extension, is a sub-discipline of biogerontology that endeavors to slow, prevent, and even reverse aging in both humans and animals. Most "life extensionists" believe the human life span can be increased within the next century, if not sooner. Biogerontologists vary in the degree to which they focus on the study of the aging process as a means of mitigating the diseases of aging or extending lifespan, although most agree that extension of lifespan will necessarily flow from reductions in age-related disease and frailty, although some argue that maximum life span cannot be altered or that it is undesirable to try. Geroscience is a recently-formulated interdisciplinary field that embraces biomedical gerontology as the center of preventing diseases of aging through science emerging at the interface of the biology of aging and age-related disease.^[24]

In contrast with biogerontology, which aims to prevent age-related disease by intervening in aging processes, geriatrics is a field of medicine that studies the treatment of existing disease in aging people.

Biological theories of aging

There are numerous theories of aging, and no one theory has been accepted. There is a wide spectrum of the types of theories for the causes of aging with programmed theories on one extreme and error theories on the other. Regardless of the theory, a commonality is that as humans age, functions of the body decline.^[16]

Stochastic theories of aging (STA)

Stochastic theories of aging is the suggestion that aging is caused by small changes in the body over time and the body's failure to restore the system and mend the damages to the body. The cells and tissues are eventually injured due to the damage gathered over time. This causes the diminishes in an organ's function related to age. The notion of accumulated damage was first introduced by Weisman as the "wear and tear" theory.^[25]

Wear and tear theory

Wear and tear theories of aging suggest that as an individual ages, body parts such as cells and organs wear out from continued use. Wearing of the body can be attributable to internal or external causes that eventually lead to an accumulation of insults which surpasses the capacity for repair. Due to these internal and external insults, cells lose their ability to regenerate, which ultimately leads to mechanical and chemical exhaustion. Some insults include chemicals in the air, food, or smoke. Other insults may be things such as viruses, trauma, free radicals, cross-linking, and high body temperature.^[16]

Accumulation

Accumulation theories of aging suggest that aging is bodily decline that results from an accumulation of elements, whether introduced to the body from the environment or resulting from cell metabolism.^[16] An example of an accumulation theory is the Free Radical Theory of Aging.

The free radical theory of aging

Free radicals are reactive molecules produced by cellular and environmental processes, and can damage the elements of the cell such as the cell membrane and DNA and cause irreversible damage. The free-radical theory of aging proposes that this damage cumulatively degrades the biological function of cells and impacts the process of aging.^[26] The idea that free radicals are toxic agents was first proposed by Rebeca Gerschman and colleagues in 1945,^[27] but came to prominence in 1956, when Denham Harman proposed the free-radical theory of aging and even demonstrated that free radical reactions contribute to the degradation of biological systems.^[28] Oxidative damage of many types accumulate with age, such as oxidative stress that oxygen-free radicals,^[29] because the free radical theory of aging argues that aging results from the damage generated by reactive oxygen species (ROS).^[30] ROS are small, highly reactive, oxygen-containing molecules that can damage a complex of cellular components such as fat, proteins, or from DNA, they are naturally generated in small amounts during the body's metabolic reactions. These conditions become more common as we age, including diseases related to aging, such as dementia, cancer and heart disease.

The DNA damage theory of aging

DNA damage has been one of the many causes in diseases related to aging. The stability of the genome is defined by the cells machinery of repair, damage tolerance, and checkpoint pathways that counteracts DNA damage. One hypothesis proposed by Gioacchino Failla in 1958^[31] is that damage accumulation to the DNA causes aging. The hypothesis was developed soon by physicist Leó Szilárd.^[32] This theory has changed over the years as new research has discovered new types of DNA damage and mutations, and several theories of aging argue that DNA damage with or without mutations causes aging.^[33]

The cross-linking theory of aging

The cross-linking theory proposes that advanced glycation end-products (stable bonds formed by the binding of glucose to proteins) and other aberrant cross-links accumulating in aging tissues is the cause of aging. The crosslinking of proteins disables their biological functions. The hardening of the connective tissue, kidney diseases, and enlargement of the heart are connected to the cross-linking of proteins. Crosslinking of DNA can induce replication errors, and this leads to deformed cells and increases the risk of cancer.^[25]

Genetic

Genetic theories of aging propose that aging is programmed within each individual's genes. According to this theory, genes dictate cellular longevity. Programmed cell death, or apoptosis, is determined by a "biological clock" via genetic information in the nucleus of the cell. Genes responsible for apoptosis provide an explanation for cell death, but are less applicable to death of an entire organism. An increase in cellular apoptosis may correlate to aging, but is not a 'cause of death'. Environmental factors and genetic mutations can influence gene expression and accelerate aging. More recently epigenetics have been explored as a contributing factor. The epigenetic clock, which objectively measures the biological age of cells and tissues, may become useful for testing different biological aging theories.^[34]

General imbalance

General imbalance theories of aging suggest that body systems, such as the endocrine, nervous, and immune systems, gradually decline and ultimately fail to function. The rate of failure varies system by system.^[16]

Immunological theory of aging

The immunological theory of aging suggests that the immune system weakens as an organism ages. This makes the organism unable to fight infections and less able to destroy old and neoplastic cells. This leads to aging and will eventually lead to death. This theory of aging was developed by Ray Walford, an American gerontologist. According to Walford, incorrect immunological procedures are the cause of the process of aging.^[26]

Social gerontology

Social gerontology is a multi-disciplinary sub-field that specializes in studying or working with older adults. Social gerontologists may have degrees or training in social work, nursing, psychology,  sociology, demography, public health, or other social science disciplines. Social gerontologists are responsible for educating, researching, and advancing the broader causes of older people.

Because issues of life span and life extension need numbers to quantify them, there is an overlap with demography. Those who study the demography of the human life span differ from those who study the social demographics of aging.

Social theories of aging

Several theories of aging are developed to observe the aging process of older adults in society as well as how these processes are interpreted by men and women as they age.^[35]

Activity theory

Activity theory was developed and elaborated by Cavan, Havighurst, and Albrecht. According to this theory, older adults' self-concept depends on social interactions. In order for older adults to maintain morale in old age, substitutions must be made for lost roles. Examples of lost roles include retirement from a job or loss of a spouse.^[35]

Activity is preferable to inactivity because it facilitates well-being on multiple levels. Because of improved general health and prosperity in the older population, remaining active is more feasible now than when this theory was first proposed by Havighurst nearly six decades ago. The activity theory is applicable for a stable, post-industrial society, which offers its older members many opportunities for meaningful participation.Weakness: Some aging persons cannot maintain a middle-aged lifestyle, due to functional limitations, lack of income, or lack of a desire to do so. Many older adults lack the resources to maintain active roles in society. On the flip side, some elders may insist on continuing activities in late life that pose a danger to themselves and others, such as driving at night with low visual acuity or doing maintenance work to the house while climbing with severely arthritic knees. In doing so, they are denying their limitations and engaging in unsafe behaviors.^[36]

Disengagement theory

Disengagement theory was developed by Cumming and Henry. According to this theory, older adults and society engage in a mutual separation from each other. An example of mutual separation is retirement from the workforce. A key assumption of this theory is that older adults lose "ego-energy" and become increasingly self-absorbed. Additionally, disengagement leads to higher morale maintenance than if older adults try to maintain social involvement. This theory is heavily criticized for having an escape clause - namely, that older adults who remain engaged in society are unsuccessful adjusters to old age.^[35]

Gradual withdrawal from society and relationships preserves social equilibrium and promotes self-reflection for elders who are freed from societal roles. It furnishes an orderly means for the transfer of knowledge, capital, and power from the older generation to the young. It makes it possible for society to continue functioning after valuable older members die.

Continuity theory

Continuity theory is an elusive concept. On one hand, to exhibit continuity can mean to remain the same, to be uniform, homogeneous, unchanging, even humdrum. This static view of continuity is not very applicable to human aging. On the other hand, a dynamic view of continuity starts with the idea of a basic structure which persists over time, but it allows for a variety of changes to occur within the context provided by the basic structure. The basic structure is coherent: It has an orderly or logical relation of parts that is recognizably unique and that allows us to differentiate that structure from others. With the introduction of the concept of time, ideas such as direction, sequence, character development, and story line enter into the concept of continuity as it is applied to the evolution of a human being. In this theory, a dynamic concept of continuity is developed and applied to the issue of adaptation to normal aging.^[37]

A central premise of continuity theory is that, in making adaptive choices, middle-aged and older adults attempt to preserve and maintain existing internal and external structures and that they prefer to accomplish this objective by using continuity (i.e., applying familiar strategies in familiar arenas of life). In middle and later life, adults are drawn by the weight of past experience to use continuity as a primary adaptive strategy for dealing with changes associated with normal aging. To the extent that change builds upon, and has links to, the person's past, change is a part of continuity. As a result of both their own perceptions and pressures from the social environment, individuals who are adapting to normal aging are both predisposed and motivated toward inner psychological continuity as well as outward continuity of social behavior and circumstances.^[38]

Continuity theory views both internal and external continuity as robust adaptive strategies that are supported by both individual preference and social sanctions. Continuity theory consists of general adaptive principles that people who are normally aging could be expected to follow, explanations of how these principles work, and a specification of general areas of life in which these principles could be expected to apply. Accordingly, continuity theory has enormous potential as a general theory of adaptation to individual aging.^[39]

Age stratification theory

According to this theory, older adults born during different time periods form cohorts that define "age strata". There are two differences among strata: chronological age and historical experience. This theory makes two arguments. 1. Age is a mechanism for regulating behavior and as a result determines access to positions of power. 2. Birth cohorts play an influential role in the process of social change.^[35]

Life course theory

According to this theory, which stems from the Life Course Perspective (Bengston and Allen, 1993),^[40] aging occurs from birth to death. Aging involves social, psychological, and biological processes. Additionally, aging experiences are shaped by cohort and period effects.^[35]

Also reflecting the life course focus, consider the implications for how societies might function when age-based norms vanish—a consequence of the deinstitutionalization of the life course— and suggest that these implications pose new challenges for theorizing aging and the life course in postindustrial societies. Dramatic reductions in mortality, morbidity, and fertility over the past several decades have so shaken up the organization of the life course and the nature of educational, work, family, and leisure experiences that it is now possible for individuals to become old in new ways. The configurations and content of other life stages are being altered as well, especially for women. In consequence, theories of age and aging will need to be reconceptualized.^[41]

Cumulative advantage/disadvantage theory

According to this theory, which was developed beginning in the 1960s by Derek Price and Robert Merton and elaborated on by several researchers such as Dale Dannefer,^[42] inequalities have a tendency to become more pronounced throughout the aging process. A paradigm of this theory can be expressed in the adage "the rich get richer and the poor get poorer". Advantages and disadvantages in early life stages have a profound effect throughout the life span. However, advantages and disadvantages in middle adulthood have a direct influence on economic and health status in later life.^[35]

Environmental gerontology

Environmental gerontology is a specialization within gerontology that seeks an understanding and interventions to optimize the relationship between aging persons and their physical and social environments.^[43][44][45]

The field emerged in the 1930s during the first studies on behavioral and social gerontology. In the 1970s and 1980s, research confirmed the importance of the physical and social environment in understanding the aging population and improved the quality of life in old age.^[46] Studies of environmental gerontology indicate that older people prefer to age in their immediate environment, whereas spatial experience and place attachment are important for understanding the process.^[47]

Some research indicates that the physical-social environment is related to the longevity and quality of life of the elderly. Precisely, the natural environment (such as natural therapeutic landscapes, therapeutic garden) contributes to active and healthy aging in the place.^[48][49]

Jurisprudential gerontology

Jurisprudential gerontology (sometimes referred to as "geriatric jurisprudence") is a specialization within gerontology that looks into the ways laws and legal structures interact with the aging experience. The field started from legal scholars in the field of elder law, which found that looking into legal issues of older persons without a broader inter-disciplinary perspective does not provide the ideal legal outcome. Using theories such as therapeutic jurisprudence, jurisprudential scholars critically examined existing legal institutions (e.g. adult guardianship, end of life care, or nursing homes regulations) and showed how law should look more closely to the social and psychological aspects of its real-life operation.^[50] Other streams within jurisprudential gerontology also encouraged physicians and lawyers to try to improve their cooperation and better understand how laws and regulatory institutions affect health and well being of older persons.