{{short description|Proposed evolutionary explanation for senescence}} {{cs1 config|name-list-style=vanc|display-authors=6}} [[File:Strengthofselectionplot.png|alt=|thumb|Strength of natural selection plot as a function of age]] The '''antagonistic pleiotropy hypothesis''' (APT) is a theory in [[evolutionary biology]] that suggests certain genes may confer beneficial effects early in an organism's life, enhancing survival or fertility, while also causing detrimental effects later in life, thereby contributing to the ageing process. APT provides an explanation of how some genes are not eliminated by natural selection even though they are associated with catastrophic health outcomes, especially in older age (e.g. [[Alzheimer's disease]] or [[Sickle cell disease|sickle cell anaemia]]).
APT was first proposed in a 1952 paper on the evolutionary theory of aging by [[Peter Medawar]] and developed further in a paper by [[George C. Williams (biologist)|George C. Williams]] in 1957<ref>{{cite journal |vauthors=Williams GC |year=1957 |title=Pleiotropy, natural selection, and the evolution of senescence |journal=Evolution |volume=11 |issue=4 |pages=398–411 |doi=10.2307/2406060 |jstor=2406060}}</ref> as an explanation for [[senescence]].<ref name="Austad_2018">{{cite journal | vauthors = Austad SN, Hoffman JM | title = Is antagonistic pleiotropy ubiquitous in aging biology? | journal = Evolution, Medicine, and Public Health | volume = 2018 | issue = 1 | pages = 287–294 | date = 2018 | pmid = 30524730 | pmc = 6276058 | doi = 10.1093/emph/eoy033 }}</ref> [[Pleiotropy]] is the phenomenon where a single [[gene]] influences more than one phenotypic trait in an organism.<ref name="Cheverud_1996">{{cite journal| vauthors = Cheverud J |year=1996|title=Developmental integration and the evolution of pleiotropy|journal=American Zoology|volume=36|pages=44–50|citeseerx=10.1.1.526.8366|doi=10.1093/icb/36.1.44}}</ref><ref name="Zhang_2006">{{cite journal | vauthors = He X, Zhang J | title = Toward a molecular understanding of pleiotropy | journal = Genetics | volume = 173 | issue = 4 | pages = 1885–1891 | date = August 2006 | pmid = 16702416 | pmc = 1569710 | doi = 10.1534/genetics.106.060269 | bibcode = 2006Genet.173.1885H }}</ref> It is one of the most commonly observed attributes of genes.<ref name="Otto_2004">{{cite journal | vauthors = Otto SP | title = Two steps forward, one step back: the pleiotropic effects of favoured alleles | journal = Proceedings. Biological Sciences | volume = 271 | issue = 1540 | pages = 705–714 | date = April 2004 | pmid = 15209104 | pmc = 1691650 | doi = 10.1098/rspb.2003.2635 | bibcode = 2004PBioS.271..705O }}</ref> A gene is considered to exhibit antagonistic pleiotropy if it controls more than one [[phenotypic trait]], where at least one of these traits is beneficial to the organism's [[Fitness (biology)|fitness]] and at least one is detrimental to fitness.
This line of genetic research attempts to answer the following question: if survival and reproduction should always be favoured by natural selection, why should ageing – which in evolutionary terms can be described as the age-related decline in survival rate and reproduction – be nearly ubiquitous in the natural world?"<ref name="Austad_2018" /> The antagonistic pleiotropy hypothesis provides a partial answer to this question. As an evolutionary explanation for ageing, the hypothesis relies on the fact that reproductive capacity declines with age in many species and that, therefore, the strength of natural selection also declines with age (because there can be no natural selection without reproduction).<ref name="Elena_2003">{{cite journal | vauthors = Elena SF, Sanjuán R | title = Evolution. Climb every mountain? | journal = Science | volume = 302 | issue = 5653 | pages = 2074–2075 | date = December 2003 | pmid = 14684807 | doi = 10.1126/science.1093165 | s2cid = 83853360 }}</ref><ref>{{cite journal | vauthors = Flatt T | title = Survival costs of reproduction in Drosophila | journal = Experimental Gerontology | volume = 46 | issue = 5 | pages = 369–375 | date = May 2011 | pmid = 20970491 | doi = 10.1016/j.exger.2010.10.008 | s2cid = 107465469 | url = http://doc.rero.ch/record/324277/files/2011_scr.pdf }}</ref> Since the strength of selection declines over the life cycles of human and most other organisms, natural selection in these species does not eliminate "[[allele]]s that have early beneficial effects, but later deleterious effects".<ref>{{cite book |vauthors = Rose MR, Rauser CL |date=2007 |chapter=Evolution and Comparative Biology |title=Encyclopedia of Gerontology |volume=2 |pages=538–547 |doi=10.1016/B0-12-370870-2/00068-8 |isbn=978-0-12-370870-0 }}</ref>
Antagonistic pleiotropy also provides a framework for understanding why many [[genetic disorder]]s, even those causing life threatening health impacts (e.g. [[Sickle cell disease|sickle cell anaemia]]), are found to be relatively prevalent in populations. Seen through the lens of simple evolutionary processes, these genetic disorders should be observed at very low frequencies due to the force of natural selection. Genetic models of populations show that antagonistic pleiotropy allows genetic disorders to be maintained at reasonably high frequencies "even if the fitness benefits are subtle".<ref name="Carter_2011" /> In this sense, antagonistic pleiotropy forms the basis of a "genetic trade-off between different fitness components."<ref name = "Brown_2018">{{cite journal | vauthors = Brown KE, Kelly JK | title = Antagonistic pleiotropy can maintain fitness variation in annual plants | journal = Journal of Evolutionary Biology | volume = 31 | issue = 1 | pages = 46–56 | date = January 2018 | pmid = 29030895 | doi = 10.1111/jeb.13192 }}</ref>
== Trade-offs == In the theory of evolution, the concept of fitness has two components: survival and reproduction. Antagonistic pleiotropy gets fixed in genomes by creating viable trade-offs between or within these two components. The existence of these trade-offs has been clearly demonstrated in human, botanical and insect species. For example, an analysis of global gene expression in the fruit fly, ''Drosophila melanogaster'', revealed 34 genes whose expression coincided with the genetic trade-off between larval survival and adult size. The joint expression of these candidate 'trade-off' genes explained 86.3% of the trade-off. These tradeoffs can result from selection at the level of the organism or, more subtly, via mechanisms for the allocation of scarce resources in cellular metabolism.<ref>{{cite journal | vauthors = Bochdanovits Z, de Jong G | title = Antagonistic pleiotropy for life-history traits at the gene expression level | journal = Proceedings. Biological Sciences | volume = 271 | issue = Suppl 3 | pages = S75–S78 | date = February 2004 | pmid = 15101424 | pmc = 1809996 | doi = 10.1098/rsbl.2003.0091 | bibcode = 2004PBioS.271.0091B }}</ref>
Another example is found in a study of the yellow [[Erythranthe|monkey flower]], an [[annual plant]]. The study documents a trade-off between days-to-flower and reproductive capacity. This genetic balancing act determines how many individuals survive to flower in a short growing season (viability) while also influencing the seed set of survivors (fecundity). The authors find that tradeoffs between plant viability and fecundity can engender a stable polymorphism under surprisingly general conditions. Thus, for this annual flower, they reveal a tradeoff between mortality and fecundity and, according to the authors, this tradeoff is also relevant for other annual, flowering plants.<ref name = "Brown_2018" />
=== Role in fecundity and senescence === Senescence refers to the process of physiological change in individual members of a species as they age.<ref name="Carter_2011" /><ref>{{cite journal | vauthors = Promislow DE | title = Protein networks, pleiotropy and the evolution of senescence | journal = Proceedings. Biological Sciences | volume = 271 | issue = 1545 | pages = 1225–1234 | date = June 2004 | pmid = 15306346 | pmc = 1691725 | doi = 10.1098/rspb.2004.2732 }}</ref> An antagonistically pleiotropic gene can be selected for if it has beneficial effects in early life while manifesting its negative effects in later life because genes tend to have larger impacts on fitness in an organism's prime than in their old age.<ref name="Wood_2001">{{cite report | vauthors = Wood JW, O'Connor KA, Holman DJ, Brindle E, Barsom SH, Grimes MA | date = 2001 | title = The evolution of menopause by antagonistic pleiotropy. | work = Center for Demography and Ecology, Working Paper }}</ref> Williams's 1957 article has motivated many follow-up studies on the evolutionary causes of ageing.<ref name="Fox_2006">{{cite book | veditors = Fox CW, Wolf JB | title = Evolutionary genetics: concepts and case studies. | publisher = Oxford University Press | date = April 2006 | isbn = 978-0-19-516817-4}}</ref> These studies show clear trade-offs involving early increases in fecundity and later increases in mortality. For example, two experiments with ''Drosophila melanogaster'' have shown that increased fertility is associated with reduced longevity. Likewise, for humans, infertile women live longer on average than fertile women.<ref name="Van_Den_Biggelaar_2004" /><ref>{{cite journal | vauthors = Long E, Zhang J | title = Evidence for the role of selection for reproductively advantageous alleles in human aging | journal = Science Advances | volume = 9 | issue = 49 | article-number = eadh4990 | date = December 2023 | pmid = 38064565 | pmc = 10708185 | doi = 10.1126/sciadv.adh4990 | bibcode = 2023SciA....9H4990L }}</ref>
One such study tests the hypothesis that death due to cardiovascular disease in women is linked to an antagonistic pleiotropy operating through inflammation and linked to fertility. Because the human immune system evolved in an ancestral environment characterized by abundant pathogens, protective, pro-inflammatory responses (which helped individuals to avoid and survive infections) were undoubtedly selected for in these environments. However, in terms of cardiovascular risk, these same inflammatory responses have turned out to be harmful as the material conditions of human existence improved – in affluent countries, where life expectancy is much longer than in the ancestral environment, strong inflammatory responses carry greater risks of cardiovascular disease as individuals age. The study looks at mortality, over a period of 3 to 5 years, in a group of 311, 85-year old Dutch women. Information on their reproductive history as well the results of blood tests, genetic tests and physical examinations was recorded. The study found that individuals with a higher pro-inflammatory ratio TNFα/IL-10 had a significantly higher incidence of death due to cardiovascular disease in old age. It also linked specific [[allele]]s to a combination of higher fertility, stronger inflammatory response and greater cardiovascular problems in old age. This finding supports the hypothesis that this gene was prevalent because it helped women in the ancestral environment to more effectively combat infection during their reproductive years. However, the pleiotropic costs of the gene in terms of cardiovascular risks are now clear because people live long enough to die of cardiovascular disease.<ref name="Van_Den_Biggelaar_2004">{{cite journal |vauthors=Van Den Biggelaar AH, De Craen AJ, Gussekloo J, Huizinga TW, Heijmans BT, Frölich M, Kirkwood TB, Westendorp RG |date=June 2004 |title=Inflammation underlying cardiovascular mortality is a late consequence of evolutionary programming |journal=FASEB Journal |volume=18 |issue=9 |pages=1022–1024 |doi=10.1096/fj.03-1162fje |pmid=15084512 |s2cid=1379140 |doi-access=free}}</ref>
=== Role in disease === The survival of many serious genetic disorders in human evolutionary history has led researchers to explore the role of antagonistic [[pleiotropy]] in disease. If genetic disorders are caused by mutations to a single deleterious allele, then [[natural selection]] should eliminate carriers of this allele over evolutionary time, thereby lowering the frequency of these mutations. Yet, research shows that the incidence of such alleles in studied populations is often stable and relatively high.<ref name="Carter_2011">{{cite journal | vauthors = Carter AJ, Nguyen AQ | title = Antagonistic pleiotropy as a widespread mechanism for the maintenance of polymorphic disease alleles | journal = BMC Medical Genetics | volume = 12 | article-number = 160 | date = December 2011 | pmid = 22151998 | pmc = 3254080 | doi = 10.1186/1471-2350-12-160 | doi-access = free }}</ref> In a 2011 review article, Carter and Nguyen discuss several genetic disorders, arguing that, far from being a rare phenomenon, antagonistic pleiotropy might be a fundamental mechanism by which "alleles with severe deleterious health effects can be maintained at medically relevant frequencies with only minor beneficial pleiotropic effects."<ref name="Carter_2011" />
==== Alzheimer's disease and atherosclerosis ==== Some researchers consider the relatively high frequency in human populations of the [[Apolipoprotein E|APOE ε4]] allele at the APOE locus as an example of antagonistic pleiotropy. APOE "is a major supplier of cholesterol precursor for the production of ovarian oestrogen and progesterone... ".<ref name=":0">{{Cite journal |last1=Jasienska |first1=Grazyna |last2=Ellison |first2=Peter T. |last3=Galbarczyk |first3=Andrzej |last4=Jasienski |first4=Michal |last5=Kalemba-Drozdz |first5=Malgorzata |last6=Kapiszewska |first6=Maria |last7=Nenko |first7=Ilona |last8=Thune |first8=Inger |last9=Ziomkiewicz |first9=Anna |date=2015-03-22 |title=Apolipoprotein E ( ApoE ) polymorphism is related to differences in potential fertility in women: a case of antagonistic pleiotropy? |journal=Proceedings of the Royal Society B: Biological Sciences |language=en |volume=282 |issue=1803 |article-number=20142395 |doi=10.1098/rspb.2014.2395 |issn=0962-8452 |pmc=4345437 |pmid=25673673}}</ref> APEO has therefore been identified as a gene that influences fertility. At the same time, it increases the risk of [[atherosclerosis]] and [[Alzheimer's disease]] with age.<ref name=":0" /> Why has not this allele, which is associated with extremely detrimental health incomes not been replaced by the APOE ε3 allele, which has beneficial health effects? The answer is that APOE ε4 appears to confer early‐life advantages in potential fertility,<ref name=":0" /> particularly in infectious environments.<ref>{{Cite journal |last1=van Exel |first1=Eric |last2=Koopman |first2=Jacob J. E. |last3=Bodegom |first3=David van |last4=Meij |first4=Johannes J. |last5=Knijff |first5=Peter de |last6=Ziem |first6=Juventus B. |last7=Finch |first7=Caleb E. |last8=Westendorp |first8=Rudi G. J. |date=2017-07-06 |editor-last=Chiba-Falek |editor-first=Ornit |title=Effect of APOE ε4 allele on survival and fertility in an adverse environment |journal=PLOS ONE |language=en |volume=12 |issue=7 |article-number=e0179497 |doi=10.1371/journal.pone.0179497 |doi-access=free |issn=1932-6203 |pmc=5500260 |pmid=28683096 |bibcode=2017PLoSO..1279497V }}</ref> It also has been shown to have positive impacts on cognitive development in early life<ref>{{Cite journal |last1=Iacono |first1=Diego |last2=Feltis |first2=Gloria C. |date=2019-01-24 |title=Impact of Apolipoprotein E gene polymorphism during normal and pathological conditions of the brain across the lifespan |journal=Aging |language=en |volume=11 |issue=2 |pages=787–816 |doi=10.18632/aging.101757 |issn=1945-4589 |pmc=6366964 |pmid=30677746}}</ref> and protection against many [[cancer]]s.<ref>{{Cite journal |last1=Wu |first1=Xiaofang |last2=Srinivasan |first2=Priya |last3=Basu |first3=Mousumi |last4=Zhang |first4=Peng |last5=Saruwatari |first5=Michele |last6=Thommandru |first6=Bernice |last7=Jacobi |first7=Ashley |last8=Behlke |first8=Mark |last9=Sandler |first9=Anthony |date=2022-10-19 |title=Tumor Apolipoprotein E is a key checkpoint blocking anti-tumor immunity in mouse melanoma |journal=Frontiers in Immunology |language=English |volume=13 |article-number=991790 |doi=10.3389/fimmu.2022.991790 |pmid=36341364 |pmc=9626815 |doi-access=free |issn=1664-3224}}</ref>
==== Sickle cell anaemia ==== Sickle cell anaemia has been identified as another example of APT. It results in an abnormality in the oxygen-carrying protein [[haemoglobin]] found in [[red blood cell]]s.<ref>{{Cite web |date=2023-08-30 |title= What Is Sickle Cell Disease? | work = The National Heart, Lung, and Blood Institute (NHLBI) | publisher = U.S. National Institutes of Health |url=https://www.nhlbi.nih.gov/health/sickle-cell-disease |access-date=2024-04-16 |language=en}}</ref> Possessors of the deleterious allele have much lower life expectancies, with [[Zygosity|homozygotes]] rarely reaching 50 years of age. However, this allele also enhances resistance to [[malaria]]. Thus, in regions where malaria exerts or has in the past exerted a strong selective pressure, sickle cell anaemia has been selected for its conferred partial resistance to the disease. While homozygotes will have either no protection from malaria or a dramatic propensity to sickle cell anemia (depending on which allelle they inherit), [[Zygosity|heterozygotes]] have fewer physiological effects and a partial resistance to malaria. Thus, the gene that is responsible for sickle cell disease has fixed itself with relatively high frequencies in populations threatened by malaria by engendering a viable tradeoff between death from this non-communicable disease and death from malaria.<ref>{{cite journal |vauthors=Aidoo M, Terlouw DJ, Kolczak MS, McElroy PD, ter Kuile FO, Kariuki S, Nahlen BL, Lal AA, Udhayakumar V |date=April 2002 |title=Protective effects of the sickle cell gene against malaria morbidity and mortality |journal=Lancet |volume=359 |issue=9314 |pages=1311–1312 |doi=10.1016/S0140-6736(02)08273-9 |pmid=11965279}}</ref>
==== Laron syndrome ==== In another study of genetic diseases, 99 individuals with [[Laron syndrome]] (a rare form of dwarfism) were monitored alongside their non-dwarf kin for a period of ten years. Patients with Laron syndrome possess one of three genotypes for the [[growth hormone receptor]] gene (GHR). Most patients have an A->G [[splice site mutation]] in position 180 in exon 6. Some others possess a [[nonsense mutation]] (R43X), while the rest are heterozygous for the two mutations. Laron syndrome patients experienced a lower incidence of cancer mortality and diabetes compared to their non-dwarf kin.<ref name="Guevara-Aguirre_2011">{{cite journal | vauthors = Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, Wei M, Madia F, Cheng CW, Hwang D, Martin-Montalvo A, Saavedra J, Ingles S, de Cabo R, Cohen P, Longo VD | title = Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans | journal = Science Translational Medicine | volume = 3 | issue = 70 | pages = 70ra13 | date = February 2011 | pmid = 21325617 | pmc = 3357623 | doi = 10.1126/scitranslmed.3001845 }}</ref> This suggests a role for antagonistic pleiotropy, whereby a deleterious mutation is preserved in a population because it still confers some survival benefit.<ref name="Carter_2011" />
==== Huntington's disease ==== Another instance of APT can be found in [[Huntington's disease]], a rare [[neurodegenerative]] disorder characterised by a high number of CAG repeats within the [[Huntingtin]] gene. The onset of Huntington's is usually observed post-reproductive age and generally involves involuntary muscle spasms, cognitive difficulties and psychiatric problems. The high number of CAG repeats is associated with increased activity of [[p53]], a tumor suppressing protein that participates in [[apoptosis]]. It has been hypothesized that this explains the lower rates of cancer among Huntington's patients. Huntington's disease is also correlated with high [[fecundity]].<ref name="Carter_2011" />
Other pleiotropic diseases include: [[Beta thalassemia|beta-thalassemia]] (also protects against malaria in the heterozygous state); and osteoporosis in old age (reduced risk of osteoporosis in youth).<ref name="Carter_2011" />
== Ubiquity in population genetics == Advances in genome mappings have greatly facilitated research into antagonistic pleiotropy. Such research is now often carried out in laboratories, but also in wild populations. The latter context for testing has the advantage of introducing the full complexity of the selection experience – competitors, predators, and parasites – though it has the disadvantage of introducing idiosyncratic factors that are specific to given locations. In order to be able to assert with confidence that a given pleiotropy is, indeed, an antagonistic pleiotropy and not due to some other competing cause (e.g. the [[Mutation accumulation theory|mutation accumulation]] hypothesis), one must have knowledge of the precise gene that is pleiotropic. This is now increasingly possible with organisms that have detailed genomic mappings (e.g. mice, fruit flies and humans). A 2018 review of this research finds that "antagonistic pleiotropy is somewhere between very common or ubiquitous in the animal world .... and potentially all living domains... ".<ref name="Austad_2018" />
== See also == * [[Evolution of ageing]] * [[Mutation accumulation theory]] * [[Disposable soma theory of aging]]
== References == {{reflist}}
{{senescence}} {{Evolution}}
[[Category:Genetics]] [[Category:Theories of ageing]] [[Category:Theories of biological ageing]] [[Category:Evolutionary theories of biological ageing]]