antagonistic pleiotropy

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The antagonistic pleiotropy is an explanatory model for the aging of organisms that reproduce sexually . The theory was put forward in 1957 by the American evolutionary biologist George C. Williams . It is assigned to the evolutionary theories of aging.

description

The antagonistic pleiotropy is based on two assumptions:

  1. A single gene can have several functions in an organism ( pleiotropy )
  2. These pleiotropic functions can have antagonistic effects on the health of an individual.

The hypothesis is that some genes are beneficial at a young age but more harmful as they age. Such genes are antagonistically called pleiotropic genes .

Since the deleterious effects of these genes only appear in old age after the reproductive phase, they have little evolutionary impact. Nature cannot select directly against a gene or its mutation that kills an individual in old age when its harmful effects do not appear until after the reproductive phase has ended. Harmful mutations that only show their effect in old age could therefore accumulate at will in the genome of an organism. This would be the case in particular if these mutations give the organism advantages in terms of reproductive success at an early stage of life.

The prediction derived from the antagonistic pleiotropy is that an artificial shortening of the reproductive phase leads to a shorter lifespan and, conversely, an extension of this phase leads to a longer lifespan of an organism.

Williams further postulated that natural selection usually invests "energy" in reproductive youth, which then lacks in old age. For this reason, the theory of antagonistic pleiotropy is also called Pay Later Theory .

Williams' ideas were translated into mathematical models by Brian Charlesworth in 1994 .

Examples

A mutation that leads to increased production of sex hormones would increase the sex drive and libido of the affected organism. As a result, reproductive efforts and reproductive success would increase. The latter is a clear selection advantage that leads to the transmission and spread of this mutation, even if this leads to a significant increase in the rate of hormone-associated cancers (for example prostate cancer in men and breast cancer in women).

Another example would be a mutation in a gene that encodes a particular enzyme . As a result of the mutation, the enzyme ( gene product ) would now be able to make a nutrient accessible to the cells that the organism was previously unable to use. This would be a clear selection advantage over conspecifics that cannot utilize this nutrient. This advantage would also assert itself evolutionarily if, for example, the development of this nutrient would simultaneously generate toxic free radicals that cause lasting damage to the organism, lead to earlier aging and a higher cancer rate in old age - if these events do not occur until after the reproductive phase.

The p53 protein is encoded by a tumor suppressor gene ( TP53 ). It ensures that a cell only divides if its genetic material is intact. In this way, it prevents normal cells from developing into cancer cells. A defect in the TP53 gene - for example a point mutation - can lead to the affected patients developing tumors in early childhood. This is the case , for example, with Li Fraumeni syndrome . p53 is therefore also known as the “guardian of the genome”. Because of this protective effect, one should expect that an increased expression of p53 has a positive effect on an organism. However, this is not the case. As expected, mice with increased p53 expression develop cancer much less often, but age considerably faster than their normal counterparts. Similar relationships were found for different genotypes of TP53 in humans. People with the proline / proline genotype have a longer life expectancy than the arginine / arginine genotype, but also a death rate from cancer that is 2.5 times higher. In the Pro / Pro genotype, the amino acid arginine in position 72 of the p53 peptide has been exchanged for proline. If the expression of p53 is reduced in the model organism Drosophila melanogaster , the lifespan of these fruit flies increases significantly. Because of these properties, p53 is seen as a pleiotropic gene.

The enzymes from the DUOX ( dual oxidase ) and NOX ( NADPH oxidases ) family generate harmful reactive oxygen species in body cells , which are seen as the cause of a number of late-onset diseases . The evolutionary advantage that these enzymes offer the organism at a young age is obviously reversed in old age and is an example of antagonistic pleiotropy.

reception

A number of laboratory tests were able to support the essential statements of the theory of antagonistic pleiotropy. Out of the multitude of theories on aging, leading biogerontologists believe that antagonistic pleiotropy is one of the most important evolutionary mechanisms that can explain the aging of organisms and their natural death.

further reading

  • F. Rodier: Two faces of p53: aging and tumor suppression. In: Nucleic Acids Res 35, 2007, pp. 7475-7484; PMID 17942417 (review); PMC 2190721 (free full text).
  • D. van Heemst et al .: Aging or cancer: a review on the role of caretakers and gatekeepers. In: Eur J Cancer 43, 2007, pp. 2144-2152. PMID 17764928 (Review).
  • A. Aranda-Anzaldo and MA Dent: Reassessing the role of p53 in cancer and aging from an evolutionary perspective. In: Mech Aging Dev 128, 2007, pp. 293-302; PMID 17291568 (Review).
  • KA Hughes and RM Reynolds: Evolutionary and mechanistic theories of aging. In: Annu Rev Entomol 50, 2005, pp. 421-445; PMID 15355246 (Review).
  • DE Promislow: Protein networks, pleiotropy and the evolution of senescence. In: Proc Biol Sci 271, 2004, pp. 1225-1234; PMID 15306346 ; PMC 1691725 (free full text).
  • KA Hughes et al: A test of evolutionary theories of aging. In: PNAS 99, 2002, pp. 14286-14291; PMID 12386342 ; PMC 137876 (free full text).
  • M. Rose and B. Charlesworth: A test of evolutionary theories of senescence. In: Nature 287, 1980, pp. 141-142; PMID 6776406 .

Individual evidence

  1. ↑ a b J. A. Blackburn, CN Dulmus (editor): Handbook of Gerontology: Evidence-Based Approaches to Theory, Practice, and Policy. Verlag Wiley, 2007, ISBN 978-0-471-77170-8 , pp. 46-47.
  2. ↑ a b P. Ljubuncic and AZ Reznick: The evolutionary theories of aging revisited - a mini-review. In: Gerontology 55, 2009, pp. 205-216. PMID 19202326 (Review).
  3. ↑ GC Williams: Pleiotropy, natural selection, and the evolution of senescence. In: Evolution 11, 1957, pp. 398-411.
  4. ↑ a b c T. Schmidt et al.: Physiological potentials of longevity and health in an evolutionary biological and cultural context - basic requirements for a productive life. ( Memento from January 12, 2012 in the Internet Archive ) In: Productive life in old age M. Baltes and L. Montada (eds.), Campus-Verlag, 1996, ISBN 3-593-35456-X , pp. 69–130.
  5. ^ B. Charlesworth: Evolution in Age-Structured Populations. Cambridge University Press, 1994, ISBN 0-521-45967-2 .
  6. ↑ C. López-Otín and EP Diamandis: Breast and prostate cancer: an analysis of common epidemiology, genetic and biochemical features. In: Endocr Rev 19, 1998, pp. 365-396. PMID 9715372 (Review).
  7. ^ DP Lane: Cancer. p53, guardian of the genome. In: Nature 358, 1992, pp. 15-16. PMID 1614522 .
  8. ↑ SD Tyner et al .: p53 mutant mice that display early aging-associated phenotypes. In: Nature 415, 2002, pp. 45-53. PMID 11780111 .
  9. ↑ G. Ferbeyre and SW Lowe: Aging: The price of tumor suppression? In: Nature 415, 2002, pp. 26-27. PMID 11780097 .
  10. ^ J. Campisi: Cancer and aging: rival demons? In: Nat Rev Cancer 3, 2003, pp. 339-349. PMID 12724732 .
  11. ↑ D. van Heemst et al: Variation in the human TP53 gene affects old age survival and cancer mortality. In: Exp Gerontol 40, 2005, pp. 11-15. PMID 15732191 (Review).
  12. ↑ LA Donehower: p53: guardian AND suppressor of longevity? In: Exp Gerontol 40, 2005, pp. 7-9. PMID 15664727 (Review).
  13. ↑ P. Dumont et al: The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. In: Nat Genet 33, 2003, pp. 357-365. PMID 12567188 .
  14. ↑ JH Bauer et al.: Neuronal expression of p53 dominant-negative proteins in adult Drosophila melanogaster extends life span. In: Curr Biol 15, 2005, pp. 2063-2088. PMID 16303568 .
  15. ↑ E. Ungewitter and H. Scrable: Antagonistic pleiotropy and p53. In: Mech Aging Dev 130, 2009, pp. 10-17. PMID 18639575 (Review).
  16. ↑ JD Lambeth: Nox enzymes, ROS, and chronic disease: an example of antagonistic pleiotropy. In: Free radical biology & medicine. Volume 43, number 3, August 2007, pp. 332-347, doi: 10.1016 / j.freeradbiomed.2007.03.027 , PMID 17602948 , PMC 2013737 (free full text). (Table)
  17. ↑ JD Lambeth: Nox enzymes, ROS, and chronic disease: an example of antagonistic pleiotropy. In: Free Radic Biol Med 43, 2007, pp. 332-347; PMID 17602948 ; PMC 2013737 (free full text).
  18. ^ L. Partridge and D. Gems: Mechanisms of aging: Public or private? In: Nature Reviews Genetics 3, 2002, pp. 165-175. PMID 11972154 .
  19. ↑ S. Knell and M. Weber: Menschliches Leben. Verlag DeGruyter, 2009, ISBN 978-3-11-021983-8 , p. 63.