Age of onset

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The age of onset is the age at which an individual acquires, develops, or first experiences a condition or symptoms of a disease or disorder. For instance, the general age of onset for the spinal disease scoliosis is "10-15 years old," [1] meaning that most people develop scoliosis when they are of age between ten and fifteen years.

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Diseases are often categorized by their ages of onset as congenital, infantile, juvenile, or adult. Missed or delayed diagnosis often occurs if a disease that is typically diagnosed in juveniles (such as asthma) is present in adults, and vice versa (such as arthritis). [2] Depending on the disease, ages of onset may impact features such as phenotype, as is the case in Parkinson's and Huntington's diseases. [3] [4] For example, the phenotype for juvenile Huntington's disease clearly differs from adult-onset Huntington's disease and late-onset Parkinson's exhibits more severe motor and non-motor phenotypes. [3] [4]

Causes

Germ-line mutations are often at least in part the cause of disease onset at an earlier age. [5] [6] Though many germ-line mutations are deleterious, the genetic lens through which they may be viewed may provide insights to treatment, possibly through genetic counseling. [7] [8]

In some cases, the age of onset may be the result of mutation accumulation. [9] If this is the case, it could be helpful to consider ages of onset as a product of the hypotheses depicted in theories of aging. Even some mental health disorders, whose ages of onset have been found to be harder to define than physical illnesses may have a mutated component. [10] The symptoms of standard mental disorders often start off non-specific. Pathological changes pertaining to disorders often become more detailed and less fickle before they can be defined in the American Psychiatric Association's DSM. The brain is a dynamic and complex system, it is constantly re-wiring itself and a major concern is what happens to the brain in earlier life that mirrors what occurs later in its psycho-pathological state. [11] The typical onset of many mental disorders in late adolescence may reflect the critical development that happens at this time. [12]

Theories of Aging

The rate-of-living theory of aging states that senescence occurs because individuals accumulate damage to cells and tissues during cell division. This theory is not supported because its postulates that aging rate should be correlated with metabolic rate [13] and organisms cannot evolve longer lifespans [14] [15] were not supported in trials. [14] [15] [16] [17] [18] The rate-of-living theory may not be used to draw conclusions about age of onset based on this.

There are two subsets to the evolutionary theory of aging: antagonistic pleiotropy hypothesis and the mutation accumulation hypothesis.

The antagonistic pleiotropy hypothesis was tested by monitoring the age-1 gene in C. elegans. [19] The age-1 gene plays a role in senescence; nematodes with mutations in this gene live up to 80% longer. [19] Mutants in the age-1 gene for allele hx546 seem to be otherwise normal until placed under stressful conditions. [19] Then, the carriers of the mutant gene appear to be at disadvantage—they do not lay eggs while being starved. [19] This evidence supports antagonistic pleiotropy as a theory of aging, and therefore as an onset cause in some cases.

The mutation accumulation hypothesis was tested by demonstrating how quickly deleterious mutations can accumulate in Musca domestica. [20] Reed and Bryant demonstrated this by limiting the lifespan of the flies to a few days, which made late-life mutations invisible to selection since they occurred after reproduction. [20] The lifespan of the flies was monitored by allowing them to carry out their complete lifespan every few generations, which was reported to decline substantially. [20] Mutation accumulation is supported as a theory of aging, and therefore an onset cause in cases of diseases resulting from mutation accumulation.

Related Research Articles

<i>Drosophila</i> Genus of flies

Drosophila is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species to linger around overripe or rotting fruit. They should not be confused with the Tephritidae, a related family, which are also called fruit flies ; tephritids feed primarily on unripe or ripe fruit, with many species being regarded as destructive agricultural pests, especially the Mediterranean fruit fly.

Senescence or biological aging is the gradual deterioration of functional characteristics in living organisms. The word senescence can refer to either cellular senescence or to senescence of the whole organism. Organismal senescence involves an increase in death rates and/or a decrease in fecundity with increasing age, at least in the later part of an organism's life cycle. However, the resulting effects of senescence can be delayed. The 1934 discovery that calorie restriction can extend lifespans by 50% in rats, the existence of species having negligible senescence, and the existence of potentially immortal organisms such as members of the genus Hydra have motivated research into delaying senescence and thus age-related diseases. Rare human mutations can cause accelerated aging diseases.

<i>Drosophila melanogaster</i> Species of fruit fly

Drosophila melanogaster is a species of fly in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the "vinegar fly", "pomace fly", or "banana fly". In the wild, D. melanogaster are attracted to rotting fruit and fermenting beverages, and are often found in orchards, kitchens and pubs.

Genetic architecture is the underlying genetic basis of a phenotypic trait and its variational properties. Phenotypic variation for quantitative traits is, at the most basic level, the result of the segregation of alleles at quantitative trait loci (QTL). Environmental factors and other external influences can also play a role in phenotypic variation. Genetic architecture is a broad term that can be described for any given individual based on information regarding gene and allele number, the distribution of allelic and mutational effects, and patterns of pleiotropy, dominance, and epistasis.

<span class="mw-page-title-main">Pleiotropy</span> Influence of a single gene on multiple phenotypic traits

Pleiotropy occurs when one gene influences two or more seemingly unrelated phenotypic traits. Such a gene that exhibits multiple phenotypic expression is called a pleiotropic gene. Mutation in a pleiotropic gene may have an effect on several traits simultaneously, due to the gene coding for a product used by a myriad of cells or different targets that have the same signaling function.

Enquiry into the evolution of ageing, or aging, aims to explain why a detrimental process such as ageing would evolve, and why there is so much variability in the lifespans of organisms. The classical theories of evolution suggest that environmental factors, such as predation, accidents, disease, and/or starvation, ensure that most organisms living in natural settings will not live until old age, and so there will be very little pressure to conserve genetic changes that increase longevity. Natural selection will instead strongly favor genes which ensure early maturation and rapid reproduction, and the selection for genetic traits which promote molecular and cellular self-maintenance will decline with age for most organisms.

Genetic assimilation is a process described by Conrad H. Waddington by which a phenotype originally produced in response to an environmental condition, such as exposure to a teratogen, later becomes genetically encoded via artificial selection or natural selection. Despite superficial appearances, this does not require the (Lamarckian) inheritance of acquired characters, although epigenetic inheritance could potentially influence the result. Waddington stated that genetic assimilation overcomes the barrier to selection imposed by what he called canalization of developmental pathways; he supposed that the organism's genetics evolved to ensure that development proceeded in a certain way regardless of normal environmental variations.

The following outline is provided as an overview of and topical guide to life extension:

<span class="mw-page-title-main">Antagonistic pleiotropy hypothesis</span> Proposed evolutionary explanation for senescence

The antagonistic pleiotropy hypothesis was first proposed by George C. Williams in 1957 as an evolutionary explanation for senescence. Pleiotropy is the phenomenon where one gene controls more than one phenotypic trait in an organism. A gene is considered to possess antagonistic pleiotropy if it controls more than one trait, where at least one of these traits is beneficial to the organism's fitness early on in life and at least one is detrimental to the organism's fitness later on due to a decline in the force of natural selection. The theme of G. C. William's idea about antagonistic pleiotropy was that if a gene caused both increased reproduction in early life and aging in later life, then senescence would be adaptive in evolution. For example, one study suggests that since follicular depletion in human females causes both more regular cycles in early life and loss of fertility later in life through menopause, it can be selected for by having its early benefits outweigh its late costs.

The stem cell theory of aging postulates that the aging process is the result of the inability of various types of stem cells to continue to replenish the tissues of an organism with functional differentiated cells capable of maintaining that tissue's original function. Damage and error accumulation in genetic material is always a problem for systems regardless of the age. The number of stem cells in young people is very much higher than older people and thus creates a better and more efficient replacement mechanism in the young contrary to the old. In other words, aging is not a matter of the increase in damage, but a matter of failure to replace it due to a decreased number of stem cells. Stem cells decrease in number and tend to lose the ability to differentiate into progenies or lymphoid lineages and myeloid lineages.

Sexual antagonistic co-evolution is the relationship between males and females where sexual morphology changes over time to counteract the opposite's sex traits to achieve the maximum reproductive success. This has been compared to an arms race between sexes. In many cases, male mating behavior is detrimental to the female's fitness. For example, when insects reproduce by means of traumatic insemination, it is very disadvantageous to the female's health. During mating, males will try to inseminate as many females as possible, however, the more times a female's abdomen is punctured, the less likely she is to survive. Females that possess traits to avoid multiple matings will be more likely to survive, resulting in a change in morphology. In males, genitalia is relatively simple and more likely to vary among generations compared to female genitalia. This results in a new trait that females have to avoid in order to survive.

Interlocus sexual conflict is a type of sexual conflict that occurs through the interaction of a set of antagonistic alleles at two or more different loci, or the location of a gene on a chromosome, in males and females, resulting in the deviation of either or both sexes from the fitness optima for the traits. A co-evolutionary arms race is established between the sexes in which either sex evolves a set of antagonistic adaptations that is detrimental to the fitness of the other sex. The potential for reproductive success in one organism is strengthened while the fitness of the opposite sex is weakened. Interlocus sexual conflict can arise due to aspects of male–female interactions such as mating frequency, fertilization, relative parental effort, female remating behavior, and female reproductive rate.

A behaviour mutation is a genetic mutation that alters genes that control the way in which an organism behaves, causing their behavioural patterns to change.

<span class="mw-page-title-main">Genetics of aging</span> Overview of the genetics of aging

Genetics of aging is generally concerned with life extension associated with genetic alterations, rather than with accelerated aging diseases leading to reduction in lifespan.

A human disease modifier gene is a modifier gene that alters expression of a human gene at another locus that in turn causes a genetic disease. Whereas medical genetics has tended to distinguish between monogenic traits, governed by simple, Mendelian inheritance, and quantitative traits, with cumulative, multifactorial causes, increasing evidence suggests that human diseases exist on a continuous spectrum between the two.

In evolutionary biology, developmental bias refers to the production against or towards certain ontogenetic trajectories which ultimately influence the direction and outcome of evolutionary change by affecting the rates, magnitudes, directions and limits of trait evolution. Historically, the term was synonymous with developmental constraint, however, the latter has been more recently interpreted as referring solely to the negative role of development in evolution.

Extrinsic mortality is the sum of the effects of external factors, such as predation, starvation and other environmental factors not under control of the individual that cause death. This is opposed to intrinsic mortality, which is the sum of the effects of internal factors contributing to normal, chronologic aging, such as, for example, mutations due to DNA replication errors, and which determined species maximum lifespan. Extrinsic mortality plays a significant role in evolutionary theories of aging, as well as the discussion of health barriers across socioeconomic borders.

<span class="mw-page-title-main">Mutation accumulation theory</span> Theory of aging

The mutation accumulation theory of aging was first proposed by Peter Medawar in 1952 as an evolutionary explanation for biological aging and the associated decline in fitness that accompanies it. Medawar used the term 'senescence' to refer to this process. The theory explains that, in the case where harmful mutations are only expressed later in life, when reproduction has ceased and future survival is increasingly unlikely, then these mutations are likely to be unknowingly passed on to future generations. In this situation the force of natural selection will be weak, and so insufficient to consistently eliminate these mutations. Medawar posited that over time these mutations would accumulate due to genetic drift and lead to the evolution of what is now referred to as aging.

Abdominal pigmentation in Drosophila melanogaster is a morphologically simple but highly variable trait that often has adaptive significance. Pigmentation has extensively been studied in Drosophila melanogaster. It has been used as a model for understanding the development and evolution of morphological phenotypes.

<span class="mw-page-title-main">Age-1</span> Gene

The age-1 gene is located on chromosome 2 in C.elegans. It gained attention in 1983 for its ability to induce long-lived C. elegans mutants. The age-1 mutant, first identified by Michael Klass, was reported to extend mean lifespan by over 50% at 25 °C when compared to the wild type worm (N2) in 1987 by Johnson et al. Development, metabolism, lifespan, among other processes have been associated with age-1 expression. The age-1 gene is known to share a genetic pathway with daf-2 gene that regulates lifespan in worms. Additionally, both age-1 and daf-2 mutants are dependent on daf-16 and daf-18 genes to promote lifespan extension.

References

  1. ↑ "National Scoliosis Foundation".
  2. ↑ Kirkpatrick, Susan; Locock, Louise; Farre, Albert; Ryan, Sara; Salisbury, Helen; McDonagh, Janet E. (2018-02-09). "Untimely illness: When diagnosis does not match age-related expectations". Health Expectations. 21 (4): 730–740. doi:10.1111/hex.12669. ISSN   1369-6513. PMC   6117493 . PMID   29424066.
  3. 1 2 Pagano, Gennaro; Ferrara, Nicola; Brooks, David J.; Pavese, Nicola (2016-02-10). "Age at onset and Parkinson disease phenotype". Neurology. 86 (15): 1400–1407. doi:10.1212/wnl.0000000000002461. ISSN   0028-3878. PMC   4831034 . PMID   26865518.
  4. 1 2 Sipilä, Jussi O. T.; Kauko, Tommi; Päivärinta, Markku; Majamaa, Kari (2017-08-28). "Comparison of mid-age-onset and late-onset Huntington's disease in Finnish patients". Journal of Neurology. 264 (10): 2095–2100. doi:10.1007/s00415-017-8600-2. ISSN   0340-5354. PMID   28849405. S2CID   37872535.
  5. ↑ Lewinsohn, M.; Brown, A. L.; Weinel, L. M.; Phung, C.; Rafidi, G.; Lee, M. K.; Schreiber, A. W.; Feng, J.; Babic, M. (2015-12-28). "Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies". Blood. 127 (8): 1017–1023. doi:10.1182/blood-2015-10-676098. ISSN   0006-4971. PMC   4968341 . PMID   26712909.
  6. ↑ Zhang, Zhongqiu; Wang, Yian; Lantry, Laura E; Kastens, Elizabeth; Liu, Gongjie; Hamilton, Andrew D; Sebti, Said M; Lubet, Ronald A; You, Ming (September 2003). "Farnesyltransferase inhibitors are potent lung cancer chemopreventive agents in A/J mice with a dominant-negative p53 and/or heterozygous deletion of Ink4a/Arf". Oncogene. 22 (40): 6257–6265. doi: 10.1038/sj.onc.1206630 . ISSN   0950-9232. PMID   13679864.
  7. ↑ Smith, Karen Lisa; Isaacs, Claudine (2011). "BRCA Mutation Testing in Determining Breast Cancer Therapy". The Cancer Journal. 17 (6): 492–499. doi:10.1097/ppo.0b013e318238f579. ISSN   1528-9117. PMC   3240813 . PMID   22157293.
  8. ↑ Fanen, Pascale; Wohlhuter-Haddad, Adeline; Hinzpeter, Alexandre (July 2014). "Genetics of cystic fibrosis: CFTR mutation classifications toward genotype-based CF therapies" (PDF). The International Journal of Biochemistry & Cell Biology. 52: 94–102. doi:10.1016/j.biocel.2014.02.023. ISSN   1357-2725. PMID   24631642.
  9. ↑ Campisi, Judith (February 1996). "Replicative Senescence: An Old Lives' Tale?". Cell. 84 (4): 497–500. doi: 10.1016/s0092-8674(00)81023-5 . ISSN   0092-8674. PMID   8598035. S2CID   10751319.
  10. ↑ Kandaswamy, Radhika; McQuillin, Andrew; Sharp, Sally I.; Fiorentino, Alessia; Anjorin, Adebayo; Blizard, Robert A.; Curtis, David; Gurling, Hugh M. D. (2013-06-01). "Genetic Association, Mutation Screening, and Functional Analysis of a Kozak Sequence Variant in the Metabotropic Glutamate Receptor 3 Gene in Bipolar Disorder". JAMA Psychiatry. 70 (6): 591–8. doi:10.1001/jamapsychiatry.2013.38. ISSN   2168-622X. PMID   23575746.
  11. ↑ Jones, P. B. (2013-01-01). "Adult mental health disorders and their age at onset". The British Journal of Psychiatry. 202 (s54): s5–s10. doi: 10.1192/bjp.bp.112.119164 . ISSN   0007-1250. PMID   23288502.
  12. ↑ Gogtay, N.; Vyas, N. S.; Testa, R.; Wood, S. J.; Pantelis, C. (2011-04-19). "Age of Onset of Schizophrenia: Perspectives From Structural Neuroimaging Studies". Schizophrenia Bulletin. 37 (3): 504–513. doi:10.1093/schbul/sbr030. ISSN   0586-7614. PMC   3080674 . PMID   21505117.
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  15. 1 2 Luckinbill, Leo S.; Arking, Robert; Clare, Michael J.; Cirocco, William C.; Buck, Steven A. (September 1984). "Selection for Delayed Senescence in Drosophila Melanogaster". Evolution. 38 (5): 996–1003. doi: 10.1111/j.1558-5646.1984.tb00369.x . ISSN   0014-3820. PMID   28555795.
  16. ↑ Partridge, Linda; Fowler, Kevin (February 1992). "Direct and Correlated Responses to Selection on Age at Reproduction in Drosophila melanogaster". Evolution. 46 (1): 76–91. doi:10.1111/j.1558-5646.1992.tb01986.x. ISSN   0014-3820. JSTOR   2409806. PMID   28564973.
  17. ↑ Partridge, L. (1987). "Is Accelerated Senescence a Cost of Reproduction?". Functional Ecology. 1 (4): 317–320. doi:10.2307/2389786. ISSN   0269-8463. JSTOR   2389786.
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  20. 1 2 3 Reed, David H; Bryant, Edwin H (2000). "The evolution of senescence under curtailed life span in laboratory populations of Musca domestica (the housefly)". Heredity. 85 (2): 115–121. doi: 10.1046/j.1365-2540.2000.00737.x . ISSN   0018-067X. PMID   11012712.
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