news-review:hallmarks-of-aging
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news-review:hallmarks-of-aging [2019/11/14 14:46] marcos [Histone Modifications] |
news-review:hallmarks-of-aging [2025/03/18 06:03] (current) marcos |
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| - | // The Hallmarks of Aging is an exemplary article for ease of reading, and doesn't really need a lot of "translation" for non-biology scientists (the goal of this site). Although it uses jargon, the sentence structure lends itself for ease of understanding. Perhaps that is why it has been cited as often as it has in other research articles. Therefore, the following review has been made as a cliff-notes version with expansions and addendums. // | ||
| ====== The Hallmarks of Aging ====== | ====== The Hallmarks of Aging ====== | ||
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| The last criterion is the most difficult to achieve. It's possible that amelioration of one hallmark can also reduce the others. | The last criterion is the most difficult to achieve. It's possible that amelioration of one hallmark can also reduce the others. | ||
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| + | === Theories help guide experimental work === | ||
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| + | "In his biography, Max Planck remarked: A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die, and a new generation grows up that is familiar with it. ... I am optimistic (or naïve?) enough to hope that Max Planck was wrong. During his whole life, Francis Crick emphasized the importance of theories and models in guiding experimental work and helping to eliminate lines of research leading to dead ends (Morange, 2008)." (Heininger 2012)((Heininger 2012 http://www.webmedcentral.com/article_view/3275)) | ||
| === Aging resistance versus pleiotropic genes === | === Aging resistance versus pleiotropic genes === | ||
| - | Evolution is not a master designer. The concept "survival of the fittest" is only part of the evolutionary pressure. Evolution does not select for the perfection of a singular organism, but instead optimizes the continuation of its brethren. Hence the existence of organism traits that favor reproductive fitness over longevity, such as altruistic behavior. | + | Evolution is not a master designer for the individual. "Survival of the fittest" is only part of the evolutionary pressure. Evolution does not select for the perfection of a singular organism, but instead optimizes the continuation of its progeny and relatives. Hence the existence of organism traits that favor reproductive fitness over longevity, such as altruistic behavior. |
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| + | So why does aging even exist? For a multicellular organism, maintaining all the cells as immortal is a costly expenditure. Having somal cells gave multicellular organisms an advantage by being able to do more with less energy. | ||
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| + | Thus, aging is an aspect of the soma. The germ line is meant to be immortal, and the resources required to maintain the germ line are provided for by the soma. The maintenance of the soma is only sufficient for the amount of time the organism might be expected to live, due to environmental dangers such as predation. | ||
| - | So why does aging even exist? One explanation is that of pleiotropic genes. Pleiotropy is where one gene influences more than one phenotypic trait. The [[https://en.wikipedia.org/wiki/Antagonistic_pleiotropy_hypothesis |antagonistic pleiotropy hypothesis]] states that a gene that can express both a beneficial and detrimental phenotype will be preserved if its benefit outweighs the detriment. An example is high testosterone in human males, which increases fitness in early life, while also increasing the risk of prostate cancer with age. Consider that life expectancy beyond 40 was something very uncommon, just a few centuries ago (Song and Johnson 2018)((Song and Johnson 2018 https://www.mdpi.com/2073-4425/9/4/201/htm)): | + | Using less energy for the upkeep of somal integrity, comes with side effects, such as pleiotropic genes. Pleiotropy is where one gene influences more than one phenotypic trait. The [[https://en.wikipedia.org/wiki/Antagonistic_pleiotropy_hypothesis |antagonistic pleiotropy hypothesis]] states that a gene that can express both a beneficial and detrimental phenotype will be preserved if its benefit outweighs the detriment. An example is high testosterone in human males, which increases fitness in early life, while also increasing the risk of prostate cancer with age. Consider that life expectancy beyond 40 was something very uncommon, just a few centuries ago (Song and Johnson 2018)((Song and Johnson 2018 https://www.mdpi.com/2073-4425/9/4/201/htm)): |
| "To die of old age is a death rare, extraordinary, and singular, and therefore so much less natural than the others: it is the last and most extreme sort of dying […] And therefore my opinion is that when once forty years old, we should consider it as an age to which very few arrive […] and since we have exceeded the ordinary bounds which make the just measure of life, we ought not to expect to go much further." (Michel de Montaigne 16th century) | "To die of old age is a death rare, extraordinary, and singular, and therefore so much less natural than the others: it is the last and most extreme sort of dying […] And therefore my opinion is that when once forty years old, we should consider it as an age to which very few arrive […] and since we have exceeded the ordinary bounds which make the just measure of life, we ought not to expect to go much further." (Michel de Montaigne 16th century) | ||
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| (mutation-accumulation theory) from the many that breed and die young. Also, "Selection pressure to invest metabolic resources in somatic maintenance and repair is limited; all that is required is to keep the organism in sound condition for as long as it might survive in the wild (disposable-soma theory)." (Kirkwood and Austad 2000)((Kirkwood and Austad 2000 https://www.nature.com/articles/35041682)) | (mutation-accumulation theory) from the many that breed and die young. Also, "Selection pressure to invest metabolic resources in somatic maintenance and repair is limited; all that is required is to keep the organism in sound condition for as long as it might survive in the wild (disposable-soma theory)." (Kirkwood and Austad 2000)((Kirkwood and Austad 2000 https://www.nature.com/articles/35041682)) | ||
| - | There is also a certain irony that we are in competition with our own genes for survival. Genes are more likely to survive in an evolutionary sense, if the gene is used in multiple biological functions. A mutation of a pleiotropic gene is less likely to be compatible in all the dependent functions requiring it for assembly. Thus, a pleiotropic gene is selfish at the cost of the adaptability of a species to its environment. Also at the cost of a continuation of deleterious phenotypes such as aging. | + | There is also a certain irony that we are in competition with our own genes for survival. Genes are more likely to survive in an evolutionary sense, if the gene is used in multiple biological functions. A mutation of a pleiotropic gene is less likely to be compatible in all the dependent functions requiring it for assembly. Thus, a pleiotropic gene is selfish at the cost of the adaptability of a species to its environment. Also at the cost of deleterious phenotypes such as aging? In some cases not, due to [[https://en.wikipedia.org/wiki/Copy-number_variation |copy number variation]] of some genes. |
| - | There is much diversity, including a few genetic outliers. The hydra and the naked mole rat are species that don't age the way other organisms do. Their chance of death does not noticeably increase with age. "The nonsenescent life history of Hydra implies levels of maintenance and repair that are sufficient to prevent the accumulation of damage for at least decades after maturity ... A high proportion of stem cells, constant and rapid cell turnover, few cell types, a simple body plan, and the fact that the germ line is not segregated from the soma are characteristics of Hydra that may make nonsenescence feasible." (Schaible et al 2015)((Schaible et al 2015 https://www.pnas.org/content/112/51/15701)) It may be possible in the future to genetically modify a mammal, or a human, with a much longer lifespan. Maybe one way of doing so, is by being a master designer, and simplifying the convoluted mess that evolution has created. | + | As an experiment, fruit flies in a protected environment, were allowed to live to old age. They were allowed to breed if they outlived their counterparts. Over multiple generations, this created a progeny with longer lifespans. The long lived fruit flies had fewer offspring, suggesting that there is a trade-off between reproductive fitness and longevity. The same result, longer lifespan and fewer progeny, was also noted in mammals living on an island without predation. (Kirkwood and Austad 2000)((Kirkwood and Austad 2000 https://www.nature.com/articles/35041682)) |
| + | There is much diversity, including a few genetic outliers. The hydra and the naked mole rat are species that don't age the way other organisms do. Their chance of death does not noticeably increase with age. "The nonsenescent life history of Hydra implies levels of maintenance and repair that are sufficient to prevent the accumulation of damage for at least decades after maturity ... A high proportion of stem cells, constant and rapid cell turnover, few cell types, a simple body plan, and the fact that the germ line is not segregated from the soma are characteristics of Hydra that may make nonsenescence feasible." (Schaible et al 2015)((Schaible et al 2015 https://www.pnas.org/content/112/51/15701)) | ||
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| + | Now in the realm of science fiction, it may be possible in the future to genetically modify a mammal, or a human, to obtain longer lifespans. Maybe one way of doing so, is by being a master designer, and simplifying the convoluted mess that evolution has created. | ||
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| + | Human genetic engineering may be necessary, as modern health care allows those with genetic diseases, like asthma, to live normal lives and reproduce. Natural selection is no longer culling the flaws. (Lesecque et al 2012)((Lesecque et al 2012 https://www.genetics.org/content/191/4/1321)) | ||
| ===== Genomic Instability ===== | ===== Genomic Instability ===== | ||
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| Repetitive elements may comprise over two-thirds of the genome. (Koning et al 2011)((Koning et al 2011 https://dx.doi.org/10.1371%2Fjournal.pgen.1002384)) These are thought to be caused by [[https://en.wikipedia.org/wiki/Mobile_genetic_elements |mobile genetic elements]] such as [[https://en.wikipedia.org/wiki/Retrotransposon |retrotransposons]], which cause gene duplication events. | Repetitive elements may comprise over two-thirds of the genome. (Koning et al 2011)((Koning et al 2011 https://dx.doi.org/10.1371%2Fjournal.pgen.1002384)) These are thought to be caused by [[https://en.wikipedia.org/wiki/Mobile_genetic_elements |mobile genetic elements]] such as [[https://en.wikipedia.org/wiki/Retrotransposon |retrotransposons]], which cause gene duplication events. | ||
| - | Transposons are [[https://en.wikipedia.org/wiki/Selfish_genetic_element |selfish genetic elements]], yet [[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874221 |serve functions that are still being discovered]] (Muñoz-López and García-Pérez 2010)((Muñoz-López and García-Pérez 2010 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874221)). | + | Some transposons are [[https://en.wikipedia.org/wiki/Selfish_genetic_element |selfish genetic elements]], yet [[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874221 |serve functions that are still being discovered]] (Muñoz-López and García-Pérez 2010)((Muñoz-López and García-Pérez 2010 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874221)). |
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| + | Other transposons function in the immune system, where they create novel antibodies against toxins or pathogens. | ||
| ==== Mitochondrial DNA ==== | ==== Mitochondrial DNA ==== | ||
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| Mitochondria is theorized to have been an independent organism that was absorbed by a larger organism, ending in a [[https://learn.genetics.utah.edu/content/cells/organelles |symbiosis]] from which we evolved. Thus, mitochondria have their own DNA, referred to as mtDNA. | Mitochondria is theorized to have been an independent organism that was absorbed by a larger organism, ending in a [[https://learn.genetics.utah.edu/content/cells/organelles |symbiosis]] from which we evolved. Thus, mitochondria have their own DNA, referred to as mtDNA. | ||
| - | MtDNA does not follow the rules of Mendelian inheritance. With rare exception, mtDNA is inherited exclusively from the mitochondria in the maternal egg cell. Because of the nature of this inheritance, even though there were many different mtDNA types at one time in history, there is now only one. Thus there was a single woman, referred to as [[https://en.wikipedia.org/wiki/Mitochondrial_Eve |Mitochondrial Eve]] from which all other women have inherited their mtDNA. | + | MtDNA does not follow the rules of Mendelian inheritance. With rare exception, mtDNA is inherited exclusively from the mitochondria in the maternal egg cell. Because of the nature of this inheritance ([[https://en.wikipedia.org/wiki/Genetic_drift |random drift]]), even though there were many different mtDNA types at one time in history, there is now only one. Thus there was a single woman, referred to as [[https://en.wikipedia.org/wiki/Mitochondrial_Eve |Mitochondrial Eve]] from which all other women have inherited their mtDNA. |
| Over time, many of the genes in mtDNA were replaced or incorporated as genes in the cell nucleus. The mitochondrial genes located in the cell nucleus are transcribed and translated into proteins that are then imported into the mitochondria from the cytoplasm. There are around 1100 genes that are imported from the nucleus into the mitochondria in this way. Around a quarter of these, around 250, are for the maintenance and expression of the genes in the mitochondria. | Over time, many of the genes in mtDNA were replaced or incorporated as genes in the cell nucleus. The mitochondrial genes located in the cell nucleus are transcribed and translated into proteins that are then imported into the mitochondria from the cytoplasm. There are around 1100 genes that are imported from the nucleus into the mitochondria in this way. Around a quarter of these, around 250, are for the maintenance and expression of the genes in the mitochondria. | ||
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| "...given that there are hundreds of genes in nuclear genome bigger that the whole mtDNA, it is remarkable how this small piece of DNA can cause so many different metabolic diseases, be causatively linked to numerous age-associated disease and influence aging process itself." (Szczepanowska and Trifunovic 2015)((Szczepanowska and Trifunovic 2015 https://www.sciencedirect.com/science/article/pii/S0005272815000973)) | "...given that there are hundreds of genes in nuclear genome bigger that the whole mtDNA, it is remarkable how this small piece of DNA can cause so many different metabolic diseases, be causatively linked to numerous age-associated disease and influence aging process itself." (Szczepanowska and Trifunovic 2015)((Szczepanowska and Trifunovic 2015 https://www.sciencedirect.com/science/article/pii/S0005272815000973)) | ||
| - | Is there a separate process for maintaining mtDNA integrity in germ-line cells? There must be a way of keeping mutations in check, if lineages of mtDNA are so well kept that it is possible to [[https://en.wikipedia.org/wiki/Human_mitochondrial_DNA_haplogroup |trace populations by their mtDNA]] to a [[https://en.wikipedia.org/wiki/Mitochondrial_Eve |mitochondrial eve]]. | + | Is there a separate process for maintaining mtDNA integrity in germ-line cells? There must be a way of keeping mutations in check, if there is only [[https://en.wikipedia.org/wiki/Mitochondrial_Eve |one mutation per 3,500 years per nucleotide]]. There are ~16569 base pairs in mtDNA, so that accounts for roughly 1 mutation per decade. It is possible to trace the movement of populations by following the [[https://en.wikipedia.org/wiki/Human_mitochondrial_DNA_haplogroup |migration of mtDNA]] to the origin of the [[https://en.wikipedia.org/wiki/Mitochondrial_Eve |mitochondrial eve]]. |
| ==== Nuclear Architecture ==== | ==== Nuclear Architecture ==== | ||
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| ===== Telomere Attrition ===== | ===== Telomere Attrition ===== | ||
| - | The protective end caps of DNA molecules are called telomeres, and they shorten with cell divisions or some strand repairs. Telomerase is an enzyme that can add length to the telomeres, but it is not produced in most somatic cells. Loss of telomeres has been shown to be the cause of cellular senescence. | + | The protective end caps of DNA molecules are called telomeres, and they shorten with cell divisions or some strand repairs. Telomerase is an enzyme that can add length to the telomeres, but it is not produced in most somatic cells. Loss of telomeres has been shown to be a cause of cellular senescence. |
| DNA repair machinery is unable to see the end of the DNA double helix because telomeres are covered by shelterin. Damage to the telomeres is thus irreparable, even in the presence of telomerase, and also causes cellular senescence and apoptosis. In animal models, both deficiency in telomerase or shelterin components leads to loss of tissue-regenerative capability. | DNA repair machinery is unable to see the end of the DNA double helix because telomeres are covered by shelterin. Damage to the telomeres is thus irreparable, even in the presence of telomerase, and also causes cellular senescence and apoptosis. In animal models, both deficiency in telomerase or shelterin components leads to loss of tissue-regenerative capability. | ||
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| Genetically modified animals with shortened or lengthened telomeres lead shorter or longer lifespans, respectively. Premature aging of telomerase-deficient mice can be reverted by reactivating telomerase in the already aged mice. "Moreover, normal physiological aging can be delayed without increasing the incidence of cancer in adult wild-type mice by pharmacological activation or systemic viral transduction of telomerase. In humans, recent meta-analyses have indicated a strong relation between short telomeres and mortality risk, particularly at younger ages." | Genetically modified animals with shortened or lengthened telomeres lead shorter or longer lifespans, respectively. Premature aging of telomerase-deficient mice can be reverted by reactivating telomerase in the already aged mice. "Moreover, normal physiological aging can be delayed without increasing the incidence of cancer in adult wild-type mice by pharmacological activation or systemic viral transduction of telomerase. In humans, recent meta-analyses have indicated a strong relation between short telomeres and mortality risk, particularly at younger ages." | ||
| + | Related article: | ||
| + | https://joshmitteldorf.scienceblog.com/2016/12/12/telomeres-too-much-of-a-good-thing | ||
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| + | Mitteldorf's article notes the existence of telomere trimming in stem cells, and then asks why telomeres that are too long would be an issue. There is a hypothesis that telomeres act to suppress gene expression, because the tails wrap back around and overlay the chromatin. Thus the presumption is that if the telomeres are too long, more genes would be suppressed than required. However, he notes there is evidence that extra-long telomeres has an overall positive effect in mice studies. | ||
| ===== Epigenetic Alterations ===== | ===== Epigenetic Alterations ===== | ||
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| Furthermore, Cruz et al showed that H3K4me3 occurrences along the chromatin has a predictable profile change with age, like sand dunes shifting in a uni-directional desert wind. The shifts increase or induce transcription at some promoters, while silencing others. Aging chromatin can also cause transcription to start from a non-promoter region, resulting in a mutated protein. 43% of yeast genes are differentially expressed after 48 hours of ageing. | Furthermore, Cruz et al showed that H3K4me3 occurrences along the chromatin has a predictable profile change with age, like sand dunes shifting in a uni-directional desert wind. The shifts increase or induce transcription at some promoters, while silencing others. Aging chromatin can also cause transcription to start from a non-promoter region, resulting in a mutated protein. 43% of yeast genes are differentially expressed after 48 hours of ageing. | ||
| - | There is much promise that supplementation of s-adenosyl methionine (SAMe) can help in maintaining chromatin methylation integrity in our 3 genomes, the nuclear, the mitochondrial, and the microbial. (Leonen 2018)((Leonen 2018 https://www.sciencedirect.com/science/article/pii/B9780128110607000036)) | + | There is much promise that supplementation of s-adenosyl methionine (SAMe) can help in maintaining chromatin methylation integrity in our 3 genomes, the nuclear, the mitochondrial, and the microbial. (Leonen 2018)((Leonen 2018 https://www.sciencedirect.com/science/article/pii/B9780128110607000036))(Detich et al 2003)((Detich et al 2003 http://www.jbc.org/content/278/23/20812.full))(Ptalzer 2014)((Ptalzer 2014 https://www.physiology.org/doi/full/10.1152/physiolgenomics.00056.2014)) |
| === AMPK === | === AMPK === | ||
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| === IIS Pathway (Insulin/Insulin-like Growth Factor Signaling) === | === IIS Pathway (Insulin/Insulin-like Growth Factor Signaling) === | ||
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| + | === TOR pathway === | ||
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| + | CR works because of the inhibition of the TOR pathway, which can be invoked independently by _____, since [[https://selfhacked.com/blog/the-truth-about-igf-1-top-10-benefits-and-potential-drawbacks |IGF is beneficial]] | ||
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| + | "... rodents may well have evolved a response to temporary fluctuations in resource availability, in which energy is diverted from reproduction to maintenance functions in periods of food shortage, thereby enhancing survival and retaining reproductive potential for when conditions improve." (Kirkwood and Austad 2000)((Kirkwood and Austad 2000 https://www.nature.com/articles/35041682)) | ||
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| ===== Mitochondrial Dysfunction ===== | ===== Mitochondrial Dysfunction ===== | ||
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| + | --- //[[user:marcos|Marcos Reyes]] 2019/12/11 04:16// | ||
| (UNDER CONSTRUCTION) | (UNDER CONSTRUCTION) | ||
news-review/hallmarks-of-aging.1573742816.txt.gz · Last modified: 2019/11/14 14:46 by marcos
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