Old Tissues Have Many Mutations, Even Absent Cancer
Cancer is the result of random mutational damage to nuclear DNA, but most such damage has no real effect, not even to the behavior of the affected cell. Cells in old tissues are riddled with mutations, but it is an open question as to how much this accumulated damage contributes to aging beyond cancer risk. Does it produce sufficient disarray in tissue function to be measured? A mutation capable of meaningfully altering cell behavior (a small subset of all possible mutations) can only have a noticeable affect when it occurs in many cells, a significant fraction of those present in a tissue. One slightly defective cell is a drop in the ocean, provided it isn't actively cancerous.
Many researchers consider that the outcome of clonal expansion of mutations in adult tissue can be achieved when the original mutation occurs in a stem cell of some kind. The mutation can spread with the long-term delivery of a supply of daughter somatic cells and their descendants. Along these lines, the studies noted in the article below raise the possibility that cancer-associated mutations can also grant this ability to spread through excessive replication, yet without immediately resulting in the production of a tumor.
The field lacks definitive studies and models that would enable researchers to put numbers to the contribution of mutational damage to degenerative aging and age-related diseases other than cancer. Clearly the boundary between production of cancer and production of functional damage isn't sharply drawn if expansion of mutations is a feature of the pre-cancerous state. Fixing the damage is usually the best way to proceed when answering this sort of question, but that is very hard to achieve for random DNA damage in isolation of all the other aspects of aging. Every cell needs custom work. More practically, delivering newly created, undamaged stem cell populations to replace old stem cell populations is a feasible form of future therapy, but it certainly doesn't isolate DNA damage as the only altered variable.
Mutations differ in normal and cancer cells of the oesophagus
Errors in DNA replication can alter a cell's DNA sequence. If such alterations occur early enough in embryonic development, the changes are inherited by all of an organism's cells. But if the alterations arise later in adult life, it is more difficult to track such changes in a small number of cells in a specific tissue, so the extent of these alterations in normal tissues is poorly understood. It is thought that cancer is initiated when cells acquire a minimum compendium of genetic alterations needed to trigger tumour formation. Understanding when such initiating mutations occur in normal cells is crucial for enabling reconstruction of the early events that lead to cancer.
Researchers have analysed the extent of mutations in human epithelial tissue from the healthy oesophagus, and how this relates to the processes that drive cancer development. They sequenced 74 cancer-associated genes in 844 tissue samples taken from the upper oesophagus of 9 healthy donors who differed in gender, age and lifestyle. For 21 of these samples, the authors also determined whole-genome sequences. A previous study assessing mutations in healthy skin cells reported between two and six mutations per million nucleotides of DNA. By contrast, here the mutations in oesophageal cells arose at a roughly tenfold lower rate. This difference is unsurprising, because skin cells are exposed to more DNA-damaging agents, such as ultraviolet light, than are oesophageal cells.
Instead, the surprise is that, compared with healthy skin, the healthy oesophagus has more mutations in cancer-associated genes. Moreover, at least a subset of these altered genes was under strong positive selection, meaning that the genetic alterations promoted cell proliferation, leading to the formation of cell clones. Compared with the samples from younger people, the overall number of mutations, the number of mutations in cancer-associated genes and the size of the clones were all greater in the samples from older people. The authors found that the donors' samples had an average of about 120 different mutations in NOTCH1, a known cancer-associated gene, per square centimetre of normal oesophageal tissue.
The clonal expansion of normal oesophageal cells after cancer-promoting genes have mutated seems to be necessary, but not sufficient, to drive cancer, so something else must happen to the cells for tumours to form. For example, gaining a large-enough number of alterations in cancer-promoting genes might be needed. Few of the mutations were present in all the cells of the normal clones, and many of the cancer-promoting mutations were often found in spatially distinct subclones. This suggests that none of the normal cells had acquired enough cancer-promoting alterations to start cancer formation.
Sui Huang's (Institute for Systems Biology - https://systemsbiology.org/bio/sui-huang-md-phd/) view on mutations as "permissive" of events (biologic attractor states), NOT causative of them, makes cancer, and many other diseases, including aging, much more understandable
A good paper of his on cancer GRNs
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2754594/
@Reason, in SENS phrase "damage" has very clear meaning. This is something that increases risk of illness . The majority of mutations are neutral, thus they are not "damage" in narrow meaning.
Large-bodied organisms have more cells that can potentially turn cancerous mutations than small-bodied organisms, imposing an increased risk of developing cancer. This expectation predicts a positive correlation between body size and cancer risk; however, there is no correlation between body size and cancer risk across species ("Peto's paradox"). In baleen whales (which have 2,000 times more cells than humans) there seems to be no evidence for reproductive senescence. Why? https://doi.org/10.1038/s41598-018-32502-2
Also, a majority of our somatic mutations occurs during ontogenesis:
https://www.nature.com/articles/onc2012281
Hi Dmitry! Just a 2 cents. It is interesting and hard to say why,
Certain animals (elephants, naked mole rats, even certain whales) have these special genetics configurations such as p53/p16/p21INK4a variants (better tumor supressors/suppressing capability or cell contact inhibition or stronger stromal barriers; the cancers don't 'get' to metastasize like in us humans and spread all over; small or huge animals, higher cellularity in large animals like gigantic whales would mean a haven for cancer formation; but, evolution countered that in them and selected tumor supressing genes). Thus, higher cellularity risk of cancer can be safely stopped in large animals. My take is that long lived bowhwead whales whom are huge size would have cancer more than humans, by their sheer size and as such higher cellularity; but, they are verrry slow growth and long-time to puberty (which means delayed growth/reduced IGF/mTOR axis (reduced growth, but 'growth' spread over a long time (which means a 'huge 'slow growing' body'), also studies demonstrated better transcription in their transcriptomes - epigenetics. Epigenetically they post-pone epigenetic drifting and demethylation of methylome, and hypermethylation of specific epigenetic islands (CpG rich); cancers are controlled by that, epimutations do have both deleterious or non-deleterious effects, they can contribute to cancer or stop it; but, clearly, there is a epigenetic pattern to cancer and cancer can be stopped by epigenetic signaturing because it is under epimethylation control. It's why you can see small animals, like mice, have cancer rapidly, or other small rodents, like naked mole rats, not have cancer - while huge elephants and baleens get no cancer...see, it's 'all over the place' with many exceptions/outliers, developmental growth is tied to cancer and cellulairity can be uncoupled from cancer, and means epigenetics are far more behind this than given credit. Nuclear mutations that lead to dysfunctional tumor suppressors or weakened immune cells cancer-killing power (T-cells/NK cells/WBC/phages) will open door to cancer in small or big animals. As for older humans, whom show less growth/slow metabolism, they have accumulated more than enough mutations (as both adaptive and - deleterious) that at that point, it's why immune cells or cancer suppressors may be defective; but, studies showed taht tumor suppressors are going full-pin in aged people, so they are doing 'double time' because of the accumulation of mutations in a aged body; many adaptive/protective, but many not so and very much deleterious/cancer causing. It's interesting because in genetically silent young animals, there is less need to adapt whatever, while in old animals it's 'from aging/getting old/getting 'adaptive/transformative' mutations to 'become old/survive being old'), but such mutational load incurs deleterious/error mutations that will cause possible cancers/rogue cell formation. Despite, all the good adaptation, errors happen and deleterious ones are the ones that open the door. In young animals, time has not advanced, there is not adaptation that has occured over time (a lifetime), thus more genetically silenced and unadapted/unmutated. It's why, young epigenetic signature is stronger to protect against cancer (despite young animals having cancer too, that is because of accelerated growth towards (pre)puberty; this can open cancer formation; oftenly, if young animals, would have cancer is genetic mutations they have already (gene defects), sometimes heriditary (from parents/grand-parents/runs in the family (all died of cancer, not just coincidence or env, there is genetic heredity)); like me, I was born with genetic defects in cholesterol (from my very far ancestors whom had these genetic defects or unique 'new' mutations Single polymorphisms (many died of atherosclerosis/heart attack back then (centuries ago)), 'given' down the chain of the children to their children etc (not a wanted gift)..can't do anything about it, so I got atherosclerosis later; children that may have these genetic predispositions would have more chances of having cancer or other diseases; while other children that should not happen because epigenetic signature and cancer-contributing genes in CpG-rich islands would be hypomethylated (namely the NANOG, SOX, OCT, TERT, Cdcs c-MYC, especially c-MYC, RAS, all these stem-cellish cancer-like genes and other cell proliferation promoting-genes that cancers highjack and use to beat the immune machine and tumor supressors to avoid being eradicated/able to grow. But, all these constellation genes, downstream nuclear epigenome). Just a 2 cents.
1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5061548/
2. https://www.sciencedirect.com/science/article/pii/S2211124718311458
3. https://www.newscientist.com/article/dn28306-elephants-almost-never-get-cancer-thanks-to-multiple-gene-copies/
4. https://www.ncbi.nlm.nih.gov/pubmed/19858485
On a different note George Church door a lengthy presentation where he casually glossed over many topics as if they were wifey accepted. Very interesting but each of the topics merits its own thread
https://www.nextbigfuture.com/2019/01/delivery-of-45-age-reversing-gene-therapies-at-once-is-under-peer-review.html
@Cuberat the most interesting thing about the presentation is his claim that they cured 5 age-related diseases when they threw their therapy at them.
@Tom
And he glossed so casually by those topics like if they were something solved long ago...
The biggest question of all to my mind - are these mutations causes or effects of aging?
@Mark
When you wrap your mind around the system biology folks view of mutations of being "permissive" (not causative) of biological attractor states, a lot of it falls into place
A good seminal paper by Huang and Ingber on the topic as it pertains to cancer
http://www.medicinaycomplejidad.org/pdf/probsal/ingber_cancer2%5B1%5D.pdf