A Small Step Towards Determining the Relevance of Nuclear DNA Damage to Normal Aging

Researchers recently reported the development of a system to generate a form of damage to nuclear DNA in a sizable number of discrete locations in a controlled, isolated way, and use it to test a limited hypotheses regarding the contribution of DNA damage to age-related epigenetic changes. This is a small step forward towards determining whether or not nuclear DNA damage is a meaningful cause of aging. This damage occurs constantly and randomly, most of it repaired, but the few mutations that slip through accumulate in tissues across a lifespan. You have more of this damage if you are old, and this is one of the reasons that cancer is an age-related disease: the more mutations, the more likely it is that the right combination to spark a cancer occurs. But beyond cancer, is this random nuclear DNA damage, different in every cell, a significant cause of aging over the present human life span? The consensus is yes, and the thinking is that these mutations cause enough dysregulation of cellular activities to be harmful, but this consensus is disputed.

What is needed is a way to either create or repair random nuclear DNA damage in isolation of other cellular processes. There are plenty of interventions to slow aging in laboratory animals that happen to slow the rate at which nuclear DNA damage occurs, but these interventions also alter vast swathes of the operating details of cellular metabolism. There is no way to pin down the relevance of nuclear DNA damage on its own in that situation. The methodology reported in the open access paper linked here is a small step towards the sort of biotechnology needed to reproduce random nuclear DNA damage in much the same way as it occurs naturally, and thus run a study on whether or not it is a cause of aging. There is still a way to go towards that end result, however:

The accumulation of DNA damage is a conserved hallmark of cancer and aging. Of all DNA lesions, DNA double-strand breaks (DSBs) are arguably the most harmful. Defects in DSB repair can result in cell cycle arrest, apoptosis or genomic aberrations and have been linked to both disease progression and a premature onset of aging phenotypes. Consistent with the latter, DSB induction was found to be sufficient to promote a subset of age-related pathologies in mice. In addition to the often detrimental effects of mutations and chromosomal abnormalities, DSBs cause significant changes in the chromatin environment both at and beyond the break site, raising the intriguing possibility that DSB repair contributes to (persistent) epigenetic defects that may eventually alter cell function. It is of note that epigenetic dysfunction in a small subset of cells may be sufficient to affect entire tissues, and possibly organismal aging.

The distinction between cell-intrinsic and systemic consequences of DSB induction is, thus, critical to advance our understanding of the role of DSBs in age-associated functional decline. However, despite numerous cell-based reporter systems for DSB induction, there is a scarcity of tools to follow the consequences of DSBs for cell and tissue function in higher organisms. Here, we describe a mouse model that allows for both tissue-specific and temporally controlled DSB formation at ∼140 defined genomic loci. Using this model, we show that DSBs promote a DNA damage signaling-dependent decrease in gene expression in primary cells specifically at break-bearing genes, which is reversed upon DSB repair. Importantly, we demonstrate that restoration of gene expression can occur independently of cell cycle progression, underlining its relevance for normal tissue maintenance. Consistent with this, we observe no evidence for persistent transcriptional repression in response to a multi-day course of continuous DSB formation and repair in mouse lymphocytes in vivo. Together, our findings reveal an unexpected capacity of primary cells to maintain transcriptome integrity in response to DSBs, pointing to a limited role for DNA damage as a mediator of cell-autonomous epigenetic dysfunction.

Link: http://dx.doi.org/10.1093/nar/gkv1482


This is the area in which I am afraid the SENS Foundation is engaging in wishful thinking. There do seem to be a load of people who think it is important.

IF DNA damage not resulting in cancer does turn out to be important, can anything be done about it?

Posted by: Jim at December 23rd, 2015 8:21 AM


Hi Jim, these studies, as this one, that affirm Nuclear damage are almost irrelevant in aging are totally shooting themselves in the foot, they could not be more wrong. Nuclear DNA is by far the most important DNA to preserve, extrachromosomal/extranuclear DNA like circular mitochondrial DNA is the other one that is extremely important to preserve (from mtDNA deletions, mtDNA deleterious mutations and mtDNA lesions (8-oxo-dG)). But nuclear DNA (ntDNA) is just as important. And the reason being is that it is the make up of the chromosomes inside the cell nucleus. When you fracture nuclear DNA you fracture chromosomes, that is one death wish... How so ? Well, Nuclear Chromosomes house telomeres at their end termimi. Telomeric DNA repeats dictate intrinsic genetic aging by the amount of irreparable DNA damage to them, all deep in the nucleus (with the exception of red blood cells who have uniquely no nucleus but do have telomeres , a real paradox that can be explained rapid turnover recycling of these cells; also showing a nucleus is Not necessary, But Telomeres DNA are). Remember the nucleus is the 'Brain' Central Genome Control of the cell, by containing extremely precious chromosomes, some also call it the Heart, but the energy production 'heart' to make the cell 'alive' is really the mitochondria.

Posted by: CANanonymity at December 23rd, 2015 10:46 AM

@Jim: A challenging problem if it is. You'd need pretty advanced platforms built on top of gene therapy or genome-scanning technologies to edit every cell differently and accurately according to its present state, or even just to identify non-conforming cells and destroy them. Frietas has envisaged chromallocyte molecular nanotechnology to do this, but we're a long way from that sort of thing.


Posted by: Reason at December 23rd, 2015 12:45 PM

I do wonder if there might be a way to sidestep this (likely) daunting DNA repair problem all together. Perhaps the cultivation and reintroduction of frozen cells from a person's youth, or the transplantation of cells from another person somehow altered so as not to be attacked by the recipient's immune system? Fixing old heavily-damaged cells with nanobots seems much harder than introducing new healthy cells. Anyone know if something like that is feasible?

Posted by: KC at December 23rd, 2015 7:05 PM


KC, It could work if eternally repeated but certain studies that tried that in mice got results in line with calorie restriction effect.
We have to find a way to make sure that our Replacement of stem cells, Removal of senescent cells and every other treatment in Combo are capable of supplanting the speed of aging; while maintaining the correct proliferation/differentiation vs self-regeneration homeostatic balance. It's a very trick thing. And nanobots could one day do that, and you are right, apparently, nanorobots will may extremely hard to 'home in/target' on the right cells and we will need trillions of them nanorobots inside of us; so we are not there yet for those (real) tiny bots; it's extremely advanced technology 'on paper' but it is barely 'invented' yet....sadly..this tech with the right degradation enzymes could remove lipofuscin, and end pigment of aging; it would Exponentially slow aging, like Nothing now, we could theoritically be immortal. Immortal animals' cells hallmark is they never accumulate lipofuscin like we do. I just hope it will happen in the next 50 or so years but I have slight reservation; these are '' Moon shots '' and not many get to the moon. But we can still aim for it, the saying is : ''Aim for the Moon, and if you don't make it, you'll be dancing among the stars ''. I'm ok with the stars too (love to look at space cosmos stars or just regular movie stars ;), if it fails in next decades.

Here is my old response to Florin that explains the mild effect of transplantation of youth like stem cells :


It could work, I think we are getting there but there are obstacles and I'm not sure stem cell replacement will make us live beyong MLSP until it is fully harnessed in mice, to make them live the age of Naked Mole Rat, until then it seems it has the Rapamycin CR calorie restriction like effect, so don't hold your breath (for now, SENS could change that, but it's going to take massssive stem cell renewal it seems, and slight 'tune up' at the doc for stem cell replacement seems is not it yet). Hopefully, we can repeat this transplatation on and on and somehow delay infinitely; but it seems a 'catch up' game, where one day or another, we lose to it and replacement can't overcome speed of aging. A transplant each month, year or so, could do it, but in mice it give calorie restriction effect result like 20-30%. This is mostly average lifespan territory by health and average lifspan extension, not maximum intrinsic aging.

'' The recent study, published in Stem Cells TM, demonstrates that infusions of mesenchymal stromal cells (MSC) can impact aging and longevity. ''

''The mean life span of control mice was 765 days (Figure 4B). However, the mean life span for mice that received young BMSCs transplants was 890 days (vs. control group, p = 0.009). The increase of life span is probably unrelated to radiation, since the mean life span of mice transplanted with old BMSCs was 789 days (vs. young BMSCs transplants, p = 0.002) (Figure 4B). In addition, there was no significant difference between control animals and mice transplanted with old BMSCs (p = 0.846). Overall, these results suggest that transplantation of BMSCs derived from young animals extends life span.''

''Human amniotic membrane-derived mesenchymal stem cells (AMMSCs) or adipose tissue-derived mesenchymal stem cells (ADMSCs) (1 × 106 cells per rat) were intravenously transplanted to 10-month-old male F344 rats once a month throughout their lives. Transplantation of AMMSCs and ADMSCs improved cognitive and physical functions of naturally aging rats, extending life span by 23.4% and 31.3%, respectively.''

1. http://www.nature.com/articles/srep00067
2. http://stemcellstm.alphamedpress.org/content/early/2015/08/26/sctm.2015-0011.abstract

Posted by: CANanonymity at December 23rd, 2015 8:15 PM

There is perhaps a corollary between the Peto cancer paradox and the question of whether nuclear DNA damage is important in aging?

Just as with cancer, if nuclear DNA damage is a stochastic process then why don't larger animals such as humans, elephants and whales age at a faster rate than mice?

Clearly larger animals have better cancer protection methods, partially eldicated recently in elephants as extra p53 genes, but probably different on a species to species basis.

Does evolution only furnish species with 'good enough' DNA repair to bring up offspring? Or does cancer mean that we have better DNA repair than is necessary when it comes to DNA damage causing aging? It is a seductive idea, but there isn't much proof either way yet.

I also saw some arguments about the fact that if each cells DNA entropy is increasing with time, why aren't embryos already intrinsically old, and newborns and subsequent generations shorter lived than their parents? Clearly there has to be some means of exporting this entropy.

Posted by: Jim at December 23rd, 2015 11:55 PM


2 cent..
Jim, Peto's solution to cancer paradox of cancer to cell number discrepancy (cellularity by animal size) is in the naked mole rat (NMR). Like bowhead whales they practically never get cancer, they live 35 years, shorter lifespan than humans yet they never die of cancer unlike mice, these are both same size rodents, NMR lives 10 times longer than rodent cousin mice with no cancer, mice live 3 years and die of cancer; ok, NMRs do not have human or bowhead whale cell numbers, still, this means something is going on. Studies showed that mice's genome become unstable rapidly despite having very high telomeres (a form of accelerated senescence/inflammaging, kind of like SAMP mice, just slower) because, unlike NMR, humans or bowhead whales, mice are not Neotenous by evolutionary specie context. Meaning their specie purpose is breeding rapidly by sexually maturing rapidly and dying rapidly from extreme non-neotenous growth to become reproductive adult. This accelerated growth allows mutations many folds, length to puberty is evolution solution to cancer and aging. As such evolution gene selection pressure in mice would select sexual genes rather than longevity genes (neotenous juvenile animals such as NMR, humans, bowhead whales, etc) for mice, the cost for hyperbreeding was a shortened life. A shortened life meant damage accrual/inflammaging) , poor investment in mechanism that block tumor formation driven by inflammation (like for example the reason NMR never get cancer is because they have extreme amounts of Highmolecular weigth Hyaluronan in their ECM that 'traps' tumors in their track and acts as a stromal shield barrier thus tumors can not spread/metastasize to organs, plus a cell contact mechanism that triggers death in cancer and their version of TNF p53 is far better adapted (the reason is because they live in hypoxia below ground in tunnels, this environment is cesspool perfect for tumor formation, tumors proliferate in hypoxia so evolution gave them tumor protection from living in the dark tunnels with little oxygenation) and deleterious mutations possibility also, it may not be so much mice's mutations causing them cancer when they have Less cells than us (thus should get less cancer..paradoxically, no) and that is because of faulty genome and poor cancer prevention mechanism adaptation rather than cellularity..

So yes you are entirely correct to say long lived animals have better cancer proof mechanisms, such as extra p53 in elephant

An extra p53 gene is a clear showing that tumors must be kept in control as longevity dramatically increases and the chances of tumor formation too spread over a long lifespan.

We don't age as fast as mice because we are neotenous (tissue replasticizing), we have excellent oxidative stress resistance cell mechanisms, better protein chaperonage, improved DNA damage response, identification and repair systems (base nucleotide repair), we have very little dramatic telomeres events (SCE sister chromatid exchange), we maintain redox biology and stem cell quiescence, etc.

You are correct to say we have DNA damage repair to prevent damage - and cancer. Cancer is highly driven by oxidative stressed inflammation increasing deleterious mutations, dysfunction and unstabilty of gene network.

Evolution furnishes organism depending on their context and evolved state, animals will get DNA damage repair if is worth getting, an animal that is long lived is neotenous and that does not work with short living ones. Evolution wants specie survival through reproduction offspring high output or longevity and a long time to just get to reproduction (Neoteny, late puberty). A long life Requires the animal to be Continuously Alive - to get to puberty sexual reproduction age capability to make specie continuation by its offspring creation (DNA damage repair acquiry Allowed that). This meant a tradeoff between short life/hyperreproduction vs long life/hyporeproduction.
Sexual resources (mice) vs Longevity DNA repair resources (humans, NMR, bowhead whales).

DNA entropy, just my opinion, is just that randomization disorder 'chaos'. It happens all the time it doesn't mean a certain order cannot be maintained. Order is necessary to stop chaos and hazardous random 'mutations'. Evolution is pure Order at its extreme form, its a hierarchical order ladder..., it always choose things in order of relevance and survival meaning, it prioritizes and Selects the DNA genes it knows will adapt the specie to survive. Selection natural is all about order, orderly balance from chaotic randomization unbalance/unstability. Stability brings order, order brings stability and as such, homeostasis. DNA is a very fine Ordered marvel of evolution, they say perfection is Order. Disorder entropy is a fun bonus that keeps 'things fun' and surprising for life is not perfect. Order is Rigid, boring, disorder is more fun , more lax/loose, it makes crazy sh... happen. Order (evolution) will come in to ReOrder the 'fun' mess entropy leaves.

Posted by: CANanonymity at December 24th, 2015 3:01 AM
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