5 replies to this topic

[reason]

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

View the full article at FightAging

[alc]

Not really a "small step", but it's a nice play of words to cover the importance of the study.

 

... bummer that the study is co-authored by David Sinclair, that is hammered constantly on fa ...

 

But now seriously, the study doesn't come as a surprise for people who were keeping an eye on David Sinclair Lab's work for past years.

 

http://genetics.med....ir/research.php

 

As we seen thing for a while, the study can be ignored/rebutted (with a "question of the month" write up), or can be considered and in turn some

important things needs to be reconsidered. "Mirror, mirror on the wall" which way will be?

 

[corb]

 

or can be considered and in turn some important things needs to be reconsidered

 

 

The high level goal of de Grey's SENS program is to develop the biotechnologies needed to repair and reverse all of the identified biochemical differences between a young person and an old person. That remit obviously includes nuclear DNA damage and mutation, but de Gray's position above is essentially an efficiency argument - other forms of difference are far more important, so the research community should deal with those first.

 

Sinclair is kinda late for the party rather than being above the curve.

The only thing people should get out of articles like this is that the lamestream is starting to get it's hand dirty with actual aging research for the first time.

Whoop de doo.

[alc]

"Sinclair is kinda late for the party rather than being above the curve.

The only thing people should get out of articles like this is that the lamestream is starting to get it's hand dirty with actual aging research for the first time.

Whoop de doo."

 

 

... it is not who gets in the game first/second/etc., but who get it right ...

 

a lot of SENS work is good and I respect that, but when they don't get it right, they need to go back to drafting board and understand why and modify their assumptions.

 

we cannot solve aging by liking or not things/ideas/people/organizations - ideas need to be proved right and studies do that: validate or not an idea/assumption.

 

if the study will not validate your idea, you either:

 

a. accept it and look under the hood to see what implies that.

 

or

 

b. not accept it and move on ... but sooner or later, the reality will catch up with you.

 

 

[corb]

"Sinclair is kinda late for the party rather than being above the curve.

The only thing people should get out of articles like this is that the lamestream is starting to get it's hand dirty with actual aging research for the first time.

Whoop de doo."

 

 

... it is not who gets in the game first/second/etc., but who get it right ...

 

a lot of SENS work is good and I respect that, but when they don't get it right, they need to go back to drafting board and understand why and modify their assumptions.

 

we cannot solve aging by liking or not things/ideas/people/organizations - ideas need to be proved right and studies do that: validate or not an idea/assumption.

 

if the study will not validate your idea, you either:

 

a. accept it and look under the hood to see what implies that.

 

or

 

b. not accept it and move on ... but sooner or later, the reality will catch up with you.

 

The question is who in your opinion has to stop and consider this?
As I pointed out SENS proponents have been accepting of this assumption. SENS is built around it.

There are other people with other ideas on the forums and they too will not have much problem with this conclusion.

 

So who else then?

 

And bare in mind this is a murine model. Mice are mice. Men are men. If someone came up with conclusive proof that DNA damage is irrelevant in humans I'd be the first to say "Hell yeah!". Not that this research is trying to prove that at all, it was looking at epigenetic diregulation specifically not at cancer, changes in metabolism or anything else that might arise from DNA damage.

Edited by corb, 05 January 2016 - 07:00 PM.

[Logic]

Nuclear DNA damage signalling to mitochondria in ageing

Mitochondrial dysfunction is a hallmark of ageing, and mitochondrial maintenance may lead to increased healthspan. Emerging evidence suggests a crucial role for signalling from the nucleus to mitochondria (NM signalling) in regulating mitochondrial function and ageing. An important initiator of NM signalling is nuclear DNA damage, which accumulates with age and may contribute to the development of age-associated diseases. DNA damage-dependent NM signalling constitutes a network that includes nuclear sirtuins and controls genomic stability and mitochondrial integrity. Pharmacological modulation of NM signalling is a promising novel approach for the prevention and treatment of age-associated diseases.

http://www.nature.co...rm.2016.14.html