NAD Precursor NMN Improves DNA Repair in Mice

Sirtuin research, much hyped and in the end producing nothing other than more knowledge of metabolism, has somewhat transitioned into a focus on nicotinamide adenine dinucleotide (NAD) these days. NAD is central in cellular energy production and mitochondrial activity, and appears involved in many of the same processes that sirtuins influence. It is still the case that compelling demonstrations of slowed aging or enhanced longevity in laboratory animals have yet to emerge from this line of research, such as via the use of the NAD precursor nicotinamide mononucleotide (NMN) as a dietary supplement. The research is academically interesting, as here where it is shown to affect DNA repair mechanisms, but from a practical point of view for the treatment of aging this still appears to be another marginal approach, lacking the ability to produce reliable and significant effects on aging and longevity.

DNA repair is essential for cell vitality, cell survival and cancer prevention, yet cells' ability to patch up damaged DNA declines with age for reasons not fully understood. New findings offer an insight into how and why the body's ability to fix DNA dwindles over time and point to a previously unknown role for the signaling molecule NAD as a key regulator of protein-to-protein interactions in DNA repair. If affirmed in further animal studies and in humans, the findings can help pave the way to therapies that prevent DNA damage associated with aging and with cancer treatments that involve radiation exposure and some types of chemotherapy, which along with killing tumors can cause considerable DNA damage in healthy cells. Human trials with NMN are expected to begin within six months, the researchers said.

The investigators started by looking at a cast of proteins and molecules suspected to play a part in the cellular aging process. Some of them were well-known characters, others more enigmatic figures. The researchers already knew that NAD, which declines steadily with age, boosts the activity of the SIRT1 protein, which delays aging and extends life in yeast, flies and mice. Both SIRT1 and PARP1, a protein known to control DNA repair, consume NAD in their work. Another protein DBC1, one of the most abundant proteins in humans and found across life forms from bacteria to plants and animals, was a far murkier presence. Because DBC1 was previously shown to inhibit vitality-boosting SIRT1, the researchers suspected DBC1 may also somehow interact with PARP1, given the similar roles PARP1 and SIRT1 play.

To get a better sense of the chemical relationship among the three proteins, the scientists measured the molecular markers of protein-to-protein interaction inside human kidney cells. DBC1 and PARP1 bound powerfully to each other. However, when NAD levels increased, that bond was disrupted. The more NAD present inside cells, the fewer molecular bonds PARP1 and DBC1 could form. When researchers inhibited NAD, the number of PARP1-DBC1 bonds went up. In other words, when NAD is plentiful, it prevents DBC1 from binding to PARP1 and meddling with its ability to mend damaged DNA. What this suggests is that as NAD declines with age, fewer and fewer NAD molecules are around to stop the harmful interaction between DBC1 and PARP1. The result: DNA breaks go unrepaired and, as these breaks accumulate over time, precipitate cell damage, cell mutations, cell death and loss of organ function.

Next, to understand how exactly NAD prevents DBC1 from binding to PARP1, the team homed in on a region of DBC1 known as a Nudix homology domain (NHD), a pocket-like structure found in some 80,000 proteins across life forms and species whose function has eluded scientists. The team's experiments showed that NHD is an NAD binding site and that in DBC1, NAD blocks this specific region to prevent DBC1 from locking in with PARP1 and interfering with DNA repair. To determine how the proteins interacted beyond the lab dish and in living organisms, the researchers treated young and old mice with the NAD precursor NMN, which makes up half of an NAD molecule. NAD is too large to cross the cell membrane, but NMN can easily slip across it. Once inside the cell, NMN binds to another NMN molecule to form NAD. As expected, old mice had lower levels of NAD in their livers, lower levels of PARP1 and a greater number of PARP1 with DBC1 stuck to their backs.

However, after receiving NMN with their drinking water for a week, old mice showed marked differences both in NAD levels and PARP1 activity. NAD levels in the livers of old mice shot up to levels similar to those seen in younger mice. The cells of mice treated with NMN also showed increased PARP1 activity and fewer PARP1 and DBC1 molecules binding together. The animals also showed a decline in molecular markers that signal DNA damage. In a final step, scientists exposed mice to DNA-damaging radiation. Cells of animals pre-treated with NMN showed lower levels of DNA damage. Such mice also didn't exhibit the typical radiation-induced aberrations in blood counts, such as altered white cell counts and changes in lymphocyte and hemoglobin levels. The protective effect was seen even in mice treated with NMN after radiation exposure.

Link: http://www.newswise.com/articles/harvard-medical-school-scientists-pinpoint-critical-step-in-dna-repair-cellular-aging

Comments

Gradual failure of DNA repair mechanisms and accumulation of DNA damage might constitute an important primary source of aging damage even if eliminating that source of damage doesn't produce interesting longevity effects in the laboratory. If DNA damage is one of multiple sources of damage that collectively constitute the important upstream sources of aging, then it makes sense that some larger set of these causes might have to be addressed before a significant effect is seen--which I thought was part of the SENS idea anyway.

Posted by: gheme at March 24th, 2017 4:59 PM

@gheme: I'm not sold on this turning out to be a large effect in practice. The typical result from work of this nature - and especially from this particular research group - is that the effect gets smaller and smaller the more work is done to quantify it and dig into the details. Initial reports on size of effect should be taken with a grain of salt, even while the underlying mechanisms are no doubt interesting.

Posted by: Reason at March 24th, 2017 6:01 PM

Is this supposed to repair stochastic DNA damage?

Posted by: Barbara T. at March 25th, 2017 10:50 AM

And is nuclear DNA damage even important in aging? My feeling, and it is nothing more than a feeling at this point, is that it doesn't amount to much in the course of a normal lifespan - this treatment might be useful for progeria sufferers however, or those with other diseases with accelerated DNA damage.

Posted by: Mark at March 25th, 2017 4:23 PM

Having said all that, if elevated NAD can protect against DNA damage it could be useful to take for chemotherapy patients.

Posted by: Mark at March 25th, 2017 4:36 PM

I get that on Aubrey de Grey's original model of aging, DNA damage isn't important except as a driver of cancer. It would be good if that's right, since fixing DNA damage after it occurs seems perhaps more difficult than fixing the other forms of damage he identifies, but there is really no reason at this point to think that his model is true on that front. He thinks DNA damage is almost always repaired (or he used to), but the research posted above seems to indicate otherwise. In fact, there is even more evidence to the contrary of de Grey:
https://www.sciencedaily.com/releases/2006/12/061221075222.htm
https://www.sciencedaily.com/releases/2016/12/161212115837.htm
I'm not saying DNA damage definitely is a primary source of aging damage, but we can't let some sort of confirmation bias obscure the facts or have us prejudge research. I'm not accusing Reason of confirmation bias--this site is amazing except for a bit of a libertarian political bias that seems less well thought-out than the stance on aging--but care in scientific assessment is needed, I think.

Posted by: gheme at March 25th, 2017 7:38 PM

@gheme: It's not confirmation bias. There is a good reason why DNA damage is not important apart from generating cancer an senescent cells. It can't be simply dismised without providing a counterargument or experimental data.

The first study you cite is not done on wild-type mice but artificially damaged mice, so it must be taken with a grain of salt.

The second study only says that DNA damage increases with chronological age and with cell division rate, not what its contribution to aging is.

Posted by: Antonio at March 25th, 2017 9:41 PM

We will see but I believe hallmarks of aging is right about DNA damage. We will find out in due course anyway.

Posted by: Steve h at March 26th, 2017 5:54 AM

I am 62. Almost 2 months into my 2 pill a day regime (mornings on empty stomach) on Elyseum NMN.
1. Seeing difference in strength around my knees. Getting up from bed like I used to 5 years ago. No hesitation, not requiring hands for support, in a smooth motion. No pain in knees. Noticed enough of a difference some 3 weeks into regime.
2. When I back the car and need to look back (don't have rear camera in car) I am able to turn my head around on my neck way more than I have been able to do in the last few years.
3. My wife said she would be convinced if I could get up from a sitting position on the floor without holding on to a chair or bed for support. She is considering taking it herself. She too is 62. (I weigh 260 pounds on a rather broad-shouldered frame and am 6'1" tall, so overweight but not not markedly so in comparison to my height and frame). So last week I tried doing that, expecting to fail. But just with support from my hand/palm on the floor I was able to do it.

I would definitely say that the muscles and/or other parts of the musculo-skeletal system (ligaments, tendons, etc.) that support my knees appear to have reversed at least 5 years of perceived aging. Also my neck flexibility is reversed at least 5 years. And my knees don't hurt any more from regular walking around.
BTW I have background in scientific research and understand placebos, confounded experiments (i.e. other variables causing the effect), etc. quite well. Nothing of consequence, as I see it, changed materially. Same diet and exercise (unfortunately much lower than my doctor would like) before and after.
I have absolutely no affiliation with any aspect of the NMN sudies or its commercializtion by Elyseum. To me the issues about aging that I was facing every day have been pushed back and I feel great. Couldn't have come in a more timely fashion. Soon this will become my new normal and I will forget these huge differences that ocurred in a relatively short period of time.
I don't particularly care if it does not reverse the aging of my muscles any further--I am OK with it holding at this level. But I am concerned the effect might just be temporary.

My wish: NMN becomes cheaper (say $20/ month) so more people can use it. The first month I paid $60 but then went to the 6-month prepay program that brought the monthly price to $45. I am not into increasing my longevity--just want to age better so I can live in better health till I die. I believe that is what most people want.

Posted by: Uttam Mukhopadhyay at April 16th, 2017 8:25 PM

One more thing to add..I can sit on the floor or bed with my legs folded in. Couldn't bring them in more than halfway. I can now sit cross-legged with my knees folded in very comfortably. Last happened at least 10 years ago. The lab mice studies at Harvard talked primarily about muscles become younger but what I have noticed the most is that I stretch a lot better.

Posted by: Uttam Mukhopdhyay at April 16th, 2017 9:19 PM

hi my Stephen. You would raze your funding goals if you went to some of the funding platform websites. They are websites that allow you to advertise to people all around the world that love to fund new start up,s. It doesn't mater what you are trying to achieve it could be that you kneed the funding to send your child to university and you kneed the money to pay the fees. ore your project. People want to fund things that they think is worthy.Some offer incentives that they the funders can earn for there donations. It would be up to you if you want to do that. I will try to give you a list of the crowdfunding websites here below

Kickstarter/ Indiegogo/Piglet / GiveCampus/Piggybackr/DonorsChoose/YouCaring/CrowdRise/GoFundMe/GiveForward/Patreon/Fundable/WeFunder/Crowdfunder/Seedinvest/PeerStreet/Real Crowd/Realty Mogul/ Honeyfund /Slated/Experiment/CarbonStory/

Theas above are 22 crowd funding websites that will let you pitch your projects to people from all around the world that are keen and eager to fund worthy projects. I wish you all the best and I hope this is helpful. Thank you Stephen

Posted by: stephen bell at November 17th, 2017 12:32 PM

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