Critical step found in DNA repair, cellular aging (2017) | Hacker News Reader

Critical step found in DNA repair, cellular aging (2017)

news.harvard.edu

238 pointsdcu61 comments

This was Dr David Sinclair, trying to convince us - again - that he found the fountain of youth, much like he did back in in 2004 with resveratrol, cashing 720m USD after selling his company to Glaxo in 2008.

He was later involved [1] in a case of research fraud involving resveratrol.

Snake oil I would say.

[1] http://retractionwatch.com/2012/01/12/so-how-peripheral-was-...

Unless I'm missing something, you're claiming that David Sinclair's research at Harvard can never be trusted because someone he doesn't seem to know and hasn't worked with (Dipak Das at University of Connecticut) and also happens to be dead committed scientific fraud.

This is beyond "guilt by association" it's "guilt by non-association."

What I am trying to say is that you just can’t take basic research and take it to the market, selling it as the fountain of youth.

And Dr. Sinclair cited Dipak Das in his research and knew him personally, when they both served together on the scientific committee of the “first international scientific conference of Resveratrol and Health” in Denmark in 2010

What I am trying to say is that you just can’t take basic research and take it to the market, selling it as the fountain of youth.

Well, I would speculate that it would require a multiphase treatment to anything like youth restoral. At the same time, I think ultimately we simply don't know. Human evolution didn't necessarily select for or against humans living indefinitely and there may fairly simple mechanism whose interruption could add X many years to human span - or there might not be.

Well, on the one-hand, the article goes on to show Sinclair did know Das, on the other hand, the article doesn't show any close connection. Moreover, the article asks "How peripheral was Das' research?" and apparently answer "well, I guess it was kind of peripheral".

The Lowe links go to spam so it's hard to figure out some of the implications too.

My humble opinion is that the cure for aging is going to involve creating some perfect stem cells for the body to regenerate from. The idea is that you could perform an analysis on a few thousand cells from an adult, and since the mutations in each adult cell are in different places, by looking at the most common variant of each base pair you can figure out what the perfect original dna strand looked like. Then you can create at least one perfect stem cell. The reason I like this approach is that fixing mutations by comparing multiple dna strands is something that evolution can’t do, whereas if the problem was some simple chemical that the body needed, evolution would have solved that problem on its own. So I’m gonna go out on a limb and say that’s probably not going to work.

There are a bunch of other things that can't be fixed by delivering youthful stem cell populations into tissues, such as the presence of garbage molecules in long-lived somatic cell populations. Even youthful tissue can't break down glucosepane cross-links, or remove senescent cells efficiently, etc. Replacing damaged stem cell populations with functional ones is just one slice of the full spectrum of rejuvenation therapies that will be needed. This is all laid out in quite a lot of detail in the SENS outline for how to bring aging under medical control.

https://www.sens.org/research/introduction-to-sens-research

I've also had this idea -- I wonder if it's chance or if this is something that geneticists have thought of as well and attempted. Sampling cells from a few different reproductive cell lines should theoretically provide a strong average, perhaps with some adjustments for more common mutations across all lines/things that are more likely to be repaired. Then regenerate the telomeres and replace the DNA in the germ layers of a blastocyst and you have the foundation to replace 50+ years worth of cells, plus provide a digital copy of the DNA for the next treatment round. Keep supplying a person with "undamaged 25 year old version of their self" cells (based on telomere length) and they can stay young indefinitely without negative side effects such as continuing to grow taller, cancer from damaged DNA, etc. Still issues with arteries clogging over time, figuring out a good way to regenerate the brain, bones and joints wearing down, etc., but I feel like those are easier problems (with the exception of the brain), perhaps to which the young stem cell therapy could also be applied.

> evolution would have solved that problem on its own

Individuals may love agelessness, but let's not kid ourselves that it's anything but a disaster for species, society, etc.

More concretely, evolutionary pressure for immortality is nil when reproduction (including evolution itself!) is a more efficient way to spread and preserve genetic material.

If anything, aging + death would be the evolved trait to ensure smoother adaptation!

> Individuals may love agelessness, but let's not kid ourselves that it's anything but a disaster for species, society, etc.

You're right, however to me what seems worse path to take evolutionarily is to choose to destroy accumulation of experiences and knowledge by not passing it to next generation and instead starting with the first rudimentary step of half DNA crossing combined with random mutation.

Though we have developed ways (books) to pass that knowledge to next generation in place of nature, experiences are still lost.

It seems like evolution is more focused on the survival than survival of the fittest.

I sometimes take solace in political issues, that “at least the people who believe that will eventually die”.

If that stops being the case it will lead to more political action. And potentially more force. Not sure if that’s good or bad for society.

Another 30 years of productive healthy life, and retiring at 90 will do fine thanks.

Agree. Immortality would be a tragedy of the commons, in my opinion. At least, in an environment with limited resources. If we were capable of interstellar travel and there was no other life out there it wouldn't be, but until that happens its ultimately good for society that it has a complete turnover every hundred years, and not just for evolutionary adaptation. Imagine if Stalin or Mao had never died. Imagine if the entire British government was run by politicians from the 1300s to the 1800s. Maybe Caesar Augustus would still be running the Roman Empire, fighting a never-ending insurgency from the prophet Muhammad.

Things might have more stability, but change and opportunity would hardly exist and each succeeding generation would be permanent underclasses of children.

"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. " - Max Planck

You’re assuming aging is bad for populations.

My assumption is historical learning is valuable up until some percentage of your memories are false and/or obsolete. Even in a perfectly healthy individual both happen continuously.

At some point an empty vessel has more utility than a trained up individual. So some heuristic that arbitrarily purges old people and their ideas is adaptive.

The real challenge is that you need young mitochondrial DNA, too, and that suffers more damage and has less sophisticated repair mechanisms than nuclear DNA. (This seems to be the reason that cloned animals suffer age-related issues so quickly— their mitochondria are “old”.)

I think if it's possible to do in theory, evolution would find a way to do it. It's just that evolution doesn't need to get rid of aging.

The only human study providing a compelling reason to try nicotinamide riboside is the one showing a drop in blood pressure in hypertensive adults [1]. But this was a very small group of patients. If it does that in most people (which it may not) then that alone is a compelling reason to use it providing the price is low.

However, it isn't a compelling reason for the sizable expense of developing this outgrowth of sirtuin / calorie restriction research. That funding and person-years of researcher time could have gone towards far more effective programs such as senolytic development, or other SENS damage repair approaches to aging.

Not all NAD+ precursors are the same. The evidence in animal studies suggests that some (such as nicotinamide [2]) do basically nothing. The most effective approaches appear to be infusions, but they are not cheap.

Currently nicotinamide riboside is produced by one company in the US, and the retail price reflects that. If you do decide to take it for the long term at the dosage from the studies of 1g/day or so, it is considerably cheaper to order by the kilogram from Chinese manufacturers (plenty of manufacturers on Alibaba) and run the necessary mass spectrometry and other tests per batch to ensure quality (plenty of providers on Science Exchange).

While you are taking it, consider that this is small potatoes. It is a tiny effect in the grand scheme of things. Exercise has a larger and more reliable outcome. The research community should be doing better than this (and is in the case of senolytics) and people outside the research community need to become better at telling the difference between marginal and useful approaches to the challenge of aging.

[1]: https://doi.org/10.1038/s41467-018-03421-7

[2]: https://doi.org/10.1016/j.cmet.2018.02.001

> and run the necessary mass spectrometry and other tests per batch to ensure quality

As someone with a background in supply chain security and fraud please DO NOT put anything purchased from China in your body without thorough testing.

Testing per batch is needed when ordering direct from any manufacturer. In my experience there isn't any real difference in quality and order fulfillment between Chinese and non-Chinese manufacturers when it comes to extracts and research chemicals, provided you stick with groups that have good reputations in Alibaba.

So all that caution that most people feel regarding Chinese manufacturers should be spread out a little more and applied to those closer to home as well.

Dr Peter Attia did a podcast with Dr Sinclair not too lon ago where they discuss this:

https://peterattiamd.com/davidsinclair/

The show notes on the episodes are always really good, and you can almost read them without listening to the episode.

Article is from March 2017, has there been follow up findings on this research?

The article makes it very difficult to follow up because no direct link to the scientific paper is given.

This lapse is unfortunately way too common and puts the author as well as the publisher in an unprofessional light.

Presumably, this is the paper:

http://science.sciencemag.org/content/355/6331/1312

Given the title, you can look up on Google Scholar:

https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=+0+R...

Click on the "Cited by" link at the bottom of the entry to see the 47 papers that have cited this one to date:

https://scholar.google.com/scholar?cites=6666909628793143847...

Reverse chronological sort didn't find anything that looked like a follow-up.

I'm not sure why the most cited article couldn't be called a follow-up or at least summary of intention to follow-up.

"A comprehensive concept that connects NAD+ metabolism to the control of aging and longevity in mammals has been proposed, and the stage is now set to test whether these exciting preclinical results can be translated to improve human health."

https://www.sciencedirect.com/science/article/pii/S155041311...

I'd be very curious to hear it indeed. We keep getting interesting articles about breakthrough, but lack to my knowledge follow-up on them. Good opportunity here to see how this went

I’m skeptical too, and a lot of this research smacks of the same mix of desperation (who wants to die?) and a market of nearly all people which has traditionally made searching for elixirs of immortality such a dangerous and unproductive pastime. Aside from a lot of geriatric mice and worms, people ordering raw compounds from Alibaba, and the occasional muttering about uploading our brains (as if we even understand what that would look like, never mind technically entail) this looks a lot like people melting cinnabar in an alembic.

Here's a link from FDA recognizing that it is safe to use: https://www.fda.gov/downloads/Food/GRAS/ucm505226.pdf

There are a bunch of expensive NAD supplements out there but dosage is nowhere close to the same as the studies and no shown efficacy in humans yet.

For those already taking this what is your daily dosage and do you split it into an Am an Pm schedule? Because if the cost just wondering if people are taking the 1g a day like the article or less (more?).

This article proposes raising levels of NAD to counter aging related dna damage.

My google search also resulted in: https://medicalxpress.com/news/2016-12-pathway-linked-slower...

TLDR; NAD+ over-activeness is associated with a deadly form of brain cancer, and the article ends with an open question from an expert if it could be modulated to not have this adverse effect.

The next step is probably figuring out the tricky balance between these two ends.

Is it possible that NAD would also repair DNA damage in cancer cells? This reminds me of those that take growth hormone in middle age with the hope that cancer will be cured before they get it.

Maybe they'll even find a cure for body dysmorphia. It's usually those people that use growth hormone.

Why are there NMN supplements, when it is essentially vitamin-b / niacin? Honest question, what am I missing?

Asking because I already get too much vitamin b3, 6 and 12 from energy drinks.

When is the best time to take NR? Mornings on empty stomach?

This is very legit. The results are tremendous. I recommend it to anyone, but with a doctor's recommendation of course.

Here is a study on adult humans: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5876407/

Edit: Comment edited.

For another sample of one, I took Elysium Basis for several months, stopped, and then took a similar dosage of NAD and pterostilibene from other manufacturers. I can't say I noticed any obvious benefit from either regimen. Looking over article, NMN looks like the more interesting compound, and it does seem like some human trials of it are in progress, e.g.[1]

1: https://clinicaltrials.gov/ct2/show/NCT03151239

I've been taking Elysium Basis for a little over a year. I've noticed no effects, secondary or otherwise. I looked really hard at their research about (likely) effectiveness, and it did seem to check out.

But it is around $50/month so I'm not sure if I will continue to take it forever. Elysium is mostly a marketing company, so hopefully they will have competition and the price will drop if more research proves NAD's effectiveness when taken by humans long-term.

> I can't say I noticed any obvious benefit from either regimen

What could you have noticed?

Not sure if you meant that as "it's obvious nonsense so of course you wouldn't have noticed anything" or if it was broader question about placebo/nocebo effect? I was just responding to the claim that taking NAD supplements could have tremendous effects - presumably I would have noticed those.

> the results are tremendous

What results are you seeing?

I was struggling to build muscle. My weight was really low. After adding Niagen (and a few other supplements) to my diet, I gained 10 pounds.

This was literally after ~1-2 years of 0 growth, and not much has changed aside from that in terms of my diet and exercise routine.

Why would an increased rate of DNA repair lead to increased muscular hypertrophy?

According to a recent study, it appears that "lower NAD+ levels are deleterious for muscle health and higher NAD+ levels augment muscle health. [1]"

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840929/

I only skimmed your paper, but it looks like any positive effect is from better mitochondrial function. While I’m sure that’s a good thing, it’s not what the article is talking about, so to say that your experience proves that it really works is a little misleading.

One person's experience never proves anything in a macro sense, as I'm sure the person you're responding to understands.

All it proves is that through actual biological processes or through placebo effect it has an effect on OP.

If you stopped the dosage, would you expect to lose the weight and muscle? Seems easy to test.

Can you share your diet and exercise routine please? I do have the same problem.

The study talks about giving the mice NMN, not Niagen. Are the two related?

Both NMN and NR (from Niagen) leads to NAD+!

I've seen it mentioned on forums. But what does science say about it?

- It WORKS in adults and is well received. [1]

- Having low NAD+ leads to all sorts of terrible, horrible, no good, very bad issues. [2]

- You need NAD+ for muscle and energy. [3]

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5876407/

[2] https://www.ncbi.nlm.nih.gov/pubmed/29295624

[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840929/

[1] does not say that it works, don't misrepresent the study. It found that certain markers were increased/changed by the supplement and that a few of the observed physiological functions appear to have improved a merit further study. Also, N=24 so ymmv. Seems like something that may be useful after further study but your conclusion is misleading.

> Having low NAD+ leads to all sorts of terrible

Maybe "the low NAD+ levels" are a symptom, not a cause, since its linked to unrelated diseases?

I don't understand the conclusion; perhaps the NAD+ is the thing connecting the diseases?

Why do you find it necessary to have a creative commons license for your hn profile?

This study is done on mice.

It's a biochemical result, not a medical study about a treatment.

OT: I now read HN comments BEFORE OP — offers a slightly different lens.

I only read the article if the discussion is interesting.

Why are people all of a sudden posting medical news on HN from one or two years ago?

Off-topic, I wonder if other people also subvocalize when reading and then get startled by passages like "already known for its role as a controller."

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