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The mitochondrial NAD+ transporter SLC25A51 is a fasting-induced gene
- aesthesia 4y agoIn mice, of course. What are the broader implications of this supposed to be?
- thornjm 4y agoFatty liver and high fat in blood is a disease and a risk factor for serious disease respectively. This study appears to show that fasting is related to inducing the gene Slc25a51 and improving those factors. I guess this contributes to the body of science around the potential health benefits of fasting.
- mistrial9 4y agook - but the purpose of publicly identifying by name, a particular genetic component, is to own that function commercially somehow - am i wrong?
- SargeZT 4y agoEventually it may be a contributor to a commercialization, but now it makes it a target for research for others. This isn't patenting anything, it's scientists saying 'this is an important bit when it comes to the effects of fasting so let's focus on this.' What would be scummy would be some pharmaceutical company discovering this, not releasing the information, and trying to develop (or worse, failing to develop) a drug on their own after internal research that was never released to the world.
- aydyn 4y agoMice are physiologically small humans with tails and fur. Findings in mice are very relevant to humans.
- jjallen 4y agoI’ve always wondered what percentage of mice (and other non human animal) findings turned out to be applicable to humans as well. Anyone have an idea?
- throwawaymaths 4y agoNot confident on diabetes. The biophysical dynamics of insulin are super different in mice - they have two, one of which is missing a highly conserved amino acid across all vertebrates that is at the hinge of the critical structural element of insulin. https://www.frontiersin.org/articles/10.3389/fendo.2021.649255/full https://www.frontiersin.org/articles/10.3389/fendo.2021.6492... Literally no one talks about this in mice metabolic research. I would not be surprised if a huge majority of mouse researchers in diabetes are unaware.
- mnw21cam 4y agoI work in human diabetes genetics. We're just publishing work on a gene that doesn't even exist in mice - https://www.medrxiv.org/content/10.1101/2021.08.23.21262262v1 https://www.medrxiv.org/content/10.1101/2021.08.23.21262262v... Part of our message is basically what you just said. We have multiple examples of genes where mutations cause diabetes in humans but don't in mice. The other one we have is the fact that human pancreatic beta cell lines in labs don't even 100% act like human pancreatic beta cells in humans.
- tsol 4y ago>The first thing to note is of those drugs which pass animal tests, 94% will fail during human clinical trials stages (Phases 1 – 3)*. https://www.understandinganimalresearch.org.uk/news/nine-out-of-ten-statistics-are-taken-out-of-context https://www.understandinganimalresearch.org.uk/news/nine-out... But to be fair, there's a huge failure rate for pharmaceutical drugs in general.
- Symmetry 4y agoFor many things yes. But humans have been under much more intense selective pressure for longer lifespans so easy interventions along those lines that work in mice have a history of not panning out in humans.
- alwillis 4y agoOne possibly obvious one: Fasting in mice turns on SIRT3 which requires NAD+ and this newly discovered gene SLC25A51 is involved in transporting NAD+ to SIRT3. There's plenty of data that shows mice can live 30% longer when calorie-restricted due to sirtuins being activated.. Anyone who's ever listed to Dr. David Sinclair speak about longevity, he almost always talks about how NAD+ is possibly the most important chemical in the human body, since we'd be "dead in 30 seconds" without it. Sirtuins are the longevity genes that are activated when organisms are under duress, which can be simulated by fasting. Your body doesn't know when you're going to eat again, so the sirtuins get activated. I wouldn't be surprised if researchers and labs are looking for ways to activate SLC25A51 chemically to get the NAD+ flowing to SIRT3 without requiring fasting. You can listen to David Sinclair and Rhonda Patrick get into the details of how all of this works: https://www.foundmyfitness.com/episodes/david-sinclair https://www.foundmyfitness.com/episodes/david-sinclair
- ChrstnBonanno 4y agoPolymorphisms in SLC25A51 might be linked to chronic fatigue or other mitochondria disorders. So that is pretty important. Sinclair, IMHO, is all protein and zero enzyme and that is his problem. Without enough zinc NMNAT will not function and will slow the SIRT cycle. And increasing SIRT activity by shoving NAD in the cell with out zinc will end up depleting zinc.
- TedDoesntTalk 4y agoRhonda Patrick is amazing. Been a subscriber to her posts podcast for 3 years. But she has tons of free content on YouTube and elsewhere. It was disappointing to hear David Sinclair makes his own resveratrol… can’t get it
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- rsync 4y ago"I wouldn't be surprised if researchers and labs are looking for ways to activate SLC25A51 chemically to get the NAD+ flowing to SIRT3 without requiring fasting." To what end ? Fasting would be cheaper, easier and less time-consuming and would include all of the related, broad-spectrum effects that we also believe fasting may produce. I guess if you're a pharma investor or existing, entrenched player it makes sense to go that direction. As a consumer, however, I wonder why (pills that might convey a subset of the benefits of fasting) would be interesting in any way.
- caeril 4y agoWhy does this tired argument always appear on HN? We share 97% of our genes with mice. Our organ systems and metabolic pathways are extremely similar. Our homeostatic mechanisms are nearly identical. Some mouse models don't carry over to us, to be sure. But the reality is that most do. Do we know for a fact that this paper applies to us? No. But it significantly updates our priors. And that's always noteworthy.
- d0mine 4y ago9 out 10 results in mice do not transfer to humans. For example, fasting for several hours in mice and in humans are completely different things (a human would have to fast for days to get similar results).
- Iwan-Zotow 4y agoWould it help with treating anorexia?
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- ck2 4y agoPaper is fascinating to the right interests but oddly extremely specific for HN? Do some people just not have Slc25a51? Does this matter? Is this supposed to be some kind of longevity insight?
- pizzathyme 4y agoI am also a long time hacker news reader and even a longevity and biology enthusiast, and I can confirm that I also have no idea what any of this means or why it is on the front page
- maerF0x0 4y agoI think this is relevant to the biohacker crowd and much of the NAD+ (and NMN) interested crowd (such as followers of David Sinclair or David Attia), and topics around the Yamanaka factors & Hormesis induced from existential threats (such as heat/cold or fasting, or fasting mimicking things like metformin inducing low blood glucose in otherwise healthy people) I'm not a doctor or a researcher etc. Just a guy who likes to watch these things play out and barely understands what I hear :)
- zahma 4y agoNAD+/NADH is kind of an important energy transporter molecule in your body. If you do not have NAD+ to be reduced to NADH, your body cannot oxidize NADH to power the electron transport chain and drive forward ATP synthase. In other words, you will die literally from exhaustion.
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- upsidesinclude 4y agoNAD & NMN are recent developments in the world of supplements. Read about them a bit, they are natural compounds in the body. Over time our ability to generate them decreases. Each can have profound effect on things like muscle & tissue repair or lifespan. This is effectively stating the mechanism for utilizing these is shown to be linked to fasting. The efficacies are already proven. A new study which accounts for the activation of the gene and utilization of the supplements will likely show a major therapeutic potential or life extension therapy
- ramraj07 4y agoCitations please? Here’s a snippet from WebMD: > While there is some evidence that suggests NADH supplements might reduce blood pressure, lower cholesterol, help chronic fatigue syndrome by providing energy, and increase nerve signals for people with Parkinson's disease, there isn't enough information to know for sure how or if these supplements work.
- threeseed 4y agoThis is one of the companies that sells NAD supplements: https://www.elysiumhealth.com https://www.elysiumhealth.com I can't speak to any of their claims but the company is legitimate.
- ramraj07 4y agoThey have a clinical trial published; it shows taking the supplement does indeed increase NAD levels. I’m not yet completely convinced personally that this helps, I’m also not persuaded that this does not harm in anyway. Please note the one thing that’s proven again and again in multiple studies: people who take supplements die faster of everything. We don’t know why, and until we do I’m hesitant of increasing my supplement load.
- krageon 4y agoWhen you have hard to diagnose chronic issues, the first thing a GP will do is give you supplements. Not very surprising the people taking them are at more risk of dying.
- Steve44 4y agoMy wife was recently diagnosed with metabolic myopathy and they ( NHS in the UK) are currently trying to identify what actual problem is; so far it's something to do with ATP and Phosphates affecting how the muscles convert fuel into energy I believe. My chemistry and biology knowledge are fairly limited, but I di like to understand things and so started looking into this and found [1]. For my level of knowledge I feel it gave a great balance between what I could understand whilst also showing how incredibly complex human chemistry is. There is currently a related discussion here in "A physical wiring diagram for the human immune system" / https://news.ycombinator.com/item?id=32381790 https://news.ycombinator.com/item?id=32381790 but the link to biochemical-pathways.com is way over my head. I found that BBC link useful and thought others may do as it's related but simple. [1] https://www.bbc.co.uk/bitesize/guides/z2vbb9q/revision/1 https://www.bbc.co.uk/bitesize/guides/z2vbb9q/revision/1
- Madmallard 4y agoHow did they even get to that point to diagnose that? I suspect taking ciprofloxacin 8 years ago caused metabolic myopathy in me as well because of its known deleterious effects on mtdna and oxidative stress well established in research, but doctors have never been helpful at even going in that direction. I had a loss of 35% VO2 max in the first year alone afterward.
- Steve44 4y agoShe was being treated for osteoporosis but as that was settling down her muscle spasms were getting worse. We had assumed they were related to the osteoporosis and so hadn't discussed much about them until the bones had 'healed', the endocrinologist wasn't that aware that they were becoming a problem. She started looking into Hyperparathyroidism as a possibly cause. As that was progressing slowly we went privately to see a consultant neurologist; he examined her and looking at things like jaw strength concluded it was metabolic myopathy related to a problem with the muscle cells and phosphate. He said he'd only seen it a couple of times before and it's very rare and not surprising it hadn't been picked up earlier. We're now going in for muscle tests, DNA tests, and all sorts to try and identify what is wrong and how/if it can be fixed. The thought is her osteoporosis was likely caused by the cells leaching nutrients from the bones as they couldn't get them normally, that has been stabilised by traditional Alendronic acid, calcium, and Vit.D.
- thesaintlives 4y agoI can't really comment on the article but I can comment on taking a NAD supplement. I take NAD every day and magnesium L threonate every few days (whenever I feel like a need a mental boost). The NAD really makes me feel better. I have no idea what it does but when I don't take it I have more difficulty getting up early in the morning. NAD, magnesium and zinc. Those are my basic supplements and I always take them. Give it a go!
- mzmoen 4y agoWhat brand do you take?
- zamalek 4y agoNAD supplementation is a contested area of research, and there are many studies showing that it doesn't achieve anything useful. Further, NAD supplementation puts stress on the methylation cycle and given that you have a 10-25% chance of an MTHFR mutation (depending on your demographic) you should be very careful with NAD supplementation.
- motive 4y agoCan you elaborate on the MTHFR mutation? I did supplementation in the past with similar results to the above commenter.
- zamalek 4y agoIt's a pretty common mutation that severely inhibits (depending on how many of the genes are mutated) methylation of folate in the liver. This is an important source of methyl groups for chemical processes, such as those that include NAD. There's plenty more on Google, including the interaction between an MTHFR mutation and NAD supplementation.
- valarauko 4y ago> MTHFR mutation I'm a geneticist and I still read that as a curse word ...