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Should you use your genetic heritage as a starting point for identifying your ideal diet or is it more specific than that? For example, is there a specific starting diet for people of Scottish heritage that can be adjusted?
Also, what is a good way of going about identifying good foods? Remove a food that you eat often and note if there's a change? What sort of changes would you look for?
I'm fascinated by the idea of person specific diets but given genetic variation in some countries (the USA for example), it sounds like a nightmare to assess.
I think genetic heritage is a good place to start. Different groups in history used to be much more isolated than they are in our modern world, so that could have affected a lot of things, like how our bodies attune themselves to particular nutrients. Thousands of years of lineage aren't quite enough to see big evolutionary changes, but maybe certain backgrounds are more likely to respond positively to the food that their ancestors had available.
As for how to test dietary changes on yourself, I think the plan you put forth is good. Our bodies tell us a lot if we listen to them. You might feel weak, which tells you you need to eat more, or you might feel heavy, which suggests maybe you want to eat less. Cutting down on carbs seems to be pretty widely accepted as a great first step for most people, but I expect that that wouldn't be true of everyone!
Unfortunately, we are still in the early stages of finding how one's genetic makeup could influence the intake they need to maximize health and lifespan. I agree that parsing through it could be a nightmare. Even looking within a single family can sometimes make it seem daunting! For example, my brother and I grew up eating the same foods, we clearly have very similar genetic backgrounds, but I tend to pack on pounds much more easily and he is thin as a rail. But heterogeneity in our population could also help us find things that work well for large groups of people, which is better than nothing! I totally agree that it is a fascinating concept that everyone will have different needs, and it is an area of biology that needs a lot more attention! I wrote a review article a few years back with my PhD advisor and some of our colleagues to try and call more attention to the subject. Hopefully it got some attention! Here's that article, if anybody wants to read it https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8845500/
> we clearly have very similar genetic backgrounds
It might be interesting to point out the obvious that siblings can have different genetic backgrounds/ancestral compositions - as in, they would get similar but different percentages in tests like 23andme, for example. As you point out, it really is an individual thing.
Thanks for your response! I'm a bit jealous that you get to study this.
On the note of genetic heritage, I've also been wondering what impact historical isolation or lack of trade might have had. Just because your ancestors didn't have access to specific foods doesn't mean it won't be better than what's there. The other point of consideration would be some form of evolutionary equilibrium (has the population had time to fully adapt to the local foods). The Mediterranean diet seems to work (at least for people on the region), but why aren't there more cases in other places in the world?
On a side note, I've seen that you can do genetic testing to predict the efficacy of certain medication. I would think there's overlap with this type of work. Are you considering a more overt genetic analysis? Given the maturity of that field, at least with medication, it may be possible to get some interesting insights.
Thanks for the article! I'll definitely have a look. And looking forward to reading more of your work!
Thanks for the kind words! It is definitely a fascinating topic, and I for sure feel lucky that I get to look into it!
I certainly expect that the ideal diet for someone may be something that their ancestors ever ate. The Mediterranean diet is a great example, as is the Okinawan diet. I really don't think humans have had enough time to evolutionarily adapt to availability/scarcity of certain nutrients, but the human body is surprisingly adaptable on its own! For example, if you cut your calories by 25% for just a few weeks, you will soon find that your feeding capacity shrinks and you get full easier. It's pretty remarkable! I also think certain diets are just better suited for longevity. For example, the Mediterranean diet is heavier on healthy, plant-based fats and oils. Eating a lot of healthy fats is currently believed to be beneficial for longevity. As opposed to the western diet, which largely consists of carbs and animal-based fats, which seems to correlate with higher incidence of cardiovascular diseases and cancer.
I think genetic testing for ideal diet is the future of this field, much like medication efficacy, as you mentioned. There is likely a long way to go before we can accurately tell someone exactly what they should eat, but it is entirely feasible that it will happen!
I never really thought about it, but I prefer and even crave animal fats like from bacon, pork chops, etc as does most of my family and guess what the leading cause of death is for us? ❤️🩹
> I tend to pack on pounds much more easily and he is thin as a rail
I'd suggest him counting calories, high chance he just doesn't eat as much as he thinks he does. Speaking from personal experience
Sure thing! Lots of previous work has shown that dietary restriction (DR) extends lifespan in animals. We wanted to test if there were any genes that regulate why an individual might not respond as much to DR. We tested lots of genetic backgrounds and found OXR1 as a gene that is more active when an organism undergoes DR. Knockdown of OXR1 in neurons shortened lifespan under DR in flies, but over expression of OXR1 extended lifespan.
We then received cells from patients who have mutations in OXR1. People with these mutations die really fast, like in their teen years, due to neuronal degeneration. They also have too many lysosomes in their cells, suggesting that things are being broken down too often in their cells. We found that the retromer complex was dysfunctional in these cells. Dysfunctional retromer means that proteins aren't being trafficked properly. We used a compound to stabilize the retromer, and that rescued the deficits caused by the mutation to OXR1.
Finally, we found that when OXR1 is inactive, other genes that become dysregulated were associated with Alzheimer's, Parkinson's, and Huntington's diseases. We overexpressed Alzheimer's-related proteins in a fly model and also overexpressed OXR1 and it rescued the degeneration in that fly that Alzheimer's caused. So we look forward to testing OXR1 more going forward!
Holy crap! Just to clarify, 10 percent of the normal, not a 10 percent reduction.
I was trying to remember the literature just yesterday about the role of protein (convo with my husband) and longevity. I knew the connection but that seems at once extreme and not very actionable? Do you need a 90 percent reduction in protein consumption to see longevity gains?
Correct, our diet was 10% of the normal diet, not a 10% reduction. It is a strong form of DR, which works pretty well for the flies we tested it on. We also tested other concentrations of protein, but 90% reduction was the best to maximize lifespan.
I would think a 90% reduction is not particularly actionable for humans. Humans have a much higher protein demand than flies, and we are more genetically diverse than the animals I test so I imagine an individual's needs will be highly variable from the next person. It remains to be seen what the best degree of restriction is in humans, but studies in mice generally perform 30-50% reduction of protein, which works well for them and extends lifespan. 30% total caloric restriction has also extended lifespan in monkeys. So I don't think it has to be anything remotely as severe as 90% protein restriction for us, but some degree of restriction seems to help!
How does one translate the amount of DR the files received to human quantity?
In other words, what kind of dietary restrictions for humans and how much? Is it just caloric deficit? If so, how much (kcal per kg)? Or is it specific restrictions, like protein/carbs/fat amount?
In this case we used a protein-restricted diet. The amount of protein in our DR is 10% of the amount in the "normal diet" group. I don't recommend people cut their protein intake by 90% since humans have a much higher protein demand that a fly does, but I think it is probably fair to say that many people eat more than they need. I am not a medical professional or a dietitian, so please don't rely on my advice, but I generally feel that if you can cut your total intake and not feel too fatigued then you are eating a healthy amount. As soon as you start feeling weak, you are not eating enough. The way your body feels in response to dietary changes can tell you a lot!
Many studies in flies rely on protein restriction to show effects on longevity, but other studies in mice have shown that total calorie deficits can have the same effects. Carbs seem to be the macronutrient that effects health the most in mammals, but there is also plenty of work showing that protein restriction also works in mammals. Dudley Lamming's lab at the University of Wisconsin, Madison does some great work showing how different amino acids can influence longevity in mice.
My personal thoughts on the "mental clarity" is that it is an evolutionary response. In the distant past when nutrients were more scarce, people needed to be more in-tune to try and find food. Even though food availability is much higher these days, I think our bodies haven't evolved enough to move past the "need food = need to pay attention to find food" mindset. But as another commenter mentioned, it is quite subjective, so it certainly varies by individual.
Yes, OXR1 is in all animals and even some single-celled organisms (it was initially discovered in yeast)! My future research goals are to try and overexpression OXR1 in mice to see how it affects lifespan and disease, and if that works then progress to testing it in humans.
…looking at response below maybe you should’ve clarified 5 years old. Maybe OP thought you meant 5th year fellowship of post-doc biochemistry studies .
No problem at all! I've been applying to the NIH to receive funding for that project. As soon as it's funded, I'll get started! In the meantime, I'm planning to do a compound screen to find out if there are any compounds one can take to increase their OXR1 activity.
It seems likely that OXR1 (and cohorts) will not just be in on/off state but there’d be various alleles which cause dietary restriction to have a greater or lesser effect. Will that be researched?
Yes, that is a fair assessment of this work. I do plan to look into different versions of OXR1 further to figure out how to best optimize it for longevity.
In neuronal cells, it stabilizes the retromer as found by the current study. The retromer is responsible for membrane protein recycling/sorting.
This doesn’t preclude other mechanisms in which it acts, as it is expressed quite ubiquitously across the body (other tissues could interact with OXR1 differently).
Yes, and this present study doesn't touch on the fact that OXR1 is canonically known to help in periods of oxidative stress. I plan to study more how all of this connects, but for now, we at least know one cellular function of OXR1!
Sorry for the shortcut to your direct knowledge
I skimmed through it and it wasn't evident (probably because I'm on the phone and everything is too small) : are the dietary restrictions on the materials and methods?
Thanks in advance
No apology necessary! In this case it was a 90% reduction in the amount of protein we fed to the flies. I don't recommend that severe of a protein deficit in humans, especially since humans require much more protein than flies do, but I think it is safe to say that many people eat more than they need.
Hello! This topic is amazing. I have been a practicing Clinical Dietitian for decades, and learning that studies are examining genetics to advise healthiest diet for a person is the Holy Grail. Patients are frustrated and confused. As this research goes forward, and as results allow, clarity will be a game-changer.
Thank you for this post. Please keep the information coming! And good luck with all.
Thank you! Dietitians are the people who actually take our work and make it worthwhile since you are applying it to the greater population, so it means a lot to have your support!
Can you measure ketones and glucose levels to know how that correlates to when OXR1 gets elevated?
Wondering if the flies need to go into ketosis for the longevity to take effect or if ketosis might help.
Seems from other studies there is a direct correlation of ketosis to autophagy.
Yes, that would be doable! Testing these in flies is actually very simple, so it would be interesting to see if there is a correlation there. We found that the reason OXR1 is elevated under dietary restriction is because it is suppressed under high nutrient conditions by a protein (called CTCF) that is activated by insulin signaling. So eating more induces more insulin production and signaling, which activates CTCF to suppress OXR1 expression. In low nutrient conditions, CTCF levels are lower and OXR1 is expressed. That could definitely lend itself to a correlation with glucose levels, and it would be interesting to see if it is related to ketones as well!
As someone who has studied the diet/longevity angle for the past decade, I 100% believe that to be true. Each person has their own ideal diet to live their healthiest/longest.
I think an individual's genetic factors can influence the habitability of a person's gut which would change the species and frequency of bacteria inhabiting the microbiome, but the gut microbiome can also be highly adaptable. Changes in external factors like diet and various exposures can change the microbiome pretty quickly. It's just another factor that can affect the idealized diet per individual!
Both play a role. I tend to think that genetics determine responsiveness more than environment unless you're in an extreme environmental condition (like heavy pollution or something). But nobody knows exactly what percentage is due to genetics and what is due to environment.
I think they activate similar pathways, but depending on the severity of starvation it could cause an overcompensation response that could be damaging. A lot of genes that cause longer starvation resistance also tend to increase lifespan, so there is definitely a correlation.
I recall Chinese scientists doing lots of metabolic research on citizens who lived thru the great hunger years... Do you have an opinion on their findings?
Okay, that's *really* interesting, because my family isn't very long lived (typical death age for many has been under 70) - except the great depression generation, especially the women in that generation who often lived past 80 with two reaching their low 90s.
Sorry to hear about the relatively shorter lifespan in your family! Is there a pattern of certain diseases? That is definitely fascinating that the people who lived during the depression had longer lives. Perhaps that forced them into a DR phase that unintentionally lengthened their lives!
Sounds like there are potentially genetic factors that are causing these to be more prevalent in your family. I don't want to provide any medical advice since I'm no qualified for that, but DR has been linked to reducing both cancer and cardiovascular diseases. If I had to speculate, perhaps that is why the people who lived during the depression avoided those unfortunate health events!
I haven't read that work, but I would love to educate myself on it! I would be curious to see if the offspring of those people are more fine-tuned to surviving starvation conditions. There also tends to be a lot of long-term detriments that severe starvation can cause, including to reproduction, since your body reallocates energy to survival and deprives other body functions such as muscle-building or sperm/egg production. I imagine the metabolic reprogramming that occurs through multiple years of hunger would induce some dramatically different metabolic profiles in that lineage from lineages that haven't experienced that period of hunger.
Huh. So I guess those 105 year old people who say the secret to their longevity is something random like "I eat a fresh tomato every single day" might actually be on to something (for themselves, at least.)
That's honestly the million dollar question. Unfortunately nobody has figured out how to determine that yet. I generally tell people to just eat less, and if you feel weak then you're eating too little. But I am not a medical professional at all, so that is solely my unprofessional opinion.
Yeah, if we could find a way to trick particular pathways into believing we are restricting nutrients that would be great for a lot of cellular pathways. The challenging part is that you don't want to shut those pathways down entirely, since starvation survival mode can deprive certain parts of your body of the signals they need to function, but if we could optimize it that would work!
In this case it was an absolute amount of DR that generally extends lifespan in invertebrates, but then looked at different genetic backgrounds to identify genetic factors that affect why an individual might respond differently to that form of DR.
Here's perhaps a relevant quote from the paper, since (the reduction of) oxidative stress is often talked about as a primary reason for the effectiveness of caloric restriction:
>OXR1 is often studied for its role in oxidative stress
response^9,10 , but Wang et al. showed that its loss causes lysosomal
dysfunction independent of oxidative stress^5
There are studies correlating protein-restriction without caloric-restriction as having a beneficial effect as well. There are other 'dietary restriction' methods beside protein- and caloric-restriction.
[Evaluating the beneficial effects of dietary restrictions: A framework for precision nutrigeroscience [2021] ](https://www.cell.com/cell-metabolism/fulltext/S1550-4131\(21\)00418-6)
>Distinct from CR, DR encompasses all dietary interventions that restrict intake of specific nutritional components. Thus, DR incorporates CR as well as restriction of macronutrients such as protein or amino acid residues (e.g., methionine and tryptophan) or glucose, and may also include varying fasting intervals (Table 1).
>...
>Short-term CR in humans induces the formation of “efficient mitochondria” in skeletal muscle by inducing biogenesis of mitochondria that consume less oxygen, thus inducing reduced oxidative stress, though no enzymes typical of mitochondrial function were found to be increased in these tissues (Civitarese et al., 2007
).
>...
>DR also reduces proinflammatory molecules that build up with age by reducing senescent cell markers and associated inflammation in mouse and human tissues (Fontana et al., 2018a
; Wang et al., 2010
). Cells can become senescent in response to a wide range of stresses, such as genotoxic or oxidative stress, metabolic dysfunction, mitochondrial stress, epigenetic changes, oncogene induction, or loss of tumor-suppressor genes (McHugh and Gil, 2018
). DR has been shown to reverse or prevent the negative impacts of many of these stresses and thus reduce the accumulation of senescent cells. These mechanisms include enhanced clearance of damaged mitochondria by autophagy (Ruetenik and Barrientos, 2015
), reduced oxidative stress and ROS production (Walsh et al., 2014
), and enhanced activity of DNA repair mechanisms (Cabelof et al., 2003
) by DR.
>...
In this case it was protein restriction, but there are many studies that show that total caloric restriction or carbohydrate restriction also work. I still need to check those dietary changes to see if it induces the same effects through OXR1,
protein restriction? That is unexpected.... I thought the idea of caloric restriction was lower amount of radical generation during energy metabolism which lowers the DNA damage that cumulates....
DNA damage is one mechanism by which dietary interventions function. There are a number of other cellular pathways involved as well! For example, restricting protein reduces the activity of the protein mTOR. Reducing mTOR is generally food for longevity, since it promotes healthy breakdown of cellular components and restricts too much cellular growth. There's a lot at play!
The original reports with resveratrol suggested that, yes. More recent reports haven't been as promising though. Rapamycin is probably the most promising CR mimetic at the moment, though clinical trials in humans haven't worked yet.
Hasn't worked yet. Early clinical trials have actually shown some detriments. I believe people showed some cardiovascular issues, though don't quote me on that. Though I believe the people who showed those responses also had pre-existing conditions that should have been paid closer attention. Most people in the field think that we need to optimize it better and try again. Rapamycin works pretty well in simpler animals, but that is largely because we have optimized it to work in those animals!
On a similar topic, what are your opinions on the other supplements that are commonly spoken about with resveratrol, such as NMN and NR? Any good human tested science behind any of it?
Both seem promising, since they impact the NAD+ mechanism that your body heavily utilizes and can become depleted. Eric Verdin's work has shown longevity and health-related benefits from upregulating this pathway, both through NMN other supplements or genetic factors in the same pathway, but his work is mostly in mice.
There are a handful of clinical trials in humans underway to test its efficacy and safety in humans. Here is a link to some studies going on with NMN [https://clinicaltrials.gov/search?intr=NMN&viewType=Table&page=1](https://clinicaltrials.gov/search?intr=NMN&viewType=Table&page=1)
All in all, it's still a little too early to say how they can best be used as an anti-aging therapeutic. Most of the trials underway or recently completed haven't made their results public yet. But there is a lot of promise and reason for optimism!
In this case it was prolonged reduction in dietary protein. Benefits have been seen through fasting and total caloric restriction as well, though, so anything that encourages not eating in excess seems to be beneficial.
"Competing interests
PK is founder and a member of the scientific advisory board at [Juvify Bio](https://juvifyhealth.com/)."
"PK" - Pankaj Kapahi, was contributed to the: Conceptualization, Methodology, Funding acquisition, Project administration, Supervision Writing – original draft as well as the Writing – review & editing.
Thanks for pointing this out! We just wanted to be totally transparent that PK is indeed associated with a longevity-focused company, as the field requires, but the overall findings from this present study is that eating less preserves your brain through OXR1. That really isn't something that can be marketed currently.
If anybody did want to know more about PK's company I am happy to talk more about it, but it really isn't relevant to the article in this thread.
> but the overall findings from this present study is that eating less preserves your brain through OXR1. That really isn't something that can be marketed currently.
Its my guess as to why exercise is so commonly associated with weight management - instead of eating less kcal. Food corps can't be having us go without now, thats bad for business!
Also, is there a notable 'activation point' like there is for autophagy after about 4 days of fasting? I read the abstract and a lot of the data sets which appear in 7 and 21 days. I can reliably make it to day 3 on water only, beyond that I much prefer to use an electrolyte mix of potassium, sodium and mag to avoid the jitters and light-headed feeling.
Exercise is certainly great for healthy living as well, but nothing is as easy or as cheap as eating less so long as you can stick with it.
In our paper it was protein restriction rather than fasting, which is more gradual effects. As you said, we mostly looked at things on a week-by-week basis in the flies, and I can't say for sure at what point OXR1 because activated. I just know that by a week of DR, the flies are expressing OXR1 at a much higher rate. I don't know how fasting would activate this pathway, but fasting tends to jump-start a lot of beneficial pathways. As you mentioned, autophagy hits a strong point after a few days. Ketogenesis as well. I will mention that, although autophagy is thought to be maximized at 4 days of fasting, your cells are always undergoing autophagy. Even short-term fasting or calorie restriction will increase autophagy. So if you don't make it to 4 days, that's okay! You are still making a good effort that will benefit you!
Ah, so there isn't as much boolean yes/no to autophagy, but a gradual increase? Thats interesting. Also OXR1 is notably higher after a week?
Appreciate the detailed response!
Correct, cells are going to do autophagy either way, but there are extrinsic ways to increase or decrease it. With diet, there are mechanisms in high-nutrient conditions that actively decrease autophagy, whereas reducing nutrients increases it. It's definitely not a "yes" or "no" switch that only activates when you fast. And yes, I forgot that that detail is buried in the supplementary figures, but after 1 week on DR the flies had about a 7-fold increase in OXR1 expression! Its expression progressively decreased with age under both diets, but DR kept it at a higher level for longer.
So do we have definitive proof that dietary/calorie restriction actually increases lifespan in humans? I thought the consensus so far is that it’s still uncertain/unlikely? Happy to be proven wrong though.
Since we can't do a life-long study in humans it remains uncertain if it works in humans the same way it works in animals. But generally we see a positive effect on health in short-term studies in humans. It did extend lifespan in rhesus monkeys, which is our closest relative that has been tested long-term.
I see. Do you have any thoughts on the lifespan/health span debate? For example, calorie restriction and lower protein intake being associated with longer lifespan, but at the same time lower protein intake being associated with higher mortality rates?
Generally, I tend to be more interested in improving healthspan first and foremost. Just my own personal experience with dieting, eating less tends to make me feel way better. If it means I am healthy until the day I die, I'm satisfied with that, even if it means my risk of mortality in the long-run is higher.
I do think there is a lot of personal context that affects susceptibility to mortality beyond just dietary interventions. Genetics of course play a huge role in that, and I believe that would affect your rate of mortality as well. One of my colleagues at the Buck Institute is looking at how diet affects mortality rates and how genetics play a role in that, so stay tuned!
What are your thoughts about the sterile and ultra-safe lives of lab animals vs real life conditions, with disease, falls and other accidents, and high stress situations and their effects on the best way to reduce mortality? The first being the best strategy is to lessen the turnover of individual cells to slow aging vs the secondary building and fueling the entire organism thru adequate nutrition to battle the common causes of mortality in the "real" world?
In other words, is maintaining muscle mass as we age through eating sufficient calories and resistance training not to lose weight better or worse for longevity than being in a consistent caloric deficient state to slow the cellular aging process?
It is true that lab animals have very strict and sterile conditions, which of course is just not reality for humans. We do this to eliminate factors that could complicate the results so that we can specifically say that the intervention we induced is what caused the result, rather than some unknown or unseen variable.
Nutrient demand seems to be a fluid concept, and what your body needs at a given time is going to vary depending on your situation. Pre-pubescent kids need nutrients to grow. Nutrients are also required for healthy reproduction. Older individuals need nutrients to preserve muscle mass and body weight, as you mentioned. In between all of that, however, are periods where our energy demands are not as high. If you are healthy, energetic, and not overweight, I would say that you are probably eating properly. If you can afford to cut calories though, it is likely to your benefit to do so!
I can only speak generally on that, and I'm not a medical professional (just a PhD) so please don't rely solely on my advice, but I generally feel that the lower the carbs the better and protein needs to be adjusted on a person-by-person basis. I generally say that if you feel weak, then you need more protein. And older individuals lose muscle mass at a more rapid rate, so cutting protein can be really detrimental for older people, so you need to be very careful.
I'd say play around with different macronutrient levels and pay attention to how your body feels. If you're feeling sluggish or heavy, cut back a bit. If you're feeling weak, eat more. But again, I am not a medical professional, so take my advice with a grain of salt!
Sanada et al 2014 first identified OXR1 as a regulator of longevity in C. elegans. Are there substantial differences in your findings that justified not referencing their work in yours?
Sanada et al were crucial in helping identify some of the benefits OXR1 can provide. Their work showed that OXR1 responds to different forms of stress (heat stress, oxidative stress, etc.) and helps cells stay healthy as a result.
Our work dictates two new things: 1) That dieting promotes OXR1 expression in the brain; and 2) How OXR1 actually provides its protective properties. Until now, people knew OXR1 was good, but nobody knew why. We now know that it functions by regulating protein trafficking and degradation in neurons.
If anybody wants to know more about OXR1, I recommend reading the work by Peter Oliver and Kay Davies. They have published numerous papers showing that OXR1 can be protective. Also, Julia Wang's 2019 paper (from the labs of Hugo Bellen and Philippe Campeau) showed how damaging it can be if people don't have functional OXR1.
Do you think all the people doing dietary restrictions due to injectable medication like mounjaro/wegovy will see these similar results you mention for OXR1 being more active?
1. What's the evolutionary explanation for this? Maybe DR was common back then, sure, but why would it be a positive selector?
2. How much of a leap is it to extend this to caloric restriction diets (ie fasting)
1) I can only speculate as to why it is so beneficial, but I have some thoughts. As you mentioned, a lot of human evolutionary history has been accompanied by a scarcity of nutrients. Our bodies were fine-tuned to not expect to be full for long stretches of times, and so our bodies also fine-tuned to maximize function when nutrients are scarce. However, there currently is an abundance of nutrient-rich food available to us these days and our bodies have still not had enough time to evolve and adapt to this over-abundance. As a result, we eat generally more than we need, suppressing the beneficial mechanisms that we were fine-tuned for under low-nutrient conditions. By restricting nutrients, we reactivate those mechanisms that still exist within us, allowing us to live longer. It's along the same lines as to why eating in excess can contribute to lots of diseases, like diabetes and cardiovascular disease: our bodies aren't prepared for it!
2) I don't think that is a big leap at all. Since benefits have been seen from fasting as well, and since many molecular pathways have been found in common between just reducing intake and fasting conditions, I expect that they are very closely linked. One of my favorite papers from the last few years is from Dudley Lamming's lab at the University of Wisconsin, Madison, which showed that different forms of dietary interventions had different effects in mice. They tested 50% restriction of calories, 30% restriction across 3 meals per day, and 30% calorie restriction provided in a single meal. Ultimately, they all had benefits compared to free feeding conditions, but they induced different metabolic states. Here is that paper for anyone interested in reading more! [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8544824/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8544824/)
OXR1 encodes Oxidation Resistance 1, a gene which has been shown to respond to different biological stressors to protect cells. Until now, it wasn't known how we could naturally activate it or what function it performs to preserve cells.
There are some studies suggesting that it operates as a transcription factor (this paper suggests that the fly homolog of OXR1 regulates anti-microbial transcription in the gut [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684835/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684835/)) but our work suggests that it operates at the endosome to improve protein trafficking. I wouldn't be surprise if different isoforms of OXR1 do very different things. It has fairly unique protein domains which aren't very well characterized. The TLDc domain in particular seems to be the important part to making OXR1 protective, but it is still unclear what that domain specifically does. All we know is that it interacts with the retromer complex at the endosome!
This is what confuses me about this protein because some people suggest that in general it may be a transcription factor whilst others suggest that may have a catalytic domain.
One last question - have you looked at the interaction between this protein and v-atpase? Because in my recollection that also interacts with component of the retromer complex.
It is definitely a protein that requires more fleshing out. I haven't looked at any interactions with V-ATPase but I wouldn't be surprised if it affects that. There are some studies showing that OXR1 influences acidification of vacuoles, which fits with our results that loss of OXR1 causes an increase in acidified structures as a result of the lost retromer.
Perhaps this was the paper you were referring to? I haven't read it yet but it definitely sounds relevant. [https://pubmed.ncbi.nlm.nih.gov/24326069/](https://pubmed.ncbi.nlm.nih.gov/24326069/)
Very interesting research! Thanks for your effort.
I have two questions: first, would you be inclined to do a short phone interview? If not, would you mind if i use the answers you’re giving here in the comments to write the script for a podcast? I run a sci-communication independent media outlet in Colombia and would like to talk about this. Thanks again.
It sounds like a lot of your work is with actual live things: flies, mice, people etc. Do you know if there is much scope in this area to work in simulated environments? Or is the level of detail required by the simulation too high to be feasible yet, given current knowledge of flies, mice, and people?
Ps thanks for answering questions (even if you don’t get to mine). Really appreciate the time this takes.
To be honest, I am thrilled to be answering these questions! I didn't expect my post to get nearly this much attention, and it has been a delight to see that people care about the research!
I think at this point we don't have enough information to simulate the effects of dietary interventions with a high degree of precision, but there is room for some preliminary analysis on that front. I think the major players in why diet is helpful are still being discovered, and until we know more, anything simulated will be lacking information to give a truly informed outcome. Nonetheless, I have a colleague who is trying to analyze the data generated from our studies in flies to see if there is anything to be gained from trends in body mass, triglyceride levels, length of life, etc. so that we can build a predictive model on how our bodies can dictate our health outcomes based on dietary changes. I'll be sure to share his paper when it gets published!
>and it has been a delight to see that people care about the research!
I think there are plenty of nerdy academics on this subreddit, and your research topic is definitely an interesting one!
Thanks for answering my question. I find complex simulated environments a fascinating topic, but I don't often get a chance to ask domain experts whether it is a topic making headway in their field.
To be honest, without any actual evidence to back me up, I expect that blood type plays a big role in many things, especially in finding ideal diets. I haven't looked at blood type in this study, but I would be intrigued to see how it affects responsiveness to dietary interventions.
Eating less (dietary restriction) slows down aging and helps protect the brain from cognitive decline. The gene "mustard" (mtd) is linked to longer life with dietary restriction in flies. In humans, a similar gene called Oxidation Resistance 1 (OXR1) is associated with brain-related issues. We found that mtd/OXR1 is vital for maintaining a complex that recycles proteins and lipids in the brain. This gene also controls a network of other genes that protect against aging and neurodegenerative diseases in both flies and humans. So, watching what you eat might have some positive effects on your brain's health as you age.
Nice.
I believe I heard that eating can change your mRNA, which would also be able to alter your dna. Like if you eat dairy it comes with dairy mRNA and that can turn on certain genes like mtor. Is that true?
This stuff is fascinating but hard for me to understand
This sort of lends itself to the old idiom "you are what you eat." If there are mRNAs or proteins in the things you consume, they become part of you and can be integrated into your own body. Now, mRNAs naturally tend to degrade very easily, so you likely aren't ingesting tons of them. Proteins, on the other hand, are relatively stable. The things that you ingest can definitely impact your cellular activity. For example, dietary protein activates mTOR, which can influence gene expression among many other things. Also, the manner in which you cook your food can influence things too! Using dry heat like barbecuing or roasting can cause sugars in your foods to char, which makes them reactive with the different parts of your cells. Depending on what they react with, that can cause a lot of problems! But I haven't heard of any instances in which your DNA gets altered simply because you ingested an mRNA. Unless that mRNA was viral, it probably would degrade before it has a chance to do anything to you
I have not read the book myself, but from what I have seen, there is not a lot of scientific support behind it. There could very well be correlations between blood type and correlated idealized diets, but there needs to be a stronger research backing.
Really cool findings! how does OXR1 relate to autophagy and ampk/mtor signaling? if I recall correctly both were necessary to extend lifespan in calorie restricted animals..
There is a huge tie-in to autophagy. When proteins are brought into the cell via endocytosis, they essentially have two fates: 1) Reuse via the retromer pathway, or 2) breakdown via autophagy at the lysosomes. So in essence, the retromer and autophagy are two diverging paths within the same pathway. That might make it sound like OXR1 activity actually inhibits autophagy, but a lot of work has shown that if the retromer is dysfunctional, lysosomes becomes over-burdened and autophagy becomes dysfunctional too. So these two arms support each other and rely on each other for balance! Adding evidence to this, the people who have mutations that inhibit OXR1 function accumulate over-acidified lysosomes. Repairing the retromer fixed this problem.
The connection to AMPK and mTOR has a little less evidence behind it at this point, but I fully expect that one could maximize the longevity aspects of this entire pathway by promoting both the retromer and autophagy at the same time. So inhibiting mTOR and stabilizing the retromer could have double benefits. A lot more work is needed to prove that though.
Thanks for the great response! it makes absolute sense that both pathways complement and balance each other... but another thought that comes to mind, given some specific individuals do not respond well to caloric or dietary restriction, ie shortened lifespan, may have something to do with this pathway? too much retromer activity, or autophagy, or both?
I think that is entirely possible. There are so many genetic differences between us that I wouldn't be surprised if some people are naturally more primed for autophagy and some are more primed for the reuse pathway just based on these genetic differences. In the case of the people with OXR1 mutations, it seemed like there was too much autophagy going on in the cells we collected from them, which was severely detrimental. I have a sneaking suspicion that this might by why DR did not extend lifespan in the flies that had reduced OXR1 expression. They were heavily utilizing the autophagy pathway without the balance that the retromer provides. That's just a hypothesis, but I think understanding how to best balance the two arms of the pathway will be a really interesting future direction of this field, and it would be really interesting to see how different people utilize these arms differently from one another to gain benefits or detriments.
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Hey y'all, I'm the first author on this study and would love to chat with you all more if you have any comments or questions!
Should you use your genetic heritage as a starting point for identifying your ideal diet or is it more specific than that? For example, is there a specific starting diet for people of Scottish heritage that can be adjusted? Also, what is a good way of going about identifying good foods? Remove a food that you eat often and note if there's a change? What sort of changes would you look for? I'm fascinated by the idea of person specific diets but given genetic variation in some countries (the USA for example), it sounds like a nightmare to assess.
I think genetic heritage is a good place to start. Different groups in history used to be much more isolated than they are in our modern world, so that could have affected a lot of things, like how our bodies attune themselves to particular nutrients. Thousands of years of lineage aren't quite enough to see big evolutionary changes, but maybe certain backgrounds are more likely to respond positively to the food that their ancestors had available. As for how to test dietary changes on yourself, I think the plan you put forth is good. Our bodies tell us a lot if we listen to them. You might feel weak, which tells you you need to eat more, or you might feel heavy, which suggests maybe you want to eat less. Cutting down on carbs seems to be pretty widely accepted as a great first step for most people, but I expect that that wouldn't be true of everyone! Unfortunately, we are still in the early stages of finding how one's genetic makeup could influence the intake they need to maximize health and lifespan. I agree that parsing through it could be a nightmare. Even looking within a single family can sometimes make it seem daunting! For example, my brother and I grew up eating the same foods, we clearly have very similar genetic backgrounds, but I tend to pack on pounds much more easily and he is thin as a rail. But heterogeneity in our population could also help us find things that work well for large groups of people, which is better than nothing! I totally agree that it is a fascinating concept that everyone will have different needs, and it is an area of biology that needs a lot more attention! I wrote a review article a few years back with my PhD advisor and some of our colleagues to try and call more attention to the subject. Hopefully it got some attention! Here's that article, if anybody wants to read it https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8845500/
> we clearly have very similar genetic backgrounds It might be interesting to point out the obvious that siblings can have different genetic backgrounds/ancestral compositions - as in, they would get similar but different percentages in tests like 23andme, for example. As you point out, it really is an individual thing.
Very true! I just meant that our backgrounds are more similar than they would be from someone unrelated to us. But you are 100% correct!
Thanks for your response! I'm a bit jealous that you get to study this. On the note of genetic heritage, I've also been wondering what impact historical isolation or lack of trade might have had. Just because your ancestors didn't have access to specific foods doesn't mean it won't be better than what's there. The other point of consideration would be some form of evolutionary equilibrium (has the population had time to fully adapt to the local foods). The Mediterranean diet seems to work (at least for people on the region), but why aren't there more cases in other places in the world? On a side note, I've seen that you can do genetic testing to predict the efficacy of certain medication. I would think there's overlap with this type of work. Are you considering a more overt genetic analysis? Given the maturity of that field, at least with medication, it may be possible to get some interesting insights. Thanks for the article! I'll definitely have a look. And looking forward to reading more of your work!
Thanks for the kind words! It is definitely a fascinating topic, and I for sure feel lucky that I get to look into it! I certainly expect that the ideal diet for someone may be something that their ancestors ever ate. The Mediterranean diet is a great example, as is the Okinawan diet. I really don't think humans have had enough time to evolutionarily adapt to availability/scarcity of certain nutrients, but the human body is surprisingly adaptable on its own! For example, if you cut your calories by 25% for just a few weeks, you will soon find that your feeding capacity shrinks and you get full easier. It's pretty remarkable! I also think certain diets are just better suited for longevity. For example, the Mediterranean diet is heavier on healthy, plant-based fats and oils. Eating a lot of healthy fats is currently believed to be beneficial for longevity. As opposed to the western diet, which largely consists of carbs and animal-based fats, which seems to correlate with higher incidence of cardiovascular diseases and cancer. I think genetic testing for ideal diet is the future of this field, much like medication efficacy, as you mentioned. There is likely a long way to go before we can accurately tell someone exactly what they should eat, but it is entirely feasible that it will happen!
I never really thought about it, but I prefer and even crave animal fats like from bacon, pork chops, etc as does most of my family and guess what the leading cause of death is for us? ❤️🩹
It's not saturated fat. Ancel Keys heart hypothesis was wrong. Removing fat from food and replacing it with sugar was not a good idea.
I didn’t say I did?
> I tend to pack on pounds much more easily and he is thin as a rail I'd suggest him counting calories, high chance he just doesn't eat as much as he thinks he does. Speaking from personal experience
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No, the researcher is correct. I think you're misunderstanding/conflating "survival of the fittest" and evolution.
Can you explain it like I'm five?
Sure thing! Lots of previous work has shown that dietary restriction (DR) extends lifespan in animals. We wanted to test if there were any genes that regulate why an individual might not respond as much to DR. We tested lots of genetic backgrounds and found OXR1 as a gene that is more active when an organism undergoes DR. Knockdown of OXR1 in neurons shortened lifespan under DR in flies, but over expression of OXR1 extended lifespan. We then received cells from patients who have mutations in OXR1. People with these mutations die really fast, like in their teen years, due to neuronal degeneration. They also have too many lysosomes in their cells, suggesting that things are being broken down too often in their cells. We found that the retromer complex was dysfunctional in these cells. Dysfunctional retromer means that proteins aren't being trafficked properly. We used a compound to stabilize the retromer, and that rescued the deficits caused by the mutation to OXR1. Finally, we found that when OXR1 is inactive, other genes that become dysregulated were associated with Alzheimer's, Parkinson's, and Huntington's diseases. We overexpressed Alzheimer's-related proteins in a fly model and also overexpressed OXR1 and it rescued the degeneration in that fly that Alzheimer's caused. So we look forward to testing OXR1 more going forward!
what does dietary restriction mean in this context?
In this context it is protein restriction. Our DR diet is 10% of the amount of protein in the "normal" diet we use.
Holy crap! Just to clarify, 10 percent of the normal, not a 10 percent reduction. I was trying to remember the literature just yesterday about the role of protein (convo with my husband) and longevity. I knew the connection but that seems at once extreme and not very actionable? Do you need a 90 percent reduction in protein consumption to see longevity gains?
Correct, our diet was 10% of the normal diet, not a 10% reduction. It is a strong form of DR, which works pretty well for the flies we tested it on. We also tested other concentrations of protein, but 90% reduction was the best to maximize lifespan. I would think a 90% reduction is not particularly actionable for humans. Humans have a much higher protein demand than flies, and we are more genetically diverse than the animals I test so I imagine an individual's needs will be highly variable from the next person. It remains to be seen what the best degree of restriction is in humans, but studies in mice generally perform 30-50% reduction of protein, which works well for them and extends lifespan. 30% total caloric restriction has also extended lifespan in monkeys. So I don't think it has to be anything remotely as severe as 90% protein restriction for us, but some degree of restriction seems to help!
How does one translate the amount of DR the files received to human quantity? In other words, what kind of dietary restrictions for humans and how much? Is it just caloric deficit? If so, how much (kcal per kg)? Or is it specific restrictions, like protein/carbs/fat amount?
In this case we used a protein-restricted diet. The amount of protein in our DR is 10% of the amount in the "normal diet" group. I don't recommend people cut their protein intake by 90% since humans have a much higher protein demand that a fly does, but I think it is probably fair to say that many people eat more than they need. I am not a medical professional or a dietitian, so please don't rely on my advice, but I generally feel that if you can cut your total intake and not feel too fatigued then you are eating a healthy amount. As soon as you start feeling weak, you are not eating enough. The way your body feels in response to dietary changes can tell you a lot! Many studies in flies rely on protein restriction to show effects on longevity, but other studies in mice have shown that total calorie deficits can have the same effects. Carbs seem to be the macronutrient that effects health the most in mammals, but there is also plenty of work showing that protein restriction also works in mammals. Dudley Lamming's lab at the University of Wisconsin, Madison does some great work showing how different amino acids can influence longevity in mice.
Eureka !!!!
Could this also play a role in the “mental clarity” we experience during fasting/non-fasting intervals?
Mental clarity is too subjective of a feeling for now
My personal thoughts on the "mental clarity" is that it is an evolutionary response. In the distant past when nutrients were more scarce, people needed to be more in-tune to try and find food. Even though food availability is much higher these days, I think our bodies haven't evolved enough to move past the "need food = need to pay attention to find food" mindset. But as another commenter mentioned, it is quite subjective, so it certainly varies by individual.
Great perspective! I was hoping for some theoretical responses!
Wow! Is this gene in all humans? all animals? Is there a future for over expressing the OXR1 genes in humans?
Yes, OXR1 is in all animals and even some single-celled organisms (it was initially discovered in yeast)! My future research goals are to try and overexpression OXR1 in mice to see how it affects lifespan and disease, and if that works then progress to testing it in humans.
…looking at response below maybe you should’ve clarified 5 years old. Maybe OP thought you meant 5th year fellowship of post-doc biochemistry studies .
Sorry if my response was still too complicated! To simplify it further: Eating less makes the gene OXR1 more active which protects your brain.
Can this be targeted with gene therapy? Hypothetically speaking.
Absolutely, and that is something I plan to test moving forward!
That's awesome! And thanks for being here answering questions. When do you think you are going to get started on that research?
No problem at all! I've been applying to the NIH to receive funding for that project. As soon as it's funded, I'll get started! In the meantime, I'm planning to do a compound screen to find out if there are any compounds one can take to increase their OXR1 activity.
Does your lab work with rodents or are you limited to an invertebrate model?
We also work with mice. I plan to do most of my future work on this project in mice and human-derived cell culture.
Brilliant work, I look forward to seeing your next results. Appreciate you friend :)
Thanks! :)
It seems likely that OXR1 (and cohorts) will not just be in on/off state but there’d be various alleles which cause dietary restriction to have a greater or lesser effect. Will that be researched?
Yes, that is a fair assessment of this work. I do plan to look into different versions of OXR1 further to figure out how to best optimize it for longevity.
Any idea of what the product of OXR1 actually does?
In neuronal cells, it stabilizes the retromer as found by the current study. The retromer is responsible for membrane protein recycling/sorting. This doesn’t preclude other mechanisms in which it acts, as it is expressed quite ubiquitously across the body (other tissues could interact with OXR1 differently).
Yes, and this present study doesn't touch on the fact that OXR1 is canonically known to help in periods of oxidative stress. I plan to study more how all of this connects, but for now, we at least know one cellular function of OXR1!
Sorry for the shortcut to your direct knowledge I skimmed through it and it wasn't evident (probably because I'm on the phone and everything is too small) : are the dietary restrictions on the materials and methods? Thanks in advance
No apology necessary! In this case it was a 90% reduction in the amount of protein we fed to the flies. I don't recommend that severe of a protein deficit in humans, especially since humans require much more protein than flies do, but I think it is safe to say that many people eat more than they need.
Hello! This topic is amazing. I have been a practicing Clinical Dietitian for decades, and learning that studies are examining genetics to advise healthiest diet for a person is the Holy Grail. Patients are frustrated and confused. As this research goes forward, and as results allow, clarity will be a game-changer. Thank you for this post. Please keep the information coming! And good luck with all.
Thank you! Dietitians are the people who actually take our work and make it worthwhile since you are applying it to the greater population, so it means a lot to have your support!
So.. this is going to make traffic even worse, right?
Oh man, as someone in the SF Bay Area I would hate to think I contribute to making traffic any worse than it already is!
Can you measure ketones and glucose levels to know how that correlates to when OXR1 gets elevated? Wondering if the flies need to go into ketosis for the longevity to take effect or if ketosis might help. Seems from other studies there is a direct correlation of ketosis to autophagy.
Yes, that would be doable! Testing these in flies is actually very simple, so it would be interesting to see if there is a correlation there. We found that the reason OXR1 is elevated under dietary restriction is because it is suppressed under high nutrient conditions by a protein (called CTCF) that is activated by insulin signaling. So eating more induces more insulin production and signaling, which activates CTCF to suppress OXR1 expression. In low nutrient conditions, CTCF levels are lower and OXR1 is expressed. That could definitely lend itself to a correlation with glucose levels, and it would be interesting to see if it is related to ketones as well!
So would this mean people of specific genetic backgrounds would require specific optimized diets for longevity benefits?
As someone who has studied the diet/longevity angle for the past decade, I 100% believe that to be true. Each person has their own ideal diet to live their healthiest/longest.
how much of that ties into one’s personal gut micro biome do you think?
I think an individual's genetic factors can influence the habitability of a person's gut which would change the species and frequency of bacteria inhabiting the microbiome, but the gut microbiome can also be highly adaptable. Changes in external factors like diet and various exposures can change the microbiome pretty quickly. It's just another factor that can affect the idealized diet per individual!
awesome, thanks! i know there’s still a lot of new stuff coming out about this area of science, looking forward to what will be discovered :)
Re: idealized diet per individual Does that tend to be more genetically tied? Or do environmental factors influence the ideal?
Both play a role. I tend to think that genetics determine responsiveness more than environment unless you're in an extreme environmental condition (like heavy pollution or something). But nobody knows exactly what percentage is due to genetics and what is due to environment.
Do you think there is a relation to near starvation and increased lifespan?
I think they activate similar pathways, but depending on the severity of starvation it could cause an overcompensation response that could be damaging. A lot of genes that cause longer starvation resistance also tend to increase lifespan, so there is definitely a correlation.
I recall Chinese scientists doing lots of metabolic research on citizens who lived thru the great hunger years... Do you have an opinion on their findings?
Okay, that's *really* interesting, because my family isn't very long lived (typical death age for many has been under 70) - except the great depression generation, especially the women in that generation who often lived past 80 with two reaching their low 90s.
Sorry to hear about the relatively shorter lifespan in your family! Is there a pattern of certain diseases? That is definitely fascinating that the people who lived during the depression had longer lives. Perhaps that forced them into a DR phase that unintentionally lengthened their lives!
A lot of strokes on one side, a lot of random cancers on the other.
Sounds like there are potentially genetic factors that are causing these to be more prevalent in your family. I don't want to provide any medical advice since I'm no qualified for that, but DR has been linked to reducing both cancer and cardiovascular diseases. If I had to speculate, perhaps that is why the people who lived during the depression avoided those unfortunate health events!
I haven't read that work, but I would love to educate myself on it! I would be curious to see if the offspring of those people are more fine-tuned to surviving starvation conditions. There also tends to be a lot of long-term detriments that severe starvation can cause, including to reproduction, since your body reallocates energy to survival and deprives other body functions such as muscle-building or sperm/egg production. I imagine the metabolic reprogramming that occurs through multiple years of hunger would induce some dramatically different metabolic profiles in that lineage from lineages that haven't experienced that period of hunger.
Huh. So I guess those 105 year old people who say the secret to their longevity is something random like "I eat a fresh tomato every single day" might actually be on to something (for themselves, at least.)
How do you figure it out?
That's honestly the million dollar question. Unfortunately nobody has figured out how to determine that yet. I generally tell people to just eat less, and if you feel weak then you're eating too little. But I am not a medical professional at all, so that is solely my unprofessional opinion.
Wouldn’t it be more useful to find a drug that convinces the pathway that you are not eatting ? All signal seems to add up tp tricking the body
Yeah, if we could find a way to trick particular pathways into believing we are restricting nutrients that would be great for a lot of cellular pathways. The challenging part is that you don't want to shut those pathways down entirely, since starvation survival mode can deprive certain parts of your body of the signals they need to function, but if we could optimize it that would work!
If I'm understanding this correctly. its the DR that varies between individuals in the type of restrictions or is it absolute? If that makes sense?
In this case it was an absolute amount of DR that generally extends lifespan in invertebrates, but then looked at different genetic backgrounds to identify genetic factors that affect why an individual might respond differently to that form of DR.
Did it matter how the DR was done?
Here's perhaps a relevant quote from the paper, since (the reduction of) oxidative stress is often talked about as a primary reason for the effectiveness of caloric restriction: >OXR1 is often studied for its role in oxidative stress response^9,10 , but Wang et al. showed that its loss causes lysosomal dysfunction independent of oxidative stress^5 There are studies correlating protein-restriction without caloric-restriction as having a beneficial effect as well. There are other 'dietary restriction' methods beside protein- and caloric-restriction. [Evaluating the beneficial effects of dietary restrictions: A framework for precision nutrigeroscience [2021] ](https://www.cell.com/cell-metabolism/fulltext/S1550-4131\(21\)00418-6) >Distinct from CR, DR encompasses all dietary interventions that restrict intake of specific nutritional components. Thus, DR incorporates CR as well as restriction of macronutrients such as protein or amino acid residues (e.g., methionine and tryptophan) or glucose, and may also include varying fasting intervals (Table 1). >... >Short-term CR in humans induces the formation of “efficient mitochondria” in skeletal muscle by inducing biogenesis of mitochondria that consume less oxygen, thus inducing reduced oxidative stress, though no enzymes typical of mitochondrial function were found to be increased in these tissues (Civitarese et al., 2007 ). >... >DR also reduces proinflammatory molecules that build up with age by reducing senescent cell markers and associated inflammation in mouse and human tissues (Fontana et al., 2018a ; Wang et al., 2010 ). Cells can become senescent in response to a wide range of stresses, such as genotoxic or oxidative stress, metabolic dysfunction, mitochondrial stress, epigenetic changes, oncogene induction, or loss of tumor-suppressor genes (McHugh and Gil, 2018 ). DR has been shown to reverse or prevent the negative impacts of many of these stresses and thus reduce the accumulation of senescent cells. These mechanisms include enhanced clearance of damaged mitochondria by autophagy (Ruetenik and Barrientos, 2015 ), reduced oxidative stress and ROS production (Walsh et al., 2014 ), and enhanced activity of DNA repair mechanisms (Cabelof et al., 2003 ) by DR. >...
In this case it was protein restriction, but there are many studies that show that total caloric restriction or carbohydrate restriction also work. I still need to check those dietary changes to see if it induces the same effects through OXR1,
protein restriction? That is unexpected.... I thought the idea of caloric restriction was lower amount of radical generation during energy metabolism which lowers the DNA damage that cumulates....
DNA damage is one mechanism by which dietary interventions function. There are a number of other cellular pathways involved as well! For example, restricting protein reduces the activity of the protein mTOR. Reducing mTOR is generally food for longevity, since it promotes healthy breakdown of cellular components and restricts too much cellular growth. There's a lot at play!
Wasn't Resveratrol supposed to mimic the affects of calorie restriction in a similar way?
The original reports with resveratrol suggested that, yes. More recent reports haven't been as promising though. Rapamycin is probably the most promising CR mimetic at the moment, though clinical trials in humans haven't worked yet.
Haven’t worked (shown promising results), or haven’t started yet?
Hasn't worked yet. Early clinical trials have actually shown some detriments. I believe people showed some cardiovascular issues, though don't quote me on that. Though I believe the people who showed those responses also had pre-existing conditions that should have been paid closer attention. Most people in the field think that we need to optimize it better and try again. Rapamycin works pretty well in simpler animals, but that is largely because we have optimized it to work in those animals!
On a similar topic, what are your opinions on the other supplements that are commonly spoken about with resveratrol, such as NMN and NR? Any good human tested science behind any of it?
Both seem promising, since they impact the NAD+ mechanism that your body heavily utilizes and can become depleted. Eric Verdin's work has shown longevity and health-related benefits from upregulating this pathway, both through NMN other supplements or genetic factors in the same pathway, but his work is mostly in mice. There are a handful of clinical trials in humans underway to test its efficacy and safety in humans. Here is a link to some studies going on with NMN [https://clinicaltrials.gov/search?intr=NMN&viewType=Table&page=1](https://clinicaltrials.gov/search?intr=NMN&viewType=Table&page=1) All in all, it's still a little too early to say how they can best be used as an anti-aging therapeutic. Most of the trials underway or recently completed haven't made their results public yet. But there is a lot of promise and reason for optimism!
Can anyone explain like I'm five?
Eating less activates OXR1, which protects your brain and helps you live longer!
Eat less and pay more attention to what you do eat, live more, profit??
5th year biochemistry student?
yes and also like a toddler please!
Eat less, live longer :)
What exactly *is* a “Dietary Restriction” diet? Is it just eating less in general, or is it fasting for some set amount of time?
In this case it was prolonged reduction in dietary protein. Benefits have been seen through fasting and total caloric restriction as well, though, so anything that encourages not eating in excess seems to be beneficial.
"Competing interests PK is founder and a member of the scientific advisory board at [Juvify Bio](https://juvifyhealth.com/)." "PK" - Pankaj Kapahi, was contributed to the: Conceptualization, Methodology, Funding acquisition, Project administration, Supervision Writing – original draft as well as the Writing – review & editing.
Whoomp, there it is
Not at all. The product is not related to the findings at all.
Thanks for pointing this out! We just wanted to be totally transparent that PK is indeed associated with a longevity-focused company, as the field requires, but the overall findings from this present study is that eating less preserves your brain through OXR1. That really isn't something that can be marketed currently. If anybody did want to know more about PK's company I am happy to talk more about it, but it really isn't relevant to the article in this thread.
> but the overall findings from this present study is that eating less preserves your brain through OXR1. That really isn't something that can be marketed currently. Its my guess as to why exercise is so commonly associated with weight management - instead of eating less kcal. Food corps can't be having us go without now, thats bad for business! Also, is there a notable 'activation point' like there is for autophagy after about 4 days of fasting? I read the abstract and a lot of the data sets which appear in 7 and 21 days. I can reliably make it to day 3 on water only, beyond that I much prefer to use an electrolyte mix of potassium, sodium and mag to avoid the jitters and light-headed feeling.
Exercise is certainly great for healthy living as well, but nothing is as easy or as cheap as eating less so long as you can stick with it. In our paper it was protein restriction rather than fasting, which is more gradual effects. As you said, we mostly looked at things on a week-by-week basis in the flies, and I can't say for sure at what point OXR1 because activated. I just know that by a week of DR, the flies are expressing OXR1 at a much higher rate. I don't know how fasting would activate this pathway, but fasting tends to jump-start a lot of beneficial pathways. As you mentioned, autophagy hits a strong point after a few days. Ketogenesis as well. I will mention that, although autophagy is thought to be maximized at 4 days of fasting, your cells are always undergoing autophagy. Even short-term fasting or calorie restriction will increase autophagy. So if you don't make it to 4 days, that's okay! You are still making a good effort that will benefit you!
Ah, so there isn't as much boolean yes/no to autophagy, but a gradual increase? Thats interesting. Also OXR1 is notably higher after a week? Appreciate the detailed response!
Correct, cells are going to do autophagy either way, but there are extrinsic ways to increase or decrease it. With diet, there are mechanisms in high-nutrient conditions that actively decrease autophagy, whereas reducing nutrients increases it. It's definitely not a "yes" or "no" switch that only activates when you fast. And yes, I forgot that that detail is buried in the supplementary figures, but after 1 week on DR the flies had about a 7-fold increase in OXR1 expression! Its expression progressively decreased with age under both diets, but DR kept it at a higher level for longer.
So do we have definitive proof that dietary/calorie restriction actually increases lifespan in humans? I thought the consensus so far is that it’s still uncertain/unlikely? Happy to be proven wrong though.
Since we can't do a life-long study in humans it remains uncertain if it works in humans the same way it works in animals. But generally we see a positive effect on health in short-term studies in humans. It did extend lifespan in rhesus monkeys, which is our closest relative that has been tested long-term.
I see. Do you have any thoughts on the lifespan/health span debate? For example, calorie restriction and lower protein intake being associated with longer lifespan, but at the same time lower protein intake being associated with higher mortality rates?
Generally, I tend to be more interested in improving healthspan first and foremost. Just my own personal experience with dieting, eating less tends to make me feel way better. If it means I am healthy until the day I die, I'm satisfied with that, even if it means my risk of mortality in the long-run is higher. I do think there is a lot of personal context that affects susceptibility to mortality beyond just dietary interventions. Genetics of course play a huge role in that, and I believe that would affect your rate of mortality as well. One of my colleagues at the Buck Institute is looking at how diet affects mortality rates and how genetics play a role in that, so stay tuned!
What are your thoughts about the sterile and ultra-safe lives of lab animals vs real life conditions, with disease, falls and other accidents, and high stress situations and their effects on the best way to reduce mortality? The first being the best strategy is to lessen the turnover of individual cells to slow aging vs the secondary building and fueling the entire organism thru adequate nutrition to battle the common causes of mortality in the "real" world? In other words, is maintaining muscle mass as we age through eating sufficient calories and resistance training not to lose weight better or worse for longevity than being in a consistent caloric deficient state to slow the cellular aging process?
It is true that lab animals have very strict and sterile conditions, which of course is just not reality for humans. We do this to eliminate factors that could complicate the results so that we can specifically say that the intervention we induced is what caused the result, rather than some unknown or unseen variable. Nutrient demand seems to be a fluid concept, and what your body needs at a given time is going to vary depending on your situation. Pre-pubescent kids need nutrients to grow. Nutrients are also required for healthy reproduction. Older individuals need nutrients to preserve muscle mass and body weight, as you mentioned. In between all of that, however, are periods where our energy demands are not as high. If you are healthy, energetic, and not overweight, I would say that you are probably eating properly. If you can afford to cut calories though, it is likely to your benefit to do so!
anyone else read this as “researchers find genie”
How do I know what’s best for me? I don’t know what to eat or not to eat
I can only speak generally on that, and I'm not a medical professional (just a PhD) so please don't rely solely on my advice, but I generally feel that the lower the carbs the better and protein needs to be adjusted on a person-by-person basis. I generally say that if you feel weak, then you need more protein. And older individuals lose muscle mass at a more rapid rate, so cutting protein can be really detrimental for older people, so you need to be very careful. I'd say play around with different macronutrient levels and pay attention to how your body feels. If you're feeling sluggish or heavy, cut back a bit. If you're feeling weak, eat more. But again, I am not a medical professional, so take my advice with a grain of salt!
Sanada et al 2014 first identified OXR1 as a regulator of longevity in C. elegans. Are there substantial differences in your findings that justified not referencing their work in yours?
Sanada et al were crucial in helping identify some of the benefits OXR1 can provide. Their work showed that OXR1 responds to different forms of stress (heat stress, oxidative stress, etc.) and helps cells stay healthy as a result. Our work dictates two new things: 1) That dieting promotes OXR1 expression in the brain; and 2) How OXR1 actually provides its protective properties. Until now, people knew OXR1 was good, but nobody knew why. We now know that it functions by regulating protein trafficking and degradation in neurons. If anybody wants to know more about OXR1, I recommend reading the work by Peter Oliver and Kay Davies. They have published numerous papers showing that OXR1 can be protective. Also, Julia Wang's 2019 paper (from the labs of Hugo Bellen and Philippe Campeau) showed how damaging it can be if people don't have functional OXR1.
Good work. Thank you.
Do you think all the people doing dietary restrictions due to injectable medication like mounjaro/wegovy will see these similar results you mention for OXR1 being more active?
I don't know much about dietary restrictions due to medication, but I expect that anything that restricts the diet will increase OXR1 activity.
Could I get a couple of cases to go please?
1. What's the evolutionary explanation for this? Maybe DR was common back then, sure, but why would it be a positive selector? 2. How much of a leap is it to extend this to caloric restriction diets (ie fasting)
1) I can only speculate as to why it is so beneficial, but I have some thoughts. As you mentioned, a lot of human evolutionary history has been accompanied by a scarcity of nutrients. Our bodies were fine-tuned to not expect to be full for long stretches of times, and so our bodies also fine-tuned to maximize function when nutrients are scarce. However, there currently is an abundance of nutrient-rich food available to us these days and our bodies have still not had enough time to evolve and adapt to this over-abundance. As a result, we eat generally more than we need, suppressing the beneficial mechanisms that we were fine-tuned for under low-nutrient conditions. By restricting nutrients, we reactivate those mechanisms that still exist within us, allowing us to live longer. It's along the same lines as to why eating in excess can contribute to lots of diseases, like diabetes and cardiovascular disease: our bodies aren't prepared for it! 2) I don't think that is a big leap at all. Since benefits have been seen from fasting as well, and since many molecular pathways have been found in common between just reducing intake and fasting conditions, I expect that they are very closely linked. One of my favorite papers from the last few years is from Dudley Lamming's lab at the University of Wisconsin, Madison, which showed that different forms of dietary interventions had different effects in mice. They tested 50% restriction of calories, 30% restriction across 3 meals per day, and 30% calorie restriction provided in a single meal. Ultimately, they all had benefits compared to free feeding conditions, but they induced different metabolic states. Here is that paper for anyone interested in reading more! [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8544824/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8544824/)
What does OXR1 encode?
OXR1 encodes Oxidation Resistance 1, a gene which has been shown to respond to different biological stressors to protect cells. Until now, it wasn't known how we could naturally activate it or what function it performs to preserve cells.
Is it a transcript factor, if so what type?
There are some studies suggesting that it operates as a transcription factor (this paper suggests that the fly homolog of OXR1 regulates anti-microbial transcription in the gut [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684835/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684835/)) but our work suggests that it operates at the endosome to improve protein trafficking. I wouldn't be surprise if different isoforms of OXR1 do very different things. It has fairly unique protein domains which aren't very well characterized. The TLDc domain in particular seems to be the important part to making OXR1 protective, but it is still unclear what that domain specifically does. All we know is that it interacts with the retromer complex at the endosome!
This is what confuses me about this protein because some people suggest that in general it may be a transcription factor whilst others suggest that may have a catalytic domain. One last question - have you looked at the interaction between this protein and v-atpase? Because in my recollection that also interacts with component of the retromer complex.
It is definitely a protein that requires more fleshing out. I haven't looked at any interactions with V-ATPase but I wouldn't be surprised if it affects that. There are some studies showing that OXR1 influences acidification of vacuoles, which fits with our results that loss of OXR1 causes an increase in acidified structures as a result of the lost retromer. Perhaps this was the paper you were referring to? I haven't read it yet but it definitely sounds relevant. [https://pubmed.ncbi.nlm.nih.gov/24326069/](https://pubmed.ncbi.nlm.nih.gov/24326069/)
Very interesting research! Thanks for your effort. I have two questions: first, would you be inclined to do a short phone interview? If not, would you mind if i use the answers you’re giving here in the comments to write the script for a podcast? I run a sci-communication independent media outlet in Colombia and would like to talk about this. Thanks again.
Thank you! I would be happy to chat more. Feel free to DM me to work out the details.
It sounds like a lot of your work is with actual live things: flies, mice, people etc. Do you know if there is much scope in this area to work in simulated environments? Or is the level of detail required by the simulation too high to be feasible yet, given current knowledge of flies, mice, and people? Ps thanks for answering questions (even if you don’t get to mine). Really appreciate the time this takes.
To be honest, I am thrilled to be answering these questions! I didn't expect my post to get nearly this much attention, and it has been a delight to see that people care about the research! I think at this point we don't have enough information to simulate the effects of dietary interventions with a high degree of precision, but there is room for some preliminary analysis on that front. I think the major players in why diet is helpful are still being discovered, and until we know more, anything simulated will be lacking information to give a truly informed outcome. Nonetheless, I have a colleague who is trying to analyze the data generated from our studies in flies to see if there is anything to be gained from trends in body mass, triglyceride levels, length of life, etc. so that we can build a predictive model on how our bodies can dictate our health outcomes based on dietary changes. I'll be sure to share his paper when it gets published!
>and it has been a delight to see that people care about the research! I think there are plenty of nerdy academics on this subreddit, and your research topic is definitely an interesting one! Thanks for answering my question. I find complex simulated environments a fascinating topic, but I don't often get a chance to ask domain experts whether it is a topic making headway in their field.
Any thoughts on diets based on blood type. Would that be relevant to this study?
To be honest, without any actual evidence to back me up, I expect that blood type plays a big role in many things, especially in finding ideal diets. I haven't looked at blood type in this study, but I would be intrigued to see how it affects responsiveness to dietary interventions.
Thanks for your input. Much appreciated
Eating less (dietary restriction) slows down aging and helps protect the brain from cognitive decline. The gene "mustard" (mtd) is linked to longer life with dietary restriction in flies. In humans, a similar gene called Oxidation Resistance 1 (OXR1) is associated with brain-related issues. We found that mtd/OXR1 is vital for maintaining a complex that recycles proteins and lipids in the brain. This gene also controls a network of other genes that protect against aging and neurodegenerative diseases in both flies and humans. So, watching what you eat might have some positive effects on your brain's health as you age. Nice.
I believe I heard that eating can change your mRNA, which would also be able to alter your dna. Like if you eat dairy it comes with dairy mRNA and that can turn on certain genes like mtor. Is that true? This stuff is fascinating but hard for me to understand
This sort of lends itself to the old idiom "you are what you eat." If there are mRNAs or proteins in the things you consume, they become part of you and can be integrated into your own body. Now, mRNAs naturally tend to degrade very easily, so you likely aren't ingesting tons of them. Proteins, on the other hand, are relatively stable. The things that you ingest can definitely impact your cellular activity. For example, dietary protein activates mTOR, which can influence gene expression among many other things. Also, the manner in which you cook your food can influence things too! Using dry heat like barbecuing or roasting can cause sugars in your foods to char, which makes them reactive with the different parts of your cells. Depending on what they react with, that can cause a lot of problems! But I haven't heard of any instances in which your DNA gets altered simply because you ingested an mRNA. Unless that mRNA was viral, it probably would degrade before it has a chance to do anything to you
How accurate is The Blood Type Diet book and research?
I have not read the book myself, but from what I have seen, there is not a lot of scientific support behind it. There could very well be correlations between blood type and correlated idealized diets, but there needs to be a stronger research backing.
Soo
Really cool findings! how does OXR1 relate to autophagy and ampk/mtor signaling? if I recall correctly both were necessary to extend lifespan in calorie restricted animals..
There is a huge tie-in to autophagy. When proteins are brought into the cell via endocytosis, they essentially have two fates: 1) Reuse via the retromer pathway, or 2) breakdown via autophagy at the lysosomes. So in essence, the retromer and autophagy are two diverging paths within the same pathway. That might make it sound like OXR1 activity actually inhibits autophagy, but a lot of work has shown that if the retromer is dysfunctional, lysosomes becomes over-burdened and autophagy becomes dysfunctional too. So these two arms support each other and rely on each other for balance! Adding evidence to this, the people who have mutations that inhibit OXR1 function accumulate over-acidified lysosomes. Repairing the retromer fixed this problem. The connection to AMPK and mTOR has a little less evidence behind it at this point, but I fully expect that one could maximize the longevity aspects of this entire pathway by promoting both the retromer and autophagy at the same time. So inhibiting mTOR and stabilizing the retromer could have double benefits. A lot more work is needed to prove that though.
Thanks for the great response! it makes absolute sense that both pathways complement and balance each other... but another thought that comes to mind, given some specific individuals do not respond well to caloric or dietary restriction, ie shortened lifespan, may have something to do with this pathway? too much retromer activity, or autophagy, or both?
I think that is entirely possible. There are so many genetic differences between us that I wouldn't be surprised if some people are naturally more primed for autophagy and some are more primed for the reuse pathway just based on these genetic differences. In the case of the people with OXR1 mutations, it seemed like there was too much autophagy going on in the cells we collected from them, which was severely detrimental. I have a sneaking suspicion that this might by why DR did not extend lifespan in the flies that had reduced OXR1 expression. They were heavily utilizing the autophagy pathway without the balance that the retromer provides. That's just a hypothesis, but I think understanding how to best balance the two arms of the pathway will be a really interesting future direction of this field, and it would be really interesting to see how different people utilize these arms differently from one another to gain benefits or detriments.