It many scientists I respect who signed it… I guess that’s enough to mark it as something memorable, when there are so many people in longevity who say more than they do (this is why I’m not signing it [though I’m also not signing for many other reasons, some of them related to the serious accident I had last year])
But it still is… like… words… and doesn’t say much that’s new.
I pondered about it as I don’t see it as being that significant, but I decided in the end to sign it on the basis that I think improving health is a good idea.
I am mildly miffed by Aubrey de Grey because of his dismissive approach to biohacking (I have spoken to him directly about it). Multiple N=1 tests of various interventions have considerable potential in working out what improves health and what does not.
I do, however, think that nuclear acetyl-CoA and mitochondrial efficiency are two key aging pathways that when modified improve healthspan. I put a mild amount of effort into offering presentations on this, but there is not much interest.
I am not personally that concerned at the lack of interest from people who in the end all have their own hobbyhorses that they have spent years breaking in and wish now to ride.
Either it works or it doesn’t work. I think it works up to a point, but time will tell.
I signed it. No downside. What do they want? Government funding of studies? Would an Apollo “put a man on the moon” type challenge work? I want to live longer but is the world better off if everyone lived longer? It is said that progress is made one funeral at a time.
Can you explain why they are the most important pathways for healthspan?
I have written quite a lot on my blog and I link to the research papers that substantiate this. However, to summarise:
acetyl-CoA is used to open up (acetylate) the histone as part of transcribing mRNA from DNA. If there is not enough acetyl-CoA then the correct mRNA is not produced. At times you get what are called aberrant splices (which is a different version of the protein to that which is normally produced).
When Stem cells are differentiated this failure to produce a protein stops them differentiating. There is also evidence that this problem is greater for longer genes than shorter ones and that this is what causes at lot of the phenotypes of Aging (viz Osteoporosis, Diabetes, Sarcopenia etc etc)
Hence problems with transcription caused by a shortage of acetyl-CoA (which arises from an under expression of SLC25A1 [the citrate carrier] in the mitochondria) is behind a lot of the differences between older creatures and younger ones.
Interestingly many cancers are exacerbated by aberrant splicing.
At the same time, however, there is an issue with the creation of proteins from mRNA by the Ribosome which is called translation. If this goes wrong then the correct proteins are not produced and what is produced is sent off to Ribosome Quality Control to be recycled. This appears to be more likely when there is less energy around. Obviously as energy (ATP) is needed to produce proteins then the RIbosome will stall if there is not enough.
The mitochondria respond to a shortage of ATP by producing more of it, but they do get less efficient and their response to the signal of a shortage of ATP (The ATP/ADP gradient) becomes lesser.
Protein production requires a lot of energy.
Hence if you make the mitochondria more efficient then you overcome this situation. This also feeds into acetyl-CoA levels because the mitochondria export citrate which the enzyme ACLY converts into citrate.
I think DNA damage is also an issue, but a lot of the symptoms of aging have patterns. Hence aging that is essentially random is most likely much less significant for now. Save that if you solve the two problems above you will then see what is left. There are most likely other stochastic elements, but they may not fit the patterns of aging.
@John_Hemming Regarding mitochondria, can we make more mitochondria instead of making them more efficient? I think one of the benefits of low intensity (fat burning) endurance exercise is the signaling to make more mitochondria. With more mitochondria, they are stressed less during high energy demand, and make less ROS. Another benefit may be to drive mitophagy is this consistent with your ideas?
In many ways that is how to make mitochondria more efficient. It is moreso a matter of recycling the ones that exist and creating new ones. (autophagy, mitophagy, fusion and fission).
Also Mitochondria can be transferred between cells.
https://www.nature.com/articles/s41392-020-00440-z
Some have suggested an infusion of new mitochondria. I am not personally persuaded that this would potentially be the best approach. I would prefer to use the body’s systems to recycle malfunctioning mitochondria.
I have signed it. I think it is important to dedicate money specifically for aeging research.
I signed it because we can not only just play around for decades with N=1 experiments. We need to get this field prioritized and move it forward in a much better way.
I said to Aubrey that I would be willing to coordinate N=1 experimenters so that we could get the benefit of multiple N=1 experimentation. He was completely uninterested. I find that a pity.
As far as I personally am concerned N=1 experimentation is not “playing around”.
If we just do experiments on a N=1 level like many do today we will not move the longevity needle much. I have seen also so many crazy and bad N=1 experiments without any collaboration with physician, testing of biomarkers and other things. We can do so much better but many people don’t have the motivation, money or time in doing really serious N=1. Everything should go fast forward etc. I have also been pushing on a more standardized way of doing multiple N=1 experiments I believe in that but we need more than N=1 experiments and MN=1:s.
I agree that we need more than N=1 experimentation. However, we need a more standardised way of doing multiple N=1 experiments. I offered to Aubrey that I would be willing to coordinate that for him, which I would have provided any reasonable funding requirements. He was uninterested.
There is a massive danger with grant funded research projects in that they will generally not be able to get funding for speculative investigations. The funders want to be reasonably certain that the research will get positive results before they start. The ITP is a variation on this and not all schemes work like that.
I am not in any way saying that N=1 or MN=1 is sufficient, but I think they have their place. As far as I personally am concerned I think I have learnt a lot from N=1 experimentation.
I think Rapa News provides a good forum for people to cooperate with N=1 experimentation. For which I thank @RapAdmin
Yes, the N=1 experiment give some value but the quality of them can increase much more I would say. There is also a lots of important data that is not shared. I want see as much pre data, post data and lots of other data as possible in a structured way. It gives not good data if someone just says my cholesterol went up. I want to see what more specific went up and how much it went up and what dose regime it was etc. So the data is not impressive in the moment. I’m not saying I’m the perfect example in this field but I’m really trying now to gather as much data as possible and from my journey and present it here.
On plan that I have is to create some kind of guide on biomarkers which would be good to take pre and post treatment so that we get a good way of starting to compare our journeys with each others in a much better way. I think that could be a good way of increasing the quality and also take one good step in the MN=1 field.
If Abrey is not interested in coordination of MN=1 could you not do this here on Rapamycin.news instead? Why let him have the last word in this.
There is no reason why Aubrey need have the last word. I think I have been open to discussing MN=1 on Rapamycin News. It would be good if a subgroup of people would agree to try to coordinate their experimentation and standardise testing. Others can participate if they wish.
In the end our host @RapAdmin needs to be happy, but I think to a great extent that is what has been happening. It could be formalised by listing experimentation that people are doing what the inputs and outputs are.
Simple tests like the impact of vitamin D supplementation on serum vitamin D levels are worth doing.
I think @RapAdmin would be very happy if we could coordinate MN=1 and increase the quality of the data around things. That is a win-win for everyone. I don’t see why we should not do it. See lets start 
I am happy to work with you on that and anyone else who is interested.
I’ll participate for sure. Sign me up
On the assumption that @RapAdmin is content I will start a new topic to look at these issues.
What could be incredibly useful as the forum is located all over the pace is an app that allows everyone to log their own data and drug/supplement regimen. I suppose there’s a privacy issue to get around but it seems to me that might be a decent start as a way to build a N of 1 database.
From a personal perspective having something I could track and log makes perfect sense as I see things going that way anyway.