Longer proteins for longer lifespan?

It seems too simple to explain much, but according to a study out of Northwestern University, large proteins are more prevalent in young animals compared to old.

For those of us who believe that aging is programmed into the life cycle, gene expression seems the most likely transmission of information about age through the body. Different genes are turned on and off at different stages of development and through the lifetime. This has been, in my opinion, the most fruitful basis for understanding aging and its remediation. For example, methylation patterns affect gene expression, and methylation patterns are the best measure we have of biological age. 

The reason that this hypothesis doesn’t lead immediately to a treatment protocol is that evolution has not engineered the body the way a human would design a machine. Human engineering is based on understanding and isolating causes. One mechanism is designed for each desired effect. Biochemistry doesn’t work that way. Every molecule has multiple functions and every function requires many chemical components to make it work. In an engineered system, there is a hierarchy of causes and effects, a few high-level switches and many low-level switches. In a biological system, there is a network of interactions. Chemicals may have a primary (low level) biological function, but the same molecule also serves as a transcription factor, affecting at a high level the output of related chemicals. 

The advantage of human engineering is that it is comprehensible. It is relatively easy to fix. If you see something that’s not working, the design specs tell you what component is likely malfunctioning and you can replace it.

The advantage of nature’s way is robustness. When a component fails, alternative pathways open up to take up the slack.

Last year, my left leg was injured so severely after I was hit by a car that the main vein returning blood from the leg was irreparable, and was surgically sealed off. During the first weeks in the hospital, my left leg swelled up to twice the size of my right because the arteries bringing blood down were fully open, but the return pathway was blocked. But over the ensuing months, other veins gradually expanded to accommodate the increased flow, and my left leg now is almost the same size as my right.

The take-home message is that we think that if we could change gene expression in an old person to mimic the gene expression of youth, the body would look and act young again. But there are thousands of genes that are differentially expressed, and the questions are still up in the air:

  1. Is there some small subset of genes that controls the others sufficiently that we can add and subtract some manageable number of components from the blood to recreate a youthful metabolism?
  2. Are these all proteins? Or are there RNAs or other signals that are essential to the process?
  3. How can we determine what is the minimal set of molecular species that needs to be modified? 
  4. And if we restore the youthful balance of signal molecules through the body, will this recreate a stable, youthful state, or is it necessary to treat the body frequently to prevent relapse to the old metabolic state?

There are presently several laboratories working with this paradigm from different angles, for example at Berkeley, Stanford, the Salk Inst, Mt Sinai and Einstein Hospital of New York. 

Leapfrogging ahead of these research institutes with a practical demonstration has been Harold Katcher. Katcher’s method is proprietary. He tells us that it is a “plasma fraction”. When I first heard this several years ago, I thought of the pioneering work of scientists in St Petersburg using peptides, which are very short proteins. I used to think the fraction must be the shortest proteins. 

In light of this new paper from Northwestern, I thought it must be the longest proteins. A brief email exchange with Katcher confirmed this guess. 

Both Katcher and the Northwestern authors mention the possibility that mRNA splicing might be impaired with age. In all eukaryotes (that’s everything larger than bacteria), genes are not stored contiguously in our chromosomes, but rather in segments that code for modules, or pieces of a protein. The mRNA is copied from the chromosome, and then various pieces of mRNA are spliced together to form a full, functional gene before the reconstituted mRNA is delivered to a ribosome to be read and translated into a protein. Presumably, longer proteins require more splicing, so impaired RNA splicing could account for a deficit of longer proteins as we age.

Katcher’s E5 is based on a process of filtering proteins from pigs’ blood plasma and selecting the largest molecular weights. It seems to work in rats, but the process of ramping up to create sufficient quantities of E5 for human trials is proceeding slowly, dragged down in part by the IP that Katcher and his partner are holding close to their chests.

Meanwhile, the four questions I listed above are not being addressed. Patent law is working against us, since Katcher’s E5 patent is for a process of extraction. If a subset of active ingredients is identified and the minimal set of rejuvenating proteins becomes known, his patent becomes worthless. Naturally occurring proteins cannot be patented. 

This is the maddening influence of capitalism and intellectual property law on anti-aging science. The most promising avenue for rejuvenation (IMO) is not attracting research attention because it cannot attract venture capital; it can’t attract venture capital because there is no attractive business model; and there is no business model because of the structure of our patent law.

141 thoughts on “Longer proteins for longer lifespan?

  1. Great post. I agree that the patent system is very much lacking in this space. However there are many business models that do not rely on patents. In these instances first to market will often dictate the dominant player in the market. Think star bucks and McDonald’s. Even Google became dominant due to early market adoption not the war chest of patents it now has. I realize that these companies didn’t need heavy research but they did become huge businesses and VCs know that.

    Many VCs will take a risk in tech if the upside is big enough and it surely is in this space. But they will need evidence of likely success and a road map to monetization. I think the FDA provides a bigger obstacle given big pharma will be negatively impacted by the successful product and is very influential, which may dissuade VCs.

  2. Hi All: I would assume that Akshay and Harold are working diligently to develop a clean supply of suitable host animals, scale up the harvesting, filtering and purification of the required blood products the plasma protein fractions are derived from. I am aware that they have retained a CRO to develop a pre-clinical and clinical trial plan as well as a regulatory strategy. All of this can continue unabated and simultaneously with the intellectual property rights. The IP process usually takes 2 to 5 years of which they are already one year in. The clinical trial process requires a similar timeline.

    I still believe that large Pharma will be more obstructive and cause longer delays than the pursuit of IP. As soon as the large Pharma researchers inform the management teams that this or any successful aging intervention will eliminate 80% of their diseases of aging market, they will open the financial floodgates and buy as many prostitutes, sorry I meant politicians, as they need.

    • Yes, I think there is a master dial. But it may not be one molecule. It may be a mix of hundreds of different molecules, because that’s the way regulation works in biology. I just wish someone was doing the experiments to find out, but as I say, it may be that there is no profit in doing this.

      • Yes. It is likely patent issues and curtailed profit potential that is holding up the research.

        What is needed is someone who is wealthy enough to care more about the process rather than the profits.

        “When something is important enough, you do it even if the odds are not in your favor.”
        —- Elon Musk

        • If I was Harold Katcher I would take E5 myself over in India when they have enough and see how effective it is in older humans having a large amount of those proteins in you. I wouldn’t wait years for the US FDA to approve it to be tried in humans. I would still go through the process of course but would self test overseas while awaiting approval for US trials.

          • Mike you will be happy to know that way before the FDA approval there would be human clinical trials in which Harold will participate.

          • That is good to hear. Appreciate all the hard work your group is doing on this. Like people have said Big Pharma has financial reasons not to develop something like this as soon as possible.

            I hope you will share some results of the topical E5 trial when you get them. Thanks

      • “I just wish someone was doing the experiments to find out, but as I say, it may be that there is no profit in doing this.”

        Yes. And on top of the funds required to do this experiment, the second challenge is to get at least 1M subjects. Not something that traditional trials can do. At least not under the form they are carried out today.

        Therefore, not surprising that several attempts have failed. See Arivale. Though a wellness company, their goal was similar: to discover signals of disease using multiplex omics technology. Arivale failed because they were not able to engage enough subjects, the program was too expensive and reserved to an elite. Other attempts based on external funding have also failed: bad technical infrastructure (e.g. through a CRO), program not patient-centric enough, too expensive compared to the profit that can be made…

        I still believe that these two challenges can be met. Something we will actually try this year at Biostarks. I’m the co-founder and CSO of Biostarks, a biotech company specialized in lab testing. This year we will launch a research program that has the ambitious goal to discover the signal that is driving aging. As Harold Katcher nicely says: cells age because the body ages, and not the other way around. We know from multiple experiments (e.g. heterochronic parabiosis) that this signal exists in blood therefore we will try to detect and characterize it in blood.

        We will do it in two steps:
        1. In order to engage enough people, we will first propose a longevity blood test, with blood collected at home in two dedicated collection devices, then shipped to one of our labs, see biostarks.com, with the analysis of a large panel of biomarkers of longevity together with recommendations that people can use to optimize their longevity interventions. The test is 90% ready, it already includes the robust measurement of NAD (that one was quite a challenge to develop because NAD is degrading in minutes after sample collection), a panel of micronutrients, and some hormones. The analytical validation of rapamycin and its metabolites is under way. We will also try to add biomarkers of senescence and some of oxidative stress. A crowdfunding campaign will be launched in ~1 month to get the funds to finalize this test. It will be available worldwide, with same logistics and lab network as for our nutrition and sport performance tests.

        2. Our labs already have the technical capacity to measure >40k small molecules, proteins and other biomarkers in the two blood collection devices that will be provided in the collection kit. The collection will only require 6 drops.of blood from a finger prick. Our labs use state-of-the-art high resolution mass spectrometry and other multiplex techniques. We fully take advantage of the highly multiplex capacity of the instruments, i.e. to use a fixed amount of blood to analyze a large number of analytes, no Theranos here, just good omics technology. As a second step, we will ask the persons who will buy the test for consent for us to do this multiplex analysis. All under the review of two independent ethics committees, one in Salt Lake City, one in Geneva, to protect the rights (and the data) of the participants. Participants will also be asked to fill a questionnaire with AI then used to find the pattern in blood that characterize healthy aging.

        The advantage of this strategy is that funding is solved, at least partially, through the financial participation of the longevity community, with participants who will pay to get recommendations and guidance for interventions that already exist. The price per test will be ~$200 during the crowdfunding campaign, then $350. This price will cover a significant part of both analyses and, we believe, should be low enough to engage 1M participants. The research program will be called Crowdtrial, because relying on the distribution of the needs of the trial over a large number of participants, unlike the centralized way trials are done today.

        We are also raising money to scale up our testing capacity. If any interest, you can contact us at contact@biostarks.com.

  3. The old science has a drawback in that the motives of the material world are taken as the basis for understanding life (living). But the material world is controlled by conscious information. There are 4 fields in nature: informational, magnetic, electrical and cosmic. The main field is informational, it controls the magnetic field. For example, I say that I increase the strength of the hydrogen magnetic field to 222,222 A/m for malic acid. Instantly, malic acid changes properties from paramagnetic to ferrimagnetic. In addition, the same acid, when taken orally, instantly stops the aging of the body and turns on the process of rejuvenation with a decrease in the biological age of the internal organs by 1 year in 45 months. The first girl underwent rejuvenation in 2022 from 23 to 16 years old. All cells of our body are controlled by our Soul, which has the structure of the information field. Information between the Soul and nerves is transmitted through Schwann cells and T-helpers. By the way, with cancer, this connection is broken and the Soul cannot control a certain part of the body – cancer cells are formed.
    Similarly, there are processes in plants that can give increased yields, be drought-resistant and have pure DNA without transposons. By the way, if the concentration of various proteins characteristic of the body is violated, then there is a deformation of the control programs in the Soul and human health will deteriorate. This applies to long proteins, blood transfusions.

  4. Human society has robustness as well. If the “veinture” capital is blocked, another mechanism could come into play. Big capitalists might have tunnel vision for dollar signs, but many ordinary people would surely understand that a return in kind (i.e. anti-aging therapies) is a perfectly good return on investment. They could be gathered together via a crowd equity raising platform. Or, anti-aging research could be orchestrated as a side-effect of an enterprise that yields dollar returns. For example, one might set up a DIYbio facility that operates profitably by collecting membership fees (as has been done), and oh, by the way, the necessary laboratory equipment and what not is available for researching aging. Or… what are other people’s ideas?

    • If college students (grad & undergrad) were enticed to investigate aging in the research projects they do as part of their curricula, that would mobilize existing resources.

  5. I think by the time a minimal but sufficient number of genes to reverse aging is discovered, our patents would have long expired, and the cost of providing each and every one of them in the correct proportions would be extraordinary.
    I start out on the basis of being able to provide E5 for everyone, which I why I started with domesticated livestock. The process of production could hardly bae simpler – and we can make it in India with no problems. using US swine offers a challenge that we believe we can respond to, so it’s just a matter of time. Do I need help – I’m not sure, but we already have help from our Johns Hopkins team, and I have some ideas of where to go next. Perhaps the most important thing is what I told Cynthia Kenyon after she told the Bay Area Aging Meeting (BAAM) not to expect to much, that there’s no real evidence that we can interfere in the aging process. I showed her my right hand and told her she was wrong – that aging is reversible. I don’t know how much she believed, but it’s all true. If nothing else (and there will be plenty else), we’ve shown proof of principle – that aging can be reversed. I believe I can solve our problems, if I cannot we will find someone who can. Believe me, I’m more frustrated than you, but we will make it work and bring it to market.

  6. Hi Josh, my take on the 4 questions listed above:
    1. Genes are a passive repository of information what we all inherit along with them is a transcription program. This program not only regulates the genes but also mRNAs and post translation regulatory actions thereby changing the proteome with time.
    2. RNAs are definitely involved. Our characterization work at Johns Hopkins confirmed this.
    3. This search is flawed. We continue to assume that by upregulating Sirtuins or NAD+ or GDF11 or reducing senescent cells we will achieve reversal of aging. It won’t happen. For complete reversal in biological age back to youthful phenotype one needs to consider only therapies that are making systemic changes safely.
    4. This has already been answered by multiple E5 studies. The legacy transcription program continues so one will need regular dosing to maintain the benefits.
    I have said this before: patent protection is necessary to protect the investor’s hard earned money. Give me examples of drugs developed by making it freeware and experimenting in hundreds of labs. There is a process and path of development and regulatory approval which one needs to traverse and it does take its time. E5 is making a massive change in your body. We can not rush it and begin biohacking. It needs to be thoroughly tested and fine tuned before it can be administered to humans. For the FDA we are deciphering in vivo mechanism of action of each category of component. We are working on standardizing dose. On the way every trial will disclose more information on use of E5 and give us further confidence to move to human clinical trials. A great group of highly dedicated scientists are working on it on weekends and late nights. We will succeed. We will achieve systemic reversal of biological age and fine tune dosing cycles to maintain it.

    • This ‘legacy transcription program’ sure is good at hiding.

      I don’t buy the idea that aging is an emergent property of thousands of small changes, that is an epiphenomena weakly correlated with many detrimental outcomes in aging. I think there must be a real mechanistic driving force like the shortening of telomeres, or the corruption of the genetic DNA blueprint.

      But hey, prove me wrong.

      • I have argued that, since aging is bad for the individual, natural selection has had to cement it in place, assuring that it can’t be circumvented by a small number of mutations. This is George Williams’s (1957) argument turned on its head.

  7. I am unable to see comments. I wanted to add that this paper is a great revelation of an aspect not studied so far. The length wise changes they are highlighting are in the transcriptome and not the proteome. But the transcriptomic changes will result in changes in the proteome not related protein length. I really liked this paper a lot.

  8. Somebody on Reddit posted a summary of this paper created by ChatGPT AI.

    “Summary from ChatGPT
    The study found that aging is associated with a global change in the transcriptome, a set of all RNA molecules in one cell or a population of cells, that can be explained by the length of transcripts alone.
    The study also found that this imbalance in transcript length can be counteracted by certain interventions.
    The eight interventions that were found to counter this imbalance are:
    Rapamycin
    3,5-diiodo-L-thyronine (T2)
    Acarbose
    17-α-Estradiol
    Metformin
    Resveratrol
    Nicotinamide mononucleotide (NMN)
    Growth hormone (GH)
    Genes with the longest transcripts were found to be associated with longer lifespans, while genes with the shortest transcripts were associated with shorter lifespans.
    These findings suggest that the transcriptome plays an important role in aging and lifespan.”

    • Lee, something is not right with this paper summary. It doesn’t tally with the lists from the published paper. If I were the suspicious type, I would suspect that an NMN retailer was involved.

      Here are the 7 (not 8) things associated with significant increase of long transcripts: “fibroblast growth factor 21 (FGF21) excess, Myc heterozygosity, rapamycin, resveratrol, S6 kinase 1 (S6K1) deletion, senolytics and Snell mice”.

      And here are the 4 things with no significant association: Ames mice, eating every other day, Little mice and metformin.

  9. I think the short mRNA are called “cryptic” mRNA. I think when the mRNA gets truncated it is rendered unreadable and the protein doesn’t get made.

    A ChatGPT summary of a different paper on cryptic mRNA:
    https://sci-hub.se/10.1038/s43587-021-00091-x

    “Cryptic transcription is the process by which genes are transcribed, or converted from their DNA sequence into RNA, without resulting in the production of a protein. In embryonic stem cells, a repressive chromatin state, characterized by specific modifications to the histone proteins around which DNA is wrapped, suppresses cryptic transcription. However, with age, cryptic transcription is elevated in yeast and nematodes, and reducing it has been shown to extend lifespan in yeast. It is unclear whether this occurs in mammals as well, but recent research has shown that cryptic transcription is elevated in aged mammalian stem cells, including in mice and humans.

    The increased cryptic transcription in aged stem cells is accompanied by changes in the chromatin state, specifically a decrease in trimethylated lysine 36 on histone H3 (H3K36me3) and an increase in other modifications, such as H3K4me1, H3K4me3, and H3K27ac. These changes resemble known promoter sequences and are bound by the TATA-binding protein, even in young cells. This suggests that the more permissive chromatin state at intragenic cryptic promoters may be responsible for the increased cryptic transcription in aged mammalian stem cells. It is currently unknown what effect this increased cryptic transcription has on the function of stem cells and on overall lifespan in mammals.”

    • It does have a significant effect. As we age at some stage in our lifecycle one paper said that more than 60% of translated proteins are negatively regulated by miRNA.

  10. I wonder if Heat shock protein (HSP)70 and others were some of the main things they were after for E5 as I think I read it goes down a lot with age and is associated with mRNA splicing.

    • I doubt the heat-shock proteins are directly involved. People forget (to don’t realize), that aging is not a cell-autonomous process, but is systemic. The body doesn’t age because cells do – cell aging is largely a myth – but cells age (or adopt an aging phenotype) because the body ages. How would you get these heat-shock proteins into cells?

      • I agree that HSP70 is unlikely to be involved; in particular it probably is not a component of E5. In reading your patent, it appears that you are concentrating plasma components which are NOT the dominant ones (albumin, globulins and fibrinogen) all of which have molecular weights of 65kD or greater. You achieve this by restricting molecular weight to some value less than 65kD.

        Regarding cellular vs systemic aging, your experiments have clearly shown that the aging phenotype in cells can be reversed by circulating factors in the blood. The first evidence of this was provided by the Horvath clock. However, as measured by that methylation clock, there IS evidence of aging in cell cultures, where the environment is obviously different from that of a living animal. In a paper by Lowe, Horvath, and Raj:

        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4890984/

        endothelial cells derived from the coronary artery of a 19 year old male were placed in cell culture. Their initial Horvath age was about 20 yrs. After 5 to 6 weeks, they reached the Hayflick limit, and exhibited a Horvath age of about 40 years. When immortalized by adding a gene for telemerase, they continue dividing, and continue to age, to 50 yrs and beyond.

        Clearly cell culture is a different environment from a living animal. Could adding E5 to the culture medium reduce their rate of aging? If so, it might provide a more convenient test bed for investigating such questions as: Which components of E5 are the active ones?

        • Gregory, no E5 has components that not only rejuvenate the cell but also the ECM and other microenvironment around the cell. Part of the rejuvenation is the crosstalk between all of this in a complex systemic environment like living body. There are techniques available to functionally characterize each category of components in E5 in vivo. That is what is being done.

        • Well you are wrong about some things but certainly correct that we had an in vitro model we could test. However, when using an animal you can check many cell types and the functioning of organs. Why believe if it works on one cell type it will work on others? The first evidence was not provided by the Horvath clock. It was really a stretch to even believe that Steven would analyze our data, but we bribed him to make a rat clock (we and Rodolfo Goya provided the young rat DNA), a concept (other than human DNAm clocks) had not been proposed. Steven’s data backed up results that already pointed to significant changes in aging as revealed by biochemical, physiological and behavioral testing – all pretty much agree with Steven’s results. So, we are glad to have Steve helping us with our work as he is the world’s greatest authority on epigenetic aging, but he did not find the first evidence of rejuvenation, although perhaps the best evidence,

        • @Gregory, ‘When immortalized by adding a gene for telemerase, they continue dividing, and continue to age, to 50 yrs and beyond.’ …

          fully functioning cells continued to divide but they continued to age’. What are the characteristic of this ‘aging’ and how did it impact these cells? What actually is Horvath measuring? Nobody knows. It might relate to differentiation state, but this probably has no meaning in an immortalised cell culture where cells can indefinitely divide with stable gene expression.

        • I am confused. Josh says that Harold confirmed that it is the heaviest proteins that are in E5. You interpret the patent as excluding proteins >65kD. Perhaps E5 is the excluded portion?

          Akshay mentions Nrf2. My google search says the human form has a molecular weight of 67.7 kD.

          • I´m certainly confused as well. Perhaps upon reading the patent, you will come to a different conclusion, but it seemed to me to describe a procedure for choosing a range of molecular weights based upon chromatography. The lower limit would be determined by what leaks through the dialysis bag, and the upper limit by the number of fractions kept (assuming those which come later are of higher molecular weight). I guessed that the upper limit was less than the molecular weight of albumin, about 65 kD, otherwise the resulting material would be mostly albumin (which is vastly more abundant in plasma than any signaling proteins).

          • I am reminded of two things regarding albumin. 1) Serum albumin is a major component in some phenotype aging “clocks” – higher is better as it decreases bio age, and 2) there are some differences in the detailed makeup of young vs. old albumin. It would be very interesting to see a plasma dilution experiment in which a 7% young albumin solution was used to replace the donated plasma instead of a 5% solution of unknown age.

          • @Michael. Yep, that was the paper I seemed to remember. Thanks for finding it for me.

  11. Hi Josh, Super interesting a usual. And great to hear you are doing well after your ordeal. Here is an idea for you. One of the largest proteins in human blood happens to be albumin, I think. And albumin happens to be great at keeping the blood (colloid) dispersed, apparently by optimising/buffering zeta potential. Could it be that a big contributor to antiaging is avoiding micro coagulation? I don’t know enough about this stuff to really know what I’m saying here. But I’d love for you to look over some of the work on this and tell us if you think it has merit. Keep up the great work.

  12. Josh, I have tried multiple machines, operating systems, and browsers, but your site does not show comments for this post. It shows comments for all other previous posts. Has there been a change to this post causing this? Also, I am getting no email notifications of new comments, either.

  13. Harold, I think that some software switch is not set right. I haven’t been able to see any comments, but I just saw yours via an email notification (which just started to work – your is the first one).

    Assuming I can get this post past the capchta. . .

  14. “This is the maddening influence of capitalism and intellectual property law on anti-aging science.”
    I think the FDA approval process burdens the development of new drugs more than IP law. If the public were allowed to try any drug which passed phase 1 safety (dozens of patients) and phase 3 safety trials (thousands of patients), without requiring proof of efficacy, the cost of new drugs would drop precipitously, and development would happen much faster. We could try things and wait for secondary proofs-of-efficacy to come from large companies with the $billions to spend on that. I’d pay more for a efficacy-proven drug, but I don’t like being stopped from trying new things that are safe. Something makes me think that large pharmaceutical companies prefer the high cost of drug development since it raises the bar for entry into the market from potential competitors.

  15. Amazing to see Harold and Akshay reporting some amazing things and their sheer passion and will. Thanks to both for being amazing scientists and human beings.

  16. Interesting and didactic post Josh. Nice to see that the metioned paper is concording with Harold conclusions.
    As usual I have many questions. But I will ask jus 2.
    a) Do you expect any paracrine effect on the topical E5 trial? Or will the topical aplication restricted to some small area of skin? I wonder that thinking of skin as the largest organ in our body. If the trial was in the whole body or in a big part of it, and so many cells were tuned to a younger gene expression, its secretome would of course change and being skin a huge organ, its propotional amount of secretome would be very important, and perhaps could balance or interact significantly wiht the old secretome of the rest of the cells. But perhaps this is an odd idea, I don’t know.
    b) When do you expect to start the human trials?

    And thanks Akshay and this time Harold as well, for taking the time to answer, explain and repport about the process. I think we all are fascinated about it.

    And Merry Christmas!

    • Hi Ines yes there should be paracrine effects. Application on entire available skin area should certainly have systemic effects: primary would be drop in inflammation levels in the 50+ age group and chronic inflammation is the precursor to most mortal diseases so it should provide some level of protection against such diseases as well. In the first human trial though we are only replicating what Harold had done: apply on the back of one hand.

      • Thank you Akshay, as kind as always.
        If you expect such effects, topical use in whole body would be a window to offer advantages of a medecine in disguise of a cosmetic/cold cream and skip FDA (and other regulators that we have in Europe). Those would be good news.
        Good luck with the trials!

        • Reading Akshay’s response to the possible paracrine effect it made me think of half measures and an idea that might be totally impractical to shorten the time to clinical trials. So if there is a paracrine effect and there is excellent safety data from the topical trial, I wonder if instead of going through larger animal studies (or in addition to them) there would be a possibility of creating an alternative formulation that has a closer to systemic effect, such as the aerosolized E5 you talked about along with a tailored treatment regimen, but is a less dramatic leap than going to injections of E5 in humans. Maybe with safety data from such a trial you could get a more direct path to making approval for a full trial of E5 seem appropriate to the FDA sooner.

          • Adam it’s a good suggestion and it probably can be done for topical E5 but if it’s entering the bloodstream which aerosolized E5 would then FDA will want to give its approval through extensive clinical trials. The only short cut could be topical E5 which may be used in a different way by biohackers assuming it’s safe to do that.

  17. It is actually not at all suprising that the longest genes are most affected by aging. Most of the genome is regulatory, not protein making, so it stands to reason that if the genome is corrupted in some way, it is most likely that this would affect regulatory regions. As long genes require more splicing, it is also the longer proteins that you’d expect to fall in concentration with age.

    This is evidence that the genome, our basic blueprint, is being corrupted by age.

    Adding the longer proteins back into the blood is a cunning idea; but you can understand why this has to be a repeated treatment, as this won’t simply reset the genome of cells back to what they were when young: for that we’ll need to replace cells with pristine ones, and for that we’ll need telomerase.

    • I have a hard time believing genome corruption could be any sort of upstream driver of aging. Genomic integrity is maintained generation after generation after generation in the germline. What would be so tough about doing the same for somatic cells?

      • I am just pointing out what the evidence is suggesting. There are many mechanisms by which genomic integrity may be compromised with age, and these are not necessarily driven by basic mutations. For example, every time a cell dies, some of its DNA is flushed into circulation as cell free chromatin particles. This can be taken up by other cells, and over time ‘repaired’ into longer sections of DNA, eventually being integrated within the legitimate DNA of the chromosomes. As cells are dying constantly, this may well be a real contributor to aging. Quiescent stem cells and germline cells may be somewhat protected in their niche, but not somatic cells. Also remember, sexual reproduction is a great filter for eliminating bad cells, so even if you had a high burden of mosaicism in sex cells, any cells too compromised would not produce young.

          • Yes it is. Michael this is one of my favourite papers. Dr. Mittra a cancer scientist was perplexed by the very high occurrence of double strand DNA breaks in our cells: 10 to 50 per cell per day! These DDBs are constantly repaired to maintain the viability of the cell but any error leads to cell death or worse cancer. So he and his team began to investigate the cause. They were surprised by what they found. Every day around hundreds of billion cells die in our body. This huge number of dead cells leave fragments or debris which circulates in our blood. Phagocytes work relentlessly to ‘eat’ this debris and digest it – clear it. But Dr. Mittra found that cell free chromatin particles released from the dead cell fragments enter healthy cells and cause double strand DNA breaks which basically snaps both the strands of the DNA. He found that the plasma consists of large quantities of these dangerous bullets circulating all across our bodies. This is a BIG discovery! Dr. Mittra hypothesizes that the that lifelong assault on healthy cells by cfChPs is the underlying cause of ageing. Again a very major discovery if it turns out to be true. I personally do not fully attribute the circulation of these dangerous particles as the cause of ageing because I am sure in the young, healthy body they can be more or less cleared by our amazing phagocytes. What happens with aging is that the efficiency of the phagocytic cells goes down which would leave accumulating amounts of this harmful circulating debris. An example of why phagocytes may lose their efficiency is the disruption of mitochondria seen in aging. Phagocytes especially require huge amount of energy provided by the mitochondria. Here is a paper on that:
            https://lnkd.in/gbfSR4UZ

          • Akshay, it is indeed a fascinating paper. Rather than pursuing the R-Cu remedy, however, it would seem to me that preventing cell death in the first place would be a better therapy. Yes, DSBs are common, but they are also repaired (to a greater degree in the young). For example, SIRT6 is known for its role in such repair. I am reminded of the turning off of repair functions at maturity in nematodes via H3K27me3. And this reminds me that DNA methylation is not the sum total of epigenetics – histone modification and chromatin remodeling are also at work and modifiable. All of which remind me that it is hard to argue that reversal of at least some aspects of aging is not possible.

          • Wayne as per current biology we can’t do away with cell recycling. Who knows in the future that may change.

        • Maybe the young can clear them out Akshay, but don’t forget more phagocytes means more phagocytes dying doing their job – so more cfChPs. Immune cells are probably one of the biggest contributors to cfChPs.

          I expect we’ll find various things that increase oxidative stress in the blood are beneficial for clearing out cfChPs – exercise for example, even moderate alcohol consumption.

          But let’s say we can stop this contributor to aging via some combination like resveratrol+Cu, exercise, etc, we still have the problem of the accumulated DNA garbage that has now integrated into various cells. It is irreversible without replacing the cell, and the older we are, the more cells we’ll have in that state.

      • The best way I can think of to replace old, dysfunctional cells is conditional reprogramming. There are a number of in vitro studies on this. You combine a rho kinase inhibitor and a telomerase activator. Fir in vivo application (age reversal!) there are a few hurdles. Thus far ‘rock’ inhibitors are only available for eye conditions, but can probably be repurposed. Small molecule telomerase activators also do not yet produce sufficient telomerase, but it may be possible to boost this significantly by increasing the various stages of telomerase creation and activity( TERT and TERC upregulation from gene, increased rate of combination in nucleolus, etc).

      • I periodically take valsartan 20mg and fluvastatin 10mg for this very reason.
        I use the “Gerosense” app which calculates biological age and resilience and can confirm it improved my resilience to that of a 40 year old and I am 61.
        n=1 I know, but still.

        “Low-Dose Fluvastatin and Valsartan Rejuvenate the Arterial Wall Through Telomerase Activity Increase in Middle-Aged Men”

        https://pubmed.ncbi.nlm.nih.gov/26214555/

        • Interesting, I never thought to check my own meds but it seems that studies have shown that Atorvastatin and Perindopril also increase telomerase activity.

        • Yes, we’ve talked about the statin/sartan combo before; do you take it for a month once per 6 months?

          I believe we can do much better than this as this combo is only indirectly hitting the targets we want (hence the long dosing period).

          Thanks for the heads up on the App; I’ve lost all faith in methylation tests so have been looking for an alternative.

  18. If the rejuvenation signal is distributed over a large number of molecular species, then it is likely that the information is more distributed in the network of small molecules than in the proteome. Proteins have been designed to have a very specific function; small molecules have been designed to work interactively.

    Nice new paper published in Cell
    https://www.sciencedirect.com/science/article/pii/S0092867422015203?s=03
    in which they showed that metabolites interactions determine cellular aging (in yeast).

  19. Thank you for the informative post Josh!

    I have a few questions for Harold and Akshay.

    Quoting Akshay’s comment above regarding the ECM.
    ‘E5 has components that not only rejuvenate the cell but also the ECM and other microenvironment around the cell. Part of the rejuvenation is the crosstalk between all of this in a complex systemic environment like living body’.

    We can’t defeat aging without regenerating the ECM. ECM proteins and
    structures can determine the cell behavior, polarity, migration, differentiation, proliferation and survival by communicating with the intracellular cytoskeleton and transmission of growth factor signals. The stem cell differentiation depends on the environment. Take the connective tissue ECM for instance. Even if we achieved cellular rejuvenation by any means, the rejuvenated cells would produce their ‘fresh’ ECM, the problem with degrading the old one remains. The old ECM must be degraded to allow the free movement of cells or the processing and deposition of new matrix (matrix metalloproteinases MMPs and ADAMTS).
    The introduction of new fibroblasts could recreate the connective tissue ECM. Regarding the plasma (the ECM of the blood), we have the plasma dilution as an option and E5 would be another one.

    1) What about the non-vascular structures like cartilage or poorly vascularized tissues like tendons which rely on synovial fluid to provide nutrition?

    2) What are your thoughts on immunogenicity of E5 and do you plan a pretreatment with corticosteroids in the clinical trials?

    3) Will the plasma peptides be produced by recombinant technology or will they be synthetic?

    Thank you!

    • Hi Darina, thank you for confirming the importance of crosstalk between cell and its environment. Answer to your first question is that sinovial fluid contents too would change with age and true systemic rejuvenation would make it potent again to maintain healthy cartilage. I am more curious about teeth. Especially lost teeth. Will they regrow? Or lost forever. E5 has no zero negative immune events in 5 preclinical trials so far. So no steroids needed. You know the components of E5 are so highly conserved that we have multiple sources to harvest from – some we are examining will shock the world if we succeed.

      • Akshay, are you suggesting that an effective anti-aging treatment might regrow teeth? This seems impossible to me – an entirely separate matter. Young people, even kids, do not regrow lost teeth. The human body simply doesn’t have this capacity. I understand some animals do, so perhaps the capacity lies dormant in the “attic” of our genome somewhere. But regrowing lost teeth would require reactivation of such, or some other technique, which has nothing to do with aging. I can imagine some sort of hyper-local stem cell transplantation, or highly focused Yamanaka factor application doing the trick. The latter might be called de-aging in a sense, but down to infancy or thereabouts. Treating ones entire body systemically so would surely have nightmarish results: teratomas, crazy growth, and well, death no doubt.

        • I agree with you about teeth and doubt E5 would do that. My guess is if you had some teeth with a lot of wear and tear it would give you back the capability to re-mineralize them like you were still a younger age.

          • I hope you are right. It be really funny to have all of us living to 200 in good form but totally toothless lol Having had a nice laugh imagining that there seems to be multiple technologies under development that show promise to regrow teeth: stem cell, anti body. One of them will surely succeed. It’s a matter of time.
            Here is an intriguing article. I have great regard for Kyoto University:
            https://futurism.com/neoscope/treatment-makes-teeth-grow-back

        • Fred in fact I said the opposite. I said cartilage may be possible but I don’t know about teeth that seems impossible.

          • No, I don’t think rejuvenation would grow new teeth, but with our newfound abilities and understanding of cellular reprogramming and the development of tooth shapes, it might still be possible to ‘construct’ tooth primordia, insert them into maxillae and mandibles, and grow a flashing white smile. Of course, artificial implants would be far easier to build, stronger, and not subject to decay as teeth. I guess that’s the first step to becoming a cyborg?

      • Akshay do you think that regular plasma donations (replaced with saline) is something that we all should currently be doing until E-5 is ready for prime time? Do you think that plasma donations keep the blood clean of old proteins and even if this doesn’t have an age reversal effect, might slow ageing down slightly?

        • Dan I can see only upregulation of Nrf2 3 times a week or rapamycin once a week as the ones showing results one can see and feel currently. Conboys and Kiprov have a protocol that they testing in humans where they replace plasma in the old with reconstituted human albumin. I have respect for all three of them and Dr. Kiprov has been working on this from 3 decades. Another good thing for all of us is that they are already doing human clinical trials. From their last n=3 human trial the benefits seemed transient and I could not see any pointers to dramatic reversal of biological age. Which is fine if it does go on to improve healthspan. It does seem to temporarily improve the immune system. The only catch is that I how many would want to sit for hours with two needles poked in them every 15 to 30 days.

        • I did the maximum plasma donations you could do for a month at one of those plasma banks that pay you (8 plasma donations total – 2 per week) which the math told me should have roughly resulted in 88% of my total plasma being replaced over that time. By about the 7th of the 8 donations I was feeling a little weak but didn’t get rejected for low protein on my 8th treatment like I saw happen to others at that place. Afterwards I felt kind of weak for a few weeks and then I just felt different for about 2 months like my body was working on itself more than it was before I got rid of the plasma. I believe my facial skin added a little collagen looking at it and felt a little stronger. The little bit of inflammation in my elbow disappeared. Before that though I realized removing that much over a short time period drains your albumin pretty good and also it seemed to deplete my Zinc like crazy which I had to supplement for a few weeks to get the levels back up. Next time I will make it a point to be eating a lot of protein while doing it to try and keep the albumin levels up a little more.

          • Thanks for sharing your donation experience. I’m coming up for my 11th plasma donation, but here in Australia we can only do them once every two weeks, which leaves plenty of time to replace albumin etc. But of course I’m probably not getting the benefit of plasma dilution like what Dr Kiprov does. I try to eat a lot of raw eggs and whey protein straight after a donation to increase Albumin. The main reason I’m doing the plasma donations is because of the Australian studies that showed it can dramatically reduce forever chemicals and micro plastics in the bloodstream, which must be a good thing

          • That is a good benefit. I guess the one good thing about these private places in the US is you arent limited nearly as much on the donation time so you can drive a big chunk of old plasma out relatively quickly. Just doing it twice in the 48 hour period the first week takes a little less out than those clinics people pay to have it removed. Our red cross here in the US won’t let you donate plasma but once every 4 weeks I think.

  20. From the beginning of Harold/Akshay Era, we have been underlining the word SYSTEMIC! This has been proven by the latest OSK reprogramming which failed to increase the maximum lifespan by more than 6%. A one could imagine transcription factor induced nucleus reorganization is enough to affect all the hallmarks of aging. I think that’s not true and it’s becoming obvious day by day, even if the virus delivery and the dose schedule is optimized enough. We are slowly but still coming to the conclusion by Akshay and Harold. Unless addressed systemically, we are supposed to fail. A great example here would be the systemic consequence of DSBs. We may upregulate HR and NHEJ through SIRT6, suppress Retrotransposable Elemets, maintain youthful gene expression pattern, maintain heterochromatin and lamina associated domains, kill senescent cells but still fail to extend lifespan dramatically. Why? Because mitochondrial DNA, Cytoplasmic chromatin fragments from mitosis, Micronuclei rupture, SASP, R-loops, Transposons, Cell replication and degradation of Nuclear scaffold protein and deregulation of negative regulators of cytoplasmic DNA are going to change, cause the activation of cGAS-STING, interferon response and tissue hyperfunction-dysfunction. I think Rapamycin is just a brilliant example how addressing systemically is the only solution. For today, there is nothing more promising than Rapamycin and E5 remains the only solution making us maintain our hopes and leave the mode of pessimism.

    • Good points. Looking at all the stuff out there right now I would think E5 is probably the only one at this time that has any chance of being a true game changer of turning the clock back safely. The only one where we may actually see a 75 year old walking around like a healthy person in their early 50s. The other big hurdle is eventually figuring out what is the factor keeping lifespan from increasing greatly in the rats.

        • That would be great to hear. Also the info on the topical trials. I am sure a lot of people will love when they can apply that to their facial skin in the future.

          • Akshay, is there a special web site for european customers for the ordering of NEEL topical gel? From what I understood, it should be possible for customers within the EU to order NEEL from February 2023?

          • Hi Ole currently you would need to buy using reshippers from US like Shipito and myus.com and others.

          • Yes thank you Ines. We are confirming this but Sima may be a lifespan record holder for Rattus Norvegicus species of rats. But my lab colleague she may live only few days more.

          • Our immediate goal is to restore youth to allow those who’ve earned it to enjoy the “Golden Years” with youth and vigor instead of infirmity and diseases of aging. Yes, there’s a lot to do to slow the process, if you believe that aging occurs at the systemic level rather than the cellular level. The “Holy Bible” of aging (in many senses) scientists is that aging occurs at the cellular level (which is what “Loper-Otin’s aging mechanisms that only apply to cellular aging, when aging is in fact a systemic process, such that young cells introduced into old bodies become old and old cells introduced into young bodies become ‘old’ (where old is one possible phenotype of the particular cell. This has been known for decades, and David Sinclair is missing the most important point: aging is systemic, though damage increases its rate of progression (by increasing the age-related probability of death)

    • The problem with rapamycin is that it only treats hyperfunction which is not aging itself. Alan Green experienced relief from his cardiomyopathy which he first thought was anti-aging. Mark has also commented that you can’t inhibit MTOR too much before you have negative effects.

        • exactly, there is a minimal mTOR a particular species can’t live without. Hence it will only make a short lived mouse a long lived mouse, and never give it the lifespan of a squirrel; it struggles to even give a mouse the lifespan of a rat.

    • I largely agree with you – but believe that the aging process and the rate at which it unfolds are differently controlled (there is evidence of that). So, the modest improvements in life span and the significant improvements we’ve produced in the quality of life are only the beginning for us. There is so much still to be learned and accomplished.

      • Just for example, the octopus is a semelparous organism that dies after its reproductive goals are met by flooding its body with cascades of inflammatory cytokines using its ‘optic gland’ in the back of its eyes. Removal of these glands prevented this and the octopus (I don’t remember the sex) resumed a normal lifestyle until it died one year later of unknown causes. Makes me think that without the ability to reproduce, its “life program” ran out – what biological purpose did it serve? Nature apparently gave its programming no other options. Sure would be interesting to know why/how that twice-born octopus died.

        • Thank you, Harold and Akshay. You are a true inspiration and a clear example that only the right ideas and the right connections are needed to change a field stuck in one direction.

          What do you think about the extremely high levels of TMAO and Carnosine in the Bowhead Whale and Naked Mole Rat-2 extreme longevity models? It might be stabilizing plasma proteins under pressure? Even though Homologous Recombination and Non-Homologous End Joining do also correlate positively and are highly upregulated in these 2 species, based on many studies where DSB repair efficiency were increased but not maximum lifespan, I am already skeptical and think that DNA repair efficiency is just another correlation like the rate of telomere shortening-although DSB is considered as a major destabilizing factor.

          • Leo interesting observation. Just found out about TMAO thanks to you. At high levels in humans it seems to be an indicator of chronic inflammation and various chronic diseases associated with it. So I wonder why it seems to be in abundance in those long lived species. May be Harold can answer better.

          • Be careful in writing off telomere shortening as only correlated with aging – perhaps telomere shortening is not the main driver of aging (or maybe it is), but if you can’t replace cells you WILL die, regardless of any other anti-aging intervention. Mostly likely MAX lifespan is set (in humans) by telomere attrition.

  21. A comment mostly intended to get notifications of future comments:

    If someone has mentioned Sinclair’s latest contribution, I missed it. As I understand the paper, DSBs cause changes in the epigenome which can be at least partly corrected with Yamanaka factors. It seems to imply that there is information encoded somewhere that describes the road back to a more youthful epigenome. He calls it the Information Theory of Aging, but the difference between information and programmed seems primarily semantic to me. In any event, the existence of levers controlling rejuvenation seems to be well established. Katcher’s rats would seem to suggest that E5 is a better way of operating them than OSKM. We shall soon know.

  22. Would someone help an old brain understand what the referenced study is saying. For example, as I understand it, transcription factors are a subset of all the proteins translated in a cell. Does the paper state that all long proteins are under represented with aging? AFAIK, the length of a transcription factor need not correlate with the length of the transcribed protein it affects – the binding site being very short and quite constant.
    I wonder if the emphasis on transcript length in the paper is just obscuring the significance of a reduction in ALL long proteins with age.

    On a separate note, I seem to remember a paper that asserted young albumin is different than the albumin of us old folks. It would seem that trials might need to consider not just the quantity of certain proteins but also their makeup. Can anyone guess if the E5 extracted from old blood would have the same effect as E5 from a young creature?

    • Wayne transcription occurs before protein production so not a subset. Transcription leads to mRNA which then gets translated to a protein. There also non coding transcripts which do not translate to proteins but have regulatory roles. This paper’s authors have discovered a stark change between the young and old: the length of transcripts. Young have long and short but as we grow older longer transcripts are not seen. One of causes could be a program that regulates alternative spicing. 98% of the transcriptome is a result of alternative splicing. There are specific patterns seen in alternate splicing in diseases and aging. To give you another perpetual of this regulation here is what happens in psoriasis a skin disease: https://www.nature.com/articles/s41598-018-22284-y

      • By subset, I meant not all proteins are transcription factors. What did the paper say about protein lengths other than TFs? Are the average lengths of such proteins also reduced? If so, one could more conclusively point to splicing failure as a cause/component of aging?

      • Unfortunately, psoriasis is not only a skin disorder anymore, but a systemic one, affecting the whole body in many different ways, such as an arthitric condition, for sample, or cardiovascular disorders. Just FYI. BTW rapamycin, the very well known antiaging compound is a promising antipsoriasic.

        • Thanks Engadin. I am not surprised about Rapamycin and I would also expect E5 to be as it lowers inflammatory markers significantly.

    • E5 extracted from the old will have the opposite effect. It needs to be extracted from the young to get the benefits.

  23. As I read it, the reduction with age of long transcription factors was not observed in all tissue types. This would seem to indicate that a causal relationship may not be involved unless not all said tissue types age?

    • Harold recently cited in another conversation that different tissues and organs have variable rate of aging. But I doubt if any tissue ir organ completely escapes aging.

      • Yes, my point was that all tissue types DO age, and if some do not have shorter TFs with age, then shorter TFs cannot be the sole cause of aging.

        • Wayne this is one of my fav papers as it takes a deeper look then conventional RNAseq. It’s findings are quite interesting. https://www.cell.com/cell-systems/fulltext/S2405-4712(17)30547-1?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2405471217305471%3Fshowall%3Dtrue
          There seems to be a splice code that governs transcription and probably leads us to our various lifestages. And yet despite such a code the number of non coding isoforms seem to be endless. The authors say “ We propose that noncoding exons are functionally modular, with alternative splicing generating an enormous repertoire of potential regulatory RNAs”. When they compare these non coding regulatory RNAs with mice they find humans have multifold more whereas the size of our coding genes is similar to mice. So what makes a more complex human vs mice lies in the much larger non coding regulation network. Changes in lengths of transcripts as we age would be result of this splicing code. We could identify it as result of accumulation of errors in the splicing machinery but as there is a temporal pattern that is seen with aging it may be because of a splicing code/program.

          • I know this community is very against the molecular damage theory of aging but may I ask you Akshay what is your opinion on hyperfunction theory of aging-continuation of growth and developmental program-Blagosklonny theory? Does not it seem very logical and relevant to your theory?

          • Hi Azza, I do like Blagosklonny’s papers and it does not contradict my own thoughts. Hyper function is caused deliberately, as part of the aging program, by Nature’s overall strategy to dial down repair efficiencies across multiple repair pathways. So by default that pushes the mTOR pendulum towards growth much more than needed. Too much of anything is going to harm. This can be corrected to some extent by low dose Rapamycin as suggested by Blagosklonny which inhibits mTOR thereby upregulating repair or by upregulating Nrf2 3 times a week which is the fountainhead of many repair pathways including the very important autophagy. Both these actions of done intermittently would rebalance mTOR function to some extent and the effects are noticeable. There are many major symptoms of aging which are erroneously attributed as cause of aging. The cause of aging is embedded in our genome even as an egg is fertilized – it is an inheritance that most living forms pass on to next generation. Transcriptional changes are constant from fertilization till death. These changes sequentially deliver a complex growth program taking us miraculously from an egg to an adult and then post puberty progressively creates various imbalances and drops in efficiencies to ensure we die. Can we adapt to prevent this inherited transcriptional program? Well some trees which also share core biology with us have succeeded in doing so. So confirms the possibility. Human technology and interventions may speed up this adaptation.

          • Thank you Akshay for your response. Despite you agree with Mikhail, I think this is fundamentally different. He thinks animals-based on predators and environmental factors grow fast and reproduce or develop slow and becomes stress resistant, then mTOR is controlled and aging too is slow in long lived organisms, therefore no purpose of self-destruction/altruism. Also, why only a Rapa is able to increase lifespan dramatically?(25-30%) and not other interventions like PB125(Nrf2 activator) or chromatin modulators?

          • Has a good quality lifespan study been done for Nrf2? I haven’t seen any. I don’t know about PB125 but I upregulate Nrf2 with the following taken together for synergy: Andrographolides, Sulforaphane with Myrosinase, Quercetin, Pterostilbene, Resveratrol and Xanthohumol. Key would be to take versions of the above that have clinical evidence of bioavailability. A reputed lab should do a lifespan study in old rats with the above combination. I wouldn’t be surprised if it achieved better results then Rapa.

          • Thank you for sharing your protocol. I know PB125 and Protandym have been studied, no effect on lifespan.

          • Azza I went through their list of ingredients. I wouldn’t take any of them to upregulate Nrf2. If the natural extracts are fat soluble then they should suspend them In phosphatidylcholine to improve bioavailability. I have tested my list on rats and after the second month of daily dosing they reversed many biomarkers of aging significantly. Unfortunately do not have bandwidth to do a lifespan but may be in future.

          • Akshay, Quercetin is known for its low bioavailability. Do you have any advice on how to boost absorption?

          • Hi Stephan I use EMIQ activated Quercetin. They have claim pharmokinetic data showing 40 times better absorption.

          • For those not familiar with Michael Lustgarten, he has a complete opposite approach, using no supplements at all (besides vitamin D during winter time). His diet is determined 100% by his blood biomarkers, and currently he is measuring 17 years younger biological age than chronological age. I like that strawberries is on the top of his food chart 🙂
            https://michaellustgarten.com/

          • Very interesting discussion on Blagosklonny accidental quasi program vs intentional aging program.

            I am agnostic on the matter, but what I will say is that if children have to compete with parents then they will have LESS children themselves and the adults will have MORE, which will slow adaptation. Therefore we should expect slower aging animals in slow changing environments and fast aging animals in fast changing environments. Surely this experiment can be done with worms or flies?

            Of course that doesn’t settle the argument for quasi vs. intentional program, as in a slow changing environment slow growth might also be selected and therefore indirectly select for slow aging.

          • I think that extended lifespan is not by itself under selection but rather a by-product of species adaptation. This implies that a new pleiotropic mutation, with one of its effects being extended lifespan, could be favored by natural selection due to its advantage to some other trait and therefore becomes fixed. This also applies to new pro-longevity mutations that occur at sites closely linked with the allelic sites under selection. If a new pro-longevity mutation arises at a site that is linked to an adapted genome region, natural selection may cause an increase in allele frequency and fix this pro-longevity mutation through linkage and allelic associations. Some adaptive genetic changes could have dual functions, i.e. adaptive and longevity effects. A pro-longevity mutation could come under selection and become fixed through direct selection or linkage and allelic association. In the same way that a pro-longevity mutation could become fixed, a geronic (pro-aging) mutation could also become fixed and lead to a shorter lifespan. In the case where environmental pressure is relaxed, pro-longevity effects may be lost. . I think the less the risk of predation and harder the environment to adapt and find an appropriate supply of food for offspring, the more stressed the body and the slower rate of growing and maturing, i.e controlled transduction signaling.

            As for aging, I don’t think because of the super high risk of death in nature, since the Earth is extremely tough, nature would program the body to age – it just cares about development and depending on the rate of Geroconversion-cell proliferation, organism ages and dies due to the hyperfunction faster or slower.

          • You might also get the case of the region under direct selection playing off against the linked region, should that region start to manifest a non adaptive phenotype. You see this in cases of high intelligence being linked to traits involved in mental instability.

            We also need to consider animals like crocodiles or turtles that have many young that grow quickly initially, slowly later, but never stop growing. They have high predation initially, but low predation above a certain size. Is this simply because they can’t get enough food to maintain early growth rates, or do they downregulate mTOR regardless of calorie input? Again, not that difficult an experiment to do…

          • Every species has its own unique characteristics. Turtles/Tortoises have shell and grow extremely slowly. Crocodiles, depending on variety, do also grow and mature later. During the first three to four years, the young increase in length by about 30 cm per year. The growth rate then gradually decreases, but growth can continue throughout life. Sexual maturity occurs at about age 10 and at a body length of about 1.5–3 metres. In addition to that, keep in mind, that aging in terrestrial mammals is very different from other vertebrates such as fish, reptiles and amphibians which all have negligible senescence. Humans have a very high degree of senescence compared to even most terrestrial mammals regarding the percent of lifespan spend in the stage of senescence. To understand senescence in terrestrial mammals one must go back 180 million years to the development of mammals. Fish had negligible senescence and gave rise to amphibians with negligible senescence which gave rise to mammals. 180 million years ago and for the first 120 million years of existence of mammals, the earth was dominated by reptiles, in particular dinosaurs. Mammals were under heavy evolutionary pressure to adapt to a challenging environment. The answer found by terrestrial mammals was faster aging(once again, depending on the environment, gain or losses). The purpose of aging was to increase adaptation in the evolution of new and improved genetic controlled traits.

  24. @ Gregory Wilkinson. Captcha won’t let me respond to your post (too old), but the following is what I would have said:

    I am confused. Josh says that Harold confirmed that it is the heaviest proteins that are in E5. You interpret the patent as excluding proteins >65kD. Perhaps E5 is the excluded portion?

    Akshay mentions Nrf2. My google search says the human form has a molecular weight of 67.7 kD.

Leave a Reply

Your email address will not be published. Required fields are marked *