Tantalizing link between microbiota activity and epigenetics reprogramming (such as histones modification and DNA methylation, likely non coincidentally a marker of biological age) in particular mediated by butyrate anti inflammatory and NF-kB inhibition activity:
"However, some of the molecular mechanisms involved in microbiota-dependent modification of histones are beginning to be elucidated. As an HDAC inhibitor, butyrate exerts anti-inflammatory activity by suppressing NF-kB and STAT1 activation (27). In addition, butyrate-induced differentiation of colonic Treg cells (Fig. 1) through enhanced histone H3 acetylation in the promoter and conserved regions of the Foxp3 locus (28). Although butyrate-induced histone hyper acetylation leads to cell differentiation and inhibits proliferation of tumour cells, butyrate’s role in tumourigenesis is still controversial (29). Hu et al., (30) found that butyrate appeared to function as a tumour suppressor and could decrease colon cancer cell proliferation and stimulate apoptosis through inhibition of miR-92a transcription. These relationships suggest that the consumption of dietary fibre or colonization of the gut by a butyrate-producing bacterium might protect against colorectal cancer. Other studies have shown that butyrate accumulates in tumour cells and acted as an HDAC inhibitor to decrease cell proliferation and stimulate apoptosis due to the Warburg effect (26). In contrast, in genetically modified animals, butyrate supplementation promoted hyper proliferation of colon epithelial
cells that appears to promote carcinogenesis (31). These seemingly contradictory results might result from the different genetic backgrounds of the mice, differences in microbial composition of animal facilities involved and different mechanisms involved in colon carcinogenesis (29)."
Qin Y, Wade PA. Crosstalk between the microbiome and epigenome: messages from bugs. J Biochem. 2018;163(2):105-112.
Yes Bryan, have seen that and wonder about the DNA methylation (e.g. measured by the Horvath clock). It looks closely related to so many morbidity phenotypes that you might wonder about a putative causative role in aging. Hence even more the importance of the reprogramming which might reverse it.
Yes Bryan, have seen that and wonder about the DNA methylation (e.g. measured by the Horvath clock). It looks closely related to so many morbidity phenotypes that you might wonder about a putative causative role in aging. Hence even more the importance of the reprogramming which might reverse it.
albedo, glad to see you still hanging about watching this emerging research.
The role of DNA methylation in ageing and cancer is being confirmed in study after study.
This will prove to be an important development as varied rejuvenation techniques are investigated. It provides a metric to help guide research thru short-term trials. Researchers now don't have to wait to follow an organism thru its entire lifespan to see if a certain compound is having the desired effect.
You have to consider with partial reprograming thru OSKM, there are so many methylation sites unnecessarily involved, do we need to reset all methylation sites, is this necessary or wise? Concider the distinct differences in the male and female epigenome where one X chromosome is silenced. Reprogramming all female somatic cells to iPSCs induces the reactivation of the inactive X chromosome. What are the consequences of indiscriminately reactivating silenced methylation sites?
Let's also consider learned immunity or other sites concerned with environmental adaptation? Scientists have observed epigenetic memories being passed down for 14 generations. Do we risk wiping out adaptations and characteristics passed down along our families germline? Will we invoke allergies to substances we've grown accustomed? Also what about your microbiome, which his friend which is foe? There is a lot of research to be done before we can be assured a particular method will do no harm.
OSKM just opened the door. Let consider other tools now being developed such as "Engineered epigenome editing proteins" that can be used to study mechanisms of epigenetic regulation and the contributions of gene regulation to cellular function and disease. Researchers have identified Programmable DNA-binding domains. What we are seeing is the rapid and widespread application of designer epigenome editing proteins. This necessitates further study of the specificity of these tools for binding target sequences, modulating transcription, and altering chromatin structure.
So I see a convergence of tools that make this the most interesting area of medical research into longevity and the amelioration of genetically influenced disease. I think as researchers focus in on specific disease states methylation markers will be correlated to these conditions. Certain sites will be identified as upstream effectors and others as their downstream consequences. So we are talking about new approaches to specific diseases and medicins tailored to correct certain health issues. We are also talking about rejuvenating an entire organism but this involves far greater risk across many different tissue types and research to chart the path.
Why make permanent changes to the DNA when spcific regions can be turned on or off to affect change.
So the techniques used in the Horvath clock, insights derived from the partial reprogramming thru OSKM and Engineered epigenome editing proteins will be combined. Methods tailored together to monitor and treat disease states as the epigenome is mapped and explored.
This topic of research is going to explode. The tools necessary to its development have arrived to separate the wheat from the chaff.
So I see a convergence of tools that make this the most interesting area of medical research into longevity and the amelioration of genetically influenced disease. I think as researchers focus in on specific disease states methylation markers will be correlated to these conditions. Certain sites will be identified as upstream effectors and others as their downstream consequences. So we are talking about new approaches to specific diseases and medicins tailored to correct certain health issues. We are also talking about rejuvenating an entire organism but this involves far greater risk across many different tissue types and research to chart the path. ....
Thank you Bryan, I need to look carefully to your post which looks full of insight. You are on top of these matters since much longer than me.
Sorry to cut badly through it but for the time being I saw your last comment particularly well aligned with my feeling and a post of Josh Mitteldorf (pretty sure you follow his blog too, he his always very insightful, do you?) who says:
"...Second, there is evidence and theory to support the idea that the methylation sites that Horvath identified are not just markers of aging but causes of aging. That means that if we can figure out how to get inside the cell nucleus and re-configure the methylation patterns on the chromosomes, we should be able to address a root cause of aging. (Before we get too excited: “Gene therapy” has been around 20 years but is still in a developmental stage; “epigenetic therapy” is what we need, and it does not yet exist, but is technically feasible using genetically engineered viruses and CRISPR.)..."
and a bit below he posts this picture matching the part on diseases of your post:
He talked about his original epigenetic clock (DNA methylation), Levine's clock (DNAMm PhenoAge) and a very interesting link to genetics in particular regarding telomere lenghts and TERT. He also mentions very shortly the Yamanaka OSKM factors at min 20:45.
He talked about his original epigenetic clock (DNA methylation), Levine's clock (DNAMm PhenoAge) and a very interesting link to genetics in particular regarding telomere lenghts and TERT. He also mentions very shortly the Yamanaka OSKM factors at min 20:45.
albedo, Strange I dont see more interest here. It appears to be coming together on a number of fronts and this might take us into some unexpected areas needing further research.
I mentioned Learned immunity, but I think we might need to observe more than immunity.
This is very preliminary and needs more research. So a word of caution as we talk about rebooting our cellular clock to live longer. If we cease to remember who we are with resetting our epigenetic markers we might need to get very specific with our targets.
Good point Bryan, I also expect implications in neurosciences, philosophy of self and identity, and if I stretch a (large) bit even back up solution as cryonics and mind upload but I am going off topic.
Isn't there also an important question about the purpose(s) in the configurations of the epigenetic clock? For example if the nature of the clock is a strong driving factor for aging then resetting it would reset the aging process, but if the nature of the clock is to compensate for the reductions of some biological capacity/integrity then resetting it would only disrupt a beneficial type of algorithm that adjusts according to it's own current capacity.
It's possible that it reacts to small damages on the epigenome and genome itself, and is being repaired during the resetting phase in which case the reprogramming factors would go a long way to extend lifespan.
Isn't there also an important question about the purpose(s) in the configurations of the epigenetic clock? For example if the nature of the clock is a strong driving factor for aging then resetting it would reset the aging process, but if the nature of the clock is to compensate for the reductions of some biological capacity/integrity then resetting it would only disrupt a beneficial type of algorithm that adjusts according to it's own current capacity.
It's possible that it reacts to small damages on the epigenome and genome itself, and is being repaired during the resetting phase in which case the reprogramming factors would go a long way to extend lifespan.
There are several theories on aging, but I tend to think our epigenetic "programming" is meant to bring our bodies to maturity for reproduction. The cellular maintenance and growth are very energy intensive, but the entire process is there to support our germ cells. So from that idea, I tend to think of the rest of the body as a host for the "germ cells." The host side of the equation finds nutrients, defends and protects itself, and supports the germ cells through the maturation stage. If it's successful it finds a mate and reproduces. Once this happens, the combined epigenetic inheritance from the parents is passed on to the child. Now once reproduction takes place, this is as far as evolution supports us. The host portion of our being has served its purpose, and there is a slow degradation of the supporting cellular structure until death. This is the protion of the process we're discussing here on this topic. I don't think of aging as programmed. I don't think there's an evolutionary advantage to longevity once the germ cells have played their role.
Agree with Harkijn. It is complex and I tend to contribute only when feeling something useful or with a discovery.
Wrt the last post by Bryan, I liked it and envy people on top of this, having an opinion on one of the many aging theories out there. I did not study this much and got confused all the times with the various "mutation accumulation", "antagonistic pleiotropy", "disposable soma" (sounds a bit as Bryan's last post), "programmed aging" theories starting now to be a bit old. Even with the more recent ones I feel each one looks reasonable at first sight but generates controversy and is "disproved" by another one (sometimes only on theoretical arguments) looking even more reasonable only to get the same destiny a bit later. I am a physicist and I try to look at experimental verification but also there I see lot of disagreement: biology is humongously complex!
Putting theories aside, I must admit, according to my very limited understanding of what they say, the SENS strategy, focusing to repair rather than interfering with metabolism and maybe (do they really say that?) not fully understanding the underlying mechanisms, is quite appealing. At the end of the day, I can leave to experts to agree on solving the problem of what aging is or is not but if I buy more time to my life without disease and go on like that, who cares? Progress is being made though and the recent work by Lopez-Otin et al on the hallmarks of aging , while sounds to me lot like SENS, in that it limits the focus areas and addresses the details of metabolism, was a revelation to me, with the reprogramming, regeneration, OSKM and epigenetics fitting well the "stem cells exhaustion" and "epigenetic alterations" boxes:
This is a great follow-up study. There have been recent musings about the supposed inverse relationship between telomere length and epigenetic aging as measured by Horvath's clock. If you combine this study with the original one, and Blasco's follow-up study on telomeres, it appears that this may not be an issue.
In other words, all of the potential rejuvenation therapies based on the Hallmarks are moving in the same direction. And furthermore, it's becoming clear that epigenetic reprogramming like this is at the very top of the hierarchy. Changing this one hallmark would likely radically change most/all of the others as well. Sounds tantalizingly close to a magic bullet. That and the fears of cancer have been somewhat allayed, at least for now.
A proper delivery mechanisms is probably not coming anytime soon, which is unfortunate. That may be one reason this isn't getting the attention it deserves. It is probably more powerful and relevant than any other possible intervention, but it seems like it's a ways off, which dampens enthusiasm here. Compare that with senolytics, which are becoming highly actionable and therefore immensely popular.
OP2040, for my understanding, is this the Blasco's follow-up study on telomeres you mention in your post?
Common Telomere Changes during In Vivo Reprogramming and Early Stages of Tumorigenesis.
There are several theories on aging, but I tend to think our epigenetic "programming" is meant to bring our bodies to maturity for reproduction. The cellular maintenance and growth are very energy intensive, but the entire process is there to support our germ cells. So from that idea, I tend to think of the rest of the body as a host for the "germ cells." The host side of the equation finds nutrients, defends and protects itself, and supports the germ cells through the maturation stage. If it's successful it finds a mate and reproduces. Once this happens, the combined epigenetic inheritance from the parents is passed on to the child. Now once reproduction takes place, this is as far as evolution supports us. The host portion of our being has served its purpose, and there is a slow degradation of the supporting cellular structure until death. This is the protion of the process we're discussing here on this topic. I don't think of aging as programmed. I don't think there's an evolutionary advantage to longevity once the germ cells have played their role.
JMHO
Bryan
I am sorry but I really cannot get it and it adds to my confusion, I mean how can we not at least suggest a kind of programmed theory of aging as epigenetics reprogramming looks now a given. At the end, doesn’t a reprogramming presuppose a program? It looks to me that the original paper posted by the OP supports somehow a programmed theory of aging and an epigenetics master regulation of it which can be later in development reset by OSKM induction (see bold below):
“…Reprogramming, currently an experimental tool to study development and cellular differentiation, may provide additional insights into the mechanisms of aging. Proposed drivers of physiological aging include the accumulation of DNA damage, increased ROS production, telomere shortening, cellular senescence, and defects in nuclear envelope architecture … Multiple studies using animal models have demonstrated that the manipulation of these aging drivers leads to the manifestation of molecular hallmarks of aging that are shared between premature aging models and physiological aging …We hypothesize that the emergence of these molecular hallmarks during organismal aging results from the translation of aging signals by a unique and universal epigenetic program.Our results suggest that this epigenetic program, which is reset during embryogenesis, can also be experimentally altered by partial cellular reprogramming at later stages of life. Resetting of the aging clock by epigenetic reprogramming, which is also observed during somatic nuclear transfer, might allow for a deeper understanding of the molecular and cellular mechanisms underlying the aging process. Eventually, it may, as well, lead to the development of therapeutic strategies …”
That is indeed the study. It shows that the reprogramming does indeed restore telomere length. And this to me shows that there is no contradiction in the science between telomeres and epigenetics.
The apparent contradiction is fostered by people who have pet theories and like to use math, statistics, databases and population studies to determine what causes aging. While there is nothing wrong with that approach per se, it should always have to change when a good empirical study comes out. This is now what has happened. The study clearly shows reversal of epigenetics aging and reversal of telomere shortening, so there can be no contradiction.
I totally get the confusion because people seem to be using different terms when they refer to "epigenetic" aging. Some will insist that the actual methylation patterns are what matters, while others will take a broader approach based on the cell as a whole. I prefer this latter method, because as I said, I don't necessarily trust huge databases and statistical analyses claiming to accurately represent reality. As a database admin myself, I can tell you that the old saying still applies "garbage in, garbage out". I'm really surprised that people take things like "phenoage", GWAS studies, etc. so seriously. The best way to use such evidence is for guiding clues rather than anything definitive.
I'm a huge fan of the "Halmarks of Aging", mainly because all it does is build some good theory based on years of empirical research. It ends up being simple, clear, concise and yet profound, which is what most scientists claim to want. There hallmarks are interconnected, progressive, and most importantly, non-contradictory. I'm fairly convinced that once some forward-thinking lab starts experimenting with more than one of these hallmarks at one time, they are going to make dramatic progress very quickly. There could be a higher-up, programmed, simpler intervention, like the hypothalamus, for example. But getting it down to 9 things, all of which we can manipulated in mice, and all of which show great anti-aging effects, is a great place to be.
Programmed vs. Non-Programmed Aging Theory Controversy
OK guys lets see what I can put together in a few minutes and keep it within this topic.
This is a hotly debated topic and why I posted it as an opinion. Epigenetics represent the most malleable part of our genetics. Here’s the basis, when we discuss evolution were talking about passing on superior traits to our offspring which brings about increased survivability. Strictly speaking we are talking about, conception, gestation as well as post birth to reproductive maturity. But following maturity as we get older errors can creep into our germ cells, so there is a limited shelf life we will live beyond.
If a epigenetic change is successful for the parent it can be conserved and eventually passed on to its offspring. Now I’m talking about epigenetic changes as opposed to DNA mutation. Mutation is likely the wrong term to throw around. We already have many survival traits that are dormant until needed. Epigenetic changes are likely more common than DNA mutation at adding adaptive advantage because its already in the tool box. On the other hand DNA mutation is closely watched and from a maintenance standpoint and our germ cells likely will go through Apoptosis before conception can take place. Then as a further filter during gestation where a still or naturally aborted birth could take place depending on the nature of the DNA mutation.
So we might look at this whole topic as DNA and as mutations but one is change to the DNA code and the other is what part of the DNA to read or silence. In fact mutated DNA can be silenced through the epigenome as a protective measure.
From a germ cell line perspective maintaining the fidelity of the DNA is paramount for a species. Germ lines express near perfect DNA maintenance, one of the few tissues to undergo such scrutiny. Germ cells have little else to do, this is their role. Apoptosis is a critical process for regulating both the size and the “quality” of the male and female germ lines.
“Natural selection is not expected to have produced the best genetic stability available in the human body, merely the best compromise of DNA repair and costs. Repair and maintenance of the vast human genome is thermodynamically expensive, and an optimal balance between DNA repair and dietary needs is likely to have originated.”
It is estimated that more than 99% of the germ cells generated during ovarian development are lost through mechanisms involving apoptosis.
Using a mathematical model and data from 325 women, the researchers found that the average woman is born with around 300,000 eggs and steadily loses them as she ages, with just 12 percent of those eggs remaining at the age of 30, and only 3 percent left by 40.
Human Ovarian Reserve from Conception to the Menopause
For instance lets look at a “conserved” adaptation that spans many spices. In difficult times with limited food resources we have “conserved” longevity genes that become active to bridge us to a time when food supplies increase to help support reproduction. This is already part of our toolkit. If a mutation adds nothing or is detrimental to the health of the offspring that trait eventually dies off. https://www.tandfonl...54.2015.1020276
Now in terms of longevity once Ovaries stop producing eggs that individual is no longer adding any advantage or disadvantage to any more offspring. Any epigenetic changes after the production of eggs stop is no longer passed down. In fact the older a female becomes the greater the risk of passing on some unwanted trait. The same can be said of male. There is a use by date and the older we become the higher the risk of errors. Prime age is around 20 for both sexes.
Advanced Maternal Age and Offspring Outcomes: Reproductive Aging and Counterbalancing Period Trends
Now my only point is from a epigenetic standpoint longevity traits are not necessarily selected for during reproduction unless the population is small enough and a long life added an advantage to the population. I believe Japan may fit this group. “Centenarians represent a rare phenotype appearing in roughly 10–20 per 100,000 persons in most industrialized countries but as high as 40–50 per 100,000 persons in Okinawa, Japan.” The numbers are small but still significant.
Genetic determinants of exceptional human longevity: insights from the Okinawa Centenarian Study
From a reproduction perspective the older the the “parent” the greater the risk of passing on a genetically born disease reducing the offsprings lifespan. By chance we may inherit an advantage that adds to longevity but right now its impossible to know before we enter Old age but that might be changing.
That bing said we are conducting a great experiment in Western cultures where women are having offspring later and later in life. This may eventually help select for women who’s germ cells do a better job of DNA maintenance into menopause. Or we may increase rates of disease. Like I said its a great experiment.
Like I began Epigenetics represents the most malleable part of our genetics. We can rewrite it with Non-Coding RNA
Well over my head to make a sensible comment but the more I read about the more I feel a programmed aging seems plausible. You rightly point to DNA mutation vs epigenetic changes. I discovered for example a Japanese study well contrasting these two aspects and reportedly supporting a “program”. Bringing some hope for a possible senior population intervention, the researchers show that defects in mitochondrial respiration are reversible by the epigenetic rejuvenation using the Yamanaka’s factors and they say:
“…We reprogrammed human fibroblast lines by generating iPSCs, and showed that the reprogramming of fibroblasts derived from elderly subjects restored age-associated respiration defects. Therefore, these age-associated phenotypes found in elderly fibroblasts are regulated reversibly and are similar to differentiation phenotypes in that both are controlled by epigenetic regulation, not by mutations in either nuclear or mtDNA. Given that human aging can be seen as a consequence of a programmed phenomenon, it is possible that epigenetic regulation also controls human aging…”
Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confers human age-associated mitochondrial respiration defects
Putting theories beside, such as mutation accumulation, programmed aging etc …, I am excited by this epigenetics rejuvenation stuff as proof of concepts are being made and DNA methylation offers now a mean to check reversal of the hallmarks in a gradual manner. The rejuvenation seems can be stopped before too late for cancer to start or reversal to embryonic status happens. For the body cells integration of the factors, I would guess the most advanced technology appearing vs the more conventional and existing ones such as viral vectors, will be CRISPR.
"The researchers then looked for genes that might be controlled epigenetically resulting in these age-associated mitochondrial defects. Two genes that regulate glycine production in mitochondria, CGAT and SHMT2, were found. The researchers showed that by changing the regulation of these genes, they could induce defects or restore mitochondrial function in the fibroblast cell lines. In a compelling finding, the addition of glycine for 10 days to the culture medium of the 97 year old fibroblast cell line restored its respiratory function. This suggests that glycine treatment can reverse the age-associated respiration defects in the elderly human fibroblasts."
I think they identified a part of the picture and proved we could reset mitochondrial function. This was a turning point for me and I have been watching with great interest since Hayashi's study.
On the programmed aging side, it looks to me like programming takes us thru maturity which is metabolically expensive. Then the body prepares for the long haul and begins to conserve resources but the metabolically expensive maintance of the germ cells continues. So strictly speaking as we age our total energy budget reduces as a long term strategy. See https://www.ncbi.nlm...les/PMC2880224/
"Physical activity energy expenditure also decreased, resulting in a decrease in total energy expenditure of 7.5% per decade for men and 6% per decade for women."
"The trade-off between survival and reproduction is the bedrock of the evolutionary theory of ageing."
Also "High-fidelity quality control that would reduce such errors to a negligible level is costly and these costs will compete with the costs of reproduction. Because resources are limited, and because extrinsic mortality will destroy even intrinsically immortal organisms, investing into error-proof somatic maintenance is wasteful and not an evolutionarily stable strategy. In this sense, the soma is disposable and investment into somatic maintenance has to be optimized to allow error-prone repair in order to invest the rest of the limited resources into reproduction"
From a cellular maintenance standpoint, there is only so much energy to go around. So from that viewpoint, I think from a programmed response some processes are given priority over others. I think this is where some cellular functions get compromised to maintain others.
So here's the kicker, from everything I'm digesting we appear to be slaves to our reproductive systems. This programing seems to dictate all else. From a cellular maintenance standpoint, our germ cells apear to be the most protected tissue in the body.
So what about free will, do I have a choice? I think this is where we as intelligent beings reject the idea that biological imperatives drive our lives. Its a humbling notion is what it is and we belive ourselves to be more.
I'm not offering any life answers here but on the epigenetic front; #1) I think there is a lesson to learn from germ cells, but I don't think its entirely transferable for our other tissues but may offer some mantinace and reprograming insights. #2) Long-lived species could provide some epigenetic strategies and ideas. 3) Cloned mammals could also provide epigenetic insights with one to one comparisons of epigenetic profiles at different ages.
Here was a pivotal study we posted in: Nicotinamide Riboside [Curated] and I rember you contributing on many such topics at that time.
The studies I've read on worms suggests once sexual maturity is reached the protective cellular mechanisms along with growth begins to ramp down. Its more like throttling down systems to protect resources for the long haul. They mention a genetic switch is flipped. The more I read the more I think of us more as vehicles to protect and feed our germ cells because thats where our immortality resides. Within us resides a cell line going back millions of years. Now if generations of women had children later and later in life this would make a difference. Studies on short lived insects and mammals have demonstrated this principal. With women waiting later in life to have children because of careers in western nations this may already be happening.
The theories are fascinating to discuss. BUT, I think we're at a point where it will hold us back to keep talking so much about which theory is correct or not. We have a target rich environment, and what holds us back more than anything else by far is the lack of effective delivery mechanisms. If we could deliver some of these things effectively, we would know immediately whether they work or now. The epigenetic hallmark is probably the single most important one, but has no good delivery mechanism. There are a very few substances (like butyrate) that seem to effect one epigenetic pathway or another, but that just isn't good enough.
The real question is how can we deliver partial reprogramming in an effective, controllable and specific way to human subjects. More mouse studies should be done for sure, but it's very far from translatable, unlike some of the other hallmarks. I personally would like to see the nano-transfection idea applied to partial reprogramming of a specific tissue. If could easily be done for a patch of skin in vivo right now, thus offering a proof of concept. However, I'm not sure how they made the chip used in that study, nor if you could just use the studies supplementary material and have the chip made for you. But once you possess the chip and the factors, it would be a really easy intervention to try. And lets say it worked, you then have that proof you can show people that will convince many that rejuvenation is a real possibility and we should get things moving fast. Anybody willing to work with me on this?
BUT, I think we're at a point where it will hold us back to keep talking so much about which theory is correct or not. We have a target rich environment
I agree we do have a target rich environment but its so vast as to make your head spin.
Finding the epigenetic targets is where we are at, and there is a lot of research in this realm, and still, a lot of ground to cover. So we are very much still in the question stage as opposed to the application stage.
In Vetro experiments are the most cost-effective at this juncture. Whole organism testing is at the root of this forum and the tools to do this and the measurement testing to see the outcomes on relatively small timescales is here, but research isn't always linear: I believe two steps forward, one step back is warranted here.
The theories are fascinating to discuss for the simple reason they provide a framework for relevant, targeted research. Much of what supports our current theories is a chromatin change following sexual maturity. From a growth standpoint the subject organism must ramp back the growth, and cell proliferation and that growth cannot be left unabated. But what about the cost of maintaining DNA and epigenetic fidelity in the "mortal soma cells?" Does the maintenance of the soma also need to ramp back? What are the epigenetic differences between the 'mortal soma' and the 'immortal germ line?'
As suggested in some of my previous posts a strategy balancing costs and rewards for the host organism follows sexual maturity. There must be certain consequences for the continued high maintenance of these "mortal soma cells" evolved over countless generations. As far as theories I believe aging is an evolutionary oversight let me explain.
George Williams proposed the theory of antagonistic pleiotropy, which operates on the principle of "benefit now, pay later." Mainly, the idea goes that evolution would select for genes that improve an individual's reproductive success in youth, and ignore any negative repercussions later in life because the genes have already been passed onto the next generation. https://www.scienced...stic-pleiotropy
On the research side here is a passage that caught my eye. "Epigenomic and transcriptomic landscapes could easily distinguish between ages, and machine learning analysis showed that specific epigenomic states could predict transcriptional changes during aging. Analysis of datasets from all tissues identified recurrent age-related chromatin and transcriptional changes in key processes, including the upregulation of immune system response pathways such as the interferon signaling pathway."
I think with a landscape this broad a machine learning approach is the only way to interpret cause and effect changes. Where do the upstream modifications occur? And are the downstream modifications just a consequence?
So as I wrap up this post nature already knows a thing or two about immortality. Our children are living examples. Much of the bacteria around us also share this state. There are also many examples of multicellular creatures we can learn from who are either immortal or very long lived. For adult Humans our germ cells are examples, but this does not extend to our "mortal soma cells" which follow the principal of the Hayflick limit.
So before I undergo, In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming, I think I want specific as opposed to general epigenetic targeting and research will illuminate that path.
Thanks for reeling me back in Bryan, I'm just an impatient person by nature. I read the scholarly news every day, and from that perspective things seem very slow. But if I think of how much has happened in the last few years alone, I have to say progress is happening extremely fast, at least on the scientific level. Maybe not nearly so much on the clinical level, which is where the frustration and impatience comes into play.
I agree that the epigenetics of aging is a really big deal. We've all been around for senolytics and telomeres and other advances. But this one seems much bigger. At t he very least, I think it supersedes and seems to rectify a number of the other hallmarks, and so it may be much closer to that magic bullet we all want.
I'm calling it right now that some day, he will get a nobel prize.
The delivery problem is the second big thing that is holding back progress. Most likely if we could deliver interventions to the body with specificity and ease, some of the terrible diseases of aging would already be pretty well tamed. In this case, now we have Crispr with no DNA damage, curing a number of diseases in mice, epigenetically. The history books may just as easily write "in vivo" or "epigenetic' revolution after all this plays out.
The delivery problem is the second big thing that is holding back progress.
There is a hierarchy built into our epigenome that we do not fully understand yet, the Yamanaka factors IMHO are a broad blanket approach. As I mentioned with the "In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming" study, they used a technique analogous to that of a hammer when a targeted approach would be better. I do not diminish the results of this study because it achieved exactly what it was designed to do and we all sit here waiting to see what results will come next.
You mention the "delivery system" which is a good point. If anyone missed this, researchers used a drug-inducible transgene in this experiment.
"To enable inducible expression of the Yamanaka factors upon doxycycline treatment, LAKI mice were crossed to mice carrying an OSKM polycystronic cassette (4F) and a rtTA trans-activator (Carey et al., 2010), thereby generating LAKI 4F mice. The fact that reprogramming proceeds in a stepwise manner allows for the induction of partial reprogramming without the complete loss of cellular identity by short exposure to the Yamanaka factors (Kurian et al., 2013). Partial reprogramming could potentially erase or delay the accumulation of aging phenotypes without leading to tumor formation."
The application of doxycycline activated the transgene.
Induction of OSKM was performed by administration of doxycycline (1 mg/ml) (Sigma) in the drinking water. The in vivo cyclic induction protocol consisted of 2 days of doxycycline administration followed by 5 days of doxycycline withdrawal. For lifespan experiments, cyclic doxycycline administration started at 8 weeks of age and continued until death. For beta cell ablation experiments, 12-month old WT 4F mice were subjected to 3 cycles of 2 days of doxycycline administration in drinking water at a concentration of 0.5 mg/ml. For muscle injury experiments, cyclic expression of OSKM was induced in the TA muscle by a weekly intramuscular injection of 30 μL of doxycycline (1 mg/ml) prepared in PBS during the course of 3 weeks."
There are a host of delivery methods in development, "In Vivo Target Gene Activation via CRISPR/Cas9-Mediated Trans-epigenetic Modulation" is one but I agree this area will hold us back. Having said that we still do not have enough information yet to know what we need to do. I hope that as as the epigenetic research delivers the right answers on that front, the delivery methods will have advanced and be ready as well.
Many projects are taking this research into Partial Reprogramming further. See In vivo reprogramming drives Kras-induced cancer development I think this study was important in showing an oncogene could be activated through this method. Keep in mind these were a group of mice with this tendency. When mutated, oncogenes have the potential to cause healthy cells to become cancerous.
The real question is how can we deliver partial reprogramming in an effective, controllable and specific way to human subjects. More mouse studies should be done for sure, but it's very far from translatable, unlike some of the other hallmarks. I personally would like to see the nano-transfection idea applied to partial reprogramming of a specific tissue. If could easily be done for a patch of skin in vivo right now, thus offering a proof of concept. However, I'm not sure how they made the chip used in that study, nor if you could just use the studies supplementary material and have the chip made for you. But once you possess the chip and the factors, it would be a really easy intervention to try. And lets say it worked, you then have that proof you can show people that will convince many that rejuvenation is a real possibility and we should get things moving fast. Anybody willing to work with me on this?
OP2040, I just wonder maybe you should contact the folks of Youthereum. They look to have a pragmatic outline of an R&D program and business model as well. You might find a way to collaborate. Maybe check with Yuri Deigin, I also wrote to them. Also refer to the various posts of Reason (I guess (?) aka Michael or Michael Rae here), also mentioning the parallel Open Longevity Initiative:
OP2040, I just wonder maybe you should contact the folks of Youthereum. They look to have a pragmatic outline of an R&D program and business model as well. You might find a way to collaborate. Maybe check with Yuri Deigin, I also wrote to them. Also refer to the various posts of Reason (I guess (?) aka Michael or Michael Rae here), also mentioning the parallel Open Longevity Initiative:
Thanks for taking the idea seriously. I'd love to get involved in that way, but I worry that I'll be wasting people's time. I'm all for the idea of "more shots on goal", and since Youthereum is probably doing some great work, I wouldn't want to distract them with these kinds of more radical ideas. I think this idea belongs more in a university setting than in a startup, and for all I know it's already being worked on.
I have a huge desire to be involved in a lot of these things because IMO, it's the next big thing, and also the best way to help ease the biggest cause of suffering in the world. Alas, I'm middle aged and frankly not sure if I'm intelligent enough to help on that level. But I'll say this, I'd rather be a janitor at a place like Youthereum than CEO of most companies.
it explains very well the positive results of epigenetic reprogramming on all but two (just not tested yet) hallmarks of aging,
much to my satisfaction, it contains a vision of what I expect a convergence between opposite theories (damage induced vs. programmed) which I also report below for reference,
it positions iPSC reprogramming vs. other longevity/rejuvenation technologies,
moving beyond the essentially cellular hallmarks of aging, it has an interesting future perspective on organoids, which I think hopefully calls for parallel paths of research and medical funding, bringing fast interventions on the market (and as side effect maybe settle down the endless discussion on theories),
it concludes: “We believe that as our understanding of aging become clearer, and hard evidence for age reversal becomes more prevalent, the dogma that aging is an immutable, irreversible process will be shattered. The field of medicine is fundamentally about challenging these limitations and revolutionizing the human condition. We believe the next revolution is upon us, as rejuvenation goes from mythology to gerontology.”
This is the part as per point 2:
“...The key concept this strategy has tapped into is the so‐called programmed aging hypothesis [45]. This idea holds that the aging phenotype is driven in large part by deterministic and programmed changes, and thus is reversible. At the cellular level, this directly points to changes in gene expression, which is reversible especially through the modes of epigenetic and nuclear lamina modifications. So if age is programmed, iPSC technology could possibly reprogram age—truly apt naming in hindsight. The dual theory is the damage‐induced aging hypothesis, which holds that aging is driven by the stochastic degradation of multiple cellular components. This damage is driven by environmental interactions as well as internal degradation as a result of metabolic processes [46]. We discussed manifestations of this in previous section, such as DNA damage, ROS damage, and proteotoxicity from accumulated macromolecules. Unlike programmed aging, the results of this damage are random and thus are not inherently reversible. iPSC reprogramming cannot directly oppose damage but it can help to mitigate some of this damage. As we have seen, it can boost expression for natural repair mechanisms, like homologous repair of DNA damage; it can promote the synthesis of new organelles. From an evolutionary perspective, the two hypotheses may be fundamentally linked. The continued accumulation of age‐related damage and the resulting loss in functionality may make retaining older individual less beneficial from a species‐level perspective. Older individuals would be less fit and less capable of performing their role in a communal society, more susceptible to and may further transmit pathogens, more likely to produce mutated or dysfunctional offspring, and still take up resources that could go to the younger generations. Thus, species may have evolved programmed mechanisms to further the decay with age and thus increase the mortality and clearing of the older individuals. This could explain why a natural rejuvenation exists but only occurs in the production of the next generation, instead of somehow being applied to retain the youthful phenotype [6], like in the case of mitochondrial biogenesis, and it can boost the clearing of damaged components by transiently increasing proteolytic activity…”
Thanks, that looks like a great read, and it definitely expresses my own view, though in a much more lucid and scientific way.
The path forward seems clear. It will be interesting to see what remains to be "fixed" after we can implement partial reprogramming, even for mice. My guess is that it will get us 90% where we want to go, but there will still be issues. I'm thinking those remaining issues might be with the following:
1. Cancer - Don't get me wrong, cancer would almost be abolished by partial reprogramming, but there's a reason that cancer is even a leading cause of death for children. Most cancers are age-related, but some are just "bugs" in the coding, so to speak.
2. Immune System - The thymus atrophies quite a bit before any obvious aging, so the decline of the immune system, may be another programmed pathway that is unrelated to aging itself.
3. ECM - Since partial reprogramming is a cell-based therapy, this is not directly addressed. The cells may work their magic and reconstitute the ecm, or we may need something like happens in embryogensis where there is a lysosomal switch that degrades the aged ecm.
Even with these caveats, I think partial reprogramming will give us our first true and consistent increases in max life and health spans. I will never understand why the folks who did the partial reprogramming paper killed the mice (not the progeroid ones) instead of seeing how long they might live.
I finally went through Bryan’s initial two large posts (here and here). So I learned about epigenetics in cancer, in DNA methylation profile, in memory and learning, in immunity and fully stand with his feeling of convergence. Let me also add here, linking to the memory and learning, also Alzheimer’s disease, just learned today (!) at a seminar at EPFL.
However, do not you have a feeling of somehow a dispersed effort? All of this not only is related to aging but might be caused by aging itself, recognized as a medical condition. With the due and huge respect for all these beautiful research results and great scientists, we are not there yet, IMHO. If the scientific community is likely close to this thinking, public is far from it. The in vivo amelioration of hallmarks and SENS are to my understanding the only two approaches addressing root causes and both are underfunded. Youthereum is desperately looking at funding an R&D epigenetics rejuvenation path to human trials and looks to have a concrete roadmap and business model. Similarly for SENS. These are complex matters and in that respect SENS approach might be more appealing to the public which understands more the damage repair aspect rather than epigenetics. I must admit I am torn as the single disease approach has the advantage that everyone agrees, it is less controversial and funding is easier to be found but might be going nowhere in the short term.
I am not a fan of SENS, though I understand if people want to go down that path. I give Aubrey all the credit for popularizing the anti-aging idea. But the Hallmarks are where it's at in terms of clarity and consistency. Although the damage theories do make some sense because there is damage, I think targeting them directly is silly and futile. Haven't we learned this from the Alzheimer's/Amyloid debacle? Bottom line is that damages are a hugely diverse set of downstream effects and they just aren't good candidates for targeting, no matter which theory you espouse.
The other salient fact about the current situation that I think everyone agrees on is that the science is moving rapidly forward, while politics and lack of will are holding us back. Although there has been some great legislation passed in the last couple years, we still aren't there yet.
Not yet listened to this presentation by Dr. Oliver Medvedik going deep in the "In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming" paper (1.5 hours). I just discovered it and wished to lot it here for the benefit of everyone:
Also tagged with one or more of these keywords: genes, genotype, yamanaka factors, partial reprogramming, epigenetics, stem cells, juan carlos izpisua belmonte
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