Dr Sasi Senga - Reversing Time: The Hallmarks Of Ageing And Cancer In A Benjamin Button Paradigm

10:57AM Sep 2, 2024

Speakers:

Leslie Kenny

Keywords:

aging

epigenetic

factors

age

mutations

gene

hallmark

idea

body

cancer

years

skin

turn

cell

gastric cancers

terms

play

oxford

younger

methylation

Right. Very Good afternoon, everyone. I'm sashimi. Singh, I'm a neurosurgical oncologist by training. I trained at the Harvard Medical School, and I also run a program at Stanford, which is on molecular genetics, and currently I'm with the University of Oxford. So the hallmarks of aging and cancer is kind of a Benjamin Button, kind of a paradigm. If you haven't watched the movie Benjamin Button, it goes along Mark Twain's quote that you should start at the age of 80, like with the experience of an 80 year old, and then gradually grow younger, because as you age, you become smarter and know have a better sense of life. So the whole idea of my talk is, can you reverse aging? So happy birthday. You're all one year younger. So just to give you a brief history of aging and the quest for reversal, Oxford has two main strengths, one is the humanities division, and other is scientific division. Today it's more of scientific. So I just want to pitch in a bit of humanities as well. So to begin with, Shakespeare, in his act, you've seen seven beautifully described the whole idea of aging All the world's a stage, but do we actually need to age? So he concludes the seven stages of human aging, and say sansti, sans eyes sense taste and sense everything where Sans is without so you lose your teeth, lose your vision, lose your taste, and ultimately you end up in a duplicative state. But do we have to? And then there are, like, anti dilivian teams on Aging, such as back to the time of Adam and Noah, where they were like, supposedly lived up to 900 years or so, and those are myths, or it might be true. We never know. But then Alexander the Great and Deleon were like were searching for the fountain of youth, long before researchers now are looking for ways to reverse aging. So it has been a team that has been ongoing for quite some time, and Plato and Aristotle view aging as a disease, and some of the researchers, modern day researchers, now agree that aging is, in fact, a pathological condition, and there is still hope a Greek dramatist called Sophocles that was able to Live to 90 and most of his phenomenal books were written when he was about 80 years old, so there was not much of a cognitive decline. And still, he got to live till 90 and all the way back to southern India, wherein tirumulla Is the person who came up with most of the current yogic practices. And in his book called tiruvannam, so all sorts of yogic techniques that the yoga that you do is in one form or other can be related to this person. And what He also proposed is something called Kaya kalpa, wherein it's kalpa meaning transformation, and Kaya is of the body, so transforming the body towards a youthful state. And for this, he proposed, like medicinal herbs, pranayama, which is the breathing technique which you all tried to do every night. I think even after my talk, there is a great work so. And among all the things he proposed, he also proposed, like driving the vital energy towards the head. And by vital energy, he was referring to the semen. And if you fast forward in modern times, if you look at where spermidine was initially isolated, it was isolated from sperms, although you find it in whole wheat germ and all sorts of food, but then it was initially isolated from sperms, so there was kind of like a synchronization between the ideology. And if you look at the Dutch painter Rembrandt, he used to do self portraits of him every single year, and he himself has documented he was not very happy towards the end with the whole outcome of aging. And aging was again beautifully illustrated by Bertoni. You can find this in the National Gallery. And long before sunny did this whole idea of holistic well being, there was another person named tapasvi Maharaj, also known as aka Krishna Singh, was supposedly born in the 1770 and lived up to 185 years. Just phenomenal. Not sure how true it is, but that's why it's humanities. You should take it with a pinch of salt now to the side effect. So there's a guardian knot between the hallmarks of aging and the hallmarks of cancer. So these two are frameworks which are in place to distill the daunting complexity of these two pathological conditions, which has to overcome multiple roadblocks within the body in order to turn into overt pathological states.

To begin with, genomic instability is known hallmark of aging, as well as an hallmark of cancer. To keep it simple, if you play some kind of music, you know The first one is whole note, and then there's the quarter note. Eighth note and the 16th note. So similarly, you have nucleotide bases such as idenine, thymine, one and cytosine, and you need them to be played in a beautiful rhythm for your symphony of life to be pleasant. But then, if there are aberrations in such bases, such as with Msh too, which is a mismatch repair gene, which is the repair gene, it can it can lead to colorectal cancers and Braco, one mutation which is a tumor suppressor, something that suppresses tumors. If there's abrasion in it, it leads to triple negative breast cancers and KRAS and C mites, or bonafide oncogenes, which can lead to cancers. And just to give you a taste of genomic instability, check it. This is a beautiful day. It's sunny. If you just walk out in the sun, just for a few minutes, every time you expose your skin to the sun. Europe, there is something called CPG, ion and methylation, and there's a mutation that's happening, and your body has to clear those mutations. And even simple, in simple terms, like the Imagine your foot pipe. You take sections of your foot pipe, which your foot pipe in scientific term, it's esophagus. And if you take sections of it, and then you take such sections from healthy individuals, people who do not smoke, and like 20 year olds, 50 year olds and 70 year olds, and these circles or mutations that are accumulated in those foot pipe sections. And as you can see, in a 20 year old, they already have hundreds of mutations per cell, and in a 50 year old, it's 2000 mutations per cell. And by the time you reach 70, even if you did not smoke ever, you will have like 100,000 mutations per cell. This is just the way it is. And these just illustrate normal esophagus and barocene esophagus, which is a precursor of esophageal carcinoma. But why does our body do that? If you grab rich and Doc, in selfish gene, there's still this whole idea that the gene, the whole core aim of the gene, is to move to the next generation and for it to survive. Similarly, the cells have the notion that they have to survive rather than maintaining the genomic integrity, they do not go to the extent of spending so much energy into repairing the mutations. Rather, they just prefer to survive and proliferate. And this leads to two pathological conditions, one being aging, and the other being cancer. But then genomic instability is more of something that's set in stone. Specifically, if it's a germline mutation with somatic mutations, you can, like, meddle with the environmental factors and potentially alleviate them, as mentioned by nonsense two hit hypothesis. There is one hit which you are born with such genetic mutations, and you get a second hit through your enrollment. So you can, like try to avoid such environmental factors. But there is a cooler aspect, which is the next Hallmark, which is the epigenetic dysregulation Hallmark in terms of aging and carcinogenesis. So epigenetics, or changes in the gene expression without changing the underlying DNA sequence. I'm pretty sure you do not get that. But then, in simple terms, imagine you have a gramophone, and then the disc that you have is your DNA sequence, the adenine, thymine, guanine and cytosine that I mentioned, like the whole note, quarter note, eight note and 16 note that I mentioned. And the reader that you have in your gramophone is your epigenetics. It can literally play the exact right tune that needs to be played in a specific cell. For example, in your brain, it will play the tune of neurons in your heart, it will play the tune of cardiac mindsets in your liver, it will play the tune of hepatocytes. So it gets to decide whether gene gets turned on or off. And even in simpler terms, if you stretch your DNA in your cells, it can be as far as six feet long. And if you stretch all the DNA in all of your cells, it can be as long as 67 billion miles, which is almost equal into 150,000 zone trips to the moon. So when, when someone says, the next time someone says, love you to the moon and back, you literally mean it. If they love you with every single cell in the body. It means they can do 150,000 trips to them. That's how much they love you. So that's epigenetics in the very simple terms. And why it is cool, because epigenetics is reversible. So the way epigenetics happens is that there are these histone tails, and on these histone tails is where these modifications happen. So you have all these compactions within the cell. You have those DNA but then there's a small tail bit, which is called a histone tail, which pops up and on which all these chemical modifications happen. There's methylation, there's acetylation, but there are demethylation as well as deacetylation. Just by the term d, you can understand that the whole phenomenon is reversible, and that's where it plays a major role in aging. Stephen Horowitz came up with the whole idea that there is a way to estimate your epigenetic age, and he termed it as the epigenetic clock, and this is done by using DNA methylation on your. Cytosine region, not a T or G, but rather the cytosine region and estimate your epigenetic age. And this is not the age your chronological age, which is the number of times the earth revolved around the sun. No, it is actually your biological age which your which we are trying to focus and reverse. And with epigenetic clock, you can reverse it. And they are compared conditions such as progeria, which is a condition which disposes you to early, pre early onset aging. And they compared the DNA methylation of such patients with aged individuals. And what they found was striking similarities in the way the DNA methylation happened between these two codes and for reversing the epigenetic clocks. They have been trying multiple different methodologies and various research papers across the world, and one among them is alpha ketoglutarate, which is a supplement, and surely, by using it for seven months, they were able to reverse the whole epigenetic clock for a whole of eight years. So you get eight years younger just by alpha ketoglutarate supplement for seven months. And spermidine has also been shown to reverse such epigenetic clots, and they did mark some swaps. You can do this epigenetic aging detection based on blood as well as even something as simple as saliva, and you can get an estimate of what's your epigenetic age. I think Nicolina will be discussing more on the glycan age, which is another whole arena. And how does this whole idea of, how does spermidine can reverse your epigenetic age? I'm not going to delve into the finer details of this, but to keep it simple, you need Sam, something called Sam as adenosine. These are methyltransferase groups wherein, as you age, you need this DNA methyltransferases to be functioning properly so that it can turn off the genes that are not required. But as you age, such, DNA methyltransferase activity drastically declines, and as a result, some pro inflammatory genes can be demethylated. Demethylation means it turns on, and as it gets, turns on these this specific gene is also found in systemic lupus erythematosus, which is an autoinflammatory disease, and as a result, you get a whole phenotype of pro inflammatory condition. But with spermidine, it has been shown that it can enhance such DNA metal transfers activity even in fairly elderly people, and as a result, it can turn off all these genes that you do not wish to be turned on. And that's how epigenetic clock works. But then there's the question, Is your tissue? Does your tissue retain the whole idea of when it was younger, like, say, your liver tissue, does it have the information of when you were a 10 year old, so that we can tap into that system in order to revert you back to a youthful state? And this is where the whole concept of vaddington comes into play. 1957 Conrad vaddington proposed the unidirectional developmental model, wherein, in simple terms, imagine you roll a ball down a hill. It can only go one way. It can cannot go up. So similarly, what is mentioned was you have stem cells, and the stem cells will go on to a terminally differentiated state, but it cannot go back to a stem cell state. So once you are old, you cannot return back to your youthful state. Once the Dutch painter is old, he cannot revert back to a youthful state. This is the old idea of Farrington, but thanks to John B girdin and Yamanaka, John B Gurdon is someone who graduated from Oxford. Sadly, he left to the other place, but then what he did was perturbation of frogs Excel, but it still went on to develop into fully functional tablets. And based on this idea, Japanese surgeon, who gave up surgery and became a scientist called Yamanaka, came up with just four factors called ocfo, SOX, 2k, of four, which is scopal like factor four and semi. Just with these four factors, he was able to induce any of the cells in your body back to a pluricott and state so that you can change. Imagine, you take your skin cell, I can drive it into a pluripotent, a pluripotent state, and then I can change it into a bone cell. So that's that's fairly cool, and that's why they hold the Nobel Prize. So they defied the whole Vatican landscape and came up with the whole idea that the developmental model is bi directional, and the Dutch painter can go back to his youthful state, you know, to continue his brilliant paintings. So stemness is the hallmark that I would like to address. There is a bit of a catch in that realm of aging, lack of stemness, it meddles with your tissue repair and you age. Whereas in the realm of carcinogenesis, cancers essentially wounds that do not heal. And in 2021 I propose de differentiation and trans differentiation as hormone sub cancer. It is essentially becoming to more of a pluricotin state. But then the whole idea is that you have to drive it to be as terminal so that it can rejuvenate and repair your tissue. But you should not drive it all the way back. A pluripotency that it loses your cellular identity, and this is exactly what Simplot did. I had the opportunity of meeting him when he was back in Australia, and he with the use of just three of the Yamanaka factors, he excluded one of the Yamanaka factors because it's a bonafide oncogene, which being semi So with just three factors, he was able to restore vision in someone, in mice models of optic nerve injury, which was phenomenal, and he is in the attempt of trying to get it into clinical trials. This is just a pictorial representation of what he did. This, this, these are optic nerve with crush injury. And this specific aspects which have, which are in blue notes, the region where you crushed the optic nerve. And these are mice models, by the way, not humans. And then we introduced three of the Yamanaka factors, and viola, you get regeneration of the axons of the optic nerve. And the mice per capital of C, again, and it's not just in this condition. They also try to regenerate skin and administered to human being, humans as well, to a kid who suffered from epididymal scoliosis. It's complicated. So for those patients, it worked beautifully. And those kids usually die off way younger. But this, this specific kid, was able to survive till 15 years old. This happened in Italy, and these are humans. And the way it works is more complicated than just yamarica factors. It involves epigenetics as well, like Polycom repressive complex, histone, three lysine, 27 trimethylation, 1011, translocation enzyme. It's all foreign language. Let's skip that. So the next hallmark is the hallmark of altered microbial now, microorganisms have been on the planet for over 3.2 5 billion years, so it is inevitable for us to like guess that there is some kind of CO evolution going on between us and the microorganisms. For example, here, nearly half of the metabolites in your body is of microbial origin, and your metagenome is like at least 100 folds more than your own genome itself. This is an illustration from one of my books cancer, simply by the hallmarks. What I'm trying to depict here is vaginal microenvironment in healthy individuals, the vaginal microenvironment is in an acetic state thanks to lactobacillus, but due to dysbiosis of microbiome, they lose out on the lactobacillus population. And as a result, HPV infections, which is ideally spontaneously cleared, if your vaginal microenvironment is acid, does not get spontaneously clear. As a result, they go on to develop cervical cancers, and there is a way of caloric restriction which can ideally replace the lactobacill species that is missing. And the next bacteria that I'd like to introduce is hatch binary h pylori. Have has been like CO evolving with us for over 50,000 years, but all we read about h pylori is that it's linked to gastric cancers. But on the other hand, it has intubated, thus numerous other beneficial role to play. For example, it is protected against gastroesophageal reflex disease, esophagus carcinoma, multiple sclerosis. Multiple sclerosis is a big thing in the realm of dysbiosis of our microbiome, because there are multiple different microbial species that can protect you from multiple sclerosis, and then IBD, and it also has been shown to protect against asthma. But then, on the other hand, it has somehow changed into an agent which can drive 90% of gastric cancers. It is alluded to the fact that it is due to high per methylation, meaning the there is an increase, increased methylation in the promoter region of a repair gene, which is linked to gastric cancers and in the in the realm of aging, there was a very beautiful study called element study, wherein they looked at how healthy individuals like age, aging, individuals who are healthy versus aging, individuals Who are in a cognitive decline or frailty, there is starking difference in the kind of microbial composition that acre sets. So you are what you eat, if you look, if you delve deeper into A into this old aspect, what you eat affects 20 generations down from now. So it is, it is phenomenal, like what you eat and your microbial composition can have a very big say on how you age. And they also looked into picroso, and the levels indicated that individuals with higher levels add more of frailty and cognitive decline, whereas individuals who have more of indole, which is again a different metabolite, add better cognitive decapability Thanks to a receptor called AHR, which is a bacterial sensing mechanism, which we do not go into now. But then, with altered microbes, did they try to, like Nether with the microbe? And then, were they successful in reversing aging? And there are, like, multiple studies which proved that some of them very nice models, where they show. They can actually restore fertility in mice models as well as restore cognitive capability in mice models and humans. They selected obese individuals whose plasma cholesterol levels were stuck in high and they introduced oral administration of amesinophilia. And what they found was that they became suddenly, they became more sensitive to insulin, which is a good thing, and the total cholesterol levels were decreased. And are you actually blessed when someone sneezes on you?

What would you say, if I asked you during paddock it will pour a bucket full of sanitizer on me. What would you say? Are you blessed when someone sneezes on your face? Yes, no, you really show so is it a 32nd facial this is exactly what a team who published in Nature Communications did. They took the caucus species, three different streptococcus strengths, namely, pneumonia, infantile one, infantile two, and they applied to 22 participants on one side of the chip and the other side of the chip. They just left it as control. They did not apply any streptococcus. And what they found was quite striking. Like this, elasticity of the skin was drastically improved. The hydration of the skin was drastically improved. The desquamation was decreased, so it was all good for your skin, back to your first take. But then the catch is, you don't want that streptococcus to enter your nose. Once it gets to your nose, it gets to your lungs, then you end up in the a&e, and you have a Carpa triad, based on the current conditions we are in. But then, in the very same paper, they used spouting as well, and they showed all these factors were also significantly improved with the use of spermidine. And additionally, they showed that lipid barrier formation in your skin, which is quite critical for you to be remaining in a beautiful state, was also maintained like this is a young skin, and this is the older individual with spermidine, and their lipid bilayer were quite intact. The next Hallmark that I would like to introduce is the hallmark of inflammation. So in the realm of aging, it's called inflammaging, and in the realm of carcinogenesis, it's called tumor promoting inflammation. This is just an example of how inflammation can promote carcinogenesis. Again, with a convolution of microbiome. There is a fungal agent called Malaysia, which enters your pancreas via a sphincter of order, which is a sphincter which which is present between your gut and your pancreas. And once it enters the pancreas, it can trigger a complement cascade, leading to tumor, promoting inflammation, and this can be elevated just by the use of antifungal agents. And in terms of aging, we go on to look into different agents to, like, specifically address different aging symptoms. So do you think there is a systemic effect in the body? Is there a control center from where it turns on and then you're all aging them? So this is exactly what they looked into, and it was in the hypothalamus region of the brain wherein they found a hypothalamus as like dendrites which protrude across the blood brain barrier. Now you have the blood brain barrier in order for you to prevent like some adverse metabolites to reach in your brain, or infections to reach your brain. But then hypothalamus neurons have some some of the dentrites protrude across the globe brain barrier in order to sample what's happening in your body. And by sampling these whole inflammatory mediators in the body, it starts a whole feed forward cascade of aging, like it triggers NF kappa B signaling and then triggers tumor necro factor alpha signaling, which in turn again increases NF kappa B signaling. And then this decreases gonadotropin releasing hormone, which is just to make you flat out. But then it does a plethora of other factors as well. In terms of evolution, when you look at it, it's okay for you to lose out on GnRH, because you lose out on fertility if it's an adverse environment. But then it also does other factors, like cognitive decline, and in terms of your skin aging as well, it plays a role. As a result, you do not want your GNR levels to be decreased, so targeting the hypothalamus is an effective strategy in order to turn off your whole aspect of aging. And there is the specific population in Ecuador, all the way in Ecuador they are called larantite dwarfism. They are like shocked. So is it a good thing to be shocked? Do you age slowly if you're shocked? What's the question that these researchers were looking into? And what they found was that, indeed, in this specific population, they have very little IGF one and their sheer absence of diabetes, Alzheimer's, cancers, if you look at the survey results from the warning, these are the diseases that everyone was afraid of, and as a result, they lived longer. And these researchers have been looking into why this is happening, and they were like, join the palace with growth hormone release. Hormone. And they even tried to delete growth hormone releasing hormone genes, and they found that it increases longevity, but it was reversed after six weeks course of growth hormone injections. And similarly, they also looked into hypothalamus, but these are fairly early studies, but there is hope that if you can target the hypothalamus, then possibly it can work in your favor. And these subjects also show a lower insulin constellation and higher insulin sensitivity. And when their cells were stressed, instead of accumulating the mutation and surviving, they were capable of self destructing this nasal pathways I really don't want to go into, it's into immune mechanism, mTOR, which so well we'll get into, and then rastraf, Mac, ERG pathways, the one which is linked to carcinogenesis. And then we have postponed the phase C and PKC, which is linked to whenever you're hungry, it gets triggered. So based on a plethora of such pathways, seems the hypothalamus might play a role in aging, and this is the circle of life, thanks to spivaline, it influences a majority of the factors and can prevent aging. And this here is my mother. She developed triple negative breast cancer and had breast brain metastasis, and I was part of her brain surgery team. And this is the whole idea, why I do not want people to age. Why I consider aging as a disease? You do. I agree that life must have an end, but it should not be in a fragile state. It should not be in a debilitative state. It should be filled with youth and vigor, so that you get to achieve everything and enjoy with your friends, and then you pass away in like good health. And the whole idea is personalized your health anti aging strategy, as the Okinawa community says, ichariba Chori very what they literally mean is that, if you I meet you once, you're my friend for life, so spread good and have that social connections in your life. And then, as the Italians say and me, Amori ebikeri debino, non Continental, semai, which means year L, your age of the number of glasses of wine that you eat. And like, one more thing, Oh, I forgot my turn. I should start dating someone Italian. So, so all these three factors, like a age wine and the number of hours should not be counted. That's what the Italians say. So do meditate and do exercise and focus on your breath. That is your pranayama and spermadin plays a vital role in many of the factors which I alluded to earlier, and have strong social bonds and hearts. I cannot stress enough about arts. It's a whole big topic. Oxytocin gets released. Like, how long do you think you should have take a guess? Oh, she knows everything. So six seconds is the threshold. Anything longer is better. So you get oxytocin released, and there are a plethora of benefits with oxytocin, because your brain has oxytocin receptors, and it can share increase the cognitive capability, the gray matter volume of your brain increases just with hearts. And if you hug your partner and give a pet every single morning, whether you live leave for work, it increases your lifespan by 10 years based on one step. And it also makes it monogamous just three percentage of the mammals or monogamous, it increases your oxytocin receptor levels in your brain, which can make you monogamous. That's huge for you. And then look into sleep, to sleep well, so that your circadian clocks are up and going and eat less and periodically, if you think about it, 50 years ago, no one had a hot shower. It's a luxury. And then now you just turn it on and stand there, and you control the temperature of your environment, and you never go hungry. You keep eating. Oxford, we have three course dinners, and we have second desserts, so which is completely not okay. You should experience hunger in regular intervals, and you should experience cold weather if you want to stay younger and do eat your cruciferous vegetables. Okay, that's it. Sasha, thank you very much. You

thank you very much. So we were very lucky to have Sashi come today. He's our commonwealth and Clarendon scholar at the University of Oxford, but he operates, as I said, as a brain cancer surgeon, Monday through Saturday. So he's actually taken time off to be here with us today, and the picture of the mother that he showed you he operated on his mother getting tissue as a researcher. It's a very unusual thing, but we are really privileged to have him here today. So a round of applause. Applause.