Dr. Aubrey de Grey cares more about me living then my parents do. Most of my family would try and have me cremated against my expressed wishes. That is sad. . .
The crossroad is at gene editing of both the genome and the mitochondria DNA with efforts like TALE and of course improving CRISPR to the point that it can remove mutations in vivo safely and systemically.
Great talk, To explain co-translational synthesis better you could say that the mRNA is targeting ribosomes on the surface of the mitochondria. I find it clarifies a few things and illustrates the process better. Thanks
Mr. de Grey, I appreciate your video! One question which I have not been able to resolve, however, is the following: does the ovum accumulate damage like all other cells in a female? If so, how is that damage not passed onto children? Let me elaborate. Every child is conceived of a sperm and an ovum. That ovum originated from an oocyte in the mother, which in turn descended from more general cells in the mother via mitosis. In the aging as damage theory, as I understand it, all cells are accumulating damage with time and especially with mitotic divisions. There is nuclear DNA damage from stochastic events such as UV radiation, free radicals, other chemical events and from errors in replication. There is proteomic damage, in the form of a build up of misfolded, mistranscribed, or mutated proteins which, in total, result in less function cell proteomic machinery than in youthful cells. There is an accumulation of intracellular aggregates in the lysosomes which the cell cannot break down. And, of course, there is an accumulation of genetic damage in the mitochondria. Presumably this is occurring system wide (though perhaps it is not), which would mean that it is occurring in the oocytes as well. Now, the oocytes may be in a quiescent state, but their activity presumably has not completely stopped (from my understanding, oocytes actually work quite hard to generate eggs with sufficient material to start a new organism). Perhaps they are receiving less damage, such as from mitosis, and perhaps they experience a reduced rate of metabolism and thus of protein aggregation, mitochondrial free radical production etc. But still, it seems that cellular damage must be occurring for them as well. And, from my reading, it sounds as though menopause and the increased incidence of genetic diseases is a result of cellular damage to oocytes. How then, I wonder, is it possible that these oocytes do not pass their cellular damage on to ova, then onto zygotes, and from there onto the next generation? Why don't we start life with the damaged mitochondria, lysosomal aggregates, and mangled proteomes of our mothers? From my reading, the information necessary to construct certain organelles, especially the ER, is contained within the organelles themselves, not in the DNA, meaning that one ER must be created from the division of another and cannot be spontaneously created from DNA in the way that viruses can create their coats just from proteins encoded within DNA. Thus, we acquire the ability to create ERs from the ER in the ova that our mothers pass onto us. Why do we not then have our mothers damaged ERs? It would seem like intergenerational aging, but I've never heard of any such thing beyond genetic mutations and, if it were occurring, then you would expect that all species experiencing it would die out after a few thousand generations at the very most. To me, it seems as though the only possibilities are 1. that cellular damage is not occurring in oocytes 2. that somewhere between oocyte and infant, all trace of cellular damage is lost or repaired, sufficiently so that hundreds of millions of generations of sexually reproducing individuals have existed on earth without any noticeable decline in the quality of mitochondria, proteomes, ERs, lysosomes etc. 3. That my understanding of sexual reproduction is faulty. Option 3 is certainly possible, but I've tried to do sufficient research. Option 1 seems unlikely though certainly worth exploring. Option two seems to be the most probable, and the most exciting in terms of implications: Most striking to me is the suggestion that, in general, our cells possess the means for full repair. Somewhere between the oocyte and the infant, the damage to mitochondria, to the proteome, to all other organelles, to the DNA--all is set back to a level that allows that infant to have just as much of a healthspan as the mother had. This appears to be the case even in instances where children are born to quite old mothers (who presumably have much more advanced damage to their oocytes than do young mothers). The only exception seems to be significant nuclear DNA damage in the form of extra chromosomes etc. Thinking just in terms of mitochondria, it seems that one possibility is that ova with mutant mitochondria cannot proliferate and die in the womb. But all oocytes must have at least some level of damage to their mitochondria, and if that were the case, unless it were repaired then you would expect the age of onset to decrease/rate of incidence to increase with each subsequent generation. Perhaps, while wild type mitochondria have a higher rate of mitophagy due to respiration, they also have a higher rate of replication than mutants. This would explain why fast dividing cells have lower rates of mutation as each division event favors the ratio of w.t. to mutated mitochondria. Zygotes are very fast dividing, and so perhaps this division is regenerative, diluting back out the accumulation of damage in the mother to reach an equilibrium between generations. Of course this is just a theory, and it only explains repair of mitochondrial damage. What about all of the other types of cellular damage? When is this repaired? Is it all at once in the formation of the ovum? Or is it a gradual process that occurs generation by generation in the developing blastocyst? The second question is, how does this happen, and could it be harnessed? This seems very relevant for any stem cell based therapy. With any therapy based on iPS, such as a new organ or heart cell regeneration, we most certainly would be bringing damaged cells back into our body and, though they could certainly be potent they would still be damaged and damaging. With ES, however, we could potentially be bringing undamaged cells into our body. Best of all would be if we could trigger this repair pathway in iPS and have cells from our own body that would avoid issues of rejection, without ethical concerns, that we could then reintroduce, and thus achieve full repair of critical tissues. I'm curious to hear your thoughts. Specifically, how is it that each new generation seems to be born without the damage of the mother, and how could this pertain to strategies for regeneration?
unassumption That's a hypothesis worth thinking about. It could be that in the older body there are cells good to go for another 100-200 years. Many defective cells overwhelms the body and the correct ones gets stressed out by the work load. There could be longevity super cells in there.
Regarding the allotopic approach (33m40s), on the After-On podcast Episode 31, Floyd Romesberg talks about how they're working on creating new base pairs and tRNA to make never before seen proteins! Perhaps the technology isn't limited to nuclear DNA applications? Regarding the 23m mark, where normal aging can be seen as a mosiac pattern of mutant mtDNA in muscle cells (1%).. and since they don't generate respiration/ROS, they don't get flagged by the mitophagy mechanism and continue to accumulate.. is it a different mechanism for cancer? i.e. do the mutant mtDNA that are thought to give rise to cancer, generate excess ROS which can cause damage to the nuclear dna in the absence of anti-oxidants? Or does the malfunctioning mitochondria in both aging and cancer exhibit the same properties?
Thanks Dr. de Grey a fan ... good root cause discussion, you sound like an engineer ... but hurry up ... 70 Going On 100 ... maybe 70 Going On 128 ... the HayFlick Limit ... or if a fan of Ray Kurzweil then this is all a Moot Point
You forget one thing ... Doctors of Medicine (PhD in medicine) only "Regurgitate" Doctors of Science (PhD in Science) ... medical doctors have no intrinsic value ... and are essentially useless without Doctors of Science ... 70 Going On 100
Dr. Aubrey de Grey cares more about me living then my parents do. Most of my family would try and have me cremated against my expressed wishes. That is sad. . .
The crossroad is at gene editing of both the genome and the mitochondria DNA with efforts like TALE and of course improving CRISPR to the point that it can remove mutations in vivo safely and systemically.
Great video, and looks like it was made inside of the SENS campus. :)
Great talk,
To explain co-translational synthesis better you could say that the mRNA is targeting ribosomes on the surface of the mitochondria. I find it clarifies a few things and illustrates the process better.
Thanks
What a strange history life on Earth has.
What a smart Dr!!! His beard is so cool!!
Thank you very much!!!
Good content but please, get a proper microphone for the recordings.
Thank you Aubrey. I appreciate the concrete information/lesson.
Great talk Dr.! hope can i meet you some day
Great information ! Thanks.
Thanks for the research.
i could not see the mitochondrial chart - is it my computer or bad photography?
audio is rubbish on my headphones, but squinting to hear, have asked friends to assist, cheers
The hydro phobic proteins can be attached to a catalyst protein.
Outstanding!
Extreme prefrontal cortex ratio detected.
What about things we can take to help with protection such as various antioxidants and Pyrroloquinoline quinone.
They do not reach the mitochondria...
How old is he now, and is his beard somehow linked to his health, like a modern Sampson, omgggg, MASTER'S RESEARCH ALERT!!!
Would an alternative be to find a substance that alerted the cell to the mutant mitochondria and rid the cell of them?
The substance that caused the mutations is ATP itself, the substance that biological organisms use as energy to do anything , you can't remove it
Can you use you tagging technique to send a Trosian horse to the bad mitochondria that signals the cell that it is defective?
Should be Aubrey de Pink
PLEASE HIRE ME! YOUR SENS NEEDS A PHD MATHEMATICIAN WHO SPECIALIZES IN DIFFERENTIAL ALGEBRA!
Mr. de Grey,
I appreciate your video!
One question which I have not been able to resolve, however, is the following: does the ovum accumulate damage like all other cells in a female? If so, how is that damage not passed onto children?
Let me elaborate.
Every child is conceived of a sperm and an ovum. That ovum originated from an oocyte in the mother, which in turn descended from more general cells in the mother via mitosis. In the aging as damage theory, as I understand it, all cells are accumulating damage with time and especially with mitotic divisions. There is nuclear DNA damage from stochastic events such as UV radiation, free radicals, other chemical events and from errors in replication. There is proteomic damage, in the form of a build up of misfolded, mistranscribed, or mutated proteins which, in total, result in less function cell proteomic machinery than in youthful cells. There is an accumulation of intracellular aggregates in the lysosomes which the cell cannot break down. And, of course, there is an accumulation of genetic damage in the mitochondria.
Presumably this is occurring system wide (though perhaps it is not), which would mean that it is occurring in the oocytes as well. Now, the oocytes may be in a quiescent state, but their activity presumably has not completely stopped (from my understanding, oocytes actually work quite hard to generate eggs with sufficient material to start a new organism). Perhaps they are receiving less damage, such as from mitosis, and perhaps they experience a reduced rate of metabolism and thus of protein aggregation, mitochondrial free radical production etc. But still, it seems that cellular damage must be occurring for them as well. And, from my reading, it sounds as though menopause and the increased incidence of genetic diseases is a result of cellular damage to oocytes.
How then, I wonder, is it possible that these oocytes do not pass their cellular damage on to ova, then onto zygotes, and from there onto the next generation? Why don't we start life with the damaged mitochondria, lysosomal aggregates, and mangled proteomes of our mothers? From my reading, the information necessary to construct certain organelles, especially the ER, is contained within the organelles themselves, not in the DNA, meaning that one ER must be created from the division of another and cannot be spontaneously created from DNA in the way that viruses can create their coats just from proteins encoded within DNA. Thus, we acquire the ability to create ERs from the ER in the ova that our mothers pass onto us. Why do we not then have our mothers damaged ERs? It would seem like intergenerational aging, but I've never heard of any such thing beyond genetic mutations and, if it were occurring, then you would expect that all species experiencing it would die out after a few thousand generations at the very most.
To me, it seems as though the only possibilities are 1. that cellular damage is not occurring in oocytes 2. that somewhere between oocyte and infant, all trace of cellular damage is lost or repaired, sufficiently so that hundreds of millions of generations of sexually reproducing individuals have existed on earth without any noticeable decline in the quality of mitochondria, proteomes, ERs, lysosomes etc. 3. That my understanding of sexual reproduction is faulty. Option 3 is certainly possible, but I've tried to do sufficient research. Option 1 seems unlikely though certainly worth exploring.
Option two seems to be the most probable, and the most exciting in terms of implications: Most striking to me is the suggestion that, in general, our cells possess the means for full repair. Somewhere between the oocyte and the infant, the damage to mitochondria, to the proteome, to all other organelles, to the DNA--all is set back to a level that allows that infant to have just as much of a healthspan as the mother had. This appears to be the case even in instances where children are born to quite old mothers (who presumably have much more advanced damage to their oocytes than do young mothers). The only exception seems to be significant nuclear DNA damage in the form of extra chromosomes etc.
Thinking just in terms of mitochondria, it seems that one possibility is that ova with mutant mitochondria cannot proliferate and die in the womb. But all oocytes must have at least some level of damage to their mitochondria, and if that were the case, unless it were repaired then you would expect the age of onset to decrease/rate of incidence to increase with each subsequent generation. Perhaps, while wild type mitochondria have a higher rate of mitophagy due to respiration, they also have a higher rate of replication than mutants. This would explain why fast dividing cells have lower rates of mutation as each division event favors the ratio of w.t. to mutated mitochondria. Zygotes are very fast dividing, and so perhaps this division is regenerative, diluting back out the accumulation of damage in the mother to reach an equilibrium between generations.
Of course this is just a theory, and it only explains repair of mitochondrial damage. What about all of the other types of cellular damage? When is this repaired? Is it all at once in the formation of the ovum? Or is it a gradual process that occurs generation by generation in the developing blastocyst? The second question is, how does this happen, and could it be harnessed? This seems very relevant for any stem cell based therapy. With any therapy based on iPS, such as a new organ or heart cell regeneration, we most certainly would be bringing damaged cells back into our body and, though they could certainly be potent they would still be damaged and damaging. With ES, however, we could potentially be bringing undamaged cells into our body. Best of all would be if we could trigger this repair pathway in iPS and have cells from our own body that would avoid issues of rejection, without ethical concerns, that we could then reintroduce, and thus achieve full repair of critical tissues.
I'm curious to hear your thoughts. Specifically, how is it that each new generation seems to be born without the damage of the mother, and how could this pertain to strategies for regeneration?
Read "Power, Sex, Suicide" by Nick Lane and you'll get all of your answers and more.
Shane Lofgren Cold the sperm play a part? That is something that is added to it. Sperm DNA needs to be young as well. There is a mystery here.
+Shane Lofgren
I'm guessing any egg that contained defective mitochondria would fail to develop into a healthy adult?
unassumption That's a hypothesis worth thinking about. It could be that in the older body there are cells good to go for another 100-200 years. Many defective cells overwhelms the body and the correct ones gets stressed out by the work load. There could be longevity super cells in there.
Regarding the allotopic approach (33m40s), on the After-On podcast Episode 31, Floyd Romesberg talks about how they're working on creating new base pairs and tRNA to make never before seen proteins! Perhaps the technology isn't limited to nuclear DNA applications?
Regarding the 23m mark, where normal aging can be seen as a mosiac pattern of mutant mtDNA in muscle cells (1%).. and since they don't generate respiration/ROS, they don't get flagged by the mitophagy mechanism and continue to accumulate.. is it a different mechanism for cancer? i.e. do the mutant mtDNA that are thought to give rise to cancer, generate excess ROS which can cause damage to the nuclear dna in the absence of anti-oxidants? Or does the malfunctioning mitochondria in both aging and cancer exhibit the same properties?
Denham Harman died after one year of filming this, at the age of 98
Thanks Dr. de Grey a fan ... good root cause discussion, you sound like an engineer ... but hurry up ...
70 Going On 100 ... maybe 70 Going On 128 ... the HayFlick Limit ... or if a fan of Ray Kurzweil then this is all a Moot Point
I and others feel your pain~!
How simple can the consciousness be broken down to fit some part of the living clones fresh brain waves
this was going on for 4 years ago..has anything happened?
GenSight Biologics just released data for ND4, SENS did ATP6 & ATP8.
so ridic he can't get more funding, step up peter thiel.
why is the cells in the gut lining the most rapidly dividing cells? because they are the first to eat of cause.
the rest of the body is a byproduct of there being excess food.
hmmmm why trust a Grey??? Dr. Aubrey the Grey... WOW
🤔👍
Aubrey you wanna end aging but your own face ain't aging too well.
Deep
Have a shave and a good night's sleep. It'll take 20 years off you ;)
That made me chuckle over my coffee this morning
How many very bad germs are in that beard ? Yuck.
Aubrey de Grey is not a medical doctor.. He's got a bog standard BA in IT/Computers... The guy's a complete nut.
Nick H a medical doctor? most medical doctors couldn't care less about ageing or doing anything about it
You forget one thing ... Doctors of Medicine (PhD in medicine) only "Regurgitate" Doctors of Science (PhD in Science) ... medical doctors have no intrinsic value ... and are essentially useless without Doctors of Science ...
70 Going On 100