• Log in with Facebook Log in with Twitter Log In with Google      Sign In    
  • Create Account
  LongeCity
              Advocacy & Research for Unlimited Lifespans


Adverts help to support the work of this non-profit organisation. To go ad-free join as a Member.


- - - - -

Paradigm Shifting - Out of Left Field


  • Please log in to reply
20 replies to this topic

#1

  • Lurker
  • 1

Posted 10 June 2004 - 08:54 AM


What a roller coaster ride! The dogma for many years was that the structure of the adult brain was relatively static throughout an individuals life - we were born with all the neurons we were going to have and the circuits those neurons formed during our childhood and teenage years were maintained till death.

Then in 1962 Altman demonstrated neurogenesis in the adult rodent brain. In 1964 Bennett demonstrated how environmental enrichment could increase cortical mass in the adult rodent brain. In 1969 Raisman demonstrated axonal plasticity in the adult rodent brain and in 1984 Purves showed dendritic plasticity in the adult rodent brain. In 1988 reservoirs of brain stem cells were found in the hippocampus and at the lateral brain ventricles. With the discovery of neural and glial progenitor stem cells one could state that the brain, barring any disease, was able to repair itself and maintain its capability to learn far into the twilight years.

Now a new discovery that looks at the regulation of genes associated with neurons in the brain sends us plummeting once more and raises new issues about cognitive competence - after the age of 40.

As per the CNN article Brain genes start to slow at 40 , (or for those with a full subscription to Nature see Gene regulation and DNA damage in the ageing human brain for the original research article) it has been shown that after the age of 40 a number of important cognitive function related genes start to malfunction.

Considering all of the other waning physiological functioning that occurs at or before this age, it should come as no surprise that cognitive performance is also affected. The diminishing returns on investment of exercise and dietary moderation are all too apparent as we get older, yet mental impairment is something we prefer not to, pardon the pun, think about. Yet as the above research so compellingly makes obvious it is something which is very real.

For those interested in the science of how this discovery was made, DNA microarray analysis methods were used to monitor the activity of approximately 460 age regulated genes in a group of 30 people with an age span from 26 to 104 years. It was found that after the age of 40, a number of genes associated with neuron function in the brain become down-regulated, in other words they either stopped or slowed down in their capacity to produce the proteins they encode. What is striking about this study is WHY they became down-regulated: accelerated DNA damage. To test if they could stop this DNA damage they cultured neuron cells that showed the same aging effect but inserted into these cells extra copies of a DNA repair gene, OGG1. Astonishingly, the cells with extra OGG1 did not show down-regulation and were able to maintain their pre-40 year old state.

Ok. So now we finally have empirical evidence. Life does not begin at 40. The brain begins to malfunction at 40 - due to ineffective DNA repair. This is scary. However, knowing why it happens provides us with vital clues on a therapeutic strategy. By increasing NER (nucleotide excision repair) function, using modern gene therapy techniques, DNA damage can be substantially reduced and gene regulation does not have to direct the cell to the aging pathway. The problem is that you wont get FDA approval for genetic therapies in seemingly healthy 40 plus year old brains just to maintain cognitive virility. But that's another story.

Back to scary. Not only is it scary for all those over 40 but for those under 40 as well - and not just because their own brain is getting older due to DNA damage. It has become indoctrinated across all cultures since time immemorial that the elderly were wise and thus became leaders or advisers of leaders. The definition of elderly 2000 years ago would be anyone over 35 (you could easily be a grandfather at 32 if your sired your first at 16). It made sense that an individual with a more extensive set of experiences would be more able to survive and be a superior leader than those with lesser experience.

These days however, thanks to some antibiotics and anti-inflammatories, we have pushed the numbers of those whose life-span exceeds 60 quite easily. Bearing in mind that at 40 the damage begins, can you imagine just how much damage has occurred to the brains of most individuals by this age? Its scary. Here's what even more scary. Actually the implications are terrifying. Do you know the age bracket of most individuals in positions of senior responsibility? Im talking about judges, senior medical doctors, politicians, etc... Do you know the average age of the supreme court justices? Would you like a biopsy of their brain so we can run a gene activity analysis? I sure would.

We are talking about competence, judgment and reasoning capacity. These are people that directly or indirectly will one day if they have not already, influence our lives. I'm not talking having your grandmother's sweet words of wisdom here. I'm talking about decisions being made everyday that require precision, competent analysis of all available information and objective consideration. These are being made by people with age-related, undiagnosed, and I will not mince words, age related brain damage!

Before you start laughing, have a think about it. If you wanted to hire someone to run as fast as possible you would not choose a 70 year old. So if you wanted to hire someone to think as sharply as possible you would not choose a 70 year old either.

To those over 40 out there... We will not always need to use a procedure as invasive as taking a biopsy to measure your neural gene regulation activity. The technology is already available to measure mRNA levels from a blood sample. Soon we should be able to measure neural genetic damage indirectly, say using methylation patterns in other cells derived from saliva, or from the DNA of hair or nail clippings. And I'm not kidding.

So, most venerable gentlemen... If you wish to keep your lofty positions in a near future of complete genetic regulation exclosure, it would be prudent to look at the benefits of NER, particularly OGG1.

How old is Rummy again? :)


Posted Image
Harold Brenner (prometheus)
Athens, Greece

Edited by prometheus, 21 June 2004 - 11:21 AM.


#2

  • Lurker
  • 0

Posted 10 June 2004 - 10:53 AM

This is probably a good reason to start taking antioxidants in your 20's. It won't stop all aging in the brain but it will mitigate the possible genetic damage (I assume) and slow the deterioration.

It seems you've suggested ways of repairing this damage, something I know nothing about, but as far as the FDA is concerned they are reaching a point where they decide whether they will approve drugs for anti-aging purposes. The FDA is not as concerned with improving people's lives through medicine if they are already the "healthy" for their age, they only seek to treat/cure diseases and other defects that prematurely end life or somehow decrease the quality of life prematurely.

#3

  • Lurker
  • 1

Posted 11 June 2004 - 04:06 AM

Problem is, that this is not about oxidants. DNA damage is caused by a whole lot more that just oxidative damage. We need to produce additional DNA repair enzymes.

What is even more insidious, is that the genes that are downregulated are encoding for receptors to neurotransmitters such as glutamate, NMDA and dopamine. So even if you use MOA's or other drugs that inhibit the breakdown of available neurotransmitters, the neuron is still losing its ability to communicate. Even more insidious, is that intracellularly, vesicle trafficking (the cargo vehicles that carry the neurotransmitters) is slowed down as enzymes associated with internal protein transportation are also affected.

Therapeutically we can block receptors of all sorts, but we cannot increase receptor production (yet). This is the problem. Big problem is the effect this has on learning because it attacks the very mechanisms associated with new memory formation. Main reason we cannot increase receptor production is that we are not able to successfully insert new genes in cells without unwanted possible side effects like cancer (yet).

Bigger problem is public awareness (even medical practitioner awareness): up until now we were led to believe that new neurons are continuously produced so it means the brain can still work fine as you get older. This is true, insofar as new neuron production is concerned. Ironically, the genes associated with maintenance of existing neurons are not affected by the aging mechanism. This means that unless you suffer from Alzheimer's disease or some other neurodegenerative condition, from a histological perspective (looking at tissue and cells) you think all is OK because you are not losing brain cells.

It's like not losing hair even though its going grey. The neurons are still present as you age but they cannot function properly, insofar as learning is concerned. This is where we need to understand that the loss of function in long lived cells such as those of the brain up until now have not been able to be determined outside of anecdotal studies where brain function is determined using cognitive performance tests or fMRI studies. It makes sense that older people have "difficulty" in capturing new ideas or concepts yet can be very competent in doing stuff they already know.

Finally, we have evidence. The picture of brain function is not pretty after 40. I would say the downregulation process begins well before that.

So the *challenge* is to define these changes as a disease. How do we do this?

By observing that the changes are heterotypic amongst populations. Thankfully the studies demonstrate the changes are heteroptypic. A heart attack at 40 is abnormal. A heart attack at 80 is, well, aging..

Thus impedance of learning function in the neuron, due to specific gene downregulation, manifested at an early age is a disease state. Presently we can only measure this via a brain tissue biopsy followed by molecular methods. However, indirect methods using less invasive procedures should become available.

sponsored ad

  • Advert

#4 lightowl

  • Guest, F@H
  • 767 posts
  • 5
  • Location:Copenhagen, Denmark

Posted 11 June 2004 - 04:26 AM

Interesting... Very interesting.

And then we have the problem with replacing all the 40+ powerful people with people under 40. There certainly is a transformation period from 20 to 30 where we cant have people in that process running the world. Also, people with to little experience is more likely to make mistakes than people with a lot. The problem it seems, is that people cant get enough experience if they only have from age 30 to age 40 to gain that experience.

That's just the main problem. I think it would be very hard to convince people to stop working at the age of 40, but that may be solved by giving people over 40 a job with less responsibility. It may be more feasible to try and fix this problem either medical or physical. In any case, it would take many decades to change the system to a below 40 leadership. By that time I think the technological developments will have reached a point where we could do something productive about it.

#5 DJS

  • Guest
  • 5,798 posts
  • 11
  • Location:Taipei
  • NO

Posted 11 June 2004 - 09:07 PM

How old is Rummy again?


Yes, "Rummy" holds the distinction of being both the youngest and the oldest Secretary of Defense. :)

I agree with you that cogntive function decreases as a result of senescence, and further, that a large percentage of our senior leadership in the US appears to be "impaired". However, I am having a hard time connecting these independent observations with a more general correlation between degradation of decision making (and creative) abilities and aging.

Using your rationale, Lincoln should have been completely incompetent in managing a nation at war. He was not.

Or how about Stephen Jay Gould? Do you really think that he could have composed The Structure of Evolutionary Theory without a life time of laborious study in the field of evolutionary theory?

I am inclined to believe that maturity and experience off set, to a large extent, the decline in cognitive functioning.

With that said, I am completely in favor of treatments geared toward halting and/or reversing cognitive decline -- not to mention out right augmentation! :) Imagine the progress and innovation that could be fostered if individuals the likes of Einstein, Darwin, Newton, etc. could maintain their "maturity", all the while possessing the cognitive processing abilities of a person in their prime!

#6

  • Lurker
  • 1

Posted 12 June 2004 - 08:08 AM

The decline in cognitive functioning as a result of DNA damage is a heterotypic. In other words just like in other aging related deficits the rate and tissue specific nature of aging varies in individuals.

Not all individuals will have their cognitive function impaired in a measurable way by the time they become 40, whereas some may experience it well before then. Occupation and lifestyle can mask the hallmarks of cognitive decline.

On the other hand, when we speak of individuals such as Lincoln, that were able to demonstrate tremendous insight and competence, and thus by inference cognitive capability, in the post-40 age group we see the exception rather than the rule. Furthermore, one could hypothesize that despite cognitive decline, individuals such as Lincoln, may have already formulated the strategy and the other cognitive foundation that enabled him to implement his revolutionary ideas. Therefore he did not need to rely on learning new and novel concepts, rather he needed to implement what he had already knew was important when he had the means to do so.

Similarly SJ Gould in TSET, may not have been formulating entirely new concepts but simply articulating and expanding on hypotheses that he had previously formulated in his youth, but given the time and resources was able to properly transcribe them and communicate them to wide audience through the medium of his book.

It is important to note the difference in types of cognitive decline. The genes that are most downregulated as described in the study by Lu et al are those associated with synaptic plasticity. My hypothesis is that the accommodation and incorporation of new and novel concepts, due to these molecular changes, is impaired. Studies show in older individuals a decline in the ability to store new information but not a decline in processing already existing information.

If decision making ability is either independent of mechanisms associated with learning of new and novel concepts, or based on strategic methodology that has been developed prior to cognitive decline, then one would be able to perform without deficit. In Lincoln's case I think it was irrelevant. His skills of understanding the nature of men, of tactics and strategy were already in place. They were, as history attests, hugely successful.

Rummy, also a superb tactician and strategist was able to conduct a superb military operation in Iraq insofar as warfare was concerned. Unfortunately the geopolitical, religiocultural and other factors were not taken into consideration. I suspect that during the years of his prime any strategy that he employed would have been successful to the full term and scope of operations. In this day and age however, the weight and importance of many factors were obviously not properly measured and adequately incorporated into the strategy. I think he did his best. I think if he was 20 years younger he would have done *the* best.

But this is not a political discussion. It is a neuroscientific one. I have used this as an example. The point I am making is that people of influence, invariably end up in these positions well after they have biologically lost a vast amount of synaptic plasticity capacity. And this is a concern, because it means that they have real deficits in some aspects of cognitive capability. This is a fact and it is something that we should all be aware of.

Biologically speaking, older may mean wiser but it definitely means more inflexible. At a time of enormous change this can be a real problem in decision making competence.

#7 DJS

  • Guest
  • 5,798 posts
  • 11
  • Location:Taipei
  • NO

Posted 14 June 2004 - 07:29 PM

It is important to note the difference in types of cognitive decline. The genes that are most downregulated as described in the study by Lu et al are those associated with synaptic plasticity. My hypothesis is that the accommodation and incorporation of new and novel concepts, due to these molecular changes, is impaired. Studies show in  older individuals a decline in the ability to store new information but not a decline in processing already existing information.



You bring up an interesting point. Let's say for the moment that your hypothesis is correct and we assume that the more "rigid" thought patterns (more prone to dogma) that are some times associated with the senior demographic are not the result of deficient personality characteristics, but a direct correlate of observable physically degradative processes.

Then wouldn't the bio-Luddites' arguments for a "natural life span" prove correct?

Based on a more conservative "Biological Immortalism" I would begrudgingly have to say yes. By no means am I a Utilitiarian, but the absolute stagnation of humanity is definitely not part of my grand vision. :))

However, by endorsing solutions (some of which blur the line between prevention and augmentation) to this particular problem associated with senescence we would, in effect, be turning the tables on the Luddites by refuting their heavily anthopocentric vision for a probable future. In this case, the integration of both the Immortalist and Transhumanist memeplexes are necessary to form a cogent system of logic. It is becoming more and more obvious to me that this cooperative relationship between the two memeplexes is exceedingly common.

#8

  • Lurker
  • 1

Posted 15 June 2004 - 01:51 AM

Thankfully any solution that provides the substrate of antiaging, that is the correction of molecular deficits, will result in a molecular regulation that approximates a relatively neotenous functional capacity rescuing synaptic plasticity in the process. For example, by protecting mitochondrial DNA from damage, we prevent the apoptotic signal from being emitted; by protecting nuclear DNA from damage we ensure that the regulatory systems associated with the synaptic plasticity genes from switching off.

Effectively we cannot have specific antiaging, the side effect of rescuing function is to modulate regulatory processes that are sensitive to aging mechanisms in the first place.

#9 DJS

  • Guest
  • 5,798 posts
  • 11
  • Location:Taipei
  • NO

Posted 17 June 2004 - 10:54 PM

I see your point. Neural degradation is part of the overall degradation of our bodies and, as such, it should not be isolated or treated exclusively when discussing attempts to stop the systemic effects of senescence.

The more I read about Aubrey De Grey's SENS project, the more I wonder whether it wouldn't just be easier to do a complete overhaul of our bodies (and eventually our minds) using synthetics... [glasses]

#10

  • Lurker
  • 1

Posted 18 June 2004 - 03:41 AM

Exactly Don. Thank you for putting it in a more accessible way.

ADG's approach is unique, as is his commitment. I think he represents the new (or perhaps timeless) breed of scientist, whose intellect transcends the conventional limiting academic and scientific paradigm and is sustained only by the food of discovery.

In respect to doing an overhaul, I know what you mean, it sounds so overwhelming. Actually, the more versed in the science one becomes the more the complexity of all the biological interactions emerges. Which, I am afraid, is why the majority of senior science workers find it difficult to maintain the optimism and vision of those not entrenched in the quagmire of facts (not to mention age related synaptic plasticity deficits), and the politics of project funding. One needs to have a sense of history and recall the time-scale proposed for the human genome projection completion back in 1990 was 40-50 years! It took one disgruntled scientist (Craig Venter) to catalyze the global effort.

I have a strong suspicion that we will see the same thing happen with anti-aging and enhancement science. However, the economic and technological constraints that Venter encountered and compelled him to seek enormous amounts of private funding in order to achieve his objective no longer exist. We are going to see a new generation of genome hackers, people, who like their historical computer counterparts, become practically self taught in the tools of molecular biology and the current knowledge of cell structure and function. DNA can easily be custom ordered and made into enormous quantities via PCR. The art is in creating the suitable delivery construct to target it into the cell and tissue of choice. Most undergraduates are doing this as part of their practical course component and the latest recipes (experimental protocols) are available online to anyone that is interested.

The consequences of the availability of this technology on our society are on multiple levels and seem surreal: modifications will be introduced in the germline during this generation; black market unregulated enhancements will be available to those who can afford them; engineered viruses will run rampant in similar fashion to today's computer viruses - spawning new industries of personal biological virus detection and elimination; of more concern are the new found opportunities for terrorists (bio-terrorism) and criminals (new drug markets) to capitalize on this technology and the subsequent compelling argument that governments will have to tightly regulate it. The time may come when it may be illegal to perform certain personal genome modifications or enhancements.

I have no doubt that we will see all of this within the next 15 years.

But back to your point as to how overwhelming it can all appear: by approaching the problem as ADG has done, which is observing the major flaws in the body and looking for present day technologies to remedy those flaws we can guarantee extending functional lifespan. We should be able to add 20 - 50 years using low risk proteome complementation techniques that seek to add function where function has been lost without modifying the genome itself. Simple things, such as replacing damaged mitochondria and their components, increasing telomere stability, increasing DNA repair machinery and promoting stem cell reservoir proliferation will alleviate most aging disease for a period and allow more sophisticated and precise technologies to be developed that will allow for global somatic gene enhancement.

#11 adering

  • Guest
  • 13 posts
  • 0

Posted 20 June 2004 - 03:47 PM

Damn! Dingo ate my baby and system wiped my message.

Second try.

As to the brain degradation. Could this be a case of "good thing people have ears or else no one could wear eyeglasses"? Perhaps the brain degrades when you reach 40 because it isn't being used as much, not because it's got a use-by date stamped on it.

By the time you hit 40, you're usually pretty well set in what you're going to be doing for the rest of your professional career. And most jobs, regardless of how important we all like to think what we do is, are the same thing.

Your job: a finite set of skills.
Your ordinary day: a subset of the abovementioned finite set.

Personally, I do pretty much the exact damned same thing each day. I am slowly climbing the walls from boredom and am already planning on returning to school for a complete career change. This time, artificial intelligence.

I recently went back to school for a semester. I was shocked. Many of the 18-year-olds in my classes were appalling. Poor organization skills, almost non-existent time management abilities, limited critical and analytical thinking abilities. As a journalist, I was particularly shocked by how poorly so many of them wrote. If you can't express the idea clearly, how the hell are you going to think about it clearly?

I may not have had the great hair or the smooth, supple body of some of those 18-year-olds. Those bastards. But you know something, my 36-year-old neurons are still firing well enough. And the ones I still have, I use more efficiently than the younger people.

(Of course, there were some young people who were frighteningly clever. There always are. I mean, in this group alone we've got Michael Anissimov. He's what? 20? 22? Have you ever looked at his Web site? Gordon P. Christ, I should hope to one day know that much. And -- barring mishap -- he's got decades to go.)

#12

  • Lurker
  • 1

Posted 21 June 2004 - 03:15 AM

There is plenty of empirical data out there supporting the "use it or lose it" mechanism in cognitive decline. I would say to stall brain aging as much as innately possible one should find themselves in a cognitively challenging environment. Whether that means getting that degree you always wanted or a change in employment or lifestyle is obviously a personal issue.

Nevertheless, cognitive decline is an aspect of the aging process. This process, manifests itself in a mosaic fashion, which is why some tissues or organs will demonstrate a more rapid deterioration than others. But no matter how healthy one particular system may be, it will be dragged down by the decline of other systems due to their interconnected nature. My point is that no matter what we attempt to forestall, the irrevocable process of aging is just that - irrevocable.

Furthermore, that this decline has now been demonstrated to strongly manifest by the age of 40 should alarm us as to the competence of those over 40 in the basis of the decision making process. Consider the following 2 scenarios:

Scenario A: you child has been diagnosed with a terminal malignant tumor and you go to seek the opinions of 2 different oncologists, one is 35 years old and the other is 65 years old. Whose opinion will you value more? Most people's instinctive choice in invariably the older specialist, the one with more experience.

Scenario B: you are running an oncology research lab and need to hire a scientist for the team working on developing a new tumor targeting therapy, you have 2 CV's, one of a 35 year old PhD and one of a 65 year old PhD. Who do you hire? Most research directors will opt for the younger guy - because they tend to be at the height of their research skills. In fact most older PhD's will more likely get work in senior administrative, teaching or private company consultative capacity.

The grim reality of scenario B is that younger scientists are far more likely to make breakthrough discoveries than older ones. This is a fact. Why? because they are at the height of their game, like elite athletes. Now knowing that as we do, and with the study on cognitive related gene regulatory changes cited in the study at the beginning of this topic, would one still choose in scenario A, the older oncologist?

Think for a moment, oncology and the treatment of cancer is a rapidly moving field, full of week by week research advances. Some of these advances are paradigm shifting in their approach. Perhaps you may be more inclined now to value the opinion of the younger oncologist. Perhaps he is more computer literate, more likely to have the time to look into the latest research studies, more aggressive and more driven in his approach - more likely to make a lateral connection to find a cure for the condition.

You may say that scenario A is a desperate situation, you are likely to try anything because you have nothing to lose which is why you are willing to place the life of your child into his more inexperienced yet more driven hands. Yes, you will do this because you are seeking a solution to a very difficult problem for which a solution has not been established. If the case was routine you are happy to leave it in the hands of the older specialist but if it requires something novel the value of the younger specialist becomes more apparent.

The fact remains, as evidenced by science research employment data, that positions that require tough science problem solving are invariably given to younger people. Whereas in societal positions with equally challenging roles, these functions are performed by older individuals no longer at the peak of their game. This paradox will remain in place until society recognizes that age does not equal wisdom in the day of the database. Prior to the advent of easily accessible knowledge bases, the offset of poorer cognitive performance against the knowledge experience of the individual could be justified.

Today, however, we must question the validity of this belief which is coming dangerously close to being an old wives tale. And we must question the competence of those who administrate and influence.

#13

  • Lurker
  • 1

Posted 21 June 2004 - 04:29 AM

Seeing as BJ has chosen to link this discussion to the home page I wanted to make a clarification to end on a positive note:

For those interested in the science of how this discovery was made, DNA microarray analysis methods were used to monitor the activity of approximately 460 age regulated genes in a group of 30 people with an age span from 26 to 104 years. It was found that after the age of 40, a number of genes associated with neuron function in the brain become down-regulated, in other words they either stopped or slowed down in their capacity to produce the proteins they encode. What is striking about this study is WHY they became down-regulated: accelerated DNA damage. To test if they could stop this DNA damage they cultured neuron cells that showed the same aging effect but inserted into these cells extra copies of a DNA repair gene, OGG1.  Astonishingly, the cells with extra OGG1 did not show down-regulation and were able to maintain their pre-40 year old state.


The very study that proved cognitive functional decline starts much earlier than most of us thought also provides the clues for a therapeutic strategy to deal with it. Gene therapy that targets brain neuron and glial cells to insert additional OGG1 (see example method described here http://www.imminst.o...17&#entry33465) would rescue function by preventing DNA damage. The implementation of such a therapy is within today's technological realms, would be economically viable and very safe.

#14 cphoenix

  • Guest
  • 2 posts
  • 0

Posted 21 June 2004 - 05:05 AM

Prometheus, there's another plausible explanation for why younger scientists may do better research. In _Discovering_, Robert Scott Root-Bernstein makes a strong case that scientists do their best work in their first ten years in a field. Unfortunately, they often don't switch fields, especially if they're successful in the first one. But those who do switch can continue to do great work regardless of age.

#15 pgptag

  • Guest
  • 1 posts
  • 0

Posted 21 June 2004 - 05:48 AM

As someone older than 40 (actually, at the wrong side of 45) I found this thread very interesting.
It is true that after 40 you can feel some degradation in your mental sharpness. In most cases you can compensate with experience: you know what is the best thing you can do in a given situation because you have seen something similar already. Of course this does not help if the situation is completely new.
Probably the best form of organization to cope efficiently with both the expected and the unexpected is a combination of younger and older people, with people moving toward advisory roles as they age.
In a novel I read a beautiful sentence thet goes more or less like: "don´t be angry at those who beat you with their experience, for they have paid for their experience by emptying a purse that cannot be refilled".
On this forum we think that someday we may be able to refill that purse. But what about the timeline? Do you people thing that we fortysomething will be able to take advantage of advances in understanding and reversing the ageing peocess, or that such advances will come too late for us?

#16

  • Lurker
  • 1

Posted 21 June 2004 - 09:31 AM

cphoenix: Indeed, a field switching fresh view can have a profound effect on discovery ("Discovering" is a wonderful book by the way) and innovation. Aubrey de Grey is a superb example of this phenomenon, switching from computer science to genetics. But, much as I hate to think about it, no matter how smart one is or how mentally active, no matter how many fields one switches to, the effects of aging spare no organ. And surely one can be productive at any age. My mother who is well into her 70's performs complex legal Greek-English translations and taught herself to use computers and the Internet only 2 years ago. She also still composes poetry and often out-reasons me on most topics. She does not take any vitamins let alone nootropics, nor does she exercise and is very overweight, yet she has low blood pressure and normal cholesterol. This is an example of good genes. If she took care of herself she would probably make 100. On the other hand, I remember her at 45 and she was a gun - unstoppable. My point here is that it is all relative.

pgtag: I love the purse metaphor. How quickly the irreplaceable contents of that purse are spent. How the impetuousness and arrogance of youth spend that precious coin with such disdain.

As for the timeline, we can definitely slow it down. We can slow it to such a rate that it almost halts (gene therapy to increase DNA repair and protection). But reversing it? Now that is something I have not dwelled on. Theoretically, stem cells should be able to replace any old cell with a new progenitor. The key is in ensuring the regulation of gene expression in the new cell is that of a young cell rather than an old cell - and that is a matter of signaling from surrounding cells, the extracellular matrix, cytokines, etc. The most profound thing that we can draw from the brain aging finding is that the aging phenotype is caused by DNA damage, a condition that can be remedied.

#17 fdotseth

  • Guest
  • 10 posts
  • 0

Posted 21 June 2004 - 05:10 PM

It is interesting to see how committed we become to the science we question. Answers are not going to be found in evaluating manifestations. Real progress is buried in our thought processes. There are three areas, which hold the key. The area of frequency application (review Royal Rife's work). The area of transmutation. And the area of Body Electronics.
By default, life is fear driven. We have to find a way to adjust this drive. We have to learn to have a balance between our nine responses. The nine responses are consciousness, fear, pain, rage, pleasure, reproduction, thirst, hunger, and homeostasis.
I repeat, we are wasting time by evaluating manifestations. We have to work outside of the box, if we want to find real answers. Research has to include, reading, personal research, thinking, and sharing.
fdotseth

#18 till

  • Validating/Suspended
  • 63 posts
  • 0
  • Location:Brisbane

Posted 25 June 2004 - 12:18 AM

I had a look at the study prometheus mentioned, and find that, like many of such studies, it lacks what I call 'resolution'. Also, in the ensuing discussion, our current ignorance about the feedback between cell-usage (or ab-usage, or lack of usage) and gene-modifcation was not taken into account. This is a relatively new field of research and I expect we will hear more of it in the future. Right now it's usually just seen as an issue of using-instead-of-losing compensating or making up for the underlying decay processes. It may be much more than that though. We'll have to wait and see. Every new day appears to bring new surprises.

I make a prediction, in the grand tradition of exact (rather than pseudo) science, and maybe, when I turn out to be right, someone will remember that I made it. It is this:

If the same study (or a similar one) were conducted with people who were classified according some index of what one might call 'mental activity', the finding would be that overall those who score higher on that index will have less apparent age-related genetic damage.

Of course, one would have to be careful here, too. After all, there may be a life-style correlation here as well, and so other factors might have to be folded into consideration as well.

The bottom-line here is that this study isn't anywhere close to providing us with even a tentative suggestion of what happens as a function of ageing, and premature conclusions are probably going to be misleading.

As far as 'mental flexibility' as a function of age is concerned, we need to consider the fact that a brain exposed to extensive 'experience', that is a brain which has an extensive 'contextual' framework, functions very differently to one that hasn't. The phenomenon is well known from neural network research. Neural nets, remember, don't have 'genetic' issues, and so the occurrence of similar issues there seems to suggest strongly that apparently age-related mental sclerosis or inflexbility may have more to do with basic issues relating the retraining of heavily contextualized networks, rather than actual brain damage.

So, people, be cautious about jumping to premature conclusions. Things often aren't what they seem, and bio-science in particular is riddled with conclusions based on a dearth of facts.

#19

  • Lurker
  • 1

Posted 25 June 2004 - 03:13 AM

I make a prediction, in the grand tradition of exact (rather than pseudo) science, and maybe, when I turn out to be right, someone will remember that I made it. It is this:

If the same study (or a similar one) were conducted with people who were classified according some index of what one might call 'mental activity', the finding would be that overall those who score higher on that index will have less apparent age-related genetic damage.


Till, I wish that your prediction were to come true. The reality, unfortunately, is grim.

One must not mistake functional redundancy, allowing an aging organism to make some compensatory adaptations, with actual changes in aging rate. It would imply that lifespan could be altered corresponding to activity. We know from countless studies that lifespan is genetically determined and the only non-medical intervention that can extend lifespan is caloric restriction (not including factors of abstaining from deliberate abuse as in smoking or glucose consumption). Even with CR the gains are very modest and bound to individual genetic constraints.

I find the discussion of cognitive decline due to aging to be the toughest issue for non-scientists to deal with. It is something very difficult to accept particularly as the threshold of decline has now been shown to commence around the age of 40. It is the reason why I titled this series of discussions as paradigm shifting .

Organs and tissues in the body age in a mosaic fashion. In some the liver will malfunction before the heart gives out whilst in others a heart attack will kill someone with a relatively healthy brain. For instance, some will lose scalp hair as they go grey whilst others will retain it. Aging is still taking place in all tissues, albeit at different rates. Also we find that organs can sustain high levels of damage they must sustain before gross manifestation of pathology becomes evident. Just how much capability is diminished is not apparent until the organ is pushed to function beyond its normal parameters. For this reason a heart condition may not be evident until the patient attempts vigorous physical exercise. Similarly, many aging processes are underlying and manifest very gradually. Many do not feel aging effects until late 20's, some rarer still do not feel until early 30's.

The issue is that the inertia of aging begins with the ending of puberty. How people can look at themselves in the mirror, see sagging, wrinkled skin and grey hair yet think that for some magical reason these external aging manifestations are not also being reflected in their internal organs is not difficult to comprehend. Particularly for those with a minimal understanding of biology and a "hope for the best" attitude it is very understandable (incidentally this is a great attitude to have - there's no need to stress over something that is beyond your reach - but in this case it disadvantageous).

Ask any surgeon, about the difference in appearance of organs that he sees each time he operates between younger and older people. Ask the pathologist who examines the tissue biopsies about the differences in how cells look and behave.

The brain and its cognitive function is the most difficult organ to observe aging in. Particularly if its your own. If you are objective enough, as you get older you may observe that you have a more difficult time recalling certain things. If you're used to high levels of cognitive performance you may note certain other changes too. The reality is that most people do not use their full cognitive potential. Everyone can learn another language, how to play the piano and the application of differential equations. But not everyone does. In similar fashion, most people, can run a few kilometers a day, lift weights and ride horses. Again, not everyone does. This does not mean that a 50 year old will run as well as a 20 year old. It also does not mean that a 50 year old will have the same cognitive performance as a 20 year old does.

Think of when you visit your doctor. He can listen to your heart beat pattern through a stethoscope and have an idea as to how well or not your heart muscle is working compared to your age. The stethoscope provides an indirect view of the inner workings of your heart and there are studies that show what sort of performance is expected from a healthy heart at a particular age. But how can your doctor do this with your brain function? Aside from some basic memory exercise questions you can be asked to help determine if you are suffering from dementia, there is no diagnostic for mental performance

There is no stethoscope for brain function - which is why the study I mentioned has such far ranging implications. For the first time we can actually look at brain function and the change that occurs during aging. This is knowledge that should be welcomed. It is easy to try to ignore the realities of cognitive aging but we do so at our own peril.

The sooner we can as a society accept that aging is manifesting much sooner than what we originally realized, the sooner we can be motivated to pursue the research to enable the discovery of solutions to treat aging as a disease. The study that forms the basis for the discussion in this topic is a seminal one. It demonstrates in great clarity the very causes and mechanisms behind altered neural function as well as a strategy for intervention.

#20 Michael

  • Advisor, Moderator
  • 1,293 posts
  • 1,792
  • Location:Location Location

Posted 25 June 2004 - 03:26 PM

All:

This (2) is an engagingly alarming story, of course. I will first state my agreement with Prometheus that the observed data are fundamentally a matter of biological aging, rather than of "use it or lose it." Indeed, the "use it or lose it" data are often presented in the media with an unwarranted degree of optimism. What these studies tend to really show is that people who are extremely mentally inactive are at greater risk of dementia compared to people who use their brains to a normal or greater degree; they provide no evidence of a 'dose-response' effect in which people who are unusually mentally active enjoy a proportional degree of extra protection against dementia.

And as one becomes older and older, conventional "healthy lifestyle choices" of all sort tend to become less and less relevant in the face of the onslaught of biological aging. As they get older, people who've spent their lives eating healthy diets low in saturated fat enjoy less and less protectioin against heart disease relative to those eating a 'standard American diet;' atheletes' physical performance becomes increasingly indistinguishable from that of their sendentary peers; etc.

For exactly this reason, I also agree with Prometheus that we really need stop dicking around with acetylcholinesterase inhibitors (see today's Lancet (11)) and antioxidants, and get scientists to work on SENS-style age-reversing interventions (8-10). Among the best ways we have to do this (unless we are ourselves biogerontologists and can lead by example) are to (a) donate to the Methuselah Foundation, and (b) help restore federal funding for embryonic stem cell research and "therapeutic cloning" (SCNT).

On an individual level, in the meantime, there is extensive evidence that calorie restriction retards brain aging in mammals -- including human mammals, and including the specific kinds of brain genome damage observed in humans in this study. Reproduced below is a recent post from the Calorie Restriction Society forum.

-----------------

RD wrote:
> New study pinpoints the genes responsible for intellectual
> decline after the age of 40. (1,2)

Careful. As the CNN story found by Judith (3) notes, "The results don't prove that such changes cause mental decline." As has been pointed out before, the question of the DIRECTION of causality is critical:

http://groups.google...k&output=gplain

http://lists.calorie...society&P=R9317

http://lists.calorie...society&P=R9704

(See also the detailed critique of these studies, which address broader methodological issues, by Miller et al (7)).

This is part of why Dr. Spindler's papers on the IMMEDIATE vs. long-term impact of CR, and of the impact of CR at young and old ages, is a big step up.

> Wonder if CR can slow it down,
> or somehow affect the expression of those genes:

Sure looks like it. We already know, of course, that by NEARLY every measure, CR slows the degeneration of both the physical structure of the brain & nervous system, & of cognitive function, with time. But there's also evidence on the specific point of the gene expression changes. I've not yet seen teh full paper (& frankly prob won't have the patience to do the legwork to figure out what all the genes "do," individually), but let's look at the results as we have them one by one.

1. INCREASED DNA DAMAGE

A pop press piece ((4) -- the best I've seen) says:

---------------
"elevated expression of genes that are associated with stress and repair mechanisms and genes linked to inflammation and immune responses ... is evidence that pathological events may be occurring in the aging brain, possibly related to gene damage.

The researchers then went on to show that many of the genes with altered expression in the brain were badly damaged and could not function properly. They showed that these genes also could be selectively damaged in brain cells grown in the laboratory, thereby mimicking some of the changes of the aging brain.

"Our findings suggest that these genes are unusually vulnerable to damage from agents such as free radicals and toxins in the environment," said Yankner. "The brain's ability to cope with these toxic insults and repair these genes declines with age, leading to their reduced expression. It will now be important to learn how to prevent this damage, and to understand precisely how it impacts brain function in the elderly." "

-------------

Likewise, per the abstract (2) : "DNA damage is markedly increased in the promoters of genes with reduced expression in the aged cortex. "

Well, we already know that CR reduces DNA damage in the brain: "Dietary restriction ... was shown to significantly reduce the age-related accumulation of oxo8dG levels in nDNA in all tissues [liver, heart, brain, kidney, skeletal muscle, and spleen] of male B6D23F1 mice and in most tissues of male F344 rats." (6)

2. REDUCED EXPRESSION OF KEY BRAIN FUNCTION GENES Now, as a result, "transcriptional profiling of the human frontal cortex ... defines a set of genes with reduced expression after age 40. These genes play central roles in synaptic plasticity, vesicular transport and mitochondrial function." (2)

When Weindruch's group examined the "Gene-expression profile of the ageing brain in mice", comparing young, old AL, and old CR mice, (5) they found that the expression of 0.7-1% of genes (in neocortex & cerebellum, respectively) changed; "Genes involved in CNS development and neuronal plasticity accoutned for 11% ... of these alterations in the neocortex and 14% ... in the cerebellum." CR retarded 20% of these gene changes. If this sounds like a weak result, remember that (a) the causality of all these changes is dubious, so CR might be influencing the ones that actually drive degeneration, & more importantly (b) since their (arbitrary) threshold for considering a change important was set so low (1.7-fold, as vs. >2-fold in their other studies), there are likely a lot of false positives in this group anyway. (This arbitrary design was itself rather problematic, as noted by Miller et al (7).

3. INCREASED EXPRESSION OF DAMAGE RESPONSE GENES "In addition to a reduction in genes important for cognitive function, there was an elevated expression of genes that are associated with stress and repair mechanisms and genes linked to inflammation and immune responses." (4) "This is followed by induction of stress response, antioxidant and DNA repair genes."(2)

And in the aging mice? "Ageing resulted in a gene-expression profile indicative of an inflammatory response, oxidative stress and reduced neurotrophic support in both brain regions. At the transcriptional level, brain ageing in mice displays parallels with human neurodegenerative disorders."

The effect of CR: "caloric restriction prevented 50% ... of the genes involved in induction of the stress response and 65% ... of those involved in the inflammatory response in the neocortex. We observed a similar pattern in the cerebellum." " Caloric restriction, which retards the ageing process in mammals, selectively attenuated the age-associated induction of genes encoding inflammatory and stress responses." (5)

So the only question is the big one: does it translate from mouse to (wo)man? You can guess how I'm betting ;) -- esp granted the direct evidence on the subject:

http://lists.calorie...society&P=R5629

-Michael



1. http://my.webmd.com/.....9531713CA348}

2. Nature AOP, published online 9 June 2004; doi:10.1038/nature02661
Gene regulation and DNA damage in the ageing human brain
TAO LU, YING PAN, SHYAN-YUAN KAO, CHENG LI, ISAAC KOHANE, JENNIFER CHAN
& BRUCE A. YANKNER
http://www.nature.co...re02661_fs.html

3. http://www.cnn.com/2...g.ap/index.html

4. http://www.genomenew...10/brainage.php

5. Lee CK, Weindruch R, Prolla TA.
Gene-expression profile of the ageing brain in mice.
Nat Genet. 2000 Jul;25(3):294-7.
PMID: 10888876 [PubMed - indexed for MEDLINE]

6. Hamilton ML, Van Remmen H, Drake JA, Yang H, Guo ZM, Kewitt K,
Walter CA,
Richardson A.
Does oxidative damage to DNA increase with age?
Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10469-74. Epub 2001 Aug 21.
PMID: 11517304 [PubMed - indexed for MEDLINE]

7. Miller RA, Galecki A, Shmookler-Reis RJ.
Interpretation, design, and analysis of gene array expression experiments.
J Gerontol A Biol Sci Med Sci. 2001 Feb;56(2):B52-7.
PMID: 11213267 [PubMed - indexed for MEDLINE]

8. de Grey AD.
An engineer's approach to the development of real anti-aging medicine.
Sci Aging Knowledge Environ. 2003 Jan 8;2003(1):VP1. Review.
PMID: 12844502 [PubMed - indexed for MEDLINE]
http://www.gen.cam.a...ens/focusPP.pdf

9. de Grey AD.
Challenging but essential targets for genuine anti-ageing drugs.
Expert Opin Ther Targets. 2003 Feb;7(1):1-5. PMID: 12556198 [PubMed - as supplied by publisher] http://www.gen.cam.a...sens/manu21.pdf

10. de Grey AD, Ames BN, Andersen JK, Bartke A, Campisi J, Heward CB, McCarter RJ, Stock G.
Time to talk SENS: critiquing the immutability of human aging.
Ann N Y Acad Sci. 2002 Apr;959:452-62; discussion 463-5.
PMID: 11976218 [PubMed - indexed for MEDLINE]
http://www.gen.cam.a...sens/manu12.pdf

11. Lancet Volume 363, Number 9427 26 June 2004
Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial
AD2000 Collaborative Group*

"565 community-resident patients with mild to moderate Alzheimer's disease ... were randomly allocated donepezil (5 mg/day) or placebo ... Primary endpoints were entry to institutional care and progression of disability, defined by loss of either two of four basic, or six of 11 instrumental, activities on the Bristol activities of daily living scale (BADLS). ..."

" No significant benefits were seen with donepezil compared with placebo in institutionalisation (42% vs 44% at 3 years; p=0·4) or progression of disability (58% vs 59% at 3 years; p=0·4). The relative risk of entering institutional care in the donepezil group compared with placebo was 0·97 (95% CI 0·72-1·30; p=0·8); the relative risk of progression of disability or entering institutional care was 0·96 (95% CI 0·74-1·24; p=0·7). Similarly, no significant differences were seen between donepezil and placebo in behavioural and psychological symptoms, carer psychopathology, formal care costs, unpaid caregiver time, adverse events or deaths, or between 5 mg and 10 mg donepezil."

"Donepezil is not cost effective, with benefits below minimally relevant thresholds. More effective treatments than cholinesterase inhibitors are needed for Alzheimer's disease."

#21

  • Lurker
  • 1

Posted 27 June 2004 - 01:24 PM

A new heading on the original Nature article, making it sound more ominous than even I anticipated...

Ageing: Death begins at 40...


The molecular basis of the cognitive decline that accompanies ageing is a major unresolved issue. Now a DNA microarray analysis of the human ageing brain reveals that a defined set of genes is downregulated in ageing — and that the rot sets in at 40. Postmortem brain samples were taken from individuals aged between 26 and 106 years. The genes identified as age-linked play a role in, among other things, synaptic plasticity — the ability of neurons to make and break connections with one another. These genes experience progressive increase in DNA damage (and faulty repair) to promoter regions, rather than simply changing their function. So DNA damage may reduce expression of selectively vulnerable genes involved in learning, memory and neuronal survival.



Gene regulation and DNA damage in the ageing human brain
TAO LU, YING PAN, SHYAN-YUAN KAO, CHENG LI, ISAAC KOHANE, JENNIFER CHAN & BRUCE A. YANKNER
Nature 429, 883–891 (2004); doi:10.1038/nature02661
| First Paragraph | Full Text (HTML / PDF) |



and here is the link.




1 user(s) are reading this topic

0 members, 1 guests, 0 anonymous users