67 replies to this topic

[niner]

oh this is getting interesting! Let me understand more. But first, I'd like you to answer: How do you define 'undamaged' in biology?

And is it true then that undamaged perfection --on the atomic level!-- is your and SENS holy grail? Is that what you're aiming at when you say that you want to stop aging?

Also, I'd like you to qualify: in your definition of damage, are the animals with negligible senescence 'damaged'?

Sorry for all these questions, but I'm sure that others would also like to hear the answers, to form a better idea of what SENS is all about.

Then, re you not approving of me calling SENS idea to 'preferentially kill' T-cell that specialize in herpes viruses stupid, would you please elucidate its wisdom, 'cause, as I pointed out earlier, this should cause the virus to not just flare up but to practically take over the host, as indeed I once saw. This, in my book, is not a favorable outcome. How would this strategy benefit the host?

Thanks niner!

 

Sorry for the delayed answer- I had a busy weekend.   The kind of damage I'm talking about is at the molecular level.  It means that bonds between atoms have been broken, or new bonds have been created where they shouldn't be, atoms have been removed, or new molecules have been attached to a biomolecule.  In some cases, the damage doesn't interfere with function, so it doesn't really matter.  In most cases, the body has ways to recognize and repair the damage.  Most proteins are recycled on a regular basis, so even if they are damaged, they get replaced soon enough.  Because DNA is so crucial, we've evolved numerous mechanisms to repair different sorts of damage, like strand breaks, mismatch errors, base dimerization and the like.  One of the DNA repair mechanisms, when broken, is responsible for Xeroderma Pigmentosum, which is sometimes categorized as an accelerated aging disease.  The relevance of molecular damage to aging occurs when we don't have a repair mechanism for a particular kind of damage, or the repair mechanisms that we have can't quite keep up with the rate that damage accrues.    There are a few specific cases that are problematic.  Elastin and collagen are extracellular proteins that get recycled very slowly if at all.  They have coiled structures that kind of act like little springs- they are stretchy.  AGE crosslinks slowly build up in these molecules, causing them to lose their elasticity.  This leads to the classic sagging skin of aging, among other problems.   If we could just figure out a way to get an enzyme or catalytic small molecule in there that would cleave the inappropriate crosslinks, we should be able to regain elasticity in our skin, blood vessels, and other sites.  That's one of the things SENS is working toward.  Others are described here.

 

The SENS Holy Grail isn't quite undamaged perfection, but rather to engineer fixes for the few cases where damage builds up due to missing or inadequate repair mechanisms.  If we could remove enough damage to return you to the level of damage of a person in their twenties, that would be a spectacular success.

 

Animals with negligible senescence aren't completely undamaged, but their rate of damage accrual and repair mechanisms are matched better than ours are.

 

I don't think anyone wants to remove our ability to deal with all herpes viruses.  The problem is that over time, CMV uses up a larger and larger fraction of Tcell memory reserve, I guess due to frequent epitope mutations, and we run out of capacity to deal with other threats.  All those CMV-specific cells are useless because CMV is a relatively harmless infection- I guess there isn't much to fight.  FightAging has an article on it here.  It's not part of the main SENS program as defined here.

 

I hope this is helpful.

[to age or not to age]

What would be foolish would be not expecting a positive effect on healthspan to not have some positive effect on lifespan.

This is correct.  Dr Stephen Austad, evolutionary and structural biologist at the Barshop Institute, explained to me on camera- that it is virtually impossible to prove a life extending

drug works in humans because you can't do the studies.  They take too long.  So

naysayers always have this line of argument.  VInce Giuliano, whom I know and like,

is intending to live to more than 200.  He is not an advocate of one particular method.

Rather, he believes this is an incremental game, and it is important to avail yourself of

the present day healthspan and lifespan advances.  Other breakthroughs will

follow, but you have to be around and healthy to try them going forward.  In a way,

Aubrey (whom I also know) is clinging a bit to the fix the damage line.  I believe he is partially correct and have expressed this to Vince, who is more skeptical of Aubrey's

approach, but thinks it is possible.  Major upstream pathways and things like stem cell

and metabolic age reversal are likely to solve some of the things Aubrey is trying to do.

So, my 2 cents is work on all levels at once, including political, environmental and social.

In the link below scientists speak about the decrease in NIH funding an condition to

advances.

https://www.youtube....eature=youtu.be

What would be foolish would be not expecting a positive effect on healthspan to not have some positive effect on lifespan.

 

[xEva]

Thank you niner for your reply!

Xenoderma is an excellent example. Not only it shows that we do have excellent repair mechanisms but also what happens when they don't work. Odd isn't it that we have to see such shocking examples to become aware of what an amazing job those repair mechanisms are doing -- while we're young that is. ..otherwise we totally forget that they exist.

It is the same with the immune system. People take it so much for granted that it led to questionable belief in 'friendly bacteria' and 'harmless viruses'. Which unfortunately you also have. Like you say:

" All those CMV-specific cells are useless because CMV is a relatively harmless infection- I guess there isn't much to fight."

If you'd look it up on CDC, wiki or Mayo sites, you'd see something like this:

Most healthy people do not experience any symptoms when infected with CMV. However, in those with a weakened immune system, CMV can cause serious disease (blindness, hepatitis, encephalitis, etc.).

I find it shocking that SENS (and you!) apparently do not understand that the reason CMV does not cause symptoms in healthy people is because a healthy immune system keeps it under control -- NOT BECAUSE THE VIRUS ITSELF IS HARMLESS. Again: it is the the immune sys relentless patrol what renders CMV 'harmless' and it is its inadequacy what allows CMV to cause serious disease.

And so when SENS offers to remove the cells that specialize in CMV, it is very doubtful that this will make patients' imune systems healthier -- but they could certainly try, though I doubt a person in his right mind would sign up for the study (I certainly would't!). What this will do though --with certainty!-- is make CMV to go into overdrive and cause a 'serious disease'. ..for the obvious reason that the immune cells that held it in check until now will no longer be there.

See, that's why I love history of science, especially medicine. It shows how our believes are shaped and how we get into trouble when we fail to update them in a timely manner. The belief in 'harmless viruses' and 'friendly bacteria' is pretty old. It predates AIDS. Before AIDS came along, there were only very rare cases of boys being born with what was called inborn immune deficiency syndrome. Though it was recognized that common organisms caused uncommonly serious illness in those boys, this was not enough to change people's views on 'harmless' bacteria and viruses -- mainly because those cases were rare oddities, sort of like Xenoderma Pigmentosa now.

It's only when AIDS came along that people sort of 'noticed' the immune system, finally. They began to really appreciate what a hard job it was doing all the time in order to keep those common bugs 'harmless'. And with that appreciation also came realization that such control came at a substantial cost to the host.

I'm afraid that SENS --and you-- have not been visited by this realization yet. And I'm afraid the same goes for the repair mechanisms. Just like this CMV example shows, they certainly know about the immune sys but at the same time they sort of don't. ..gotta run now, later

Edited by xEva, 25 November 2014 - 05:06 AM.

[xEva]

And so it consolidated in my head. Here is my brief definition of aging and approach to it:

Aging is the progressive failure of the existing repair mechanisms to do their job.

I know many will disagree, as this discussion shows (but it has not convinced me), still, I claim that these repair mechanisms exist and work fine while we're young, which our youthfulness well into our 20s, and often late 30s, amply demonstrates.

This is a better definition, because it offers a tangible goal and pragmatic approach:

identify these mechanisms as well as the causes of their failure, and then find ways to upregulate them.

No need to invent anything new.

Edited by xEva, 25 November 2014 - 09:04 AM.

[Brett Black]

SENS may not have to be thought of in terms of damage. I know Aubrey frames it like this, but it may not be necessary, and it may lead to people dismissing SENS because it is framed in this way.

I would like to propose another way to view it: simply as a difference between two states (young and old.)

Here's how(in a very broad sweeping sense):

First, characterize both a young healthy human state and an old declining human state. By "characterize", I mean sufficiently thoroughly analyze and extract the characteristics of each state at a biological, cellular and/or molecular level (note that it doesn't necessarily have to be a perfectly detailed characterization, it just has to be comprehensive enough to capture the relevant details. My understanding is that SENS claims this has already been broadly accomplished.)

Next, derive the relevant biological *differences* that exist between the *young human state* and the *old human state.* When deriving these differences, attempt to do so in a way that allows these differerences to be defined by as minimal a number of characteristics as possible, whilst still retaining sufficient information/detail to be actionable. (SENS claims that these differences can be reduced to seven categories.)

In other words, try to figure out reductionistic generalizations of the differences, thereby reducing the number of interventions that will be necessary to revert the old human state to the young human state. (It may also be that some biological differences between young and old states do not induce any subjectively deleterious macroscopic impact on human wellbeing and therefore these differences may potentially be ignored without detriment - thereby helping to reduce the difficulty of the task further.)

Finally, develop and implement methods to revert the old human state back to the young human state by using interventions that undo the relevant biological, cellular and/or molecular differences that exist between these two states.

So that's it basically - instead of thinking about it in terms of damage, or in fact in terms of any *process* (e.g. damage accumulation, programmed aging, failure of repair mechanisms etc), just think about it as a *difference in states* between old and young. Then reverting that state no matter what chronic ongoing processes may have caused it.

Ultimately, we don't care so much about what processes caused the change from young state to old state, so much as we care about the young state being much peferrable to the old state.

When a car comes in for repair, it doesn't matter to the mechanic what events or processes caused the dents in the panels (e.g. rock impacts, vandals, manufacturing error), he just knows that he needs to make the panels return to the state they were in when they were new. Likewise, our task is to find tools/methods that will revert the differences between the old state and the young state; it doesn't ultimately matter *how* or *why* the differences occurred.

[corb]

SENS may not have to be thought of in terms of damage. I know Aubrey frames it like this, but it may not be necessary, and it may lead to people dismissing SENS because it is framed in this way.

I would like to propose another way to view it: simply as a difference between two states (young and old.)

Here's how(in a very broad sweeping sense):

First, characterize both a young healthy human state and an old declining human state. By "characterize", I mean sufficiently thoroughly analyze and extract the characteristics of each state at a biological, cellular and/or molecular level (note that it doesn't necessarily have to be a perfectly detailed characterization, it just has to be comprehensive enough to capture the relevant details. My understanding is that SENS claims this has already been broadly accomplished.)

Next, derive the relevant biological *differences* that exist between the *young human state* and the *old human state.* When deriving these differences, attempt to do so in a way that allows these differerences to be defined by as minimal a number of characteristics as possible, whilst still retaining sufficient information/detail to be actionable. (SENS claims that these differences can be reduced to seven categories.)

In other words, try to figure out reductionistic generalizations of the differences, thereby reducing the number of interventions that will be necessary to revert the old human state to the young human state. (It may also be that some biological differences between young and old states do not induce any subjectively deleterious macroscopic impact on human wellbeing and therefore these differences may potentially be ignored without detriment - thereby helping to reduce the difficulty of the task further.)

Finally, develop and implement methods to revert the old human state back to the young human state by using interventions that undo the relevant biological, cellular and/or molecular differences that exist between these two states.

So that's it basically - instead of thinking about it in terms of damage, or in fact in terms of any *process* (e.g. damage accumulation, programmed aging, failure of repair mechanisms etc), just think about it as a *difference in states* between old and young. Then reverting that state no matter what chronic ongoing processes may have caused it.

Ultimately, we don't care so much about what processes caused the change from young state to old state, so much as we care about the young state being much peferrable to the old state.

When a car comes in for repair, it doesn't matter to the mechanic what events or processes caused the dents in the panels (e.g. rock impacts, vandals, manufacturing error), he just knows that he needs to make the panels return to the state they were in when they were new. Likewise, our task is to find tools/methods that will revert the differences between the old state and the young state; it doesn't ultimately matter *how* or *why* the differences occurred.

 

 

When a car comes in for repair,

 

You blew it.

[Brett Black]

When a car comes in for repair,

You blew it.

Ahahahahaha! That one made me laugh ;-)) I did blow it.

Ok, so I normally think about it in terms of "damage/repair" too, I suppose that's why I let that slip through in the car analogy.

Mabe there's some insight to be gained from this though...

I think that to some degree it is a semantic issue, and there is a degree of circular reasoning involved.

In a real sense I was/am merely defining the *end state* (which in this case is an old car that is not functioning/looking as it did when new) as being "damaged." I'm not actually saying that the end state was cased by a *process* of damage.

Instead of "damaged" I could just as well use the term "dysfunctional", and instead of "repair" I could use "restore" or other terms. The same goes for old humans.

"Damage" is subjective and dependent upon values. One person's battered old decaying table is another persons expensive antique furniture. Perhaps "damage" is really just a term for "undesirable change of state."

[Antonio2014]

I don't see your point. You only changed the name. It's like using an euphemism. If it's damage, call it damage.

 

And not, it's not subjective. Using your example, damaged antiques are lower valued than well-conserved antiques. For example, a century old, well-conserved coin is highly expensive, but a century old, rusted coin is almost worthless.

Edited by Antonio2014, 01 December 2014 - 08:59 AM.