A Concrete Example of the Point

As indicated by some of the comments to a recent post about resveratrol - and why I'm not hot on research to slow aging in comparison to research aimed at repairing aging - I'm failing to clearly make what I consider to be the most important point. I made another go at it as a sequence of ideas in the most recent Longevity Meme Newsletter:

3) Practicing calorie restriction is free, but research is not. The present purposing of the aging research community to metabolic manipulation is expensive, but money isn't the real concern. An opportunity is being lost: the real cost is the slowdown in developing a research infrastructure that is instead purposed towards identification and repair of aging damage, a more efficient way forward to extended healthy lives. This is the difference between tuning your engine and taking it to a mechanic: tuning gets you so far and so far only; at some point, you're going to have to repair the components.

4) It does you no good in the long term to buy an extra decade of healthy life if that's all you get; it was only useful if researchers spent that decade working hard on repairing aging, rather than further metabolic science. There's only so much you can do with slowing aging through metabolic manipulation - the elderly wouldn't benefit, for example - but a working repair mechanism for the cellular damage associated with aging could be used to restore the aged and hold off aging over and over again. It's more efficient and effective.

5) There is more than enough money in the world to have your cake and eat it - to fund both lines of research, metabolic tinkering and repair of damage. But this is not happening now. Successful fields have gravity - they attract new researchers and shape the course of science on a timescale measured in decades; without a great deal of work, the fight against aging will be metabolic manipulation and little else for the foreseeable future. That would leave us rather stranded twenty years from now.

Which earned me some rather sarky comments in private email from one of those fellows who sells resveratrol. So, let's try again, by means of example this time; I'll pick out two early stage technologies that are starting to show promise for a game of compare and contrast. Both involve the age-related damage wrought by free radicals that occurs in - and is caused by - mitochondria, vital cellular components that convert food into more convenient forms of energy to power your cells. You might first want to take a look at a post from last month that summarizes the latest view of the mitochondrial free radical theory of aging, and explains how the accumulation of damage to mitochondria is a root form of aging damage.

First up is the enhancement of the anti-oxidant catalase:

"Rabinovitch's group genetically engineered mice to produce a natural antioxidant enzyme called catalase. The mice lived 20 percent longer than normal mice - on average they lived five and a half months longer than the control animals, whose average life span was about two years


We had differing hypotheses about where putting catalase might do the best in terms of the advantage to life and health of the mice," Rabinovitch explains. So they targeted the gene in three different places in the mouse cells - the cytoplasm, the nucleus - where they thought it might protect the all-important DNA of the cell - and the powerhouses of the cells, the mitochondria - where cells "burn" glucose for energy and churn out high levels of these oxidizing free-radicals. The mice that lived longest had the gene in their mitochondria.

"What we learned was that increasing the levels of catalase specifically in mitochondria was the way in which we could most effectively increase the 'healthspan,' as we call it, the increased time of healthy life for the mice," Rabinovitch says. Mice with high catalase levels in the other cell structures showed only modest life extension.

The catalase soaks up some portion of free radicals before they can attack your vulnerable mitochondrial DNA. Damage to this DNA, as explained in that post I referenced above, leads to an unfortunate chain of events that causes entire cells to rabidly produce damaging free radicals and export them throughout the body. But stop a fraction of the original mitochondrial free radicals from attacking their birthplace, and you have slowed the rate at which one cause of aging happens - you have slowed down aging, and extended healthy life.

Great, right? Well, yes, considered in isolation - and if you are young. If you are old and already damaged, you're pretty much out of luck. Gene therapy to boost your levels of catalase isn't going to do much for you, no matter how many hundreds of millions of dollars were spent getting it from the laboratory and into clinics. It can't repair what has already happened. It's also not so great if you were young at the outset, and after twenty years of research focus and construction of a multibillion dollar industry and scientific infrastructure, there has been little progression beyond ever more sophisticated manipulation of metabolism in this sort of way - you're still aging, and you will still suffer and die as a result.

Let's look at the second technology: protofection. This is a methodology demonstrated to be a means by which scientists will be able to completely replace the mitochondrial DNA in your cells:

Today our team confirmed our previous preliminary data showing that we can achieve robust mitochondrial transfection and protein expression in mitochondria of live rats, after an injection of genetically engineered mitochondrial DNA complexed with our protofection transfection agent. A significant fraction of cells in the brain is transfected with this single injection even though we so far did not optimize the dose.

This achievement has important implications for medicine: protofection technology works in vivo, and should be capable of replacing damaged mitochondrial genomes.

Replacing damaged mitochondrial DNA means completely shutting down the consequences of free radical damage. You're not slowing this aspect of aging, you're stopping it - and for the already aged, you would be reversing this form of aging damage. With a mature protofection technology, people could repair mitochondria every time it was needed - and consider that most folk make it through their first 30 years just fine at the present rate of damage.

It should be quite clear that protofection is a far superior and more efficient answer to free radical damage of mitochondria than any form of antioxidant therapy. Now consider this: in the present day of highly regulated medicine and expensive development, both these technologies would likely cost much the same in money and time to move from where they are now to widespread, safe use in humans. Where would you invest the time and money?

That, then, is the point - the practical difference between slowing aging and reversing (or repairing) aging. Presently, that portion of the scientific community invested in longevity and aging research is heavily - almost completely - weighted towards slowing aging and manipulating metabolism, such as in the case of the catalase work above. If work in repairing aging had as much interest, backing and support, then we could have our cake and eat it - use techniques that slow aging as stepping stones to live in good health to take advantage of techniques that reverse aging. But that is not the case today, and without a great deal of hard work (by organizations like the Methuselah Foundation, amongst others) it will not be the case tomorrow either.

The bottom line is this: we can miss the boat or not - it's up to us.

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As Aubrey de Grey has alluded to, a large part of the problem is that mainstream aging research is being led by scientists and not engineers. Scientists have been conditioned to pursue the more fundamental solution regardless of whether it's the most effective one. In the case of aging, the more fundamental solution is metabolic tinkering, while the most effective one is repairing damage. I think there is hope though. The biomedical sciences seem to be becoming more cross disciplinary. As different backgrounds enter the game the mindset of the players may change.

Posted by: D at November 7th, 2006 11:13 AM

I've been taking resvertrol (90mg/day -- upping that to 180/day now, based on Sinclair's high dosage) for two years now. I'm 45, and I want to live long enough to live forever. That should be our slogan. (Thanks, Kurzweil.)

There's just too much evidence pointing in favor of this molecule being a near miraculous PRO-HEALTH molecule. In large part thanks to the French and their poor eating habits.

The young have time to wait until there's more proof for resveratrol, but the 40+ among us are fools for not jumping on the bandwagon now. It might not specifically mimic CR, but it's very clear it leads to a healthier life, and that likely translates into extra years anyway.

Resveratrol is merely a stepping stone until SENS or something similar comes along. Even the 20 years old's among us might need this stepping stone one day. Progress is never predictable.

Posted by: Scott Miller at November 7th, 2006 1:32 PM

Your post would make sense if the following
were true:

(1) it's possible to completely repair and reverse aging in the next 10 years

(2) funding and research in metabolism slowing
aging is preventing the amelioration of aging
and stretching 10 years into 30

In this case, anyone who is in their 60's and 70's would be really missing out by this needless
research into the slowing of aging.

In reality, people who are in their late 60's and
70's, I'm sorry to say, are going to die. It's a
cruel tragedy that the timeline of their birth left them out of the amazing singularity that we're approach in the coming decades. But this
is the reality. If all the $$$ that were pouring into metabolism were poured into repairing and reversing aging, there would be little difference in the timeline. This is my thesis and it is the opposite of yours.

So get real, we'll need both approaches. And by "we", I mean people in their 50's and under.

Sorry, that's life (and it's too short)

- Joel

Posted by: Joel at November 8th, 2006 9:09 PM

Hmm. Your post would make sense if:

1) It possible to completely repair and reverse aging in the next 30-50 years

But (1) is false for many reasons, for example: SENS has a $800 funds/month
which is even not sufficient to pay internet bills to keep this blog updated. Come on.

I'm no biologists but I've read enough to notice that SENS is just a idea, a kind of science- fiction, loosely based on science. Face the fact none of 7 deadly things of SENS are going to be solved anytime soon (ie. one of them is a robust cure for cancer which we fight with all we've got since 30 years)

Conclusion: Don't put down those over 60 because your situation isn't any better. We're all going to die;) Sorry.

Posted by: Tom at November 9th, 2006 1:06 PM

I wonder why you would bother to visit
a site like this one ? Just to annoy like
minded people ? Also, you clearly think
Aubrey is an idiot. But do you think
Kurzweil is an idiot also ? If so, then
I think most people would conclude that you're
the idiot. If not, then your logic is twisted.

- Joel

Posted by: Joel at November 9th, 2006 7:34 PM

No, actually I think Aubrey de Grey is a genius type. If he was a cheater he would have a lot better self-presence, social skills and higher self-esteem. Which is why he's so ineffective. One thing’s for sure no one can develop very complex anti aging medicine if his resources are limited to a pair of old shoes and a personal computer, even if he's truly brilliant.
We're very far from reaching SENS goals. 30years is absolute minimum but only if SENS is pursued with maximum efficiency. But it is so not. Which is why I'm pessimistic about it.
But you're taking 30years timeframe as a fact which is wrong. I think that everyone's chances are the same, it could be 1 year (i.e. telomerase) or it could be 1000 years (to reach SENS goals). No one knows, because you can't predict discoveries.

Posted by: Tom at November 10th, 2006 11:09 AM

you go from 30 to 50 years being "false for many reasons" to "30 years is the absolute minimum" --
you're all over the map.

if I were taking "30 years as fact" then I wouldn't care about resveratrol for crying out

I have absolutely no idea what the timeframe is, which is why I like a dual track of slowing aging and making progress toward SENS. I think the shorter the timeframe one postulates, the less likely it is.

Posted by: Joel at November 10th, 2006 9:10 PM

30 is the absolute minimum only _if_ SENS is developed at full sppeed. It is not. I conclude 30 years is unrealistic.

If you have no idea then why are you saying that people in their late 60's won't benefit?

Also what makes you sure that you won't die in your 40's or 50's from cancer? You have a quite good chance, as everyone.

Posted by: Tom at November 11th, 2006 12:10 AM

Tom, SENS is indeed underfunded and in its infant stages. That doesn't make it a pipe dream though.

Yes, the 7 things are hard as hell to solve, Aubrey only points to therapies beginning to develope in them, not saying they're near being solved.

The point being, work is started, and the intent is to spread the word to garner funding. Pay attention to the media, more than ever people are talking about slowing aging, antioxidants and all the shit on TV.

Although, I do think Aubrey and Kurzweil are a bit optimistic in their futurology (I don't know how you can come up with the number of years, even in estimations), but I guess they need to be as promoters.

Posted by: Tyciol at November 20th, 2006 11:15 AM
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