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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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January 21, 2008

Breaking the Contract of Aging

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Posted by Derek

Update: Prof. de Grey responds to Jim Hu's criticisms below

I didn’t note it at the time here, but back in November there was a very interesting paper in Nature that bears on aging and life extension. A group at the Hutchinson Center in Seattle did a survey of compounds, looking for whatever might show up that seemed to extend lifespan. (That’s just the sort of see-what-falls-out screen that C. elegans is good for, since the little beasts are so small, and they only live for about 20 days or so).

They screened 88,000 compounds - by far the largest direct survey ever run for longevity, as far as anyone knows, but (I should point out) still a tiny run by industrial standards. But they came up with a few hits: 1083 compounds made the first cut (roundworms still alive longer than they should be), and 115 of those repeated with statistical significance. 13 compounds increased lifespan by 30 to 60%. Interestingly, I don't think that they list all of them in the paper, but they did note that one of the strong hits looked very much like a known hit set of serotinergic antagonists.

They ran a set of analogs through the assay, and had a high hit rate. All the compounds that worked were 5-HT2 antagonists, such as marketed drug mianserin, although they each have some other activities as well. (It should be noted that the reuptake inhibitors, the Prozac/Zoloft type compounds, had no effect). But the 5-HT2 subtype, particularly 5-HT2c, has long been regarded as important in food intake, so the guess is that these compounds also tie into the whole caloric restriction story for aging. Restricting food intake and giving one of these drugs at the same time didn't add anything, the group found. It may be that these compounds set off metabolic signals that tell the roundworms that they’re short of food, even they they really aren’t, and thus do a sort of fake caloric restriction on them. At any rate, mutant nematodes that can't make serotonin showed no lifespan extension with exposure to these compounds, so one way or another, it seems to be involved.

Now, I wouldn’t advocate running out and trying this on a human being just yet, though, since we’ve come up with several higher brain functions for our serotinergic receptors that roundworms don’t have much call for. There’s also the question of what this strategy would feel like in a higher animal: would you want to live longer, but always feel as if you were starving, for example? I know that the people who are trying CR on themselves say that this isn’t the case, at least after the first few weeks or months (!), but there’s no telling what would happen with a pharmacological approach.

What this study does point out, though, is something that I think that a lot of people haven’t really caught on to yet: first, it’s increasingly clear that there are deep connections between metabolism and lifespan. All sorts of genes related to food intake and insulin signaling affect how long model organisms live, and there’s every reason to expect that the same is true of us.

Second, the settings for our lifespans may not be optimal – or what we’d now consider optimal. There’s every reason to expect that this relationship has been under very heavy selection pressure. Evolutionarily, this would be the balance between reproductive fitness and everything else an organism might do, and evolutionarily, reproductive fitness is going to be the big winner every time. But there’s no reason that we necessarily have to accept whatever tradeoffs were made during the development of our species.

We’re going to have to be very careful, of course. There may be all kinds of catches to extending lifespan – susceptibility to cancer and other diseases being the first one that everyone thinks of. But ever since our brains became large and complex enough for language and culture, and ever since we started growing our own food, we’ve been altering the evolutionary bargains that all other species have had to make – predator/prey relationships, availability of food, and so on. We may yet be able to draw a black line through another paragraph of the contract, and make it stick.

I don’t think that many people realize that this is possible, or that it’s an area of active research. Most of the large drug companies, in fact, seem to be staying away from it for now, content to let the smaller ones take on the (considerable) risks. Some people may not be able to get past Aubrey de Grey’s hair, and may have decided the whole subject is out on the fringe. But, increasingly, I don’t think it is. This stuff could work, eventually, and if it does, it’ll be one of the biggest inflection points in the history of the species.

Update: Jim Hu has more to criticize about de Grey than his hair - see here and here, for starters. Of course, as Jim himself points out in the comments, criticizing de Grey isn't the same as criticizing research on aging. Perhaps de Grey's high profile is doing as much harm as good for the field. . .

Comments (17) + TrackBacks (0) | Category: Aging and Lifespan


COMMENTS

1. Ageless on January 21, 2008 9:30 AM writes...

In species after species, it does seem as if there is a simple switch that can be flipped (biochemically or by caloric restriction) that tremendously extends lifespan, etc. That switch is just sitting there, waiting to be flipped.

Our species lives longer than most of our closest cousins.

Perhaps, in our case, the switch has already been flipped The would be anti-climactic.

Perhaps in other species, flipping that switch provides no evolutionary benefit to the species as a whole.. it just slows down evolution ~two-fold, making it harder to adapt to parasites, etc. But in our case, longer lifespan made longer adolescence possible, which gave more time to learn culture/technology, which is the main thing our species has going for it.

As our understanding of the relevant genes deepens, we may (if we have enough paleo-DNA samples) be able to determine if/when the switch was flipped. It would be interesting to correlate that to, say, widespread dispersion of our species.

Permalink to Comment

2. Jim Hu on January 21, 2008 11:01 AM writes...

I've been critical of deGrey on my blog. It's important to understand that criticism of de Grey's specific proposals regarding aging, which IMO are spectacularly dreadful, is not the same as opposing research on lifespan.

The main problem with de Grey isn't his hair; it's the specifics of his engineering approach to lifespan, which strike me as having the plausibility of Kevin Trudeau's approach to AIDS. YMMV.

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3. Shannon Love on January 21, 2008 11:24 AM writes...

I am a little dubious human lifespan can be increased significantly by manipulating a small number of compounds. Nothing else in biology really works that way.

Humans most likely already live as long as our innate design will allow. We live two to three times longer than other mammals of similar size. In preliterate times, the elderly served as walking databases providing an enormous survival advantage to their offspring and relatives. Selection would have favored as long a lifespan as possible for such useful people.

I think we will find ourselves forced to coordinate the actions of dozens, if not hundreds of factor,s to significantly increase lifespans.

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4. Barry Krakow MD on January 21, 2008 11:50 AM writes...

Anti-aging research would benefit immeasurably by focusing on sleep and evaluating what's already been done in the field of sleep research. One of the more remarkable findings in our field is observed when a person enters into a treatment program to enhance sleep quality; those around the individual will comment that he or she looks healthier, less tired, more alert...and guess what, younger!

The most obvious example of this phenomenon is sleep-disordered breathing (aka obstructive sleep apnea, upper airway resistance), which causes two major physiological disruptions: fragmentation of brain waves and destabilization of the oxygen baseline. In the first instance, sleep fragmentation means the individual is constantly cycling back and forth between light and deep sleep stages and sometimes constantly waking up for short bursts (unawares) and falling back a sleep. We're talking about hundreds of times per night. This sleep fragmentation plays havoc with brain function. Oxygen fluctuations occur a thousand times per night in sleep breathing patients; whereas, a normal oxygen baseline can remain relatively constant for long stretches, say 1 to 10 minutes at a time with little to no change. But, in sleep breathing patients, minor fluctuations of 1 to 4% are occurring repeatedly within as little as 5 to 30 seconds, often all night long. Recent research in rats shows that brain dysfunction occurs from even these minor fluctuations.

Last, these adverse sleep processes are likely to interfere with biochemical pathways, neurotransmitters, and hormones, through effects on insulin, cortisol, and possibly serotonin as well as being implicated in oxidative stress pathways.

Surely, this perspective is something to sleep on, but not for too long, as it is always to one's advantage to resolve sleep problems sooner than later.

Rest Wishes,

Barry Krakow MD

Blogging at www.sleepdynamictherapy.com
Center at www.sleeptreatment.com

Permalink to Comment

5. Daniel Newby on January 21, 2008 1:03 PM writes...

"One of the more remarkable findings in our field is observed when a person enters into a treatment program to enhance sleep quality; those around the individual will comment that he or she looks healthier, less tired, more alert...and guess what, younger!"

That could conceivably result from changes in metabolism and energy balance via the orexin/hypocretin system, which seems to simultaneously govern wakefulness, hunger, and energy conversion. Drugs that work on the orexin system might not only extend the absolute length of life, they could conceivably increase the wakeful fraction without the usual deleterious effects.

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6. ZZMike on January 21, 2008 1:27 PM writes...

Let's not forget the societal aspects of longevity. Assume that a drug becomes available.
The first treatments will be extremely expensive, and therefore available to those who can afford it. That'll cause societal friction between the "longs" and the "shorts".

Beside that, as people live longer, either the birth rate is going to have to go way down, or parenthood postponed to age 80+.

Clearly, this life-extension isn't going to happen worldwide. The gap between 1st- and 3rd-world countries will widen even further.

We should also expect the unexpected - the unintended consequences. Even the little life extension we have nowadays, over what we had in the Middle Ages, lets us live longer, but long enough to fall from diseases we didn't get a chance to have back then - like Alzheimer's.

If we do manage to extend a lifespan to 150 or 200 years, what new (and possibly more devastating) diseases might we expect?

Permalink to Comment

7. Pete on January 21, 2008 3:50 PM writes...

I, for one, would happily be the victim of a fatal disease at age 190.

Of course, I probably will not feel that way then.

Permalink to Comment

8. milkshake on January 21, 2008 3:53 PM writes...

DeGray suffers from heavy case of wishful thinking - but he is nice on a personal level and does harm to nobody so you have to take him as one of people that add flavor to academia. He is a great debater and if he inspires more funding for the field it is a good thing.

There is one evolutionary speculation that longer lifespan of women was selected because grandmas are generally less grumpy than granpas - and are more likely to care for little kidies and teach them some useful survival skills - such as how to dig for nutritious roots.

Permalink to Comment

9. kieth on January 21, 2008 4:12 PM writes...

I am 71 years old and, no surprise, I associate with older people including some in their 90s. Brain function has deteriorated in my own case and in every person I know over 70 (sometimes barely noticeable, sometimes plainly evident). Extending life without somehow getting a simultaneous extension of good brain function would be a big disappointment.

Permalink to Comment

10. milkshake on January 21, 2008 7:22 PM writes...

"Your tumour has now progressed beyond the point when you would benefit from a surgery. And you have been diagnosed with an onset of Alzheimer disease also. I am sorry".

"Oh that's alright. At least I don't have a cancer."

Permalink to Comment

11. MTK on January 21, 2008 10:53 PM writes...

milkshake,

The theory of nice grandmas for longer female lifespan certainly seems like a stretch to me. I guess I find it hard to believe that selective pressures would be significant when it would effect your offspring's offspring. Even if it did, wouldn't those pressures select for nice grandparents rather than just nice grandmas?

I'll posit this as an alternative, the longer female lifespan is not due to any direct selection but rather is an indirect result of other selection pressures which led to males having higher muscle mass, less body fat, and higher resting metabolism rates. This would also fit with the effects seen with caloric restriction. Burn slower, live longer.

Permalink to Comment

12. milkshake on January 21, 2008 11:45 PM writes...

To be even more offensive ogre: Whats the evolutionary advantage of women living long post menopause? Just have a look at the current ghetto tribal girls - they have their first child when they are most fertile, around age 14. And who raises these children of children? Grandmas do.

I was married to a pediatrician who worked in a Brooklyn ghetto hospital. All our friends were doctors too. And they all say that these young mammas are useless taking care of their kids well until the age of 30 - by which time they turn granmammas.

Happy Dr. Luther King Day!

Permalink to Comment

13. Aubrey de Grey on January 22, 2008 9:04 AM writes...

I was alerted via this blog to Jim Hu's blog posts of the past year or so critiquing SENS, and I wrote him a response which he has posted there (see link in his comment above) along with his re-response. Suffice to say that he's no longer describing SENS as "spectacularly dreadful." My second response to him, which I've just emailed him, may also appear at his blog shortly.

Permalink to Comment

14. PharmaChemist on January 22, 2008 9:09 AM writes...

Derek,
Did the paper really describe the compounds as 5HT2c ANTAGONISTS? This is curious as it would be agonists that would be expected to reduce food intake and caloric restriction, at least in mammals.

Permalink to Comment

15. Derek Lowe on January 22, 2008 9:43 AM writes...

PC, they did. I think that the idea was that they stimulated the hunger pathways that would be found in low-food conditions, rather than inhibited feeding and doing real caloric restriction. Kind of a bounce-shot approach, eh?

Permalink to Comment

16. MTK on January 22, 2008 10:07 AM writes...

Milkshake,

I'll concur: that is offensive.

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17. Anonymous Big Pharma Researcher on January 23, 2008 7:45 AM writes...


Hmmm, this is waay out of the aspects of drug discovery on which I work so I might be talking nonsense, but...

PC's posting, and Derek's followup, suggest to me a rather disturbing possibility: if drugs can simulate the physiological state of being hungry and thereby extend life, then might drugs that reduce appetite by simulating the physiological state of being fed risk SHORTENING life? Certainly in other areas we've seen evidence that a "good" biomarker might not be so good for outcomes (Pfizer's torcetrapib disaster last fall comes to mind), and cholesterol numbers represent one of the areas where we think we understand the MOA pretty darned well.

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