Sunday, April 10, 2005

The Seven Pillars of Senescence

A few more thoughts on Aubrey de Grey's work, written down as notes while updating the
"anti-aging" chapter in "The Path to Posthumanity" as I prepare the final version of the manuscript...

Check out de Grey's site here, it's well worth a few hours reading even if biology isn't one of your main interests...

Of all the senescence researchers out there, no other has done as much as Aubrey de Grey to improve our integrative understanding of the overall picture of the phenomenon of aging. I don’t always agree with his proposed solutions to particular sub-problems of the aging problems, but I find him invariably energetic, rational and insightful. Although he says he’s not a big booster of caloric restriction for humans, because he thinks its effect diminishes rapidly with the size of the organism, he’s also one of the skinniest humans I’ve ever seen, and he gives the appearance of being robustly healthy, so I suspect he’s practicing some approximative variant of the caloric restriction diet.

de Grey’s buzzword is SENS, which stands for Strategies for Engineered Negligible Senescence – a very carefully constructed scientific phrasing for what I’ve loosely been calling here “anti-aging research.” The point of the term is that it’s not merely slowing down of aging that we’re after – it’s the reduction of senescence to a negligible level. And we’re not trying to achieve this goal via voodoo, we’re trying to achieve it via engineering – mostly biological engineering, though nano-engineering is also a possibility, as in Robert Bradbury’s “robobiotics” idea.

As part of his effort to energize the biology research community about SENS, de Grey has launched a contest called the “Methuselah mouse prize” – a prize that yields money to the researcher that produces the longest-lived mouse of species mus musculus. In fact there are two sub-prizes: one for longevity, and the “rejuvenation” prize, given to the best life-extension therapy that’s applicable to an already-partially-aged mouse. There is a complicated prize structure, wherein each research who produces the longest-lived mouse ever or the best-ever mouse-lifespan rejuvenation therapy receives a bit of money each week until the his record is broken.

His idea is that, during the next decade or so, it should be possible to come pretty close to defeating senescence within mice – if the research community puts enough focus on the area. And then, porting the results from mouse to human shouldn’t take all that much longer. Of course, some techniques will port more easily, and unforeseen difficulties may arise. But of course, if we manage to extend human lives by 30 or 40 years via partly solving the problem of aging, then I’ll have 30 or 40 extra years in which to help the biologists solve the other problems….

Theory-wise, de Grey (correctly IMO) doesn’t believe there’s one grand root cause of senescence, but rather that it’s the result of a whole bunch of different things going wrong, because human DNA wasn’t evolved in such a way as to make them not go wrong. On his website, he gives a table of the seven causes of senescence, showing for each one the date that the connection between this phenomenon and senescence first become well-known to biologists – and also showing, for each one, the biological mechanism that he believes will be helpful for eliminating that particular cause.

The seven causes are:

1. Cell loss, cell atrophy

Discovered: 1955

Potentially curable, according to de Grey, via: Stem cells, growth factors, exercise

2. Nuclear [epi]mutations


WILT (Whole-body Interdictionof Lengthening of Telomeres)

3. Mutant mitochondria


Allotopic expression of 13 proteins

4. Cell senescence


Ablation of unwanted cells

5. Extracellular crosslinks


AGE-breaking molecules/enzymes

6. Extracellular junk


Phagocytosis; beta-breakers

7. Intracellular junk


Transgenic microbial hydrolases

Seven basic causes – is that really all there is? Well, as de Grey puts it, “the fact that we have not discovered another major category of even potentially pathogenic damage accumulating with age in two decades, despite so tremendous an improvement in our analytical techniques over that period, strongly suggests that no more are to be found -- at least, none that would kill us in a presently normal lifetime.” Let’s hope he’s right….

One of these “Seven Pillars of Aging” should be familiar to those of you who read my essay on mitochondrial DNA and Parkinson’s disease (pointed to in a blog I posted yesterday or the day before): mutant mitochondria. Looking at this case a little more deeply is interesting for what it reveals about the strength and potential weaknesses of de Greys “engineering” based approach. The term “engineering” in the SENS acronym is not a coincidence -- de Grey came to biology from computer science and he tends to take a different approach from conventional biologists, thinking more in terms of “mechanical” repair solutions. Whether his approach will prove the best or not, remains to be seen; frankly I’m not biologist enough to have a strong general intuition on this point. The mainstream molecular biology community seems to think de Grey’s proposed solutions to his seven problems reveal a strange taste, but this doesn’t mean very much, as the mainstream’s scientific taste may well be mortally flawed.

Regarding mitochondrial DNA damage, de Grey’s current proposal is to fix it, not by explicitly repairing the DNA as in GENCIA’s protofection technique mentioned in my article on Parkinson's disease, but rather by replacing the flawed proteins produced by the flawed mitochondrial DNA. This could work because there is already an in-built biological mechanism that carries proteins into mitochondria: the TIM/TOM complex, which carries about 1000 different proteins produced from nuclear DNA into the mitochondria.

What de Grey proposes is to make copes of the 13 protein-coding genes in the mitochondrial genome, with a few simple modifications to make them amenable to the TIM/TOM mechanism, and then insert them into the nuclear chromosomes. Then they’ll get damaged much more slowly, because the nuclear chromosomes are a lot more protected from mutations than mitochondrial genes.

Sensible enough, no? Whether this or protofection is the best approach I’m really not certain, although my bet is tentatively on protofection, which seems a bit simpler (since as de Grey admits, fooling the TIM/TOM mechanism in an appropriate way could wind up to be difficult). Unfortunately, neither approach is being really amply funded at the moment, though.

Similarly, each of de Grey’s other six categories of aging-related damage is amenable to a number of different approaches – and we just need to do the experiments and see which one works better. A lot of work, and a lot of micro-level creativity required along the way – but straightforward scientific work of the kind that modern biologists are good at doing. It may well turn out that senescence is defeatable without any really huge breakthroughs occurring – just via the right combination of clever therapeutic tricks like protofaction or mitochondrial protein replacement.

Depending on how well this work is funded and how many “hidden rocks” appear – and what happens with the rest of 21’st-century science and technology -- the process of scientific advance may or may not be too slow to save us from dying. But it seems nearly certain that for our grandchildren, or great-great-grandchildren, “old age” may well be something they read about in the history books, along with black plague and syphilis, an ailment of the past.


Mentifex said...

As part of my Ai Has Been Solved campaign, the Rejuvenate mind-module solves the robotic immortality problem by erasing old, unused memories in order to make room for fresh, incoming memories. If Aubrey de Grey or Ben Goertzel or Peter Pan or Ponce de Leon succeeds in making human beings immortal, how will the problem of lifelong human memory capacity be dealt with?

Anonymous said...

Ben, early in 2000 I believe, it was discovered that a cell goes into senescence because some fibres at the end of chromosomes (telomeres) responsible for sequence replication in cell division become flush with the end and therefore no more telomerase is produced and the cell dies. Wouldn't you think that telomere research would be the key to Aubrey's SENS project? ie via artifical production of telomerase for example?

Anonymous said...

Also perhaps you may be curious to see this most recent info on related topic:
New Books Discussing Aubrey de Grey Ideas
Shorter link: