May 29, 2014
Can GDF11 Really Extend Lives?

The hope is that reversing the decline of a protein in the blood will make the aging body partially rejuvenate itself. Can GDF11 partially reverse the aging process?

Cambridge, MA, May 4 - Harvard Stem Cell Institute (HSCI) researchers have shown that a protein they previously demonstrated can make the failing hearts in aging mice appear more like those of young health mice, similarly improves brain and skeletal muscle function in aging mice.

In two separate papers given early online release today by the journal Science which is publishing the papers this coming Friday, Professors Amy Wagers and Lee Rubin, of Harvard's Department of Stem Cell and Regenerative Biology (HSCRB), report that injections of a protein known as GDF11, which is found in humans as well as mice, improved the exercise capability of mice equivalent in age to that of about a 70-year-old human, and also improved the function of the olfactory region of the brains of the older mice they could detect smell as younger mice do.

Clinical trials in 3 to 5 years. Sound exciting?

Rubin and Wagers each said that, baring unexpected developments, they expect to have GDF11 in initial human clinical trials within three to five years. Postdoctoral fellow Lida Katsimpardi is the lead author on the Rubin group's paper, and postdocs Manisha Sinha and Young Jang are the lead authors on the paper from the Wagers group.

Why to temper your enthusiasm: All those cells that damped down their activity due to declining GDF11 with age are dangerous. They are a far greater risk every time they divide than is the case with young cells. Why does GDF11 decline with age? Same reason I suspect many hormones (e.g. testosterone) decline with age: on average it is safer that way.

The body's many cells accumulate damage with age. Turn up the metabolic knobs on those cells and you run the risk of turning them cancerous. Also, even when cancer becomes curable we'll still face at least one other problem from stimulating old cells to divide a lot: if cells are stimulated to divide more times they'll wear out sooner (due to shortening telomere caps) and go senescent (stop dividing at all and become dysfunctional). I've made these points back in 2003, again in 2005 (about research that used young blood to serve the same role to stimulate cell growth in old rodents), again in 2006 and since then.

I'd really like to get as excited by GDF11 as many other reports have. But we need cures for cancer as well as ways to kill senescent cells (since killing senescent cells delays old age diseases in mice). Plus, we need ways to extract cells from our bodies, select for cells with little DNA damage, and then rejuvenate and convert the cells into stem cells of various types. Then we could introduce these cells back into the body, feed in the GDF11 (and likely other as yet undiscovered growth factors as well)

The cancer risk is not decisive in all cases. Imagine yourself at, say, age 60 and with early signs of heart disease or some other generation of an organ. Your risk of dying from something side from cancer could be judged so high that turning up aged repair systems in your body could lead to overall odds of longer life. If your ticker isn't going to let you reach 65 then why not run some marginally higher risk of getting cancer?

Share |      Randall Parker, 2014 May 29 12:02 AM 


Comments
Cluebat said at May 29, 2014 6:22 AM:

Very good analysis. Thank you.

DdR said at May 29, 2014 12:10 PM:

Randall,

What's the evolutionary advantage of a 70-year-old man surviving with little desire to replicate due to low testosterone?

In other words, why would mother nature select for humans to live to 90+ and beyond, but not preserve their hormonal state in order to keep reproducing? Why would mother nature select for humans to hang around at all long after their reproductive window?

My guess is that grandparents contributed to the survival of the infant by being babysitters, conveying knowledge, and helping around the house. This required less physical and mental faculties, thus the selection for declining hormones and brain power over time. If we maintained our hormones and mental/physical power well into our 90s, then we would be competing with our children too much for resources and mates.

Coincidentally, a person's crystallized memory increases over time. This obviously helps grandpa tell better stories of ancestors and lessons learned.

I think increased rates in cancer is a coincidence for increased hormonal levels. A person who gets cancer at this later stage in life has already reproduced, so this disadvantage would never be selected against.

And can you evidence the same? Because what I've seen is that for men who begin supplementing testosterone there are improvements in all-mortaility causes.

Otherwise keep up these interesting posts. I think your suggestions on how to increase longevity are on the right path, but it'll have to be coupled with humans expanding beyond Earth, otherwise you'll have too many people and too much competition for resources.

Tim Hogan said at May 30, 2014 7:46 AM:

GDF11 diminishes because aging is programmed in one reason being to prevent famine leading to extinction. Maybe its progressive DNA methylation changing protein expression which drops GDF11. It won't be just GDF11 either. There are probably at least a few others that need to be maintained or administered for optimum longevity but GDF11 could be the primary protein. Once GDF11 becomes widely administered and the average age passes 200 or so a new protein will have to be invented to prevent famine.

Nick G said at May 30, 2014 3:44 PM:

Randall,

It's seems clear to me that lifespan is programmed genetically. Bats and Naked mole rats both live about 10x as along as rats. Humans live 2x as long as chimps, and 20x as long as Great Danes. In these cases of longer lifespan cancer is delayed along with other signs of senescence: it's not a tradeoff. Something tells the body when to stop repairing itself, when to stop replacing or killing cells, etc., and everything falls apart at pretty much the same time.

Evolution uses proven sub-systems as building blocks for more complex creatures: I suspect that the switches and compounds that regulate this clock and implement it's timing will turn out to be fairly simple.

Unfortunately, we have systemic barriers to finding these keys to longevity. Those barriers include an inability to patent natural compounds, which means that drug companies pour enormous resources into creating vastly inferior synthetic compounds; and fear of drugs which are too effective, which would wipe out existing drug company revenue streams (what really happened to the synthetic resveratrol compound that was purchased for $720M, then quietly discontinued?).

I'm beginning to wonder if real change will come out of left field (like Tesla): maybe from a private institute like Buck, or from Shanghai.

Nick G said at May 30, 2014 3:47 PM:

otherwise you'll have too many people and too much competition for resources

That's easy to fix - it's fixing itself right now. Each generation just has to be smaller than the one before, and pretty soon you'll have a steady-state and stable population, no matter how long people live.

We're already close: Japan, Italy and Russia have very low fertility rates: each generation is much smaller than the one before.

coolball said at June 1, 2014 8:09 PM:

Regards cancer, some mice are highly immune to cancer. It is the case that it seems a fraction of the human population is also highly immune to cancer(e.g. the 60 cigarettes a day centenarian).

That said, nature has ways to prevent cancer that do not cause aging, e.g. negligible senescent species.

That said, it's been seen that there are detrimental mutations that provide replicative advantage to subpopulations of sperm precursor cells causing these to outcompete healthy sperm precursor cell lines. This results in genetically less fit progeny and an increase in probability of progeny disease. What does this mean? That just like the case of the westermarck effect and incest avoidance in order to avoid less genetically fit progeny, aging could very well be genetically caused to prevent age related less genetically fit progeny.

Brett Bellmore said at June 2, 2014 3:42 AM:

Coolball: This doesn't seem to be an issue for naturally long lived species such as the Galapagos Tortoise.

The notable thing about naturally long-lived species, is that they generally inhabit environments where, once you achieve adulthood, your prospects of dying from predation are very low. I think the key driver of genetic longevity is having a long evolutionary history where individuals with the potential to live a long time actually get to do so. Then the chance to reproduce at age actually gets used, and can drive evolution. Nature, always content with "good enough", does not build it's creatures to last longer than they get the opportunity to last.

What we're seeing with human longevity is merely the consequence of a long evolutionary history where something would kill you before you got past your 30's. Evolution had no drive to assure health at an age you wouldn't reach.

We do a lot of longevity research in mice, and other short-lived species. That's understandable, you have time to observe longevity changes from interventions, but we're more likely to increase our own longevity by adopting strategies other species have used to live a long time. There are a lot of solutions other species have found, for us to copy into our own genome.

Brett Bellmore said at June 2, 2014 3:43 AM:

Coolball: This doesn't seem to be an issue for naturally long lived species such as the Galapagos Tortoise.

The notable thing about naturally long-lived species, is that they generally inhabit environments where, once you achieve adulthood, your prospects of dying from predation are very low. I think the key driver of genetic longevity is having a long evolutionary history where individuals with the potential to live a long time actually get to do so. Then the chance to reproduce at age actually gets used, and can drive evolution. Nature, always content with "good enough", does not build it's creatures to last longer than they get the opportunity to last.

What we're seeing with human longevity is merely the consequence of a long evolutionary history where something would kill you before you got past your 30's. Evolution had no drive to assure health at an age you wouldn't reach.

We do a lot of longevity research in mice, and other short-lived species. That's understandable, you have time to observe longevity changes from interventions, but we're more likely to increase our own longevity by adopting strategies other species have used to live a long time. There are a lot of solutions other species have found, for us to copy into our own genome.

coolball said at June 2, 2014 5:20 PM:

"This doesn't seem to be an issue for naturally long lived species such as the Galapagos Tortoise."

We would need genetic analysis of the germline cell lines to be sure. It is possible that they're an anomaly like multicellular animals that reproduce asexually or through cloning. Alternatively if the progeny are thrown into the ocean with high mortality, that would do away with the less fit progeny making it unecessary for aging to take place as a measure against less genetically fit progeny.

Brett Bellmore said at June 3, 2014 3:42 AM:

The Galapagos tortoise is entirely land-dwelling, but, in as much as they can lay 20 eggs at a time, there must be a good deal of infant mortality.

Of course, we have a good deal of that ourselves, much of it occurring before birth.

Randall Parker said at June 9, 2014 8:28 PM:

Guys,

I do not find the "programmed to die" argument convincing. What kills us? Accumulated damage. We get too many mutations in cells and they go cancerous. Or our immune systems become too weak from accumulated damage and a bacteria kills us. Or we get too much accumulated damage in arteries and we get a stroke. et cetera.

What selective pressure does: it boosts fertility and competitive ability when we are young in ways that cause our bodies to wear out more quickly. The selective pressure isn't to kill us later. It is to make our engines over-rev.

The declining hormone levels are more likely selected for to prevent the body from dying even sooner. Sometimes those decline rates will be too steep and hormonal supplementation could extend the lives of some. But for others the opposite is probably the case: burning too brightly and burning out sooner as a result.

If genetic programming is lowering our levels of testosterone or GDF11 in order to kill us then testosterone or GDF11 ought to make us live longer. Time will tell. But I would rather have replacement cell and tissue therapy along with great ways to kill precancerous and cancerous cells. Those approaches will extend lives.

Nick G said at June 10, 2014 3:01 PM:

Yes, accumulated damage seems to be the problem. But what dictates the rate of wear and repair, and why? As a race, we're immortal - our reproductive cells are able to keep errors at a very low level, or repair them. Why not other cells?

Humans clearly have clocks, including telomeres, puberty and menopause. Clearly some animals do too - salmon die within days of reproducing, as do some other creatures.

A 10 year old dog looks very much like a 70 year old person: the same constellation of symptions, but much earlier. What's the difference?

Some things look very, very complex until you figure out the organizing principles, like the spheres of astronomy that were needed until we figured out solar-centric orbits. I suspect most of aging will turn out to be like that.

Nick G said at June 10, 2014 3:05 PM:

The bottom line: there's no conflict between our views, because almost all medical research is good. You never know what will cross-fertilize with what.

We simply need *much* more fundamental research across the board, so we're not just working via trial and error.

And then, we need much, much better ways to get research into clinical practice.

Randall Parker said at June 10, 2014 9:11 PM:

Nick,

What keeps germline mutations down: Lots of things. Spontaneous abortions during pregnancy. Death during early childhood (at least before the modern era). Possibly a winnowing process against eggs before a baby girl is born.

10 year old dog and 70 year old person: The humans have been selected for to have longer lasting parts. How? e.g. species differ in their DNA polymerase error rates. There are costs to lower error rates. Each species has been subjected to different selective pressures and different chance mutations for DNA replication accuracy.

Nick G said at June 11, 2014 3:18 PM:

Randall,

The idea that aging is caused by parents no longer being needed is one of several competing theories of aging. The clock theory makes more sense to me: organisms are more successful when great-grand parents don't compete with their progeny. Also, generational turnover is essential to maintain genetic diversity, but excess longevity reduces turnover, thus a clock-limited lifespan is needed to keep population down.

What keeps germline mutations down: I have the impression that DNA protection and repair is much more effective in the germ cells. For instance, that egg winnowing process appears to be shut down in sperm, and carefully regulated in eggs to get just the right amount of variation in the next generation to optimize survival.

As noted in your second reference, "Successful organisms have thus evolved the means to repair their DNA efficiently but not too efficiently, leaving just enough genetic variability for evolution to continue". In other words, DNA error rates aren't random - they're at the level "chosen" by evolution.

So, what's the difference between the dog and the human?

"There are costs to lower error rates"

Do you have info on what those are? In theory, it seems to make sense, but I've never actually seen evidence that a certain kind of repair mechanism takes a certain amount of somatic energy, and that therefore too much repair is too "costly".

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