life and death why

Have you ever wondered why all living things eventually die? And, by the way, whether anything can be done about it?

As I was pondering these questions, I came across a delightful video with the provocative title, The Animal That Wouldn’t Die. It is part of Robert Krulwich’s NPR series Krulwich Wonders. Krulwich is an award-winning science correspondent for NPR and co-host of one of my favorite radio shows, Radiolab.

The animated video tells the story of an odd little pond creature that is known as the hydra, a living thing that apparently lives forever. Watch it before reading on. It only takes about 4½ minutes and is well worth your time. You will not only learn about the hydra’s failure to die, but also about a young man named Daniel Martinez who studied the creature and eventually wrote a paper, Mortality Patterns Suggest Lack of Senescence in Hydra, that described his observations. You will also have a chance to admire Krulwich’s genius at presenting the wonders of nature.

 

Why the hydra?

The video raises the question: Why the hydra? If non-senescence, or biological immortality, is an option in nature, how come this particular mini-bit of pond scum got the big prize? Why not the gastrotrich, another pond scum that only lives seven days? Or for that matter, why not us? It’s a really profound question.

As we learn in the video, the hydra is made up of barely differentiated embryonic stem cells. This little pond scum creature has no moral hangups about continuously getting rid of the old cells and replacing them with new ones. In fact, the hydra replaces all of its cells every twenty days. There are no senescent (aged) cells—ever—in the hydra. If that’s not enough, consider this: If you cut a hydra in half, each half would regenerate itself to make a complete daughter hydra, indistinguishable from the mother hydra.

So, the answer to the question, what allows the Hydra to live forever?, is that it continually ejects and replaces all of its old cells with new ones. Our own stem cells are immortal as well. But in us, and all other mortal organisms, the stem cells differentiate into the various tissues that make up the body: heart, liver, brain, skin, and so forth. These cells age with time and get disposed of in various ways.

Having multiple mechanisms to get rid of this garbage (or is it “cellular ageism” to refer to the elderly cells as garbage) suggests that it is terribly important. A senescent cell is an easy target for environmental insults, and because of that, it accumulates mutations. These mutations cause a lot of problems for us, not the least of which is cancer. When we are young, our garbage disposal works well and we get rid of the decrepit old cells. But as we age, the garbage collection and disposal mechanisms slow down (like everything else) and we start to accumulate defects here and there.

Our senescent heart muscle gets weaker; our chondrocytes (cartilage cells) fail to make new cartilage so we get osteoarthritis; our fibroblasts (skin cells) make less connective tissues; and, OMG, our skin thins and we get wrinkles. More seriously, our intestinal cells accumulate mutations and we get colon cancer, and senescent brain cells may develop into brain cancer. That is why you and I and even Robert Krulwich will definitively and terminally die…and the hydra won’t.

If cell senescence is so deleterious, you might wonder why natural selection didn’t get rid of the creatures who have it and select for the ones who don’t? In other words, why don’t hydra dominate the world? The answer is that it’s all about reproduction. Having a long lifespan doesn’t make an animal more likely to succeed at reproducing because selection pressure works on the young. Once you have finished replacing yourself with offspring, natural selection doesn’t really give a fig about whether you die of cancer or whether you live to be 1000.

 

Seeking immortality

Leave it to the ingenuity of humans: We never give up on the dream of living forever. Well, not quite forever but a whole lot longer than we do now. A while back, Stephen S. Hall described the work of a Harvard University cell biologist, Amy Wagers, in an interesting article in Science Magazine:

“In a series of experiments that have captivated both the field of regenerative medicine and its many lay spectators, Wagers and a diverse army of collaborators have shown that when the blood of a young mouse circulates through the murine equivalent of an old geezer, startling physiological changes occur. Many of the trademark depredations of old age—withering muscles; stiff, oversized hearts; cognitive decline; and even the fraying of the myelin coating that insulates nerve fibers—are slowed, repaired, or even reversed.”

Wagers and her collaborators proceeded to isolate from the young blood the rejuvenation factor, a protein called GDF11. This protein is also present in us humans.

It would be naíve to assume that this is the only protein that regulates senescence, and as quoted in the Science article, Wagers is the first to acknowledge that the biology is far from settled,

“This is a complicated and robust system of regulation, so there are likely multiple signals.”

Since that time, Wagers, who has since become a Harvard professor, has had 3 papers coming out of her lab retracted. To her credit, when fraud (image manipulation) by a post-doc member of her team was detected, she wasted no time in informing the scientific world about it. This is admirable conduct for which she should be applauded (have you seen any of our elected officials retract their lies recently?).

Still, it raises a yellow flag of caution. So far, no mouse studies outside Wager’s lab have been able to replicate the original finding suggesting that GDF11 is, in fact, a rejuvenation protein. Interestingly, an article in The New Yorker titled, Silicon Valley’s Quest to Live Forever, revealed that “the drug company Novartis promptly did a study that suggested the exact opposite, you should blockade GDF11.”

 

The quest continues

Thomas Rando’s lab at Stanford has been pursuing blood-borne factors in older mice that seem to suppress stem cell activity and blunt their regenerative capacity. Irina and Michael Conboy’s lab at UC Berkeley reported that levels of the hormone oxytocin in the blood decline with age, and increased amounts of oxytocin seem to play a major role in activating adult muscle stem cells and improving muscle regeneration—within a couple of weeks! Wyss-Coray, who worked in the room next to Rando’s lab, reported in Nature Medicine that infusions of “young blood plasma” reversed the neural and cognitive impairments of old mice—largely by rejuvenating the function of synapses.

Not confused yet? Here is yet another wrinkle in the story. All the above studies employed the technique of parabiosis, meaning that the blood circulation of the old and the young mice in the pair was joined. But this raises a question: How do you know which blood had the major effect? Was it the young blood that rejuvenated the old mouse, or was it through shared organs? In a new study, Conboy and her colleagues created a way to exchange the blood of young and old mice without joining their circulation and thus without sharing their organs, and the mixture was 50-50. What they found raises even more questions; the exchange affects tissues within a few days. In old mice, there was some improvement in muscle repair and liver fibrosis, but young mice paid a stiff price; they experienced worsened cell formation in the brain hippocampus and impaired coordination. The declines happened rapidly, suggesting an inhibitory factor(s) contributed by the old blood.

What do all those publications, some complementary, other conflicting, mean? My take is that the field is rife with new discoveries, and only time and hard work in the various labs will bring order to the creative tumult.

I can’t but echo Robert Krulwich:

“Whoa! Life is a puzzlement.”

And infinitely amazing.


This post was first published September 29, 2014. It was reviewed and updated on 07/14/2017 to reflect the current state of the science.

Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.

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