Musings of a Cancer Doctor
Wide-ranging views and perspective from George W. Sledge, Jr., MD

Tuesday, October 25, 2016

A Quest to Live the Longest

Every now and then I see an article trumpeting "the oldest" this or that—sometimes human, sometimes a non-human vertebrate, sometimes a tree. The "oldest human" competition is one you never actually want to win. It seems something akin to "longest stretch on death row": an achievement, no doubt, but not one that you would feel comfortable owning.

Still, these stories have their own charms. Recently, some Danish biologists anointed the Greenland shark as "the oldest living vertebrate." Greenland sharks, as their name suggests, hug the coast of Greenland in the North Atlantic and Arctic Ocean. Why they do not, like Canadians in January, migrate to the Florida Keys is a mystery. What science knew about them until quite recently was limited: they are quite long (up to six meters) and they grow at a glacial pace (a few centimeters at most per year) and swim quite slowly (1.22 km/h). Katie Ledecky would have no trouble swimming faster than your average Greenland shark.

In an attempt to get at the age of the Greenland shark, investigators carbon-14 dated a shark's eye lenses. Why the lens? Because Greenland shark lenses do not change after birth. To their very great astonishment, they came up with a life expectancy of 392 +/- 120 years. There may be Greenland sharks swimming in the Arctic that were born around the same time as William Shakespeare.

An interesting side note: Greenland sharks have high concentrations of trimethylamine oxide and urea in their flesh. The trimethylamine oxide (an adaptation to living in deep waters) is converted to trimethylamine when you eat a Greenland shark, and can make you quite drunk. Kæstur hákarl, an Icelandic delicacy made from the Greenland shark, smells like urine and has been described by Anthony Bordain as "the single worst, most disgusting and terrible tasting thing" he had ever eaten. Also, Greenland sharks don't reach sexual maturity until they are 150 years old. Or maybe they just can't stand the smell of each other.

So, to summarize: if you are a Greenland shark you live in the darkest, coldest water on the planet, you smell bad, you move very slowly, and you cannot get a date until midway through your second century. Why would you want to live four centuries? Because you can, apparently.

The World's Oldest

The "oldest living" list for animals includes: tortoise (250 years), lizard (117 years), and koi (226 years). Vertebrates don't match up all that well against invertebrates, alas: a clam named Ming lived 507 years, and would have lived longer except that, as a delightful USA Today headline stated, "Scientists accidentally kill world's oldest animal."

Note to old folks: stay away from them scientists.

Trees do even better than animals in "the oldest living" competition. The winner for "oldest tree" is a Norway spruce named "Old Tjikko" that lives in the harsh terrain of Sweden's Dalarna province. It clocks in at 9,550 years, though it is something of cheat for "world's oldest" in that it is a vegetatively cloned tree. The tree we see is relatively young (the tree trunk only lives for 600 years or so) and is a sprout off of the ancient root system. Old Tjikko is named after the dead dog of its geographer discoverer, not that it matters.

A Bosnian pine holds the European record for non-clonal trees at ~1,075 years old. The oldest non-clonal tree in the world is said to be a bristlecone pine tree from California's White Mountains named Methuselah that is around 5,000 years old. There was an even older one named Prometheus that (to quote a Mental Floss article on old trees) "was accidentally felled by a scientist who didn't realize the tree was as old as it was." I'm beginning to see a pattern here: per William Blake, "We murder to dissect."

Forever Young?

What all of these "world's oldest" seem to have in common is that they live in the world's barren places: mountains, deserts, the bottom of the Arctic Ocean. Not much grows there, and what grows does so at a leisurely pace. A Nature paper from 1999, entitled "Ancient stunted trees on Cliffs," found that vertical cliffs around the world "support populations of widely spaced trees that are exceptionally old, deformed and slow growing." These trees have radial growth of less than 1 mm per year.

Stunting your growth, then, is a good thing if you want to live forever. That, at least, seems to be the lesson from natural history studies. But it is also true at the mammalian end of the spectrum. Starve mice of calories and they live significantly longer.

Caloric restriction is probably a good idea for human as well, though it is unlikely to double one's survival, let alone allow a Methuselah-like existence. I've written, in previous blogs, about anti-senescence drugs (senolytics) and blood transfusions from the young as ways of warding off death. The latter derives from experiments in which a young mouse and a senescent mouse are sewn together, a process known as parabiosis, with resultant de-aging of the old guy. Now, it seems, such approaches are becoming popular among the wealthy.

Peter Thiel, a Silicon Valley tech investor best known for speaking at Donald Trump's Republican National Convention earlier this year, is an investor in Ambrosia. Ambrosia is a Monterey, Calif., company that has started a trial called "Young Donor Plasma Transfusion and Age-Related Biomarkers." As trials go, it is unusual: you pay the company $8,000 to participate. For anyone between the ages of 35 and 80, participation involves receiving the blood of plasma donors ages 16 to 25.

I looked up Ambrosia's trial (NCT02803554, in case you are interested) on ClinicalTrials.gov. The trial design is pretty simple: draw some blood, infuse plasma, draw some more blood a month later.

Lots of blood. The blood drawn is examined for biomarkers of aging, including—and this is only about a third of what is being tested—Interleukin-5, Interleukin-6, Interleukin-7, Interleukin-8, Leptin, Macrophage Inflammatory Protein-1 alpha, Macrophage Inflammatory Protein-1 beta, Macrophage-Derived Chemokine, Matrix Metalloproteinase-2, Matrix Metalloproteinase-3, Matrix Metalloproteinase-9, Monocyte Chemotactic Protein 1, Myeloperoxidase, Myoglobin, Neuron-Specific Enolase, Plasminogen Activator Inhibitor 1, Prostate-Specific Antigen, Free, Pulmonary and Activation-Regulated Chemokine, Serum Amyloid P-Component, Stem Cell Factor, T-Cell-Specific Protein RANTES, Thrombospondin-1, Thyroid-Stimulating Hormone, Thyroxine-Binding Globulin, Tissue Inhibitor of Metalloproteinases 1, Transthyretin, Tumor Necrosis Factor alpha, Tumor Necrosis Factor beta, Tumor necrosis factor receptor 2, Vascular Cell Adhesion Molecule-1, Endothelial Growth Factor, Vitamin D-Binding Protein, von Willebrand Factor.

You pretty much need the plasma infusion to survive the bloodletting. The clinical trialist in me says that the next time I drive to Monterey it will be to visit the aquarium. And would shooting up with a 20 year-old's plasma really be all that useful? What if the plasma you needed was from a 6-month-old? Ambrosia is looking to recruit 600 patients: we'll see how they do.

Ambrosia, you will remember, was the nectar of the gods in ancient Greece. Our modern gods appear terrified by the prospect that their billions will not suffice to render them similarly immortal, hence their interest in anti-aging technology. Meanwhile, another Silicon Valley company, Alkahest, is performing the PLASMA (PLasma for Alzheimer SymptoM Amelioration) Study with neurologists at Stanford. According to ClinicalTrials.gov, this one has more modest aims, being primarily a feasibility study with a few dementia metrics thrown in as secondary endpoints. Let's hope it works. I'm burning through cortical neurons at an alarming rate.

Anyways, modern science is now in hot pursuit of anti-aging strategies. Whether the pursuit of Greenland sharkdom or Ming the Clam or Methuselah the bristlecone pine is worthwhile I will leave to your philosophical imagination. I tend to side with Gilgamesh of Uruk on this:​

What you seek you shall never find.

F​or when the Gods made man,

They kept immortality to themselves.

Fill your belly.

Day and night make merry.

Let Days be full of joy.

Love the child who holds your hand.

Let your wife delight in your embrace.

For these alone are the concerns of man.