The Levin laboratory has found the developmental blueprint that tells the embryo how it must grow. The language of morphology is not genetic or epigenetic, not biochemical at all, but bioelectric. If, as I and others have speculated, aging is an extension of development into a program of self-destruction, then maybe aging follows a bioelectric blueprint. Maybe electrical interventions have a role in anti-aging therapies, supplementing or replacing the biochemical interventions that have dominated research in gerontology. Below I review a prospective analysis from the Levin lab.

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Background — Levin’s laboratory has put bioelectricity on the map

Michael Levin is my favorite living scientist. He is firmly rooted in laboratory biology, yet he has devised and interpreted his experiments so as to cast new theoretical light on biological mechanisms, again and again.

Levin studies morphology first. Why do bodies take the form that they do? How does the developing body know which organ to grow in which location? How does a hand know to generate exactly five fingers? How does the limb know when it is the right size, and it’s time to stop growing?

His signature thesis is that embryonic development is guided by electrical patterns, rather than gene expression. There are patterns of electrical potential that are maintained by cell walls that selectively allow the passage of some ions but not others. Voltage patterns imprinted across embryos contain detailed information about the shape and form of the adult, and how the embryo is to develop toward that goal.

At this point, you are wondering where the electrical patterns come from. The egg and sperm didn’t have these imprinted patterns, and the only information they carried was genetic and epigenetic. This is a crucial question, as Levin acknowledges, but he doesn’t yet have an answer.

Levin’s favorite model animal is the flatworm, Planaria. These worms rarely go through the trouble of sexual reproduction (which is essential in the long term for preserving the integrity of the genome). Commonly they reproduce clonally. Any small piece of a worm can regenerate a full body. As a result of long periods of asexual reproduction, the genomes of these worms are a mess, with different chromosomes — even different numbers of chromosomes — in a mosaic through the body. But no matter! The worms seem to develop their adult shape and function fully independent of what selection of genes happen to be available.

In one of Levin’s signature experiments, he is able to modify the electrical pattern in a piece of a worm, not touching any of the biochemistry, and the result is a worm with two heads and no tail. Or two tails and no head. Both seem to be perfectly viable, and survive well, at least in the lab environment. The two-headed worm breeds true, in that pieces of a two-headed worm will regenerate another two-headed worm, and pieces of a two-tailed worm will regenerate another two-tailed worm. But if the experimenter artificially induces a change in the electrical pattern, he can cause the progeny of either of these to revert to the boring phenotype with one tail and one head. The two-headed worms and the no-head worms do not differ genetically from the normal type.

I’m in danger of getting carried away with these results before I even get to Levin’s paper on aging. I’ll just mention two more.

Learning. You can train a worm in simple behaviors. Then cut off its head, and the tail grows a new head that remembers the behavior you taught to the old head. This is one of several counter-examples to the universally accepted common sense that memory lives in the brain. (The experiment was repeated in Levin’s lab, but originated decades ago.)

Adaptation. Barium salts poison the ion channels that cells use to maintain their electric potentials, and in planaria they cause a worm’s head to shrivel up. The worm grows a new head, and it is resistant to barium salts. Levin notes how unexpected this is. Worms in nature never encounter high enough concentrations of barium to cause a problem, so this is not an evolved adaptation to barium. And yet it is immediate. The worms know to turn on a handful of genes that are otherwise silenced and it solves their problem.

the cells detect (and act on) highly processed state information several steps removed from the proximal events at the membrane. In this case, the many ways to depolarize tissue could be naturally coarse-grained to represent a single problem: a change in membrane voltage addressable by a single set of transcriptional actions… Acting on such coarse-grained information is a simple form of meta-processing (i.e., “higher-level” information processing that controls some lower-level process). [ref]

Connections

Most of the paper is reviewing relationships between electricity and aging. The list is impressive, but perhaps this is because electricity is the unsung hero of many biological processes. The last 50 years of bioscience have been focused so intensively on the chemistry of DNA and proteins that we have a distorted idea of their importance. Life depends on electric forces within and between cells. Nerves operate via pumping Ca and Mg ions across membranes to create electrical signals. Exchange between Na and K ions causes muscle cells to contract. Mitochondria provide energy to all our cells by converting chemical energy to electric energy, The zeta potential is a charge on blood cells moving through our arteries, while preventing clotting.

Some of the relationships of bioelectricity to aging, all of which were new to me:

• Rejuvenation via exosomes was shown to work (among other mechanisms) via modification of K+ and Ca++ ion channels
• Oxytocin, identified by the Conboys as a key anti-aging blood factor, works by regulating depolarization and firing of neurons.
• Rapamycin and resveratrol both inhibit voltage-gated K+ channels
• Quercetin and other senolytics regulate ion channels
• Unsurprisingly, brain aging is intimately linked to Ca++  ion pumps, which form the basis of neuronal signaling. Calcium channel blockers can protect against Parkinson’s.
• The heart is dependent on bioelectric function both to run its clock and to fire the pump muscles. Levin lists some ways that CV aging is connected to bioelectricity.
• Cancer is a special case…

Cancer

Levin’s lab has rediscovered a new property of cancer cells that came to light only late in the game, and still occupies a backwater of cancer research.

“It has been known for decades that tumorigenesis begins with the bioelectric decoupling of cells from the somatic morphogenetic network (2003; 2010; 2006).”

Normal cells are in electrical communication with all their neighbors. But cancer cells cut off all communication, and each cell is isolated from information about its surroundings. Levin was able to revert cancer cells to well-behaved growth simply by restoring their electrical contact with neighbors.

The old theory about the etiology of cancer is that it starts in the nucleus, with a series of compounding mutations. Schaefer and Israel disproved this, to my mind, by transplanting mutated nuclei of cancer cells into normal cells (they remained normal cells) and transplanting healthy nuclei into cancer cells (they remained cancer cells). Despite this clear demonstration almost 30 years ago, most oncologists still believe that cancer is caused by mutations, rather than that mutations are caused by something outside the cell nucleus. Schaefer and Israel seemed to show that the the real source of cancer is in the cytoplasm. But their work is also consistent with Levin’s hypothesis — cancer is all about electrical communication networks.

How are adjacent cells connected?

Cells are enclosed by their individual cell membranes, and within these membranes are embedded proteins called connexins that can hook into connexins from an adjacent cell, forming a bridge. The bridge conducts charged ions and small molecules across the gap junction, leaving large molecules on either side.

(This sounds like synapses connecting nerve cells. Synapses have gap junctions, but their gap junction channels do not involve connexins. Levin reminds us frequently that the electrical networks formed by neurons are just one manifestation of a ubiquitous and much older phenomenon of electrical communication between animal cells.)

How is this useful for cancer therapies? Levin has experience using drugs to open and close ion channels between cells and create a desired pattern of electric potential in a group of cells. He has done it successfully for years in planaria. Can the same technique be used to recreate healthy relationships among tumor cells, redirecting the transformed cells to become functioning team players in the body? The part that has already been accomplished (using voltage reporter dyes) is to measure electrical patterns. The challenge, as Levin reports, is to create computer models which will predict the effect on these patterns from various combinations of ionophores.

Another, simpler idea is immediately available. Animal cells almost always carry a negative charge, maintained by assorted ion pumps in the cell membrane. Cancer cells tend to collect positive Na+ ions and lose their negative charge. The simple remedy is to deliver an ionophore drug that tends to pump positive ions out of the cell. Preliminary experiments suggest this has both a preventive effect and could be a treatment for cancers that have already developed [ref]. Bioelectric drugs were shown to have anti-cancer effects in cell cultures of human glioblastoma [ref].

 

“Regeneration and longevity are intrinsically linked”

This idea is the underlying motivation for Levin’s foray into the science of aging. Evolutionary theory would suggest that animals that have long gestation times, slow development, and gradual reproduction have greater investments in each individual and a greater need for a capacity to regenerate; but this does not imply that loss of regenerative potential is related to the root of aging. Salamanders are the best example of the correlation; they have extraordinary ability to regenerate, and they have extraordinary lifetimes for their size, up to 30 years. Planaria don’t age at all, and their capacity to regenerate is even more impressive than salamanders. Sea stars also have remarkable regenerative capacity, and their lifetimes are long, but less impressive than salamanders. On the other hand, octopuses can regenerate entire legs, but their lifespans are short for their size. Giant octopuses over 100 pounds only live 5 years.

 

Regeneration sounds attractive — but does it address aging?

Here’s a factoid I remember reading more than two decades ago, but in all that time, I’ve never been able to rediscover the reference. Sea stars have regeneration ability comparable to planaria — you can cut them up in small pieces, and each piece generates a whole new sea star. But unlike planaria, sea stars reproduce sexually and they age gradually, with a fixed lifespan of about 8 years. If you cut off a sea star leg, it will regenerate the whole body, but the body will remember the age of the original animal and die on the same schedule. A weaker example of which I’m more certain is the octopus. Octopuses have limited regeneration ability, but they can grow back one or several severed tentacles. Octopuses are semelparous, and the fact that they grow back new tissue doesn’t change the fact that they will die following reproduction.

The relationship between regeneration and aging is largely unexplored. The Levin lab is way out in front studying regeneration. It will be interesting to see if aging can be addressed with the ionophores and other “morphogenetic” tools that they use to modify voltage patterns in animal tissues.

Programmed aging — where is the program?

Approaches to anti-aging medicine have been divided between those that work at the cellular level (bottom up) and those that work at the systemic level (top down). You probably know that I have been an advocate for top-down from the beginning. The body knows how to repair itself, and just needs the orders to do so.

I have imagined those orders to come from signal molecules in the blood — hormones and cytokines and ribozymes = active RNA. Levin’s lab has elucidated another level of centralized control using electrical signaling. Aging is programmed. To what extent is aging programmed chemically and to what extent electrically? It’s a question to be explored with new experimental paradigms.

You’ll forgive me, knowing who I am, if I point out that the weakest part of this paper is that it considers only the loss of electrical information, and never the possibility that electrical information could be purposefully modified in a manner that is destructive to the integrity of the organism. For example, the use of the word “corrupted” shows that the authors are thinking in terms of lost information rather than deliberate rewriting of the pattern.

A key question for the biomedical applications of morphoceuticals for aging is how the bioelectrical pattern is corrupted over time and if an enhancement/repair of it will lead to proper maintenance or rejuvenation.

The introduction pays lip service to “programmed aging” as one of the viable theoretical frameworks, but this idea is clearly not digested. References cited for “programmed aging” are all for authors who are hostile to the idea. My book is not cited, nor are cogent accounts of the experimental case for programmed aging by people with reputations far greater than mine [ref, ref, ref, ref].

I find it interesting that even though Levin is always thinking in terms of logic circuits and electric controls, the tools he uses are always chemical. Drugs are used to move ions around and modify electric patterns. No one, not even the Levin lab, has found ways to modify the patterns of electrical potential directly.

Programmed aging requires a reference time, localized or spread through the body, a repository of information about age. If we could find the clock and set it back, like rewinding the odometer of a car, the body would make the appropriate repairs and adjustments to recreate a young body.

I have speculated the clock is in the hypothalamus, where chemistry and electrical memories meet; or maybe it is distributed in the epigenetic state of cells throughout the body. But how does it keep time? Is it logically possible for the clock to be homeostatic without some external reference time? Are there multiple clocks that consult each other and find a consensus (what Aubrey calls ‘“crosstalk”)?

Is one of these age clocks, at the highest level of control, based on patterns of bioelectricity?