Forever Young: Peter Pans of the Animal Kingdom

The Fountain of Youth is said to have restorative powers, such that those who drink its waters remain forever young. It has thus been highly sought after by humans: we who are destined (if we are fortunate to live long enough) to grow old, and consequently, decrepit. It is not a fate that any of us would choose; but for most of us it beats the alternative. Even that can only be delayed however, because aging into decrepitude invariably leads to death.

Why do we lose our youthful vigor as we age?

Some animals do not. Such animals are, in essence, biologically immortal. In this hub I will introduce you to some of the more famous examples, as well as some lesser known candidates with remarkable regenerative abilities that bear consideration. Then I will discuss how this informs our understanding of senescence in other animals (including humans), and our prospects of finding a Fountain of Youth that prevents this from occurring.

Cnidarians are a large group (phylum) of relatively simple animals that include marine jellyfish (scyphozoans and hydrozoans), corals and sea anemones (anthozoans), and freshwater Hydra (hydrozoans). Many cnidarian species have a life history characteristic known as metagenesis—an alteration of generations between distinctly different forms: polyps, which reproduce asexually (by self-cloning), and medusae, which reproduce sexually. Polyps can produce either additional polyps or medusae that are genetically identical to the original polyp, whereas medusae produce haploid gametes—sperm and eggs—which fuse to form a diploid zygote (a single cell that is a new genetic individual with one set of chromosomes from each parent) that then develops into an embryo that will give rise to a new polyp.

Some Cnidarian species undergo only one or the other phases of the life cycle. For example, Hydra only exist as polyps, which reproduce both sexually (via haploid gametes) and asexually (via cloning). The ability to reproduce asexually (i.e., to clone oneself) is a particularly striking manifestation of life’s inherent capacity for regeneration, which occurs through cellular reproduction (i.e., cloning via mitosis.) In Hydra, all of the cells in the body column (trunk) proliferate continuously from the middle section of the trunk; in the process, cells get displaced toward the head of the animal, eventually entering the tentacles, where they die and are replaced. In addition, proliferating trunk cells produce new lateral buds that grow into a completely new polyp. Thus, although a single Hydra is a homeostatic structure, it is continually regenerating itself. Damage to the organism is repaired by replacement of the damaged cells with new cells. This regenerative capacity is quite remarkable: if a Hydra is cut in half, each half regenerates the missing half (hence the name). As far as we know the continuous regeneration of a Hydra can go on forever. In other words, they are forever young.

Another hydrozoan, Turritopsis nutricula, forms both polyps and medusae. Although the medusae can reproduce sexually, they also have the remarkable ability to revert, via de-differentiation of somatic cells, to the asexually reproducing polyp stage, an animal that clonally regenerates itself like Hydra. Turritopsis is the only known animal that has the ability to revert to a sexually immature stage of development; in all other known animals, sexual maturation is the beginning of the end, the gateway to senescence. Not so in Turritopsis, which thus has the potential for biological immortality.

Planarians (flatworms), members of the phylum platyhelminthes, are another group of primitive aquatic animals with extraordinary regenerative abilities. Thomas Hunt Morgan (1866-1945), the great biologist whose later work with fruit flies established the field of developmental genetics, showed that when a flatworm is cut into many tiny pieces, each piece will regenerate a whole new animal. We now know that this ability depends on neoblasts, undifferentiated stem cells that continuously regenerate the flatworm. Unlike in ‘higher’ animals (such as us) wherein somatic stem cells represent a vanishingly small fraction of the total population of cells, planarian neoblasts represent ~7% of the total. Like Hydra, some planarian species grow continuously, and reproduce asexually by cloning (fission) when a certain size is reached. These animals also have the ability to de-grow in response to starvation, a process in which cells commit suicide (‘apoptosis’). As a result the body of the animal gets smaller, while maintaining the same form (i.e., everything stays in proportion). When food is encountered the animal will then begin growing again. Owing to their remarkable regenerative abilities, asexually reproducing planarians, like Hydra, appear to never grow old, and have the potential for biological immortality.

Moving along the animal family tree to a branch closer to our own, we come to my favorite phylum, the echinoderms: asteroids (sea stars), ophiuroids (feather stars), echinoids (sea urchins and sand dollars), holothuroids (sea cucumbers), and crinoids (sea lilies). Sea stars are famous for their ability to regenerate lost arms, or (in some species) even an entire animal from a single arm. But they aren’t immortal—the adult lifespan of a sea star varies, but is typically just 3-5 years. This is also true for some species of sea urchins. On the other hand, the red sea urchin Strongylocentrotus franciscanus can live for over a hundred years, with no apparent signs of aging: the oldest known specimens remain just as gravid (able to reproduce sexually), and appear just as vigorous, as specimens that are much younger. The old urchins are however much bigger—like many other long-lived animal species, red sea urchins never stop growing, a phenomenon known as 'indeterminate growth'. And indeed, as might be surmised from the foregoing examples (which also have indeterminate growth) entry into senescence appears to be intimately linked to the genetically programmed cessation of growth ('determinate growth') that occurs during the ontogeny of many animals at about the time of sexual maturation.

Although in many echinoderm species individuals appear to die of “old age” after living relatively short adult lives, their overall lifespan may actually be quite long. The reason is that most echinoderms develop to adulthood indirectly, via a microscopic larva that lives and feeds in the plankton before undergoing a dramatic metamorphosis to produce the juvenile stage of the adult form. The ‘planktotrophic’ larva is in essence a completely different animal than (albeit genetically identical to) the adult, a life history characteristic similar to the metagenesis of cnidarians discussed above. Sea urchins (for example) develop via a pluteus larva, an animal about a half a millimeter long which looks something like an alien spaceship, and nothing like a sea urchin. The juvenile sea urchin develops within the body cavity of the pluteus, from a small group of embryonic stem cells nested within one side of the larval gut. During metamorphosis most of the larval tissues constituting the pluteus undergo programmed cell death and are absorbed into the growing body of the sea urchin. However, when food is relatively scarce, development of the juvenile sea urchin is suppressed; instead, resources are diverted into growth and maintenance of the larval body. No one knows how long this developmentally arrested state can be maintained—I have maintained larvae in the laboratory on a subsistence diet for several months with no loss of viability or signs of decrepitude. With just the right amount of food, such larvae appear to undergo continuous homeostatic regeneration, much like Hydra and planaria, and can reproduce asexually by cloning (raising the interesting possibility that the biphasic life cycle of echinoderms is indeed another example of metagenesis). The larvae of other echinoderms (such as sea stars) have similar regenerative characteristics. It is possible that under the right circumstances, echinoderms with planktotrophic larvae—even those whose adult lifespans are limited to a few years—can live indefinitely as larvae, never growing up; and thus remaining, like Peter Pan, forever young. It is not inconceivable that that sea star you once happened across while walking the beach, which had an adult lifespan of only 5 years, came from an incredibly lucky (albeit underfed) larva that lived in the plankton for as many years, if not for decades or even centuries.

This brings us to the fifty million dollar question: why do we age? The answer has two sides: physics and biology. The physical explanation for aging is simply the second law of thermodynamics (which I like to refer to as the One Law), which is the basis for the eventual deterioration of anything and everything, the reason that time’s arrow is irreversible. Now, some biologists have argued that the second law is not the cause of aging; that it does not even apply to biological systems, which are open and far from thermodynamic equilibrium. Moreover (so the argument goes), biology is inherently regenerative (which is true, as noted above), so when biological structures undergo normal physical deterioration they are easily replaced. But this argument is fallacious: for if (for whatever reason) the regenerative capacity of an animal (or a tissue within that animal) is compromised, then that animal (or tissue) will be subject to the depredations of the One Law. And this is exactly what happens in animals that age: they are less regenerative than animals that do not age, and as a result succumb more readily to the ultimate destructive effects of the One Law. But the explanation for why that is the case is not found in physics, but rather, in biology.

The most commonly accepted biological explanation of aging is based (like most biological explanations) on Darwinian Theory, and was articulated in 1957 by George C. Williams (1926-2010), in a paper entitled “Pleiotropy, Natural Selection, and the Evolution of Senescence”. The idea, now referred to as “antagonistic pleiotropy”, is as follows. First, for any organism, the probability for survival decreases with time (i.e., with the passage of time the cumulative probability of death, for any reason including accident, increases); thus, the probability of reproducing also tends to decrease with time. Second, many (perhaps most) genes have pleiotropic effects—that is, they influence the development of more than one trait. Some of these effects will develop before others. Thus, it is likely that many genes exist that promote the development of some traits early in life and other traits later in life. Third, natural selection is based on reproductive success, so if the chance of reproductive success decreases with time, the effectiveness of selection—i.e., the stringency with which it acts to remove deleterious genes from a population—also decreases. Therefore, if an organism has genes that increase its reproductive success by way of traits that develop early in life, and if these same genes produce detrimental effects later in life, those genes will selectively accumulate within the lineage, because the selection for their early-acting beneficial effects will outweigh the selection against their late-acting deleterious effects. Senescence then is the result of many genes that produce deleterious effects late in life. Such genes compromise regenerative capacity, allowing for the accumulation of damage that eventually overcomes the organism.

If this is true, then what of the relatively simple animals described above? Why don’t they age?

The reason appears to lie in a prediction Williams made (based on his evolutionary theory) in his 1957 paper: that if development is arrested, senescence would not occur. It can be argued all of the animals described above enter a state of arrested development, in which they continue to grow (not only in size, but also by reproducing asexually), and never fully mature. As a result, the cumulative probability of reproductive success decreases slowly, if at all, and the force of selection remains sufficiently high to remove deleterious genes.

The question then gets back to why maturation often entails a declining probability of reproduction. Recall that the probability of survival invariably declines, because the longer you live, the more chance you have of dying, even if only by accident. However, this does not always entail a declining probability of reproduction. For example, for highly regenerative animals (like Hydra and planaria) that reproduce asexually, in times of plenty the probability of reproduction remains more or less constant. Likewise, for long-lived sea urchins like Strongylocentrotus franciscanus, which reproduce sexually by releasing millions of gametes (sperm or eggs) into the water, and which probably maintain a high rate of survival beyond the onset of sexual maturity, the probability of reproducing declines slowly (if at all). In contrast, for complex animals such as humans and other higher vertebrates, the probability of reproducing after the onset of sexual maturity declines owing to a complex set of factors, including (for example) precipitously declining survival rates in adulthood (owing to predators, disease, etc.), and biological and social factors (such as child-rearing) that inhibit or otherwise interfere with serial reproduction.

Which brings us to a concept that I think is key to understanding the biology of aging: complexity. The astute reader will note that a common feature of all of the “Peter Panimals” described above is that, compared to humans and other vertebrates (or even insects), they are relatively simple. And indeed, there is a negative correlation between organismal complexity and regenerative capacity. Moreover, there is a positive correlation between organismal complexity, the requirement of sex for reproduction, and genetic individuality. Indeed, the concept of individuality is less than clear-cut for primitive organisms such as Hydra that reproduce by cloning. Being genetically identical, clones are in essence separate extensions of the parent; thus, if the body of the ‘parent’ dies, its genetic essence lives on in the bodies of its identical offspring. This idea, and its implications for the concept of Darwinian selection, is eloquently articulated by Leo Buss in his landmark book The Evolution of Individuality.

In short, it appears to me that ‘higher’ animals (meaning animals, such as ourselves, that have evolved more recently than those described at the beginning of this hub) are fated to age because, in us, life has achieved a level of complexity that is incompatible with the full-bodied regenerative homeostasis that characterizes simple animals like Hydra and planaria. Our complexity manifests in many ways: anatomically (e.g. the central nervous system, immune system), metabolically (e.g. endothermy), and cellularly (the number of different specialized tissues and cell types). Thus, while some of our tissues are highly regenerative (e.g. blood and skin), others have very little regenerative capacity (e.g. bone and brain), which declines precipitously after maturation. Interestingly, organismal complexity also appears to correlate with susceptibility to cancer, and the concomitant evolution of tumor suppressor genes, whose activity interferes with the cell proliferation required for regeneration. Tumor suppressor genes provide a concrete example of the ‘antagonistic pleiotropy’ predicted by George Williams.

My assertion that a certain level of complexity is fundamentally incompatible with regenerative homeostasis is just a hypothesis that requires testing, which is challenging because the concept of ‘complexity’ is still not sufficiently defined in a way that allows quantitative description (and hence measurement). But work in that direction is beginning to show promise. Unfortunately, if the hypothesis is correct then the Fountain of Youth may be an impossible dream: the biological equivalent of alchemy, or of the ‘perpetual motion machine’ sought by engineers in the early nineteenth century.

But aging has both physical and psychological aspects. And there is physical growth and psychological growth. I will end by suggesting that although the genetically programmed cessation of physical growth may consign our bodies to eventual senescence, there is no limit to psychological growth. While we may not be able to escape physical aging, we can remain forever young in spirit. And so in closing I quote the song “Reach” by John and Johanna Hall:

Sometimes I stop and wonder why I can’ let myself enjoy

All the space I’m in, and all the wonderful places I’ve been;

My eyes are on the future, I can’t think about the past—

My aspirations always exceed my grasp.

 

You’ve got to reach a little bit higher

When the light within becomes a fire

Hey hey—whoa-oh, you’ve got to grow.

You’ve got to reach a little bit higher

To get a hold on all that you desire

Stretch your soul and you’ll never grow old.

 

When the habits of a lifetime become a painful cage,

You want to break out, but you don’t know how to change;

You may have a vision, or you may have a friend

Who will come to you and say these same words again:

 

You’ve got to reach a little bit higher

When the light within becomes a fire

Hey hey—whoa-oh, you’ve got to grow.

You’ve got to reach a little bit higher

To get a hold on all that you desire

Stretch your soul and you’ll never grow old.