When we aspire to a long life, we tend to visualize a healthy long life – what should really be called healthspan. But how do we decide what’s “healthy” anyway, and how does healthspan relate to lifespan? Those are the subjects of the research report that inspires this post.
Straight Talk About Worms
First, let’s talk about what worms have to do with it. The worm in question is seen crawling across the image window above. Its name is Caenorhabditis elegans, a large mouthful that means new(ly discovered) rod-like elegant (animal), and it does move rather elegantly. More simply, C. elegans. This type of worm is called a nematode or more commonly, a roundworm.
Roundworms are very small animals, typically just one millimeter (1/25 inch) long. They are literally everywhere around us: in deep and shallow ocean waters; in fresh water; on the ground and deep underground; and in both hot and cold climates. There may be a million separate roundworms living on a square meter of land. There are many varieties of nematodes and the majority of them are parasites, including those responsible for trichinosis in pigs and humans, and heartworm in dogs.
Before you say “eeeew” and switch to another channel, let me mention that many types of roundworm, including our star performer today, are “free-living,” meaning non-parasitic. And C. elegans is a very special worm, easily the most famous worm in the lofty world of research.
The Superstar of Worms
This particular worm is a great research subject because it doesn’t have to be paid, and doesn’t sass the researcher. Sorry, I couldn’t help saying that. No, here are some unique features that make C. elegans a great animal in the lab:
– This worm is easy to grow in “bulk populations” – huge quantities. And after you grow them, you can freeze them until you need them; thaw them out and they come back to life, ready to be studied by the next grad student. Wow!
– The worms live only a few weeks, so it’s possible for that grad student to study many family generations during the time it takes to earn a PhD.
– Every C. elegans worm has a genetically determined number of body cells. Most of the worms are hermaphroditic and have exactly 959 cells each. (A mere 0.1% are males, and those have 1031 cells each because of their extra, er, equipment.) The worm can grow bigger, but not by adding cells: instead, the existing cells just grow larger. And because its cellular makeup is so predictable, the developmental fate of every cell, from creation to death, has been mapped.
– The animal is transparent, making it easy to study under a microscope while it’s alive.
– This worm has earned at least one researcher a Nobel Prize (Sydney Brenner, the 2002 Nobel Prize in Physiology or Medicine).
– Ageing processes in C. elegans have been extensively studied and a great deal is known already.
Because of its popularity in the lab, C. elegans has achieved some “firsts”:
– It’s the first multicellular organism to have its complete genome sequenced;
– It’s the first organism to have its nervous system (which consists of exactly 302 neurons) completely mapped.
With this background, let’s look at some important recent work. Prof. Heidi Tissenbaum, Univ of Massachusetts, is principal investigator on research that may be the very first to clearly define and measure healthspan, independently of lifespan.
Defining & Measuring Healthspan
One of the biggest problems the researchers faced was defining healthspan. A dictionary definition is easy to come by: here are two:
“Optimal health”? “Generally in good health?” Those are pretty fuzzy terms. To carry out research in healthspan, we need a precise definition.
Think about this: how would you define healthspan, or duration of good health, for a human?
Would you measure:
– Amount of chronic pain, on a 1 to 10 scale?
– Mental performance, measured by memory and reasoning?
– Physical mobility, measured by time to run 10 kilometers or climb a flight of stairs?
– Resilience to withstand external stress – for example, how long can a person sit in a sauna without passing out?
The point is that so far as I can determine, there’s no accepted scientific definition of healthspan for a human being. We may think that we know healthy ageing when we see it; but that’s far from giving a scientist something to measure, to understand, and try to apply to human needs.
Now consider defining healthy ageing in such a simple animal as a worm. Lifespan is pretty straightforward: if you touch it and it doesn’t move, it’s dead. But healthspan is much more difficult.
After considerable discussion, Prof. Tissenbaum’s research team chose two principal measures of worm health, each measured by several tests:
– Frailty (analogous to human mobility) was measured by: “thrashing” motion in liquids; distance traveled on a solid surface; and feeding rate as observed through a stereomicroscope.
– Resilience to stress was measured by: exposing the worms to heat; exposing them to an oxidative solution; and internal fluorescence (which increases with age and peaks at the worm’s death).
Healthspan was defined as the number of days of life before the worm’s health declined to 30% of the peak functionality of an average wild worm. Gerospan, or length of frail old age, was defined as the number of days below 30% functionality until the worm died.
Four Ways to Extend Life
Various researchers have found that they can turn individual genes on and off in C. elegans, by very simple means. They pack bacteria with appropriate pieces of RNA, then deliver the bacteria by feeding the worms, injecting them, or simply soaking the worms in a bacteria-laden solution. Those bits of RNA attach to the worm’s genes and create mutant strains of the animal in which certain genes are turned off.
Scientists who are interested in the ageing process and extending lifespan have found that they can create mutant roundworms with much longer life than the normal worm. The normal “wild type” C. elegans typically lives for 30 days. Here are four different genetic changes that lead to longer-lived critters, along with the longer lives they exhibited in the UMass study:
– Insulin-Like Growth Factor 1 is a signaling protein that contributes to ageing in many animals, including humans. The C. elegans mutation known as daf-2, which suppresses IGF-1, lived an average of 57 days, about 90% longer.
– eat-2 is a mutation that simulates calorie restriction, which extends lifespan in some animals and may improve healthspan and lifespan in humans. These mutants worms lived 36 days, about 20% longer than wild worms.
– clk-1, a mutation that suppresses mitochondrial activity in the cells, extended the lifespan 10%, to 33 days.
– ife-2, a mutation that suppresses the synthesis of certain proteins, extended the lifespan 40%, to 42 days.
The Worm Healthspan Study
We now have all the ingredients. We know what we mean by healthspan in C. elegans, and we know four ways to extend the lifespan of C. elegans. The next step is to measure roundworms – a lot of them – and see how healthspan does or does not correlate with lifespan.
Healthspan of Extended-Life Research Subjects
Yes, the research subjects here are still the roundworms, C. elegans. This heading was just a test, to see whether you were still on board.
Here is the data on measured healthspan for the four different long-life mutant worms:
The black numbers are data that exactly equal the wild (non-mutated) animal. The green numbers show a healthspan that is better, that is, longer, than the wild creature. The red numbers show a healthspan that is shorter than the wild worm.
A person might look at this chart and say, “huh?” There are sixteen measurements for the mutated long-life roundworms. In seven instances, the long-life worms had a longer healthspan and in eight cases a shorter health span. What should we conclude?
– On the basis of sheer numbers of examples, healthspan seems to be unaffected by increased lifespan – sometimes more, sometimes less.
– Looking more closely at the data, if it turns out that “heat” and “solid mobility” for worms are measures that are relevant and analogous for human beings, then all these mutations that lead to longer life also lead to longer healthspan, that is, more time in good health. Bring on the genetic engineers!
But before you rush out to try calorie restriction or experimental (and therefore risky) gene treatments, you need to see the rest of the story. In the world of science, silver bullets are very rare, and most dramatic and wonderful results deserve more than one look.
Healthspan as Percentage of Lifespan
The picture drastically changes when we consider healthspan as a percentage of lifespan. After all, as we previously quoted, the mutations that lead to a longer lifespan give C. elegans an immensely longer lifetime, up to almost twice its unmutated lifespan; however, the improvements in healthspan, when they occur, are not nearly so dramatic.
So the researchers also analyzed the data as follows: to measure healthspan as a percentage of lifespan. Here are the results:
Just as before, red means that the mutant performed more poorly than the unmutated wild strain of animal. And in this case, almost every case measured showed that longer lifespan led to a healthspan that was a smaller and smaller percentage of lifespan.
Science Speculation: Naturally, we would like to know whether any of this applies to us as human beings.
Scientists who study ageing have a personal interest in the human application of their work. When they use animals as test subjects, it’s not because they are especially fond of mice, or macaques, or worms – although years of working with them probably breeds a certain tolerance if not affection. It’s because ethics, economics and practicality severely limit the experiments you can conduct on human beings.
It’s normal for new medical treatments to start with an “animal model” that may be relevant to people; if the treatment succeeds, someone will try to extend it to a closer-to-human animal and eventually to carefully supervised trials on human beings. That’s the normal way of things: what happens in worms is certainly not ready for application to you and me, but it can be an important signpost or predictor for research that will help people.
A Jump from C. elegans to H. sapiens
Let’s take a speculative leap and see how the UMass roundworm results would look if we applied them to humans. We’ll take a specific example to make it clear: the “calorie restriction” mutation, since that represents a kind of gene modulation that every reader of this blog could choose to try for themselves, if they were into self-experimentation. And since personal mobility is a relevant measure of health for humans, let’s take mobility on a solid surface as the measure.
The wild strain of roundworm lives an average of 30 days, and has at least 30% of its peak mobility for 17 days of that time. The “calorie restricted” roundworm lives for 42 days, and has healthy mobility for slightly longer, 19 days. So here are the findings: the roundworm who suffers the discomfort of a calorie-restricted diet experiences an increase in healthspan from 17 days to 19 days; however, it also experiences an increase in “gerospan,” that is, frail old age, from 13 days to 23 days. In other words, a mere 10% extension in healthy lifetime is accompanied by a doubling of time spent, so to speak, on life support.
Here’s a human translation: suppose that a human being would normally live 90 years and enjoy vigorous health for his first 51 years. He is offered a magic diet – calorie restriction – that will extend his lifetime to an amazing 126 years! However, he will only enjoy good health for the first 57 years. His time as a less-than-healthy person will increase by thirty years, from 39 years to 69 years. Ouch!
Healthspan Research Conclusions
Of course, we cannot extrapolate so easily from an animal with 1000 body cells to a human being with 37 trillion cells. Perhaps if our brains remain sharp and clear, we would accept some physical disability in order to enjoy life for such a longer time. At this point, we just don’t know all the dimensions necessary to define human healthspan, and if we knew them, we don’t know enough to measure and increase healthspan.
The most important points dramatically made by the UMass research are:
– Extending lifespan does not necessarily extend healthspan; more specifically, the genes responsible for longer life may be a different group than those yielding extended good health.
– Extending lifespan with no concern about healthspan could lead to immense numbers of frail or suffering elderly people, which would be a terrible human situation as well as an overwhelming healthcare challenge.
– Research aimed at conquering, or at least beating back, age must look at improving healthspan as a major objective; lifespan alone is not a satisfactory goal.
People Are Impatient
Of course, humans are not waiting for the orderly march of science to deliver them the Fountain of Youth. There is vigorous work to extend human lifespan and healthspan, ranging all the way from careful research to over-the-top hype that hopes to sell you miracle vitamins and supplements.
Is aging programmed? …unlike development, which is clearly of benefit to the organism, aging has not been selected for. Aging arises as a result of lack of selection against late-life deleterious events because such events do not decrease evolutionary “fitness.” These are subtle arguments…
Subtle arguments indeed!
Differently stated, Nature, Evolution and Creation all “want us” to be fruitful and multiply, that is, pass along our genes to future generations. Thus efforts to cure disease for people of child-rearing age have eons of support from the natural world, which is pushing in the same direction.
However, once we are old enough that we are being cared for ourselves, rather than helping the next generation, Nature has no interest in our well-being. Thus, if we human beings are interested in lifespan and healthspan in our older years, we’ll just have to tackle that problem ourselves!
How “healthy” would your Healthspan need to be, if you were to judge that longer life is a Good Thing rather than a Terrible Burden?
Image Credit: Crawling C. elegans,” by Bob Goldstein http://labs.bio.unc.edu/Goldstein/movies.html (Own work) [GFDL or CC-BY-SA-3.0], via Wikimedia Commons
Usage Comment: This post, except in the final quotation, uses the word “ageing” throughout in preference to “aging,” although the latter is stated to be US standard usage. After reading an extensive discussion of one versus t’other, I prefer “ageing” because its meaning can be quickly grasped at a glance. But hey, that’s just me.