Of Monotremes and Mole-Rats: Metabolism, Membranes, and More

1 - Introduction

Perhaps this says more about human psychology than about the animals we tend to find "unusual", but nature's capacity to surprise us nevertheless remains unmatched by even our most strident efforts to comprehend the vast diversity of animal forms we share the planet with.

This is no more evident than in the case of the monotremes -- the first platypus specimen, brought from Australia to the Department of Natural History at the British Museum in 1799¹, was actually suspected to be a hoax!

Monotremes (that is, platypi and echidnae) not only look unusual to humans accustomed to seeing mainly domestic dogs, cats, and barnyard animals, but have unusual and fascinating physiologies. They are classified as mammals due to being warm-blooded, having a four-chambered heart, etc., but they share some attributes (such as egg-laying) with birds and reptiles. In some respects they resemble remote ancestors of other modern mammals, whereas in other respects (such as their ability to sense the electrical fields of prospective prey) they are highly specialized in directions that no other known mammals have even approached.

From the order Rodentia, mice and rats are probably the most common mammal models for studying aging and testing environmental/dietary/medical influences on maximum lifespan. The Methuselah Mouse Prize -- a contest intended to inspire research projects into mammal longevity through awarding of prizes to researchers whose mice live the longest -- is predicated at least in part on the notion that if we can find ways to keep mice healthier longer as they age, some of those methods might eventually translate to human medicine.

Of course there is no guarantee that will be the case, as mice and humans do differ in some significant ways -- nevertheless, mouse models have their advantages in longevity research, as they are inexpensive, prolific, and (compared to humans) short-lived. However, the mouse is not representative of all rodents in the fact of its 1 - 3 year lifespan, and there is one rodent in particular that caught my interest in looking for examples of unusually long-lived animals: the naked mole-rat.

I'd never even heard of naked mole-rats until about five years ago, when I happened to glance at a nature show playing in a doctor's waiting room (of all places). On the screen appeared these tiny, pink, wrinkly, buck-toothed things burrowing through dark tunnels, with the voice-over noting how they were actually capable of chewing through concrete. That definitely made an impression, however, I had no idea at the time that I'd eventually find myself poring over mole-rat research in the process of studying one of my major interests -- longevity.

As of 2008, though, neither of these animals are new to the longevity spotlight. Articles in USA Today⁴, Science Daily⁶, and The Longevity Meme (which has made frequent mention of both naked mole-rat longevity and echidna longevity) have been chronicling these creatures since at least 2006. However, with rapid news story turnover these days, and given just how cool and interesting the echidna and naked mole-rat are, I figured it was well worth revisiting the available literature on these creatures and hopefully introducing them to a few more people in writing about them here.

2 - Implications

"Aging", as a generic term, simply means "getting older" or "existing across an ever-increasing span of time". However, when most people think about aging in the context of human health, they are usually referring to the process by which our bodies change physically as they get older. Gerontological research has revealed a fair bit about how humans and various other animals age physically, however, as of yet there are no reliable, known means to mitigate the parts of aging that lead to unpleasant, deadly health problems (heart disease, increased susceptibility to cancer, etc.) as people enter their eighth and ninth decades.

Nevertheless, we humans (like the naked mole-rat) already also live longer than our size would predict -- considerably longer than any other land mammal roughly our size.² It seems well worth looking at mammals who share this feature with us, as such study might offer clues regarding the various different routes via which exceptional longevity in a species can occur. The more we know about how and why some animals live longer than conventional wisdom would have us believe they would, the more avenues of potentially productive research come into play.

This is where the implications of what we might be able to learn from monotremes (specifically the echidna Tachyglossus aculeatus³) and mole-rats lie. The more we find out about how mammals can age, the better.

3 - Findings

So, what is known so far about longevity in mole-rats and echidnae? Well, perhaps not as much as is known about mice, but certainly a fair amount -- and the pool of knowledge is growing all the time.

One thing to note is that longevity in mammals more or less seems to decrease as body size decreases, and as metabolic rate tends to increase (the typical mouse's heart rate is between 400 and 800 bpm⁵). Hence, while some much larger rodents (e.g., beavers) can also live upwards of 20 years, naked mole-rats are more interesting from a longevity standpoint because of how longevity and body scale usually correlate in mammals. It is highly unusual for an 8 - 10 cm long creature to live anything near 20+ years, and yet, it is not uncommon for wild naked mole-rats (which are native to East Africa) to live up to 20 years. One naked mole-rat in captivity managed to reach 28 years!⁴.

While most monotremes do maintain a somewhat constant temperature within different environments, their normative temperature tends to be around 90 degrees Farenheit, in contrast with the 98+ degree averages of humans and many other mammals. Additionally, at least one known monotreme (the short-beaked echidna) can alter its temperature regulation toward a more mammalian norm in warmer, more active conditions, and toward a more "reptilian" adjustment to the ambient environment in cooler, less active times.⁷ The short-beaked echidna (Tachyglossus aculeatus) is of particular interest here because of its known capacity to live up to 50 years, which is up to 3.7 times longer than its size would predict.³

One theory regarding exceptional longevity in mammals, as detailed in the paper Life, death and membrane bilayers⁹ is the "membrane pacemaker" theory of metabolism:

...which proposes that the relative balance between monounsaturated and long-chain polyunsaturated acyl chains in membrane bilayers is a fundamental determinant of metabolic rate of a species.

Essentially, what this means is that some findings suggest a relationship between metabolic rate and the health over time of the various fatty-acid membrane structures that comprise animal physiology. Animals are, in a sense, made possible by membranes -- life is dependent upon being able to direct functional pathways along specific routes, and to contain chemical materials where they are needed (that is, where they can perform their life-sustaining activities). Longer-lived species, according to the membrane pacemaker theory, are likely to have more peroxidation-resistant membrane lipids than shorter-lived species.¹⁰ This is a significant idea because it is well known that oxidation and metabolic activity over time go hand in hand, and that oxidation can definitely cause plenty of damage to cells.

Per the membrane pacemaker theory, one would expect that naked mole-rats and short-beaked echidnas might display membrane composition throughout life in accordance with their impressive longevity.

Lo and behold, this does seem to be the case: gas-liquid chromotography has demonstrated not only that naked mole-rat membrane structure actually remains largely unchanged with age, but that the chemical composition of mole-rat membranes is more lipid-peroxidation-resistant than that found in mice.¹¹ Similarly, analysis of phospholipids from the short-beaked echidna indicated a higher monounsaturate/lower polyunsaturate membrane concentration than one would guess from merely looking at their body size.³

These studies demonstrate that in at least some species, membrane chemistry is more significant than body size in predicting lifespan. It is also intriguing to note that in animals such as the ones discussed here, despite their generally lower-than-human body temperature and ability to switch off and/or "pulse" metabolism, they do expend decent amounts of energy while alive. Oxidative reactions can and do occur in the mole-rat, for instance -- they just don't seem to cause much in the way of harm.

Interestingly, one of the most well-known effective animal longevity interventions -- calorie restriction -- may actually tie into the membrane pacemaker theory. Calorie restriction can alter the peroxidation susceptibility of membranes within the body via changing their chemical composition, which in turn affects membrane-related activity and downregulates metabolism accordingly. The idea that membrane lipid compositions within the body could serve as a primary metabolic regulator is a fascinating one indeed, as if proven out thoroughly, it seems possible it could lead to better and more precisely targeted medicine.

There are two primary gerontological schools of thought when one looks at the landscape of medical longevity research -- one which seeks to determine the mechanisms through which aging damage occurs (with the idea that these mechanisms themselves could potentially be altered so as to damage the organism less), and another which is more interested in classifying the damage itself and studying ways to repair it. Sometimes these schools of thought seem to be at odds, however personally I see them as having at least some practical overlap.

Metabolism is so complex, and so many essential systems depend on it, that the notion of modifying it significantly while maintaining the health and safety of the organism poses extreme challenges. Nevertheless, we can still work on finding ways to regulate metabolism and affect how it operates. Calorie restriction demonstrates the efficacy of this approach, and while even highly effective CR-mimetic drugs would not provide as drastic gains in healthspan as we'd all probably like to see, there is certainly logic in combining a damage-preventative approach with a damage-cleanup approach.

In any case, I look forward to learning more of what such creatures as mole-rats and echidnas may be able to teach us about themselves, about aging, and about the curious interplay between metabolism, chemistry, activity, and all the other processes that make life possible.

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References and Notes:

1 - Museum of Hoaxes - Duck-Billed Platypus
2 - The only mammals that live longer than we do are aquatic (certain species of whale), though it is interesting to note that elephants might outlive us if only they had access to a better dental plan!
3 - The exceptional longevity of an egg-laying mammal, the short-beaked echidna (Tachyglossus aculeatus) is associated with peroxidation-resistant membrane composition.
4 - USA Today - Naked mole-rat's longevity secret cloaked in mystery
5 - The Mouse ECG and Heart Rate Variability: Methodological Considerations
6 - Ugly Duckling Mole Rats Might Hold Key To Longevity
7 - Wikipedia entry on Echidna
8 - Wikipedia entry on Naked Mole-Rat.
9 - Life, death and membrane bilayers, by A. J. Hulbert, Metabolic Research Centre and Department of Biological Science, University of Wollongong
10 - Fowl play and the price of petrel: long-living Procellariiformes have peroxidation-resistant membrane composition compared with short-living Galliformes.
11 - Oxidation-Resistant Membrane Phospholipids Can Explain Longevity Differences Among the Longest-Living Rodents and Similarly-Sized Mice