“[Aging isn’t] some general breakdown process, like the way cars rust. Aging is an optional feature of life. And it can be slowed or postponed” – Dr. Rose
This article originally appeared in Pro-Rat-A, January/February 2009 (number 169). This electronic format contains an extended bibliography. While originally written for rat fanciers, the methods discussed here can easily be modified and applied to just about any domestically kept species.
Wouldn’t it be wonderful if we could make tumors on rats uncommon? What if we could double rats’ life expectancy? These may seem like impossibilities, but they’re not.
Scientists have long recognized the concept of biological immortality. Cancer cells, for instance, grow indefinitely. Some animals, such as tortoises and crocodiles, continue to grow throughout their lives. Biologically immortal organisms die from injury, infectious disease, or starvation, rather than cell deterioration (old age).
Germ cells, which produce gametes that become sperm or eggs, are immortal. Unlike somatic (body) cells, they can replicate themselves infinitely. Barring disease, most human somatic cells divide about fifty times before they die. It was theorised that apoptosis (programmed cell death) evolved to protect the body from replication errors resulting in cancer; yet germ-line derived tumours are extremely rare, and thus demonstrate that an immortal cell line need not have a heightened risk of cancer.
If aging is not inevitable, why hasn’t natural selection (or even artificial selection by breeders) favoured genetic immortality in humans, rats, and so many other creatures? Selection works to preserve the population, not the individual (at least not after they have been able to reproduce). Oddly enough, the result is that aging is a side effect of selection.
Selective pressure is strongest on mutations that affect the young. For example, human children affected by a genetic disease that will kill them before they turn ten, have a fitness of zero because none survive long enough to reproduce. There is strong natural selection against that mutation. In contrast, there is very weak selection against a disease that kills people over 60 years of age because they have already had as many children as they are going to have (and most of those children have probably had children of their own as well).
Even if we found a medical cure for tumors, our rats would still age and die, just like we do. Aging is the wearing down of the body. Consider our own teeth which have relatively thin enamel that is worn down by use, eventually resulting in cavities and permanent tooth loss. Why don’t we have stronger teeth, or ones that grow indefinitely as our rats do, or replaceable teeth like reptiles have? These abilities have costs. Stronger teeth take longer to grow and need more nutrients. Teeth that continuously grow require more nutrients too. Replacement teeth also put heavy demand on nutrients and tend to come in misaligned. In early humans, those who had well aligned teeth, that could be used as soon as possible, were more likely to survive to reproduce.
When it comes to artificial selection, breeders make the same “mistakes” that nature does. For example, feeder breeders maximise their profits by selecting for rats that grow fast, will breed as young as possible, and produce large litters. Breeders of companion animals, even when they genuinely try to select for good health, fall into the same trap, but for a different reason. Focus is on cosmetic issues like colour and coat texture. Temperament usually figures into selection as well. Although good breeders do consider health, it usually doesn’t extend beyond retiring rats with bad infections or that have (or carry) obvious genetic deformities or megacolon.
Fearing infertility if they wait too long, breeders tend to breed early. When establishing a new or rare variety, the temptation to breed early is even stronger for there are few if any other breeders to get replacement stock from; infertility of just a couple rats could mean a loss of the new variety. Unfortunately, breeding early selects for animals needing to be bred earlier, creating a vicious circle. S
election’s effect on aging and longevity is not speculative. Scientists have drastically altered the average life span of mice, rats and flies. Most famously, Dr Rose was able to create a long-lived line of flies called Methuselah flies. He also demonstrated how selection could create a population of flies with much shortened life spans by reversing the selection process.
To create the Methuselah flies, Dr Rose bred from only from older flies. “This forced natural selection to pay attention to the survival and reproductive vigour of the flies through their middle age,” he explained to Claudia Dreifus, in an interview, for the New York Times. “The flies evolved longer life spans [showing that aging isn’t] some general breakdown process, like the way cars rust. Aging is an optional feature of life. And it can be slowed or postponed.”
The average life span for fruit flies is 30 days, while that of Dr Rose’s Methuselah flies was 130 and they did not die of old age but from injuries that left them unable to compete for food supplies. If we could do with rats what Dr Rose did with flies, our pets would be living ten years!
Selection for longer life spans can be maximised with diet. As early as the 1930’s it was found that calorie restriction nearly doubled the lifespan of rats. Renewed interest in this diet has resulted in more experiments successfully extending the lives of worms, flies, rats and mice. It seems that the restrictive diet itself is more important than maintaining a healthy weight and exercising. In rats and mice, those that ate normally but ran on exercise wheels didn’t live longer than the inactive animals that were calorie restricted; genetically obese animals on the diet lived longer than their normal-weight relatives.
Calorie restriction is theorized to work by causing low-intensity biological stress on the animal. This elicits a defense response so that it can survive adversity, resulting in improved health and longer life. This response is likely controlled by longevity genes as well, which means that the two methods, diet and artificial selection, when used together, should provide the most dramatic improvement in life span.
The drawback is that the diet must be very carefully balanced so that it still contains all the nutrients the individual needs, otherwise the result will be that of malnutrition: poorer health and shortened life. Because I have my doubts about laboratory formulated diets which are used in calorie restricted diets, I have never tried this intervention. I feed a dry mix supplemented with fresh produce because I believe that organic, whole foods are better than conventional, processed ones, and that variety in diet is beneficial to emotional health. Because rats love to stash their food, I got into a habit of skipping feeding every few days to make sure that they ate their stash, instead of just their favorite bits. Timing this before cage-cleaning created a 12 to 24 hour period of restricted food intake or fasting.
As it turns out, intermediate fasting can confer similar benefits to calorie restriction. Tests with rats that compared the effects of fasting 1 day in 4, 3 and 2, showed that fasting 1 day in 3 was most effective in extending life span (15% in does and 20% in bucks) and in retarding mammary tumor growth. Animals on restricted diets also tend to have lower levels of the pituitary growth hormone (GH), thyroid stimulating hormone, IGF-1, and gonadotropins. Mutations that affect these and other hormones have also been shown to prolong life span. Animals on these diets also tend to have delayed puberty and smaller litter sizes, effects which are also seen in the selection for longevity, be it in laboratory rodents, or flies.
The Guinness Book of World Records lists the record rat lifespan at 7 years 4 months!
When I became interested in rats in the early 90’s, the rat fancy was not well established in my area (US Midwest). The breeders who mentored me said that 18 months was a good age for a rat to reach, although does would almost certainly be developing tumors by then. We’d joyously announce when one of our rats joined “The 2 Year Club”. At that time, we bred does very young, as it was believed that their hips fused at 6 months; breeding rats as young as 3 to 4 months was not uncommon. Pelvic fusing was proven to be a myth (likely transposed from the cavy fancy), and the preferred age to breed a doe for the first time gradually became 6 to 9 months, with a second litter at one year or a little after. Soon after this shift in breeding ages, many more rats were living past two years of age. At the time, there was no one thing that stood out as responsible for this shift because fanciers were learning about, and trying, all kinds of new things (beddings, diets, etc.). Retrospectively I am certain that disproving the pelvis myth made the most difference. It changed how we bred rats, which in turn selected for a population that could live a little bit longer.
Some of my first rats were shipped from the west coast, and introduced variegated, pearl, dumbo and tailless traits to the Midwest. Unfortunately, after 8 to 12 months, (well after they were bred once, if not twice), they often turned against cage mates, killing them. I couldn’t afford to ship in replacements, and if I scrapped the line, the Midwest could have lost several new mutations which helped to popularize rats as pets to the public (at pet fairs, which could have hundreds of thousands of attendees, the tailless and pearl rats were excellent ambassadors to people who were initially squeamish about rat’s tails, wild colouration or pink eyes.) For these reasons, I was determined to perfect the line.
Instead of keeping one or two rats from a litter to breed, I held back four or six. The rest were placed as solitary animals, since their hostility was not directed to humans. I kept in touch with these people to track temperament and health. While I bred the rats I held back, I did so as late as was believed safe at the time. In most cases, if the rat turned hostile, I had not yet bred the offspring, and thus could pet place them without perpetuating their genetics. Rats that did not become hostile I would try to breed a second time, even though it was pushing the upper age limit. Some of these did not reproduce, but that was okay because I had their offspring to work with. Those rats that did breed a second time later in life passed on genes that increased the length of rats’ fertility. I also gave preference to breeding rats that had more (or all) of their litter mates remain friendly. In time, I was able to eliminate the temperament problems.
Since I was also able to collect data on which rats developed tumors, I applied the methods I used for improving temperament to deal with this. In the beginning, nearly every doe suffered tumors, so I favored those that developed them later in life. Gradually, more does lived out their lives without getting tumors. Their offspring were moved to the top of my list of potential breeders. If I was choosing between two rats who both had mothers that did not develop tumors, I then looked at the occurrence of tumors in their siblings and grandparents. I did this as much with the bucks as with the does; while the bucks may not have developed mammary tumors, they carried genes influencing them.
By selecting against mammary tumors, and waiting to breed second and third litters later in life, I happened to select for rats that had delayed puberty, remained fertile later in their lives, and lived longer. While my lines have smaller than normal litter sizes, this does not worry me since infertility is not generally a problem. These changes are the same that were seen in longevity experiments such as with the Methuselah flies. Today, I don’t even worry about when I breed that first litter. I have successfully bred rats for the first time at the age of two and three years, and I have not seen mammary tumors in my rats for around four years now.
Because I strongly inbreed, I have been able to concentrate favorable genetics quickly. New lines can be brought in without much difficulty by breeding a new rat to a rat from the long-lived line. These offspring are then inbred or line-bred until their life spans and tumor rates are close to that of the established line(s). Three to five generations is usually sufficient, after which the new and old lines can be mingled.
When I began, I had the resources to house a lot of rats. Do not be discouraged if you don’t have such resources! An excellent way to get around this obstacle is to keep in touch with pet owners to see how their rats are aging. Also, place your second choice rats with people that you trust to honor a contract which allows you to borrow the rats back if you find you need them for breeding.
If several breeders were to work together, I think they could also obtain similar results with less inbreeding if that is their preference. In the beginning, selection requires “baby steps”, but within a few years this will add up to dramatic improvement.
Anton J. Carlson and Frederick Hoelzel. Apparent Prolongation of the Life Span of Rats by Intermittent Fasting. Journal of Nutrition Vol. 31 No. 3 March 1946, pp. 363-375 Online at: http://jn.nutrition.org/ cgi/reprint/31/3/363
Bartke A, Brown-Borg H. Life extension in the dwarf mouse. Curr Top Dev Biol. 2004;63:189-225.
Dreifus, Claudia. A Conversation With Michael R. Rose: Live Longer With Evolution? Evidence May Lie in Fruit Flies. The New York Times, 6 December, 2005. http://www.nytimes.com/2005/12/06/ science/06conv.html
Koubova J, Guarente L. (2003). “How does calorie restriction work?”. Genes & Development 17 (3): 313–321. http://www.genesdev.org/cgi/doi/10.1101/gad.1052903
McCay, C.M., Cromwell, M.F., and Maynard, L.A. 1935. The effect of retarded growth upon the length of life span and upon the ultimate body size. J. Nutr. 10: 63-79.
Miller, R.A., Austad, S., Burke, D., Chrisp, C., Dysko, R., Galecki, A., Jackson, A., and Monnier, V. 1999. Exotic mice as models for aging research: Polemic and prospectus. Neurobiol. Aging 20: 217-23
Rose, Michael R. The Long Tomorrow; How Advances in Evolutionary Biology Can Help Us Postpone Aging. Oxford University Press, New York. 2005.
Silver, Cheryl Simon. Eat Less, Live Longer? Genome News Network, 9 July, 2004. http:// www.genomenewsnetwork.org/articles/2004/07/09/calorierestriction.php
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