Dog Aging Project Taps Rapamycin for Longevity

Man’s best friend is now the focus of the Dog Aging Project, a comprehensive study that is examining virtually every factor of canine longevity.

Researchers believe many of the findings will be relevant to human aging, including intervention with the drug rapamycin.

“The biological aging process is very similar in dogs and people,” says University of Washington researcher Matt Kaeberlein, who is spearheading the rapamycin studies. “One piece of evidence for that is dogs get many of the same age-related diseases as people. They just happen seven times faster.”

The shorter lifespan of dogs means longevity studies that would take decades with humans can be done in a few years. Dogs also share our environment, something that can’t really be replicated in a lab.

Dogs are no doubt a refreshing change for Kaeberlein, who has three of his own and previously worked with less engaging species, namely yeast, flies, worms and mice. And when word first got out about the Dog Aging Project, there was a bit of a media frenzy to cast some positive light on the still emerging science of aging.

“People really love their dogs,” says Kaeberlein. “So this study engages the general public in geroscience in a way that nothing else can.”

“Geroscience” is the recently-minted term for the science of aging.

Since age is the single highest risk factor for many chronic conditions, including heart disease, cancer and Alzheimer’s, Kaeberlein says it makes sense to concentrate more on the aging process itself.

“If we’re successful at understanding aging and can learn how to manipulate those processes, we have the opportunity to really delay the onset and progression of multiple, age-related diseases,” he explains. “From a therapeutic perspective, targeting aging is the ultimate preventative medicine. The idea is to keep people, or dogs, from developing these diseases of aging in the first place.”

Of course, manipulating the aging process is easier said than done. But progress is being made. In recent decades, technology has allowed scientists to better understand how cells age. Researchers discovered cellular pathways that regulate lifespan and began genetically manipulating the proteins that control them in simple organisms, boosting longevity.

That technology has led to a handful of potential medical interventions, including NAD+ (nicotinamide adenine dinucleotide) precursors, senolytics (senescent cell eliminators), parabiosis (young blood transfusions), and the diabetes drug metformin. There’s some evidence that all of them, and some others, can increase lifespan, but Kaeberlein chose rapamycin for the Dog Aging Project because it’s the best studied of the lot.

“When you look at the literature, there’s not as much evidence to support the other interventions,” he says. “With the exception of caloric restriction, rapamycin is by far the most robust and reproducible intervention for not only increasing lifespan but also for delaying a variety of age-related diseases.”

Rapamycin was discovered in soil samples from Easter Island in the early 1970s. Produced by a bacterium, it proved to have anti-fungal, anti-cancer, and immune-suppressing properties. Developed into pharmaceutical drugs, rapamycin is primarily used today to treat certain kinds of cancers and as an anti-rejection therapy for transplant patients.

In 2006, Kaeberlein and colleagues found that rapamycin could boost the lifespan of yeast.¹ Subsequent studies found similar results with flies, worms and mice.^2,3

Rapamycin inhibits mTOR, a pathway for cellular growth.

Excess mTOR can stimulate cell growth and block autophagy, which is removal of accumulated waste products inside cells.

Many of the problems that come with aging arise from uncontrolled growth or aging cells that have accumulated so much internal cellular debris that they lose healthy functionality.

Examples of the problems that excess cell proliferation creates include cancers, osteoporosis caused by overzealous osteoclasts (cells that remove older bone), and Alzheimer’s which is associated with the accumulation of abnormal proteins.

Kaeberlein explains that mTOR “is kind of like a stoplight for the cell. Basically, it’s involved in the decision point where it’s either a good time to grow or stop growth and become stress resistant. One of the key things impacting that decision point is food availability. More calories generally mean more growth. Rapamycin tones down mTOR activity. So in some ways, it’s like a caloric restriction mimic because it kind of tricks cells into thinking there isn’t more food around.”

Rapamycin also seems to be safe, a critical consideration when developing a study using people’s pets.

“In a lot of ways, the Dog Aging Project is like working with people’s children,” says Kaeberlein, whose wife Tammi, a University of Washington research scientist, was the lead coordinator for the first trial. “It’s really important not to hurt anybody’s dog.”

The researchers already had data from veterinarians who’d used the drug to treat certain forms of cancer, so they had guidelines for dosage and potential side effects. The primary goal of the first phase of the planned three-phase study was to make sure rapamycin would do no harm to the precious pooches.

“It’s a balance between what’s the most likely intervention to work and also one we were fairly confident could be administered safely to healthy, older, companion animals,” says Kaeberlein.

For the double-blind, placebo-controlled study, the team recruited 24 middle-aged dogs from the local Seattle area and administered rapamycin to 16 of them over the course of 10 weeks. They found no side effects in terms of blood chemistry and changes in behavior, and the rapamycin-treated dogs showed better heart function than the control group.

The dogs got echocardiograms at the beginning and end of the study to test for three parameters of ventricular contraction – how well the heart pumps blood – which declines with age.

“In the rapamycin group, two of the three cardiac parameters were significantly improved, but all three showed positive direction,” says Kaeberlein. “That was surprising to me given the short duration and small sample size.”

Phase 2 has started and is being conducted at the Texas A&M College of Veterinary Medicine where a rolling enrollment of dogs continues. Eventually, 50 of them will be treated with either rapamycin or a placebo for 6 months, then followed up for 6 months.

“In Phase 2, we’re looking at two things,” says Kaeberlein. “First, can we replicate the positive heart function we saw in Phase 1 over a longer period? And second, are there any persistent effects? Do changes last after dogs come off rapamycin?”

Phase 3 will be a 600-dog study with Texas A&M as the primary clinical site along with four or five other veterinary teaching hospitals. The dogs will be treated, or not treated, with rapamycin for 3 years, then followed for the rest of their lives.

“The idea is to have a cohort of dogs that are aging rapidly, so if rapamycin has beneficial effects, we’ll actually be able to see them in Phase 3,” says Kaeberlein. “Unlike Phase 1, which is mostly about safety, and Phase 2, which is mostly about cardiac function, Phase 3 is about lifespan. And to detect an expected 15% increase in lifespan over a 3-year period, the math said we needed 600 dogs aged 7 or older.”

In all three phases, the dogs have to be middle-aged and at least 40 pounds, because big dogs age faster than small ones.

The rapamycin studies are only one part of the Dog Aging Project, which actually had its origins at the University of Georgia a decade ago.

An evolutionary biologist named Daniel Promislow had been studying aging in mammals since his days at Oxford University as a Rhodes Scholar, and he began focusing on dogs after seeing a Science journal cover story on the genetic role in determining the wide range of sizes in canines.

“I began to look at size and longevity in dogs,” says Promislow, who was working at the University of Georgia. “In general, larger species of mammals live longer than smaller ones. In dogs, it’s the opposite. And a gene that explained the size differences, insulin-like growth factor 1, had, in previous lab studies, also been implicated in aging.”

In 2007, Promislow got his hands on a large veterinary database detailing the longevity and cause of death of some 80,000 dogs.

“It was an amazing data set but I knew nothing about veterinary science,” he recalls. “So I reached out to the veterinary school and they put me in touch with an assistant professor named Kate Creevy. She and I started working together, and that’s when the Dog Aging Project was really born. We published some papers and got excited about the potential of the dog as a model system for aging.”

When Promislow’s wife got a job in Seattle a few years later, he contacted Kaeberlein and soon landed a position at the University of Washington.

“Matt immediately saw the potential of the Dog Project for intervention studies,” says Promislow. “We began putting together the Dog Aging Project grant proposal to fund a nationwide, long-term longitudinal study of aging.”

The longitudinal study, which Promislow oversees, is slated to kick off this year. It will involve 10,000 dogs in its quest to understand why some dogs live longer than others. Dr. Creevy, now at Texas A&M, serves as Chief Medical Officer. The team also includes University of Washington veterinarian Dr. Silvan Urfer, graduate student Kelly Jin and Tammi Kaeberlein. There are four parts to the project.

One is simply how to define aging in dogs.

“With humans, a geriatrician can tell if a person is a healthy ager or not with very simple measurements, like grip strength and the time it takes to walk 10 meters—simple measures that are very predictive of future survival,” says Promislow. “We don’t have that kind of thing for dogs. So the first thing we want to understand is what healthy aging looks like in a dog.”

The second element is to understand the genetic factors that influence whether or not a dog is going to be a healthy ager.

The third is systems biology, a multidisciplinary approach to understanding how the entire network of biological systems works holistically in the aging process.

“We want to understand the mechanisms by which genes affect downstream traits, to see if we can identify biomarkers of aging, ways of measuring a dog that will show whether it’s biologically older or younger than its chronological age should be,” explains Promislow.

The fourth part, involving about 5% of the dogs, is Phase 3 of the rapamycin study.

Both Promislow and Kaeberlein are optimistic about funding from the National Institutes of Health, and the response from dog owners who want their pets to participate has been encouraging.

“Pets are important to people, and that’s why the Dog Aging Project has had so much resonance,” says Kaeberlein. “We’re not just going to learn about human aging and how to impact human health; we also have the potential to improve the quality and quantity of life for people’s pets.”

For more information contact Dr. Kaeberlein at kaeber@uw.edu or visit the Dog Aging Project website at www.dogagingproject.com.

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References

1. Powers RW, 3rd, Kaeberlein M, Caldwell SD, et al. Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev. 2006 Jan 15;20(2):174-84.
2. Johnson SC, Martin GM, Rabinovitch PS, et al. Preserving youth: does rapamycin deliver? Sci Transl Med. 2013 Nov 13;5(211):211fs40.
3. Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature. 2013 Jan 17;493(7432):338-45.