Aging Dogs Can Provide Insights for Human Longevity

During his graduate studies at the Massachusetts Institute of Technology (MIT), Matt Kaeberlein initially aimed to explore structural biology. However, a lecture by MIT biologist Leonard Guarente during his first semester shifted his focus to the biology of aging. Since then, Kaeberlein's passion for this field has only grown.

Currently, Kaeberlein serves as a biogerontologist at the University of Washington. In 2014, he partnered with Daniel Promislow, also from the University of Washington, and veterinary internist Kate Creevy from Texas A&M University to establish the Dog Aging Project. So far, the initiative has enrolled over 44,000 dogs and started collecting data on lifestyle, lifespan, and age-related health issues such as heart and brain conditions. While the project primarily focuses on observational studies, it also investigates whether a drug named rapamycin can prolong lifespan in healthy older dogs. The ultimate aim is to gain insights into aging processes in both dogs and humans, while improving the quality of life for pet dogs.

Beginning the Dog Aging Project

Kaeberlein's interest in studying dogs as models for aging started during graduate school while researching aging in yeast. Yeast represents a basic organism, and he later examined aging in the nematode Caenorhabditis elegans, transitioning to work with mice.

All prior studies on aging took place in laboratory settings. Although such studies offer the benefits of precise control, they sometimes fail to translate to real-world experiences. In 2013, while co-directing a summer course at Woods Hole Laboratory, Kaeberlein joined Promislow to examine the biology of aging and consider dogs as models for this research. Kaeberlein's appreciation for dogs and their faster aging process provided a unique opportunity to study aging within a practical timeframe. Dogs, unlike laboratory animals, experience similar environments to humans — except for diet — which highlights potential methods to enhance the health and longevity of these pets.

Kaeberlein emphasizes that increasing healthy longevity in dogs is valuable regardless of what the research may reveal about human aging. Notably, there are significant parallels between aging in dogs and humans. Kaeberlein believes insights gained from studying dogs will translate to developments in human longevity.

The Effect of Rapamycin on Aging

Kaeberlein's interest in studying rapamycin stems from consistent findings on aging modulation. Caloric restriction is highly effective, but rapamycin proves to be the most reliable small molecule for enhancing lifespan and health in laboratory animals. Implementing a strict caloric restriction trial in pet dogs is impractical, and the risks of caloric reduction may outweigh those linked to rapamycin.

Research has indicated that initiating rapamycin in middle age yields considerable benefits—a vital factor for potential clinical trial applications. Studies in mice showed observable improvements within a few months of treatment. These improvements were apparent through echocardiogram results, immune system responses to vaccination, and reduced inflammation.

Fortunately, the Comparative Oncology Trials Consortium had already conducted trials involving rapamycin for osteosarcoma in dogs. This prior work provided crucial information about dosing, safety, and side effects, similar to a pediatric clinical trial framework, allowing Kaeberlein's team to assess risks while ensuring adequate safety measures.

Mechanisms Promoted by Rapamycin

Rapamycin has a fascinating history, arising from Streptomyces hygroscopicus, a bacterium found on Easter Island, or Rapa Nui. Initially examined for antifungal and anticancer effects, rapamycin was shown to inhibit a protein called mTOR, named after the drug.

Over the past few decades, research has uncovered mTOR's role as a central regulator of growth, development, and reproduction across eukaryotic cells. It helps cells and organisms assess their environment and decide on growth or maintaining stress resilience. Rapamycin curtails mTOR activity by signifying unfavorable conditions for reproduction.

The impact of rapamycin on aging can vary among species. In mammals, scores of healthspan benefits associated with rapamycin derive from its potential to restore immune balance in older organisms. Age-related declines in immune function incorporate the immune system's inability to respond correctly to pathogens, alongside increased autoimmune activity—commonly seen across aging individuals. Rapamycin effectively diminished this internal inflammation, potentially allowing the immune system to regain balance.

Discoveries from Early Rapamycin Trials

The first trial examined rapamycin's safety over ten weeks in a double-blind, placebo-controlled format across two different dosing levels. Results indicated significant improvements in two echocardiographic measures among dogs treated with rapamycin, and intriguing activity increases were reported by owners in those dogs.

A second clinical trial conducted at Texas A&M lasted six months, with half the baseline dosage applied from the initial study. Results revealed no significant fluctuations in echocardiograms; nevertheless, owners again noted increased activity. Notably, no significant side effects were observed in either trial.

Next Steps in Research

Kaeberlein's team is initiating their third clinical trial — the largest yet. This trial, named TRIAD, involves 580 dogs. Participants will be split into two groups, with half receiving a placebo and the other half receiving rapamycin for one year, followed by a two-year assessment phase. This careful design enables identification of as little as a nine percent change in lifespan.

The trial had just commenced prior to the COVID-19 pandemic, necessitating adjustments as veterinary clinics limited operations to emergencies. With clinics now back in action, Kaeberlein expects to conclude the randomization for all 580 dogs by the year's end. In a year, they will finalize treatment, and results will be available after two more years of follow-up.

Earlier, SSP reported that ancient DNA revealed indigenous dog lineages at Jamestown, Virginia.