Aging typically means increasing morbidity and functional decline that eventually results in the death of any organism, not just humans. It is the largest risk factor for numerous human diseases, and understanding the aging process may be the pathway for new treatments for age-associated diseases.
Humans for such research are limited in a number of ways, including ethical issues, environmental and social factors, and long natural life span. These are the basic core pillars of the One Health concept, the interface of animals, humans, plants, and the ecosystem.
Increasingly, these same considerations – ethics, environmental impact – affect animal testing, with the heightened public interest in animal welfare and expressed outrage at past practices, resulting in limitations and protections, and properly so.
Within this framework, it is important to recognize that animals populate all environments -air, water, terrain and subterranean, and water- and are subject to similar stresses. We need to appreciate the unique and incredible benefit such cross-species research provides in studying human aging, without invasive “testing”. Below is a sense of this complicated subject.
Animal research and aging limitations
Much of “aging” knowledge is the result from studying mice, rats, and fruit flies. These are easy to handle, have short generation times, allow for producing strains and standardized husbandry. Such nonhuman substitutes have produced a wealth of information including well-annotated genome sequencing data.
Another advantage of these creatures is that there is readily commercial availability of models, and cell lines comprising embryonic stem cells, but they are not “near human”. They can, however, be used in conjunction with genetic engineering tools such as CRISPR/Cas systems, to garner further deep relevant information.
Taken together, there is much promise in increasingly understanding the biological mechanisms for aging.
Primates, our closest relatives
Chimpanzees, orangutans, bonobos, marmosets and other primates are of great interest for gerontology research, but limited by substantial financial, ethical, legal, and species conservation considerations, and by long lifespans.
In 2015 the U.S. National Institutes of Health (NIH) announced it would stop using chimpanzees in biomedical studies. But research can go on, as researchers find that rhesus monkeys and marmosets are useful models to learn about the mechanisms that “lead to age-related decline seen universally, across species.”
Corinna Ross, a primatologist at the Texas Biomedical Research Institute in San Antonio, who studies aging in marmosets, noted that “The goal isn’t to increase the number of 120-year-olds who are living in nursing homes. We want more 80- and 90-year-olds who are living independently.”
And while in the past worms and rodents were the living creatures principally used for aging studies, a 2017 paper by National Institute on Aging researchers makes the point that nonhuman primates share 92 percent of genes with humans and thus have an “aging process that more closely resembles the human experience.”
Other important aging research in animals
An article in Frontiers about alternative animal models in aging research provides a sampling of the wide range of animals that have something to add to aging knowledge. Below are some of the emerging animal models that have attracted the attention of gerontologists.
Bats can live over 41 years and do so with a high metabolic rate that results in a lifespan-energy expenditure exceeding that of other mammals by as much as 2 times. Bats have highly efficient antiviral immune responses and tight inflammation controls, and there is much to learn from them.
For examples of how research is carried out with minimum disturbance to animals and what can be learned, consider the work of Irish bat biologist Emma Teeling of University College Dublin and her team. They are engaged in catching brown mouse-eared baby and mother bats who return to local Gothic church belfries and collect their blood to sequence their DNA, and then quickly release them to freedom.
Given that the mothers repeatedly return to their birthplaces to deliver babies, the church belfries offer a perfect setting to recapture the same bats and study how they’ve aged. And the findings can be surprising: “Bats can tolerate viruses, rarely get cancer and don’t show signs of aging,” says Teeling about her research findings.
African mole-rats are subterranean rodents that have attracted the attention of gerontologists for more than 20 years due to their generally high longevity, e.g maximum lifespans of over 20 years.
For example, one study found that among African mole-rats there is variation between species with respect to the role of telomere (structural components of DNA) shortening in aging, and the replicative theory of cellular senescence (aging of cells). Another study found that the blind mole-rat has effective telomere maintenance, preventing early cellular senescence induced by persistent DNA damage response (DDR), thereby contributing to its longevity and healthy aging.
Some birds have increased life expectancy by more than 50 years, despite higher body temperatures, glucose levels and metabolic rates – as compared to size-matched mammalian species.
Among birds, parrots are especially long-lived. Morgan Wirthlin from Carnegie Mellon University with colleagues from other research entities conducted a comparative genomic analysis of an endangered parrot species, the blue-fronted Amazon, comparing it with 30 other long- and short-lived birds, including four additional parrot species. The study identified a suite of genes previously not known to play a role in longevity and deserving of further study. Other studies such as this one carried out by the University of La Laguna and the Institute of Tropical Diseases in Tenerife, bring in new fascinating results:
Whales are among the longest-lived mammals, with life expectancy comparable to, or exceeding, that of humans. The bowhead whale typically populates the cold seas of Greenland and represents the longest-lived extant mammal, being able to survive beyond 200 years of age. Research has shown that one reason that they live so long is that they have unusually vigorous DNA repair processes, slowing the accumulation of damage in their genomes.
Another study on the bowhead whale genome and two transcriptomes from different populations identified genes under positive selection and bowhead-specific mutations in genes linked to cancer and aging. In addition, they identified gene gain and loss involving genes associated with DNA repair, cell-cycle regulation, cancer, and aging.
Among the numerous research possibilities, one is the “annual killifishes” which are able to adapt to the seasonal alternation of wet and rainy seasons and inhabit ephemeral ponds that last a few weeks.
The duration of the ponds sets a pressure for rapid maturation and an upper limit to the post-hatch lifespan of these fishes. As a result, annual killifishes become sexually mature within a couple of weeks and show rapid age-dependent physiological decline.
Research on annual killifishes has already given interesting results. One study found that natural populations of some annual killifishes have a selective force that can shape the evolution of lifespan and its variation across populations beyond the effects of the pond’s habitat. Other research using the African turquoise killifish as an in vivo model found several aging hallmarks in the killifish retina and brain that eventually result in a diminished visual performance.
Giant tortoises often lived past 100 years, showing little evidence of physical aging, with the genomes of giant Galapagos and Aldabra tortoises having unique genes for DNA repair, and inflammatory mediators.
But there are also smaller turtles that can live more than 60 years and are more suitable for laboratory study. Long-term field studies exist (since 1953) in examining the demographic landscape under which their adaptations have evolved. Notably, one study examined age-related decline in 52 species of captive turtles and tortoises in zoos and aquariums, finding that in captivity, without the stress of finding food and avoiding predators, some did not appear to age at all².
How turtles avoid aging is still a bit of a mystery, but one theory is that cold-blooded animals are better equipped to manage the wear of aging because they rely on the environment to calibrate their body temperatures instead of the energy-draining metabolisms of warm-blooded animals. Another theory is that they are able to quickly kill off damaged cells and that they are resistant to DNA damage that accumulates over time as cells divide.
In demographic studies with species of freshwater polyps it was shown that several of them have constant low mortality and high fertility rates over long periods of time These studies predicted that at least 5% of the Hydra population would reach an age of more than 1000 years under laboratory conditions.
Among the most interesting studies is the one carried out by researchers from Kiel University together with the University Medical Center Schleswig-Holstein (UKSH) who examined why the polyp Hydra is immortal and unexpectedly discovered a link to aging in humans. They found that the ‘FoxO” gene exists in all animals and humans and plays a role in stem cell aging.
When people get older, more and more of their stem cells lose the ability to proliferate and thus to form new cells. Aging tissue cannot regenerate any more, which is why for example, muscles decline. Elderly people tend to feel weaker because their heart muscles are affected by this aging process as well.
Studying animal tissue such as those of Hydra – an animal full of active stem cells during all its life – may deliver valuable insight into stem cell aging as such. It would thus appear that this high potential for longevity has largely evolved as a by-product of Hydra’s regenerative capacity which allows these animals to fully restore any part of its body within days in the event of injury.
And pets also help us age better and healthier
“In recent years, the dog has grown to be one of the most important animals for researchers who aim to understand the biological background of complex traits,’ said Dr Enikő Kubinyi, an ethologist at Eötvös Loránd University in Budapest, Hungary.
A key driver has been her university’s Family Dog Project, founded in 1994 on the principle that the family home is dogs’ natural environment due to their adaptations over many thousands of years to live with people.
Now one of the world’s largest dog research groups, the initiative was expanded in 2016 with the Senior Family Dog Project, or EVOLOR, to look specifically into cognitive aging.
The study detected significant age-related deterioration of brain and brain function even in healthy dogs, but aging has a bright side as well. Older dogs are calmer and more knowledgeable, and in association with these traits, they were reported by owners as more often dominant over younger individuals when kept in groups.
The EVOLOR results are expected to provide guidelines for a healthy lifestyle towards successful aging, to increase both canine and owner welfare, and to aid our understanding of the biological background of human cognitive aging.
A potential breakthrough in animal research in aging
A biotechnology company, Life Bio announced preclinical data in nonhuman primates (NHP) for a novel gene therapy candidate which has been shown to reverse aging, improve vision, and extend lifespan in mice, but whether epigenetic reprogramming would work in primates was not known.
A co-founder of Life Bio and Harvard Professor in the Department of Genetics and Co-Director of the Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School, Dr. Sinclair put it this way:
“Demonstrating rejuvenation in nonhuman primates is a major step forward in advancing cellular rejuvenation as a way of treating both common and rare diseases in the eye and potentially other tissues. What we’ve learned in NHPs has important ramifications for research on reversing aging and is likely to be highly translational to humans. This data moves us an important step closer to the first clinical trials of how cellular rejuvenation technology could treat aging-related diseases.”
Why we need ethical animal research to better deal with aging
Ethical animal research is an essential tool in understanding human aging and ways to make later years healthier and more productive. With rapidly aging populations around the world, the need to find ways to reduce the burdens on health and care providers becomes ever more urgent.
A broad strategy drawing on technology across multiple disciplines promises a much greater understanding of the biological mechanisms for aging compared to silo-style research within the boundaries of a single discipline.
We need to keep in mind that we humans are simply only one part of the broader animal, plant, and environment continuum, known as One Health. As the primary sentient beings, we must be responsible caretakers for all, aware of their interdependence and interaction.
Editor’s Note: The opinions expressed here by the authors are their own, not those of Impakter.com — In the Featured Photo: Image used in University of Georgia’s article calling for 30,000 dogs needed for research in its Dog Aging Project that seeks to understand the determinants in canine aging (April 23, 2021)