Aging is inevitable, but can the diseases of aging be thwarted or at least postponed? New tools, including genetically varied mouse populations and advanced imaging technologies, hold promise for untangling the myriad mechanisms of human aging.
The Jackson Laboratory makes these and other tools available to the worldwide aging research community, with support from the National Institute on Aging. JAX has one of six NIA-funded Nathan Shock Centers of Excellence in the Basic Biology of Aging, and the grant has been renewed for a total of $5,347,630 over five years.
“The JAX Shock Center has been a resource for the geroscience community for more than a decade,” says JAX Associate Professor Ron Korstanje, Ph.D., co-director of the center. “We provide data and samples from our studies, but most importantly, we offer a pilot project program for investigators.”
Twice a year, the JAX center puts out a request for applications for pilot projects, Korstanje explains. “We get about 15 to 20 applications per round. We select the best of those and work with the investigators to conduct the experiments at JAX, providing the preliminary data they can use for grant proposals or papers.” In some cases, JAX invites participating investigators with special expertise to come to JAX for the duration of their experiments.
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Understanding genetic diversity
For decades, mice have been essential to aging research. Lifelong studies are practical in an animal that lives an average of two years in laboratory care. And as fellow mammals, mice and humans share the genetic code that both enables life and programs its eventual deterioration.
Until recently, JAX Shock Center aging studies have been conducted with the world’s most widely used inbred strain of laboratory mouse, the famous C57BL/6J “Black 6” mouse. The Black 6 genome was the first to be sequenced after the human genome, and more is known about the biology of this mouse strain than any other. However, even the mighty Black 6 has limitations: Its very genetic uniformity means that it represents only a sliver of potential genetic variations.
To better represent humans with all their genetic variability, in the early 2000s an international research team, including JAX Shock Center Co-Director Professor Gary Churchill, Ph.D., developed the Collaborative Cross and the Diversity Outbred mouse populations by intercrossing genetically defined mouse strains. The mice from the CC and DO populations are genetically diverse and, in the case of the DO mice, unique individuals, like each human.
Aged JAX DO colonies have produced some of the longest-lived mice ever recorded, nearly five years, more than twice the average life span of most laboratory mice. These individuals could provide valuable insights into the genetic components of a long and healthy life. The JAX Shock Center has conducted several large studies on DO mice over the past decade, and Korstanje says investigators are now able to submit applications for their own projects using DO mice.
Exploring senolytic drugs
The JAX Shock Center is also launching a project to explore senolytic drugs, a hot topic in aging research. Senolytics target senescent cells, cells that have stopped dividing and are the hallmark of many diseases of aging as well as aging itself. “All studies so far have been performed in just a single inbred strain, Black 6,” Korstanje says, “so there’s really nothing known about the effect of these senolytics and genetic variation. Our plan is to do a large intervention study, where we compare one group of aged DO mice that get the senolytics to another group that does not.”
Deploying machine learning
A new Image Analysis Core at the JAX Shock Center will use machine learning to analyze age-related histological profiles. “We’re doing this in close collaboration with the Geropathology Research Network,” Korstanje says, “which is an NIA-funded network of pathologists from different universities that are working on standardizing geropathology. Korstanje, whose own lab focuses on age-related kidney diseases, has already launched a study of kidney tissues. “And we’re going to expand this to be able to quantify aging lesions in the heart, liver, lung and possibly other tissues.”
Aging and COVID-19
Other planned Shock Center projects include aging colonies of several new mouse models for COVID-19 research currently being developed at JAX. “Aging is an important factor in COVID-19, and we want to provide aged mouse models for the community to do pilot experiments.” The Shock Center at JAX is also collaborating with the one at the University of Washington to support the production of a video lecture series on aging research for use in undergraduate and graduate biology courses.
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Preventing blood cancer
Recently the JAX Shock Center convened with the researchers of the National Cancer Institute-funded JAX Cancer Center . JAX Associate Professor Jennifer Trowbridge, Ph.D., who studies age-related blood diseases, notes, “We now understand that the greatest risk factor for cancer development is aging, and yet we know little about why and how aging increases risk of cancer development. We have a unique opportunity at JAX to bring these independent groups of investigators together as a think-tank to tackle these challenging questions.”
Trowbridge notes that her lab bridges these two concepts: “We are actively studying how and why aging of the blood system increases the risk of blood cancers, with the primary goal of identifying intervention strategies to prevent blood cancer development in aging populations.”
Korstanje says he wants the geroscience community to know about all the resources available from the JAX Shock Center. “We can do much more than just provide the aging mice,” he says. “We can be your collaborator to innovate your research programs.”
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THE WEAKENING LINE OF DEFENSE: AGING AND IMMUNE FUNCTION
We change as we age.
On the surface, that’s a completely obvious statement. But most of the actual mechanisms of biological aging are invisible, occurring underneath our increasingly wrinkled skin. And many of those hidden processes, which change functions over time at a molecular level, remain poorly understood.
What happens to our bodies between ages 25 and 45, between 65 and 85, and every decade along the way? Why do we become ever more susceptible to various diseases over time? And do we all age in the same way, or are there differences?
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A vital element of the aging process involves our immune responses. Decades of observational clinical data have shown that immune systems grow weaker and more prone to dysfunction as we age. What serves as an effective protective mechanism in our youth becomes far less reliable, and it can even cause active harm. The elderly are therefore more prone to infections and inflammation and less responsive to vaccines than their younger peers. Researchers have also observed that immune responses differ between men and women, and that those differences can become more important with age. For example, on average women are more susceptible to autoimmune diseases, while men are more prone to infectious diseases. The exact reasons why have remained elusive, but advances in research capabilities allow scientists to probe exactly what happens within us as the years pass.
And while all the differences are clinically meaningful, the recent COVID-19 pandemic has increased both the awareness and urgency around understanding them in more detail. It quickly became apparent that the incidence of severe disease and death increased markedly with age, with anyone over 70 being particularly vulnerable regardless of their prior health status. Men and women also had significant differences in their responses to infection. While the pandemic crisis will hopefully ease, it has shown, in stark terms, how essential it is to study our immune mechanisms and improve our ability to address vulnerabilities.
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How can one determine age-related immune differences? The ideal situation would be to follow people over a long period of time, taking the sample specific samples at regular intervals. But these so-called studies, take decades to provide usable aging data. Instead, researchers at The Jackson Laboratory and UConn Health have teamed up to match healthy people as best they can between different age groups. Their early findings show that men and women experience immune changes with age, as expected, but both the changes themselves and the timing of the changes differ.
The study co-leaders, JAX Professor Jacques Banchereau, Ph.D., and Associate Professor Duygu Ucar, Ph.D., approach the work with very different perspectives and areas of expertise.
Banchereau is an immunologist who has extensive experience studying the molecular pathways involved with immune function. His research covers many facets of the field, including how the immune system mounts a defense against infectious pathogens, how it can be activated for cancer immunotherapy, and how vaccines can be developed to activate the best possible protective immune response. Banchereau is particularly interested in figuring out how to improve vaccine effectiveness in the elderly, who can be vulnerable to both familiar pathogens, such as influenza, and emergent pandemics.
Ucar is a computational biologist who specializes in assessing the state of the genetic material within cells and how it can affect particular genes’ activity. These molecular traits reveal essential characteristics of specific cells and identify functional differences between them. Ucar can detect even subtle changes with age between the same kinds of immune cells.
Banchereau and Ucar’s research has revealed some intriguing insights into what happens to immune function as we age, and why changes occur. It has shown that many aspects of immune activity make a transition from mostly helping us to sometimes hurting us, especially once we reach certain ages. For example, a preliminary study looked at which genetic regions are more active in immune cells from young people than those from their older counterparts. It found changes in gene activity associated with adaptive immune function, the part of the immune system that responds to new situations, such as a new infectious microbes, and “remembers” the microbes to protect against them in the future. Not surprisingly, adaptive immunity-related genes are more active in younger people than in the elderly.
On the other hand, genes involved with innate immune activity (which provides initial, non-specific immune responses) and inflammatory processes are increasingly active with age. Inflammation involves chronic low-level immune activity even in the absence of pathogens, associated with autoimmune disease or obesity. And chronic inflammation has been linked to many diseases, including cancer.
Subsequent work has further revealed the specific ages at which significant molecular changes affect our immune function. The first was detected in the late 30s and early 40s, and the timing was similar in both sexes. The second, however, differed in both timing and magnitude between men and women, taking place in men between ages 62 and 64 and women, less profoundly, between ages 66 and 71. Interestingly, adaptive immune activity can increase in women over 65, giving them an advantage over men in fighting infections and providing a possible explanation for the increased incidence of autoimmune disorders. Men see increased activity associated with innate immune cells, which are less effective against pathogens and can be associated with inflammation.
The results are significant enough to have implications for clinical care. Men and women often need different therapies for them to be maximally effective. A better understanding of the changes can also help researchers explore ways that we might be able to target certain immune functions for enhancement or suppression. This would allow us to retain immune function like that of our youth.
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