Frontiers Interaction + Infrastructure = Innovations in Healthy Aging

Ida died of heart disease at age 84. Pearl, however, beat chronic lymphocytic leukemia at age 50, and now, at age 95, is still doing well. Although Pearl has declined physically since she had a fall two years ago, mentally she’s nearly as sharp as ever.

What accounts for the differences in health and life span between Pearl and Ida? Clearly, genetics—which are the same for identical twins—cannot be the only factor in how well we age. 

The issue of how we age is becoming increasingly important as the age distribution in American society is shifting toward a much older population. The number of people over the age of 65 has more than doubled since 1970, and those over 85 have tripled. People over 65 are expected to comprise nearly one-quarter of the population by 2050.

Although the average life span is currently much longer than before, individuals are not necessarily healthier, since aging is by far the biggest risk factor for most human diseases and overall functional decline. In 2019, the National Center for Health Statistics reported that 83 percent of Americans aged 60–79 are taking one or more prescription drugs, while 34 percent are on five or more, with the most common being beta-blockers, cholesterol-lowering agents, and antidiabetic medications.

Thus, there is an urgent need to understand aging’s biological underpinnings, with the ultimate goal of finding interventions that increase the number of healthy and productive years of human life, known as our health span. 

To address that need, Salk has established the Healthy Aging Initiative, part of the Institute’s Campaign for Discovery, a seven-year, $750 million comprehensive fundraising effort to expand Salk’s deep expertise by attracting additional exceptional talent and taking advantage of recent technological innovations to address six important research areas: healthy aging, cancer, immunobiology, neuroscience, plant biology, and computational biology.

Recognizing that everybody ages at a different rate and manner depending on their unique genetics, lifestyle, and environment (and how these factors interact), the Healthy Aging Initiative aims to focus resources on fundamental aging and health-span research that will inform the development of personalized health-span interventions. 

In order to ensure success, Salk is relying on its time-tested formula: interaction + infrastructure = innovations.

InnO₂vations

When talented research teams have supportive infrastructure, innovation is bound to follow. Salk scientists often develop new tools and techniques that revolutionize how research is done.

Because chronological age doesn’t necessarily align with biological age, better biomarkers are needed to help predict disease risk and life span. Salk Professor Tatyana Sharpee and Professor Alexey Terskikh at Sanford Burnham Prebys recently developed an imaging-based approach to quantify aging and its inverse—rejuvenation. Terskikh had developed a new experimental imaging approach to monitor changes in chromatin (DNA plus proteins) and in the epigenetic “tags” attached to DNA in single cells. This experimental approach produces a lot of data obtained at the limit of imaging resolution, and therefore, requires novel statistical methods to extract appropriate signals. Sharpee’s group was working on methods of just this kind, using geometry techniques that capture rapidly expanding data divisions in a tree-like manner. Combining the duo’s experimental and statistical innovations makes it possible to predict biological age more accurately. The approach can also detect how changes at the microscopic cellular levels in blood correlate with organism physiology and behavior, such as sleep and mobility, even among individuals of the same age.

“So much of our understanding of aging is based on population-level data, but that doesn’t really explain what’s going on with any particular individual,” says Sharpee, who holds the Edwin K. Hunter Chair. “The beauty of our new approach is that it advances our understanding of how individual-level biomarkers of aging at the cellular level predict physiologically relevant parameters, which is an important first step in personalized interventions for aging.”

Sharpee is a member of both the Computational Neurobiology Laboratory and the Integrative Biology Laboratory, and also researches how the brain’s billions of neurons use energy and exchange information.

Salk is highly prolific when it comes to innovations in neuroscience, including ways to study Alzheimer’s disease.

While Alzheimer’s disease is one of the top 10 causes of mortality in the US, it’s also uniquely awful in the way it robs people of their identities and relationships with loved ones. Salk researchers are investigating this disease from many different angles, making the idea of effective treatments in our lifetime seem possible.

In 2015, Gage pioneered a method to create brain cells from the skin samples of older people that retained age-related signatures, making the cells invaluable for studying age-related diseases like Alzheimer’s and Parkinson’s. The technique advanced research into brain aging because, before that, “reprogramming” skin cells into stem cells that could be turned into, say, neurons, erased all the signatures of aging. These new techniques are the cornerstone of the aforementioned aging and disease modeling efforts in both the AHA-Allen Initiative and the Shock Center.

More recently, Gage’s lab found that neurons from people with Alzheimer’s disease have a loss of functional activity, impaired metabolism, and increased inflammatory properties. The neurons show deterioration and undergo a late-life stress process called senescence. But administering a custom drug cocktail to the cells reduced the number of senescent neurons to normal levels. The work suggests that targeting senescent cells could be a useful approach for slowing the neuroinflammation and neurodegeneration seen in Alzheimer’s disease.

“Age-related neurodegeneration and the concomitant cognitive decline is inevitable and relentless,” says Gage. “Our goal is to define the cellular and molecular mechanisms that contribute to accelerated decline, as in Alzheimer’s disease. By identifying the molecular mechanisms and the cells that are most affected, we can develop methods of intervention to slow that decline and preserve health. Interestingly, many of the targets we have identified, so far, are cancer-related pathways for which drugs and therapies have been developed. We are currently repurposing cancer drugs for the treatment of age-related cognitive decline.”

Professor Joseph Ecker, holder of the International Council Chair in Genetics and a Howard Hughes Medical Institute investigator, pioneered a method to tag DNA, RNA, and chromatin (DNA plus proteins) in the same cell. The method allows researchers to measure all three types of information simultaneously, and all without destroying the cell, both major innovations. This genomic technology, called snmCAT-seq, took five years to develop and is already proving useful for comparing cells from healthy human brains with those from brains of individuals affected by Alzheimer’s and other neurodegenerative diseases.

Associate Professor Nicola Allen studies astrocytes, star-shaped brain cells that play a key role in helping neurons develop and work properly. She found that neurons and astrocytes work together to form healthy synapses, the connections between neurons. Synapse loss is associated with cognitive impairments, such as those seen in dementia. Allen and her team are studying whether astrocytes can be manipulated to stimulate neurons to repair synapses or form new ones in disorders such as Alzheimer’s disease.

In yet another insight into Alzheimer’s disease, Professor Alan Saghatelian, in collaboration with UC San Diego scientists, discovered that a class of lipids called SGDGs, which change and decline in the brain with age, has anti-inflammatory effects. Saghatelian, holder of the Dr. Frederik Paulsen Chair, says that SGDGs clearly represent a novel piece in the aging puzzle, thereby warranting further study.

Finally, a study by Research Professor Pamela Maher showed how cannabinol (CBN), a non-psychoactive compound derived from cannabis, can protect nerve cells from oxidative damage, a major pathway to cell death. (Brain atrophy from cell death is a prominent feature of Alzheimer’s disease.) She found that CBN works in this context by protecting mitochondria.

Maher is also responsible for a phase 1 clinical trial for CMS121, a compound developed and studied at Salk over the last 15 years. The story of CMS121 illustrates how long it takes to develop therapies derived from basic research. Maher began working on the research that resulted in CMS121 in 2006, but the compound did not reach the clinic until 2022, and will require additional time and money to complete all three phases of clinical trials required to bring a drug to market.

“Our first-in-human study with CMS121 in young and old healthy adults showed good safety and tolerability, so we are now trying to get funding for a trial in early Alzheimer’s disease patients,” says Maher. “We think CMS121 has real promise, as it targets a novel pathway and is also effective against multiple risk factors for Alzheimer’s.”

The time and resources involved in finding effective therapies is significant, which is why, despite Salk’s impressive track record of obtaining funding from NIH, private philanthropy is still crucial for pushing research forward.

The complexity of aging—it’s not just genetic or epigenetic or metabolic or biochemical—suggests that the traditional research model of studying each aspect independently is not the most effective. Instead, the Salk strategy of bringing the best researchers from different areas together, to collectively approach an issue and to inspire each other, offers more promise.

“We are in an exciting new era of research on aging, where we know many of the cellular and molecular processes involved,” says Professor Gerald Shadel. “Given Salk’s long-standing foundational research in aging and age-related diseases—coupled with its unique formula of infrastructure, interdisciplinary collaboration, and integrative approaches—we are uniquely poised to capitalize on support for our Healthy Aging Initiative and fundraising campaign.”