AGING

People are living longer, but not necessarily healthier—and aging is by far the biggest risk factor for most human diseases and overall functional decline. The National Center for Health Statistics reported in 2019 that 83 percent of Americans aged 60-79 are taking one or more prescription drugs, with the most common being beta-blockers for heart conditions and high blood pressure, cholesterol-lowering agents, and antidiabetic medications.

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

And yet aging research has been hampered by two key factors. First, it has historically been approached with tunnel vision, each discipline studying the issue in a silo. In other words, geneticists might look at only the genes involved in aging. Metabolic researchers might think the key is in mitochondrial function. Immunologists might focus only on inflammation.

Consequently, the many conditions for which aging is the major risk factor—heart disease, neurodegenerative diseases, diabetes, cancer—are each treated separately as well. Second, not all individuals age the same owing to their personal genetics, lifestyle, and exposure to pathogens and environmental stresses that make each person’s aging journey unique.

Salk is home to several experts in the known hallmarks of aging—for example, genome instability, mitochondrial dysfunction, and inflammation—but the secret sauce is they interact with each other to understand how these hallmarks interact with each other, in contrast to the typical siloed approach.

In addition to a person’s inherited genetics, Salk researchers are also deeply concerned with how environmental factors and lifestyles affect the trajectory of aging. Diet, exercise, and pathogen/toxin exposure all change the needle, and we need to understand how and why so we can intervene effectively and in a manner tailored to each individual.

When talented researchers in diverse areas have supportive infrastructure and work in a collaborative culture, innovation is bound to follow. For example, Professors Jan Karlseder and Gerald Shadel routinely go to each other’s lab meetings. It’s not something you’d expect from scientists in two different fields. Karlseder’s lab studies telomere biology— specifically, how telomeres (the protective caps on chromosomes that shrink as we age) prevent cancer formation. Shadel’s lab studies the role mitochondria (the powerhouses of the cell) play in human disease, aging, and the immune system. But at Salk, such cross-disciplinary interactions are common.

From their interactions, Karlseder and Shadel discovered that when telomeres become very short, they communicate with mitochondria, which sets off an inflammatory response that destroys cells that could otherwise become cancerous. Their finding was surprising in that three different hallmarks of aging—shortened telomeres, mitochondrial signaling, and immune inflammation—were teaming up to prevent an additional consequence of aging: cancer.

Someone studying only telomeres or only mitochondria or only cancer would not have come across this connection. Karlseder and Shadel plan to further examine the molecular details of these pathways and explore the therapeutic potential of targeting them to prevent or treat cancer and autoimmune diseases.

Here are a few additional recent examples of innovative aging research at Salk:

Professor John Reynolds identified a possible reason why half of older adults experience short-term memory problems: dysfunctional mitochondria at synapses (the connections between neurons) fail to meet energetic demand, supplying either too much or too little power. This energy mismatch may contribute to age-related memory loss, as well as the neurodegeneration underlying Alzheimer’s and Parkison’s Disease.

Professor Susan Kaech determined how inflammation—acute or over a lifetime—is partly to blame for our immune T cells becoming less effective with age, making us more prone to infection and cancers. In a recent study, she discovered that beta-blocker drugs can help revive these immune cells, making them better at destroying cancer.

Professor Satchin Panda discovered that time-restricted eating, or intermittent fasting, is helpful for glucose intolerance in middle-aged mice, also a common feature of human aging. While mice are not humans, his study of firefighters (ages 21–59) showed that time-restricted eating significantly improved blood sugar and blood pressure in those with elevated levels to begin with.

Professor Tatyana Sharpee and collaborators developed an imaging-based approach to quantify aging and its inverse— rejuvenation. The approach examines images of chromatin (DNA plus proteins) and epigenetic “tags” attached to DNA in single cells, looking for patterns that correlate with aging and rejuvenation. So far, the technique offers accurate aging trajectories, which is key to predicting how an individual will age over time.

Professor Christian Metallo studies how our bodies metabolize molecules like glucose, fats, and amino acids to generate the building blocks and energy needed to perform life-sustaining tasks —and how changes in metabolism occur as we age and contribute to disease. Metallo has made key discoveries about the metabolic pathways that drive age-related conditions such as cancer, peripheral neuropathy, and macular disease—pathways that can be influenced through dietary changes or targeted therapies.