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The science of healthy aging

Martin Hetzer, Juan Carlos Izpisua Belmonte, and Jan Karlseder

Martin Hetzer, Juan Carlos Izpisua Belmonte, and Jan Karlseder

What was Ernest Juller's secret? In his 97 years, Juller was rarely sick, hardly saw a doctor and, until the very end of his life, remained healthy, active and a gardener of particular persistence. Was it his daily glass of white wine? Was it his regular leisurely walks in the Austrian forest? Or maybe his exceptional vitality stemmed from the same tenacity that kept him, year after year, attempting to grow an alpine forest in lowland Austria.

"He lived in a region situated at a much lower altitude than Alpine plants typically grow," recalls Juller's grandson, Jan Karlseder, a professor at the Salk Institute. "He was never completely successful with his Alpine garden, but that didn't deter him. He was a botany professor, and he loved mountain plants. It's impossible to say exactly what kept him healthy and active for so long—maybe it was good genes. If so, I hope he passed them on."

For most of us, explaining the mystery of people like Juller, who live remarkably long and healthy lives, is a matter of making casual observations. We catalog aspects like diet, exercise, sleep and other salubrious elements of a person's life as we attempt to identify their formula for success. For Karlseder and other scientists at Salk, however, deciphering the secrets of healthy aging is a full-time occupation. Equipped with cutting-edge scientific tools, such as high-resolution imaging, whole-genome sequencing and bioinformatics, they are exploring how our bodies age at the molecular level. Line by line, they are filling in the blueprint for the biological mechanisms that maintain our cells and organs, repair damage from injuries and fend off diseases as we get older.

The science of aging has never been more important. Currently, about 40 million Americans are over 65, and by 2030 those numbers are expected to grow to more than 72 million. As the proportion of older people rises, so too does the incidence of age-associated disease, with its attendant personal, social and economic costs. Largely as a result of this trend, healthcare spending is expected to increase by 25 percent by 2030, and Medicare spending will grow from $555 billion in 2011 to $903 billion in 2020.

Makoto Hayashi, Anthony Cesare and Jan Karlseder

From left: Salk scientists Makoto Hayashi, Anthony Cesare and Jan Karlseder

It is against this backdrop that the Salk Institute has launched its Healthy Aging Initiative as part of the Campaign for Salk, the Institute's first-ever major fundraising campaign. Through support for research on aging, the initiative seeks to explain why aging is the number-one risk factor for conditions such as neurodegeneration, cancer, diabetes and cardiovascular disease. But Salk scientists aren't just asking why aging often leads to illness. The initiative is also a crucial step in developing therapies that target the causes—not just the symptoms—of such diseases and disabilities.

"Every person's medical history stems from a mix of genes, lifestyle and environment, but what we want to find are the common factors—at the molecular, cellular and organismal levels— that allow some people to remain robust late into life," says Karlseder, the holder of Salk's Donald and Darlene Shiley Chair. "If we understand these mechanisms, these programs that run our cells and organs, we can use them to help increase the human 'healthspan,' the length of time people stay healthy during their lifetimes."

Karlseder's research centers around telomeres—complexes that cap the ends of chromosomes, the structures that contain our DNA. Telomeres help protect and repair our cells, and they play a central role in cellular aging by shortening every time a cell divides, a molecular method of marking time. When telomeres become too short, they signal the cell to stop dividing and self-destruct, making way for new cells.

Telomeres are also involved in DNA repair, a process by which cells fix damage done from normal physiological wear and tear and environmental factors such as UV light. Because tumors attack the body by bypassing these safeguards, scientists are also actively studying telomeres' involvement in cancer.

Recent discoveries by Karlseder's team explain how telomeres serve as sentries, keeping cells operating in an orderly fashion and protecting our bodies from cells containing damaged DNA. In one study, they showed that telomeres begin to degrade rapidly when a cell takes too long to divide—a sign of genetic damage. This sends a warning signal that tells the cell to shape up or ship out: repair its DNA or self-destruct. It is a crucial check on cellular growth that prevents cells with damaged DNA from propagating. In another experiment, the scientists found that telomeres act as anchors that organize chromosomes as a cell divides. Under a microscope, they observed that telomeres move to the outer edge of a cell's nucleus after the chromosomes are duplicated during cell division.

"Our cells aren't simply bags containing an unorganized mix of chemicals, but rather are complex three-dimensional machines, in which the gears and wires are made up of molecules," Karlseder says. "What we found suggests that telomeres don't just protect our cells; they help orchestrate this molecular machinery in the nucleus, which is the cell's control center."

In fact, Karlseder believes that telomeres may play a central role in controlling how our cellular programming—the genetic "software" that runs our cells—changes as we get older. The code that runs these programs is stored in our DNA sequences and in a collection of extra-genetic chemical markers known as the epigenome, which can turn genes on and off, thereby guiding cellular function. Integrated into the chromosomes that house and organize these codes, telomeres are well placed to influence how cells behave.

Martin Hetzer and Emily M. Hatch

Martin Hetzer, professor, Molecular and Cell Biology Laboratory and Emily M. Hatch, research associate

"The more we learn about telomeres," Karlseder says, "the more they appear to affect gene expression profiles and how the genome morphs over time. By understanding these mechanisms and learning how to influence them, we may be able to intercede in the genomic and epigenomic programming that changes with aging. The idea would be to bolster the cellular programs that protect and renew our bodies and stifle those that lead to premature aging."

The research of Martin Hetzer, another Salk professor studying the cellular roots of aging, focuses on another important component of a cell's nucleus: the molecular gates, known as nuclear pores, that allow the genetic control center inside the nucleus to communicate with the cellular machinery outside the nucleus, in the region known as the cytoplasm. These pores also protect the valuable genetic material from toxins found in the cytoplasm.

Hetzer's team found that nuclear pores of neurons contain certain proteins—which they dubbed extremely long-lived proteins (ELLPs)— that have a remarkably long lifespan. While most proteins last a total of two days or less, the researchers identified ELLPs in the rat brain that were as old as the organism. This was the first time scientists had discovered an intracellular component made up of molecules of this age, and their results suggested that the proteins lasted an entire lifetime without being replaced.

The longevity of ELLPs may help explain in part why brain function often declines as people age. Previous studies by Hetzer's group showed that the nuclear pores weaken over time, allowing proteins to leak from the cytoplasm into the inner sanctum of the nucleus. For instance, in older cells a protein called tubulin, which should be found only in the cytoplasm, gums up the nucleus with long filaments. Associated with several neurodegenerative diseases, including Parkinson's, the filaments are found in the substantia nigra of many Parkinson's patients, the part of the brain that is involved in dopamine production and that is affected by the condition.

"What we think is happening is that ELLPs deteriorate over the years and aren't replaced, which leads to dysfunction and vulnerability," says Hetzer, who holds the Jesse and Caryl Philips Foundation Chair. "It's as if you regularly take your car in for routine maintenance, but one critical component was never replaced or repaired. Eventually, that part will stop working, and that will have a cascade of effects, causing the whole engine to go haywire."

The deterioration of proteins may extend beyond malfunctioning nuclear pores. Unlike cells of the skin or other high-turnover areas of the body, most of our neurons stay with us our whole lives. Other important components of neurons may contain ELLPs and thus may be similarly prone to wear and tear. In addition to being embedded in the membrane surrounding the nucleus, ELLPs are found on the plasma membrane, the outermost surface of the cell. They are also part of the chromatin, the bundles of DNA and proteins found inside the nucleus, which help to organize and control the function of a cell's genetic operations. In each case, ELLPs serve a vital role in coordinating the dizzying array of cellular activity that keeps our nervous system healthy.

"The reason we keep neurons so long is that it's important to have consistency; otherwise we wouldn't be able to learn and remember or to respond quickly to our environment," Hetzer says. "If we had to replace neurons all the time, it would constantly interfere with our ability to function in the world. But stability comes at a cost: it tests the durability of those neurons. We know that genetic activity changes with age, and we think that results in part from deterioration of nuclear pores and other longlived cellular components."

Emmanuel Nivet and Juan Carlos Izpisua Belmonte. Seated: Ignacio Sancho Martinez

From left: Emmanuel Nivet and Juan Carlos Izpisua Belmonte. Seated: Ignacio Sancho Martinez

Like Karlseder, Hetzer is curious why some elderly people seem relatively unaffected by aging, while others suffer from, Parkinson's, Alzheimer's and other neurodegenerative disorders. Through fully understanding how certain people maintain normal function and ward off disease, his team hopes to identify and possibly bolster genetic and epigenetic mechanisms that protect us as we age.

Other Salk scientists, such as Juan Carlos Izpisua Belmonte, holder of the Roger Guillemin Chair, are looking to our most immature cells to explain what it means to get old. Izpisua Belmonte's lab studies how stem cells differentiate and give rise to over 200 cell types that constitute the human body. This research not only helps explain how our bodies maintain and heal themselves, but also offers the possibility of using stem cells in regenerative medicine.

In one study, Izpisua Belmonte's team generated induced pluripotent stem cells (iPSCs) from skin cells obtained from patients with Hutchinson-Gilford progeria syndrome, a condition which causes them to age eight to ten times faster than the rest of us. The Salk scientists then differentiated the stem cells into smooth muscle cells displaying the telltale signs of vascular aging. In addition to providing insight into Hutchinson-Gilford progeria, the study offered a new method for studying age-related disease in the laboratory at an accelerated pace.

More recently, Izpisua Belmonte's group used iPSCs to generate neurons that exhibited characteristics of Parkinson's disease due to mutant genes inserted into the cells' DNA. This allowed them to study the molecular underpinnings of the disorder in the laboratory, overcoming the difficulty of obtaining human neurons for experiments. His lab is also using iPSCs to study Werner syndrome, a premature aging condition that more closely resembles normal aging, compared to Hutchinson-Gilford progeria. Using these laboratory models, he and his team are studying the links between genetic instability, aberrant epigenetic signatures and cellular aging. Like Karlseder and Hetzer, Izpisua Belmonte emphasizes that studying the normal process of aging is crucial to understanding how things can go wrong.

"Pluripotent stem cells give rise to all the tissues and organs in our bodies, and stem cells continue to repair and replace old cells throughout our lives," he says. "If we know precisely how this happens—the exact molecular mechanisms— we might be able to boost this capacity for self-healing."

Karlseder offers Ernst Juller as an example of what could become the norm if the science unravels the mysteries of healthy aging. "Obviously, advances in science and medicine have played a large role in helping us live longer," says Karlseder. "Now we need to focus on keeping us healthy longer. My aspiration is to stay as healthy as my grandfather as I get older, and I think the science we're doing now can help make that happen."