Aging is the major risk factor for many diseases including diabetes, Alzheimer’s, heart disease, and cancer. This symposium highlighted the work of scientists Nir Barzilai, Judith Campisi, and Tony Wyss-Coray who are trying to understand what makes a person live longer and to find targets to delay or prevent aging. I summarize their presentations below.

Senescent cells drive aging

Recent evidence from mouse studies show that many of the diseases of aging are driven at least in part by the presence of senescent cells. These cells come about when normal cells are stressed, for instance, by exposure to toxins or mechanical damage. Three characteristics define senescence:  Cells stop proliferating, they produce molecules that affect other cells, and they resist cell death.

Senescent cells are an evolutionary balancing act. They prevent cancer by suppressing the proliferation of stressed or damaged cells, and they optimize tissue repair by producing factors that favor wound healing.  However, the chronic presence of these cells during aging can drive multiple diseases associated with old age, including cancer.

Senescent cells increase with age in every vertebrate species that has been carefully examined, from humans to zebrafish.  In her presentation, Dr Judith Campisi from the Buck Institute for Research on Aging showed that it is what these cells secrete that makes them problematic when they are chronically present. Senescent cells produce factors that stimulate inflammation and enzymes that destroy other proteins. These can have negative effects on neighboring, healthy cells.

Campisi’s group wanted to find a way to get senescent cells to die. They made a transgenic mouse where they could use the otherwise benign drug ganciclovir to selectively kill senescent cells. Using this method, they were able to eliminate senescent cells by 70-80% in 23-month-old (aged) mice and improve symptoms of many age-related diseases, including atherosclerosis, Parkinson’s disease, and osteoarthritis in transgenic mice that were prone to develop these diseases. 

Young blood rejuvenates old tissues

Dr. Tony Wyss-Coray from Stanford University takes a different approach to target aging. His lab became interested in studying how age affects the proteins that circulate in our blood and that carry out various functions in the body. They were specifically interested in proteins that communicate inflammation, such as chemokines and cytokines.

They sampled the blood of healthy people and measured 1300 proteins to see how they were affected by age. They found that approximately one-third of all the proteins were significantly different in old and young people. For example, proteins like growth factors decreased with age, while proteins involved in inflammation, such as chemokines and cytokines, increased. These major changes occurred between age 50 and 80.

To see whether they could somehow stop these changes from occurring, they turned to mice and used a technique called parabiosis. In this technique, one mouse is joined to another via their circulatory systems in such a way that their blood is shared between them. This technique is analogous to conjoined twins who share their blood supply, or to animals that share a placenta in the womb. In this case, Wyss-Coray’s group joined a young mouse to an old mouse. Their intention was to test whether young blood could rejuvenate the old animals.

Using the parabiosis technique, other researchers found that young blood could rejuvenate the pancreas, the liver, and the heart of old mice. Wyss-Coray’s lab found that it could also rejuvenate the brain and make it function better. His group found increased activity of the stem cells in the brain, reduced inflammation, and better memory in the old mice that received young blood. They observed the same beneficial effects when they repeatedly transferred plasma from young mice into old mice.

On the other hand, the young mice suffered from exposure to old blood. When they injected old plasma into young mice they observed exactly the opposite effect: Reduced stem cell activity, increased inflammation, and reduced memory.

The secret to long-lasting youth

Human studies of long-lived individuals have given us clues about what makes some people age more slowly and live longer. Dr. Nir Barzilai from the Albert Einstein College of Medicine studied four siblings who were born between 1910 and 1920 and who each lived for at least 102 years despite the smoking habit of one them. Like them, there are many other centenarians in his study cohort who led “unhealthy” life-styles but seemed to be protected from their environments.  Many got sick during their last 5 months of life, whereas people that lived up to age 70 were usually sick for 5-8 years.

Barzilai’s group sequenced the genome of 44 healthy centenarians and discovered that they had over 230 variants or mutations that should have made them sick. These included mutations associated with Parkinson’s disease and dementia. Therefore, they don’t have the perfect genome, but they have something that slows their aging and protects them from disease.

The secret to living longer, healthier lives may lie on the levels of growth hormone (GH) and insulin-like growth factor 1 (IGF-1)- two molecules that promote growth during early life and whose levels decrease with age.

Barzilai’s group sequenced the IGF-1 receptors of their centenarians and found that more than 50% had some impairment in either IGF-1 or the growth hormone, even though they were significantly taller than the average population. Centenarian women with the lowest IGF-1 levels lived twice as long as those with the highest IGF-1.  Similarly, female mice that were treated with an inhibitor of the IGF-1 receptor showed a 15% increase in longevity even though the treatment started when the mice were already old.

Barzilai is one of the scientists that will lead the TAME (Targeting Aging with Metforming) trial, which will test whether Metformin, a drug used to treat Type II diabetes can be used to delay the appearance of diseases like diabetes, cancer, and cardiovascular problems in aged individuals. Metformin has already been shown to extend the lifespan in mice, and to prevent diabetes, cardiovascular disease, and most cancers in humans. It has also been shown to delay cognitive decline in Alzheimer’s patients and to lower mortality in people with diabetes.

Today, we are closer to the possibility of living longer, healthier lives. We now understand much more about how we age and what we can target to delay that process. Understanding that aging is the major risk factor for disease has opened many possibilities for research. This symposium showed how we have advanced in this regard.

If you would like to contribute to this blog, please contact Luisa at lft9@cornell.edu

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