Diseases like cancer, diabetes, neurodegeneration, and heart disease all have one trait in common: the number one risk factor is age. For the past two decades, scientists have been making strides in understanding the underlying biology of aging, in the hopes of lowering disease risk and improving quality of life for older people.
Most famously, a researcher named Cynthia Kenyon in 1993 found that manipulating a single gene in the Caenorhabditis elegans worm could double its lifetime. As a postdoctorate, Sylvia Lee, Molecular Biology and Genetics, was struck by the dramatic results.
“I became interested in aging research because of its fascinating biology and the implication that we can tackle multiple age-dependent diseases by focusing at a common cause. But I was drawn in by a lot of the first exciting data that came out,” says Lee. “Aging is so complex, yet it was amazing to think that you could simply manipulate a single gene and have such a drastic effect.”
Studying C. elegans, a Worm, for Insights on Longevity
In her lab today, Lee explores several molecular pathways that determine longevity in the C. elegans worm. Her hope is that what the researchers can learn about C. elegans aging can be conserved in mammals and humans. To that end, Lee’s lab focuses on C. elegans genes and proteins whose mammalian and human counterparts are already known.
One of the lab’s projects centers on the C. elegans pathway related to insulin signaling. The mammalian counterpart is well understood to regulate glucose homeostasis, yet the worm’s signaling pathway is strongly related to longevity. When insulin signaling is partially reduced in the worm, it has a much longer life span. This finding was initially surprising, but researchers have now shown that this pathway affects longevity in many organisms, including mammals—maybe even humans.
But how? That’s what Lee and others in the field are trying to figure out. Her lab specifically studies HCF-1, a protein that regulates the transcription factor DAF-16. DAF-16 mediates many outputs of insulin signaling, including longevity, metabolism, and development. Lee’s data suggest HCF-1 inhibits DAF-16 in order to regulate it—preventing it from becoming fully active. What has captured Lee’s interest recently is that the human counterpart to HCF-1 has been shown to affect stem cell health.
Knowing this, the researchers are interested in comparing and contrasting the functions of HCF-1 in relation to both aging and stem cells in C. elegans. “If the two are linked, we can get some insight about how aging affects stem cell functions and vice versa,” says Lee. “It’s relevant because we already know that in humans, as we age, stem cells do change and it affects our regenerative capacity.”
Lee’s lab also looks at a C. elegans gene called cep-1. Her lab discovered that it plays an important role in fighting against poor mitochondrial function. The mitochondria make energy, ATP, and are central to life. When their function is compromised, there’s a suspected increase in free radicals in the cell and in the organism, which should typically have detrimental effects. But it turns out there is a small window during which it can actually extend life, thanks to cep-1 (and other genes that await characterization), which creates a stressor response.
What’s compelling is that the mammalian counterpart to cep-1 is p53, which is a well-studied protein in the context of cancer and tumor suppression. “Now we’re making a new connection to p53," says Lee. “It’s possible that p53, like cep-1, can sense mitochondrial dysfunction and in the process it extends longevity.”
The next step is to test that free radicals directly and physically engage with cep-1, in order to confirm that this is the manner in which cep-1 extends longevity.
DNA and Aging
Finally, Lee studies the epigenetic regulation of genes, meaning the non-genetic aspects that affect DNA and in turn, the biological outcome of aging. To do this, Lee’s lab examines chromatin, the complex around which DNA packages itself. Using high-throughput sequencing, they look at how chromatin structures age. The researchers literally march along through the whole genome in search of specific regions that affect the organism’s life span.
Lee’s crucial question is whether the research findings in C. elegans are also true in mammals, particularly humans.
So far, the lab has discovered one histone mark called H3K36me3 that appears to help provide gene expression stability through aging, and in turn, a longer life span. Genes displaying low levels of the mark showed much greater differences in mRNA expression through the aging process. Genes displaying high levels of the mark were much more stable. They also found that globally reducing the mark in C. elegans led to a shorter life span.
“We show that there’s a cause and effect with this mark and that it is really important for maintaining gene expression stability through aging,” explains Lee. “Without that, it leads to a shorter life span.”
In all of Lee’s work, the crucial question she asks is whether the research findings in C. elegans are also true in mammals, particularly in humans. The goal is to eventually test these findings in mammalian model organisms and data sets.
Collaborative Aging-Related Research
Lee is not alone in her search for answers about aging. She is part of a group called AIMS (Aging, Inflammation, Metabolism and Stress), which includes professors and labs across the Cornell campus studying topics around aging. The group meets once a month, and Lee says that it’s been critical in advancing aging-related research across campus.
Most important to Lee, however, are the graduate student and postdoctoral fellow researchers working alongside her. “We largely depend on graduate students and postdoctoral fellows to accomplish research,” says Lee. “We invest in them, train them, and view them as our colleagues. Graduate students and postdoctoral fellows are really our intellectual driving force at Cornell.”