In 2023, a study was published in the journal Science sharing a breakthrough within the longevity field. This study used synthetic biology to alter the gene networks of yeast cells, and what they found was incredible. They were able to increase the lifespan of yeast cells by 82% compared to control cells. Various media outlets have covered the study, and the study’s findings might sparke a wave of transformative advancements in the longevity field.
This episode is an in-depth discussion with the lead scientist who worked on this 2023 study—Dr. Nan Hao. Dr. Hao provides a behind-the-scenes look into the motivation and the science behind this study.
During the discussion with Dr. Hao, we go into detail about this novel paper. We ask him about the gene network he created, why he picked the genes he did, and how what he discovered can transform longevity science going forward.
- Intro and Dr. Hao’s background: (00:00–4:16)
- Synthetic networks and oscillator gene networks: (4:17–14:34)
- How the SIRT2 and HAP genes impact longevity: (14:35–17:48)
- Dr. Hao’s research on SIRT2 and HAP: (17:49–26:26)
- 82% lifespan extension observed in Dr. Hao’s study: (26:27–31:52)
- Cellular networks and stress: (31:52–35:44)
- Intermittent fasting and autophagy: (35:45–41:09)
- Heterogeneity in cancer cells: (41:10–48:00)
- How stress impacts the body: (48:01–52:50)
- Factors that impact our stress response: (52:51–55:13)
- Top tip for optimal health: (55:13-end)
About Dr. Nan Hao
Dr. Nan Hao received his PhD in Biochemistry and Biophysics from the University of North Carolina at Chapel Hill. He was a postdoctoral fellow with Timothy Elston at the University of North Carolina and Erin O’Shea at Harvard University Howard Hughes Medical Institute.
The goal of Dr. Hao’s lab is to understand how network architecture governs the dynamics and function of regulatory responses in the context of stress, aging, and diseases. His lab has three main focuses: Decoding the dynamics of stress responses, probing the causes of cellular aging, and quantifying the heterogeneity in cancer cells.
What is synthetic biology?
Every cell contains proteins known as transcriptional factors. Transcription factors help convert the information stored in DNA into RNA. This process is essential for controlling how genes are expressed and how cells function. Simply put, these proteins ensure that the right genes are activated at the right times to carry out various tasks in the body.
Transcription factors influence one another, creating what is called a gene regulatory network. Gene regulatory networks play a crucial role in determining how genes are expressed and ultimately govern many of our biological functions. Gene regulatory networks function naturally within cells. The field of synthetic biology studies ways to manipulate these gene regulatory networks to achieve a specific desired outcome.
Dr. Hao explains there are two ways to manipulate gene regulatory networks within synthetic biology:
Scientists can construct entirely new gene regulatory networks by introducing components that don't naturally exist in the cell and connect them in specific ways to perform functions that the cell cannot achieve on its own.
Scientists can work within the existing gene networks in the cell and modify how they interact with each other to change their functionality.
Dr. Hao’s research utilizes the second approach—he manipulates existing gene regulatory networks in specific ways, aiming to extend lifespan.
Findings from Engineering longevity—design of a synthetic gene oscillator to slow aging
Dr. Hao’s study explores how to synthetically modify two longevity genes in a way that avoids damage accumulation, extending lifespan of a model organism. In this paper, Dr. Hao’s lab constructed an oscillatory gene network within a yeast model. "Oscillations refer to the periodic fluctuation of the components within a gene network. In this case, both gene A and gene B are transcription factors that will oscillate, meaning their expression levels will periodically change over time.”
Two important longevity genes
Dr. Hao’s research focused on two key longevity genes: SIRT2 and HAP. During the natural aging process in a cell, SIRT2 and HAP mutually inhibit each other, forming what's called a mutual inhibition network. When one gene is high, it represses the other, and vice versa, creating two distinct states. This means aging cells naturally have one of two fates; they have elevated HAP and low SIRT2, or they experience elevated SIRT2 and low HAP. Both scenarios are problematic because both of these genes promote longevity. So, low levels of both genes are detrimental to the longevity of cells.
- If HAP is low: Mitochondria become damaged, leading the cell down the aging pathway of mitochondrial decline.
- If SIRT2 is low: DNA will become unstable, as the function of SIRT2 is to stabilize and protect DNA.
A typical aging cell follows one of these pathways—low HAP or low SIRT2—until it dies.
Dr. Hao utilized synthetic biology to change the natural mutual inhibition network into a negative feedback network to combat the aging of yeast cells. This alteration caused levels of the two genes—SIRT2 and HAP—to oscillate, periodically cycling between high and low. This alteration allows the cell to switch between aging pathways, slowing down damage accumulation and allowing the cell to avoid being stuck in a detrimental state.
Findings and takeaways of Dr. Hao's study
Dr. Hao expresses his excitement with his study findings, noting that his synthetic oscillation network led to an 82% increase in lifespan compared to control cells. He shares that this is the most pronounced lifespan extension ever observed in a yeast cell.
Dr. Hao compared the oscillator yeast cells with previously identified long live yeast mutants, and his experimental model outlived all of the other longevity mutants. “By playing this oscillation trick we can generate super long-lived yeast cells—way longer than previously defined,” he says.
Can this method of lifespan extension apply to humans?
While Dr. Hao conducted his research in yeast, it is important to note that both of these pathways are highly conserved in Eukaryotes, including humans and animals. As a result, SIRT2 and HAP play significant roles in human aging. Dr. Hao's discovery not only sheds light on these important factors but also paves the way for further research in the field of aging, suggesting that altering the gene network may also be relevant for human cells.
Dr. Hao's research reveals that oscillation has the potential to significantly increase lifespan. Oscillation keeps the expression levels of certain genes within an optimal range, promoting longevity. This discovery underscores the importance of using gene networks to achieve life extension in longevity research.