It’s perhaps ironic then that O’Rourke, in sharing the story behind the research, is among those currently thinking aloud about the pros and cons of engineering dramatically longer lives.
The researcher said firmly, “There’s a discussion around anti-aging therapeutics that society needs to have.”
Working Out the Wrinkles
Scientists have known for more than a decade now that several genetic and biochemical pathways can either extend or shorten a person’s life. The long answer to why the genome evolved this way is complex, O’Rourke said. The short answer resides in reproduction.
“Nature cares about organisms becoming healthy reproductive adults,” she said. “But once we have produced as many babies as we are capable of, nature doesn’t care about our health.”
Should our muscles atrophy, or remain firm and tight? We can obviously improve our muscle tone by exercise, for example. But at some juncture, instructions meant to optimize development and survival earlier in life begin to tell the body to slow down. Obsolescence is in our genetic programming.
In that regard, our bodies are complex communication networks. The inputs and middle links in aging communication were identified prior to the UVA research. And acting on that accumulated knowledge, previous scientists indeed figured out ways to slow down, and even reverse, aging in animals such as lab mice.
But one reason you may not have heard about all the developments has been the ugly tradeoffs: compromised immunity, cancer.
“The problem with playing around with many of the input and middle-link genes is that – as they are such important players in the cell and control so many things – it is very hard or even impossible to find a condition in which you can only get the good effects of changing their activities,” O’Rourke explained.
In her attempt to solve this problem, O’Rourke assembled a Hoos-who of UVA scientists.
The team that yielded the revelatory research was led by biology graduate student Abbas Ghaddar and postdoctoral fellow Vinod Mony, with the contributions of graduate students Swarup Mishra, Elisa Enriquez-Hesles and Mary Kate Horak; undergraduate students Samuel Berhanu, Emma Harrison, James C. Johnson and Aaroh Patel; and aging expert Jeffrey S. Smith, a professor of biochemistry and molecular genetics.
The Worms Crawl In (To Help)
Traditionally, worms have been associated with death. In science, however, worms – in particular, roundworms – have been responsible for some major health breakthroughs, winning Nobel Prizes in physiology and medicine (along with their scientists).
The type of roundworm O’Rourke and company used wasn’t the parasitic type sometimes found in our pets, but rather C. elegans, which grows to about a millimeter long and is clear-bodied. As the first multicellular organism to have had its entire genome sequenced, the roundworm is transparent in more than one way. The creepy-crawly may seem far removed from us humans, but its chemical pathways are remarkably analogous.
This microscopic image from O’Rourke’s lab shows how roundworms glow for adh-1. The brightest signal is in their heads. (Contributed image)
Using the worm as a key model for this research, the team sought to decipher what happens at the end of those previously mentioned communication chains that control aging (as opposed to the inputs or middle links).
Specifically, O’Rourke wanted to find the molecular players most responsible for aging, which are those that break or repair cells, and by extension, tissues and organs. The thought was that by being at the end of the communication chain, playing around with the genes might mean fewer unwanted effects.
They set out by looking at biology’s natural process of cellular cleanup and repair, called autophagy. The command to renew cells has long been thought to underlie longevity.
“Autophagy is a process that clears the unwanted and recycles parts of the cells,” O’Rourke said. “When cell components go bad, they need to be disposed of. To this end, autophagy breaks them down to use the parts to make new cell components.
“So autophagy was the main anti-aging candidate, in particular because we had already defined that the mid-link gene we were studying acted as a switch to turn autophagy on when animals were fasting, a dietary intervention that extends lifespan.”
Goodbye Autophagy, Hello Adh-1
If their hypothesis was correct and autophagy was promoting longevity, then by stopping it, animals would not live longer.
