People, Like Worms, May Have Distinct Biological Ages
By Deborah Borfitz
November 3, 2022 | The timing of age-associated vigorous movement cessation (VMC) is highly correlated with lifespan across populations, but the reason may be some unknown upstream factor that throws into question the way biomarkers are sometimes used to track the benefits of anti-aging therapies. At least that’s what is suggested by a new study using a “Lifespan Machine” to follow the life and death of tens of thousands of nematodes.
Markers of biological age can change without turning a fast ager into a slow ager, report researchers from the Centre for Genomic Regulation (CRG) in Barcelona in an article published in PLOS Computational Biology (DOI: 10.1371/journal.pcbi.1010415). An analogy would be two runners where one is sprinting on asphalt where the other is slogging through sand, offers Nicholas Stroustrup, Ph.D., group leader for the CRG’s systems biology research program.
VMC and lifespan do not appear to be outcomes of a single underlying aging process but a pair of independent aging processes, he says. In other words, they are “[not] two stops on the same subway line” but they are both subject to a “hierarchical process model” causing their average rates to go faster or slower together across a population.
As Stroustrup explains it, the hierarchical process model explains the paradoxical “uncoupling” of VMC and lifespan not because of mutations and anti-aging interventions but despite them. It also suggests that the indirect interactions between the two outcomes undermines the use of vigorous movement as a biomarker of overall health.
Further, if the nematode C. elegans has at least two distinct aging processes, then people by virtue of their greater size and complex tissue types probably have even more coupled aging processes. “There is just a lot more space for different aging processes to be coexisting independently, or partially independently, in humans.” That is, they have stem cells niches in most of their somatic tissues that are separated by distance and protected by guard cells.
To date, no accurate and highly predictive test for biological age has been validated, partly because the causes of aging are unknown and therefore can’t be measured, says Stroustrup. Definitive progress in the field will require validating biomarkers throughout a patient’s lifetime, which is impractical and why laboratory animals are used.
Findings of the latest study in nematodes have implications for consumers being offered biological age tests using panels of biomarkers purported to be meaningfully diverse. Even if they measure hundreds of body characteristics, they might all be confounded in an identical way.
People working on biomarkers as a commercial product may or may not take inspiration from this basic research paper, but if they are being careful “this is a warning of what can go wrong,” Stroustrup says. In organisms experiencing multiple age-associated physical declines, correlations between mid-life biomarkers and late-life outcomes can be a result of any number of confounding systemic factors including environmental conditions (e.g., temperature and food sources) and genetic variations.
Many changes happen contemporaneously as people age, including getting gray hair and wrinkly skin, says Stroustrup, in making the point that people don’t consider these co-occurring characteristics to be responsible for their poor health. “We are trying to piece out the causal structures among the different outcomes of aging that might happen, and we chose two, death and vigorous movement cessation,” both of which are as true for humans as they are for nematodes.
It was demonstrated two decades ago in C. elegans that worms moving vigorously for longer also have longer lifespans, he notes. But interventions designed to alter aging can disproportionately affect VMC in comparison to lifespan—and vice versa—and the CRG researchers wondered why that would be. So, they developed the Lifespan Machine allowing them to measure outcomes on large populations of the worms and statistically map out the distribution of their vigorous movement.
Interestingly, in the latest published study, the research team introduced a way to “dial up and dial down” the lifespan of nematodes by feeding them different amounts of a hormone that controls the activity of RNA polymerase II (the enzyme that makes messenger RNA). In the past, old-school poisons such as α-Amanitin—isolated from the death-cap mushroom—were commonly used to knock down transcription.
Stroustrup developed the Lifespan Machine about a decade ago as a graduate student at Harvard Medical School, he says. The idea was sparked by a conversation with a postdoctoral student about the irony of some of the world’s smartest people spending their time peering into microscopes and poking at worms to see if they were alive or dead. “Like human aging, there is a lot of randomness to worm aging”—anywhere between about five and 18 days in the nematode world.
For large populations of C. elegans, keeping an eye out for signs of life would get arduous, he says. The repetitive task was a perfect occasion for automation, in this case computer-generated image analysis.
The Lifespan Machine is a relatively mature and cheap-to-build DIY system that gets enough pixels to scanners for capturing the changing posture of nematodes wriggling in their petri dish, explains Stroustrup. The components can be purchased from consumer electronics companies.
As described in a 2013 article, the Lifespan Machine detects micrometer-scale twitches of the worm’s tail. Each of 50 off-the-shelf scanners scans 16 dishes once per hour. The setup includes a worm browser allowing a researcher to “validate worm identification and death decisions.”
Development of the Lifespan Machine was funded by a grant from the National Institutes of Health, which is also supporting ongoing work where the machine is being used for drug screening trials, Stroustrup says.
The worm-monitoring technology in theory works for anything that sits on an agar plate, he says. “The major constraint is we focus on a 2-D situation” accommodating nematodes that are typically only about one millimeter long.
That said, nematodes are a versatile model for the study of aging, Stroustrup adds. Their average two-week life expectancy makes it easier to collect behavioral and lifespan data that would require centuries with humans.
A few years ago, he collaborated with another lab to use the worms and Lifespan Machine to better understand the molecular mechanisms of resistance to treatment for a nasty pathogen affecting cystic fibrosis patients.
Many scientists engaged in aging research are looking to extend life indefinitely, but not Stroustrup. The whole idea here, he says, is to “build up a strong foundation of basic science that can then in unexpected ways help the translational pipeline.”
From his standpoint, “there is no single right way to do research... what needs to go on now is what is [already] happening,” says Stroustrup, referencing the diversity of translational methods and breakthroughs such as the CRISPR genetic engineering technique. “You never know where progress is going to come from.”
The CRG research team will continue working with the Lifespan Machine to understand the relationship between healthy lifespan across a wider range of dimensions than vigorous movement, Stroustrup says. They are currently trying to “look under the hood” to find new aging processes based on outcomes statistics.
“You have to do these things indirectly because gene processes aren’t physical objects,” he continues. “They are models of collective changes across many groups and components that eventually produce an outcome.”
Moving forward, CRG researchers will no longer be looking at a cohort of genotypes but “a cohort of gene regulation as it differs across cell types between individuals and trying to see if we can map the organismal aging processes that are more mechanistic,” says Stroustrup. “If we can find genes that seem to be correlating in... aging processes, [they] will give us the key to what the actual mechanisms are and the physical manifestation of these aging processes.”