Identifying Which “Healthy” Interventions Actually Increase Lifespan

Buck researchers are part of a study that highlights the importance of genetics in clinical trials of aging interventions

Slowing the aging process to improve health in older adults seems like a no-brainer. But the story is not that straightforward, said Gordon Lithgow, PhD, who is a senior author on a massive study in worms that looked at the effects of three anti-aging interventions. The results have implications for clinical trials in humans and for consumers who are taking various supplements to support healthy aging.  

“With an intervention that extends lifespan, we are learning that some health indicators are good and others not so good,” said Lithgow. “I hate this; it’s not a universal increase in health that we’re seeing here. It’s not the results we were hoping for.”

Some compounds exert a strong impact on aspects of health without an equally strong impact on lifespan. “And vice versa; even something that extends lifespan isn’t universally a panacea for health,” he said. “We don’t really understand why.”

To figure out what is at the root of the discrepancy, Lithgow and teams from the University of Oregon, led by Patrick Phillips, PhD, and Rutgers University, led by Monica Driscoll, PhD, used a variety of genetically different tiny research worms to evaluate compounds thought to promote longevity in different ways. In findings published in the April 12 issue of Aging, the teams found that the variables of age, genetics, and type of health intervention each can contribute separately to the effects on lifespan, or lack thereof.

“The findings were quite complex, but really interesting,” said Lithgow. Although this research was done in the research worms C. elegans, he said, the findings present a compelling case for the importance of the role that genetics play in determining whether any lifestyle activity or drug or supplement will be beneficial for aging. The work is also a reminder that to optimize the health benefits of any interventions in humans likely may require personalization tailored to the individual.

The team explored the effects of three representative anti-aging interventions: resveratrol, nitrophenyl piperazine‐containing compound 1 (NP1), and propyl gallate. Resveratrol has long been touted for its health benefits. NP1 is a compound discovered at the Buck Institute, which is thought to induce a state mimicking dietary restriction. Propyl gallate is implicated in protection against oxidative stress. “We chose resveratrol because of its position in the public eye, NP1 for its known abilities to improve health and increase lifespan, and NP1 because we had no idea what it was going to do.”

Testing these three compounds in tens of thousands of worms revealed that the relationships between lifespan and the measures of health (specifically, they measured oxidative stress resistance, thermotolerance, and mobility vigor) were complex, with no easy answer to how each compound affected health measures or lifespan. Inexplicably, some compounds that exerted a strong impact on health measures did not have a correspondingly strong impact on lifespan.

This study was done on such a large scale, with the number of worms and number of tests far exceeding anything that has been done in mice, said Lithgow, that “they uncover things that you just wouldn’t see normally in the lab.”

There is no equivalent amount of data in humans. The lack of data becomes a problem in clinical trials, where often some participants respond to an intervention and others do not. “Non-responders in clinical trials are a major issue,” said Lithgow, adding that strong effects of an intervention may be diluted by participants who do not respond due to their specific genetics.

“What we know now from this research is that, even though it was done in worms, genetics is really important in any species,” he said. “We’re going to have to understand a lot about the population that we’re studying going into a trial of any intervention.”

For now, Lithgow is following up on an intriguing result of the study, which is that resistance to heat stress correlates with lifespan. “So, we are actually using this now as a way to find new drugs for aging, to look for things that induce heat stress, or improve heat stress,” he said, adding that his team is investigating how to measure the same in human trials to see what works to increase lifespan.

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Note: Lithgow, Driscoll, Phillips, the three senior authors of the publication, direct the Caenorhabditis Intervention Testing Program (CITP), a National Institute on Aging initiative that aims to reduce variability in the research done screening for lifespan and healthspan effects of different interventions in C. elegans.

CITATION: “The coupling between healthspan and lifespan in Caenorhabditis depends on complex interactions between compound intervention and genetic background”

DOI: https://doi.org/10.18632/aging.205743

Other Buck researchers involved in the study include: David Hall, Theo Garrett, Delaney Inman, and Mackenzie Morshead. The study’s lead authors are: Stephen Banse, E. Grace Jackson, and Christine Sedore, all from The University of Oregon.

Acknowledgements: This work was supported in part through funding from National Institutes of Health.

COI: The authors declare no conflicts of interest related to this study.