The Tradeoff of Working with Short-Lived Laboratory Species

It is cheaper and faster to study aging - and potential approaches to treat aging - in short-lived species. The disadvantage is that much of what is learned and achieved will be irrelevant to aging as it occurs in longer-lived species such as our own. The response to calorie restriction, an upregulation of cellular housekeeping mechanisms that lengthens life, fortunately evolved early on in the development of life, and the biochemistry is surprisingly consistent even across widely divergent species. Thus much can be learned of it in lower animals with short life spans. Unfortunately, it turns out that this class of intervention doesn't affect life span in longer-lived species like our own to anywhere near the degree it does in short-lived species. This is the tradeoff of working with short-lived models, in a nutshell: more can be done, but all of that work may turn out to be of very limited utility.

Wouldn't it actually accelerate progress if we instead did most testing in far shorter-lived animals, like the roundworm C. elegans or the fruit fly Drosophila? On its face, that's a totally reasonable question: time is ticking for all of us, and we want to get longevity therapeutics into people's hands as quickly as possible! And certainly these short-lived animals have taught us a lot about the roles of different biological signaling pathways.

Some interventions that work in C. elegans act by altering the worms' early developmental processes, which isn't terribly helpful to those of us who "have the misfortune of already being alive." That's also becoming increasingly evident in mice. We've known for about twenty years now that mutations that block IGF-1/growth hormone signaling in mice slow down their aging and extend lifespan. But those mutations dampen down signaling through these pathways throughout the animals' entire lives. To take advantage of that discovery and develop a longevity therapeutic that would work in middle-aged and older adults, a large part of the anti-aging effect would have to be due to the hormone still being low during adulthood. Instead, studies have shown that almost all the benefit of IGF-1 signaling inhibition goes away if growth hormone production is brought back to normal during the very earliest period of life.

The preceding examples apply to studies based on trying to usurp the regulation of metabolism to slow the aging process down. SENS Research Foundation is instead grounded in the direct "damage-repair" strategy of SENS. If we're going to use an organism as a test animal for rejuvenation biotechnology, it has to accumulate similar kinds of aging damage as we do, and it must do so in similar tissues and with similar pathological results. And here C. elegans and Drosophila just aren't qualified for the job. For instance, C. elegans don't live long enough to accumulate cells overtaken by mitochondrial DNA deletions, and there is no clear link between other kinds of mitochondrial DNA damage and the rate of aging in these worms. C. elegans also have no bones, so no osteoarthritis or osteoporosis either. And they lack any of the cells dedicated to the immune system.



I'm calling on someone to create a database of, and market place for, volunteers for longevity-related research. I'd even pay to participate in some studies, even knowing there is a 50/50 of being in the control group. I'd consider it a contribution to longevity research, and would likely find the medical test data of interest and of use in some cases.

How hard would it be to have a demographic and health/treatment status questionnaire, reasonable privacy guarantees, and advertisements for up-coming studies? I get these ads ad-hoc periodically anyway in browser panels. It should be centralized and made convenient and informative.

Of course, I'd need to trust the researchers. Any researchers and institutions that have been involved with questionable studies or sponsors would be a red flag (for example, there are large companies that do research I wouldn't get anywhere near).

Posted by: Thomas Schaefer at March 30th, 2023 8:06 AM

Go straight to willing humans. ~55 million over 65 die every year world wide. If you are old you are going to need to take some chances because death is on its way. I think the risk/reward calculation by the regulators and the public is terribly wrong.

Posted by: Lee at March 30th, 2023 8:33 AM
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