One Plus One Cellular Modification Gives Five Times the Anti-aging Effect in Worms

Scientists at the MDI Biological Laboratory, in collaboration with scientists from the Buck Institute for Research on Aging in Novato, Calif., and Nanjing University in China, have identified synergistic cellular pathways for longevity that amplify lifespan fivefold in C. elegans, a nematode worm used as a model in aging research.

These pathways are also in humans. If the lifespan effects of each pathway was additive then the combined effect would only be a 130% increase instead of 500%.

The increase in lifespan would be the equivalent of a human living for 400 or 500 years, according to one of the scientists.

The research draws on the discovery of two major pathways governing aging in C. elegans, which is a popular model in aging research because it shares many of its genes with humans and because its short lifespan of only three to four weeks allows scientists to quickly assess the effects of genetic and environmental interventions to extend healthy lifespan.

The discovery of the synergistic effect opens the door to even more effective anti-aging therapies.

The new research uses a double mutant in which the insulin signaling (IIS) and TOR pathways have been genetically altered. Because alteration of the IIS pathways yields a 100 percent increase in lifespan and alteration of the TOR pathway yields a 30 percent increase, the double mutant would be expected to live 130 percent longer. But instead, its lifespan was amplified by 500 percent.

This also suggests that the combination gene therapy and other combination life extension treatments could have far larger antiaging effects.

The elucidation of the cellular mechanisms controlling the synergistic response is the subject of a recent paper in the online journal Cell Reports entitled “Translational Regulation of Non-autonomous Mitochondrial Stress Response Promotes Longevity.”

The authors include Jarod A. Rollins, Ph.D., and Aric N. Rogers, Ph.D., of the MDI Biological Laboratory.

“The synergistic extension is really wild,” said Rollins, who is the lead author with Jianfeng Lan, Ph.D., of Nanjing University. “The effect isn’t one plus one equals two, it’s one plus one equals five. Our findings demonstrate that nothing in nature exists in a vacuum; in order to develop the most effective anti-aging treatments we have to look at longevity networks rather than individual pathways.”

The discovery of the synergistic interaction could lead to the use of combination therapies, each affecting a different pathway, to extend healthy human lifespan in the same way that combination therapies are used to treat cancer and HIV, Pankaj Kapahi, Ph.D., of the Buck Institute, has said. Kapahi is a corresponding author of the paper with Rogers and Di Chen, Ph.D., of Nanjing University.

Reduced mRNA translation delays aging, but the underlying mechanisms remain underexplored. Mutations in both DAF-2 (IGF-1 receptor) and RSKS-1 (ribosomal S6 kinase/S6K) cause synergistic lifespan extension in C. elegans. To understand the roles of translational regulation in this process, we performed polysomal profiling and identified translationally regulated ribosomal and cytochrome c (CYC-2.1) genes as key mediators of longevity. cyc-2.1 knockdown significantly extends lifespan by activating the intestinal mitochondrial unfolded protein response (UPRmt), mitochondrial fission, and AMP-activated kinase (AMPK). The germline serves as the key tissue for cyc-2.1 to regulate lifespan, and germline-specific cyc-2.1 knockdown non-autonomously activates intestinal UPRmt and AMPK. Furthermore, the RNA-binding protein GLD-1-mediated translational repression of cyc-2.1 in the germline is important for the non-autonomous activation of UPRmt and synergistic longevity of the daf-2 rsks-1 mutant. Altogether, these results illustrate a translationally regulated non-autonomous mitochondrial stress response mechanism in the modulation of lifespan by insulin-like signaling and S6K.

23 thoughts on “One Plus One Cellular Modification Gives Five Times the Anti-aging Effect in Worms”

  1. RIght. I didn’t mean to imply that living exclusively in freezing water makes things live longer. So far as I know, this is the only whale that never goes to warmer waters, and I think it’s pretty evident that being in cold water all the time has caused it to evolve and adapt by maintaining a cooler body temperature, greatly reducing energy expenditures for staying warm.

    This in turn, is almost certainly involved in extending their lifespans by reducing the wear and tear on things caused by operating at a higher temperature.

  2. Obviously, we are the same species or there would be no point to mentioning them.
    There are still true hunter-gatherers, and if anything, they have it worse than the hunter-gatherers many thousands of years ago…because people who live off farming and herding have taken all the best land and interfered with animal migration. And they are more vulnerable to contagion because there are so many of us for them to accidentally run into. We have stronger immune systems because dozens to hundreds of times our cities have lost half their population due to some disease or another (mostly from our animals).
    Using the bow, or spears, or whatever has been done for as long as humans have been human. The bow is probably at least 61,000 year old, and we inherited spears, and probably many other things. Most of this stuff just does not preserve well:
    What is domestication? I propose in this context that it is being fed independent of labor…or the vast majority independent of their labor. And secondly, some reduction in aggression and willingness to crowd to some extent beyond the natural conditions. The reduction in aggression is achieved to some degree by killing or banishing those who kill and abuse others. And those who can’t handle crowds probably lag in disease resistance, and later when something really bad comes along…they are probably less likely to survive.

  3. Whales are homeotherms just like we are. The Bowhead has a cousin the Right Whale. Its internal temperature is the same as ours. And guess what, it lives about the same length of time as we do…about 70 years. The Bowhead though runs cooler…about 92.5 degrees F or 33.6 degrees C if you prefer.
    I think that is the whole story right there. If humans can be modified to operate at that temperature (and we did not overheat badly when the temperature goes up) we should live much longer.
    You can’t just try to be hypothermic. We are the temp we are because we have enzymes that only work properly in a narrow temperature range…which is why being too hot or cold is unpleasant. Widening that range, and the body seeking that lowest suitable body temp could extend life dramatically. Nearly all the biochemical aging is driven by heat…methylation, crosslinks, free radical damage…

  4. There is a huge advantage to longer life for a creature like us (in nature). Experience is very valuable; we eat many different things so there is a lot to know. Secondly, our young are very helpless because their heads can only be so large and still pass the birth canal…and are essentially born premature. We are actually more like marsupials in that regard…but without the useful pouch. And that means they can slow the group and can require a lot of carrying and such. So the larger the proportion of the time the group can be old enough to move at the adult pace, the more likely they will find all the food they need…especially in hard times. I think the main reason our natural lifespans are hundreds of years is that we often heal poorly after a major injury such as a broken limb…and injuries accumulate in the wild. It is sort of like if we were professional American football players for several decades. It is going to slow you down and make you delay getting going in the morning. They are not going to abandon one of their most skilled hunters just because he is a little slow…even though in the long run this may be costly.
    If we healed beautifully, even if an arm was bit off by alligator, or crushed by a falling tree, I think our natural lifespans would be much higher.
    As it is nearly everyone looses hearing to some degree, the ability to focus close, reaction time slips, memory slips…even if you did not get bit by a hyena trying to keep the deer you killed…or..

  5. Well sure. Domesticated dogs live almost twice as long as wild ones. But these are people, not dogs.

    People aren’t really wild (except maybe for one of my cousins . . . after forty years he’s still a work in progress).

    Point being, no human population really is, or has been, wild in a very long time. The first thing we domesticated was ourselves. That bow that guy has, for example, was not something he just thought of and whipped together a couple of years ago.

    Members of modern industrialized populations get a pass on a lot of stuff that is a serious risk to these guys (getting eaten by wild animals, killed by curable diseases, etc.). They have their risks, we have ours, like eating too much and having a coronary, or getting killed in a car crash.

    Yet, barring accident or disability, we can still figure on them having double the life their relative size suggests due to a relatively low incidence of being eaten or seriously hurt by other things. This lets evolution reward those that can live and reproduce longer (so long as they can also outrun, outfight, or outwit other predators), and then double again (way past child-bearing age) for being under the care of humans (themselves).

    So yeah, same lifespan as us, potentially. The tribesmen that get eaten by wolves, and the Euros that get killed by eclairs or the autobahn, they are just individuals, not the whole species. In point of fact, the tribesmen, and everybody else, are the SAME species.

  6. “Humans were recently discovered to have a genetic “footprint” that indicates we are evolved for about a 38 year lifespan.”
    That study only looked at DNA methylation. But we know that is not the only relevant factor in aging. Antioxidants make a huge difference. We make far more potent free radical scavenging molecules than most creatures. There are 3 main groups our bodies make SOD (superoxide dismutase) is the most important of these groups. Chimps actually should live longer than us using their methods. But despite great treatment in zoos, they don’t live nearly as long as we do. They eat better than we do, have better protection from the sun… But they normally live about 20 years less than us. And that is likely because their SOD levels are lower than ours.
    We don’t talk much about antioxidants in the context of life extension much anymore. But that is not because antioxidants don’t mater, it is only because we make high levels of these naturally, so we don’t benefit nearly as much as rodents and other animals who have very low levels.
    I think the best indicator for species like ours is the age at which females can no longer have children. Add to that the years to get their children to maturity and possibly a couple more for helping take care of the grandchildren when needed, and showing the daughter how to parent. So 50 + 16 + 2, or something like that. So 68 would be my guess for the natural lifespan…ignoring those who don’t make it to reproductive age.

  7. I had that thought, too. But I would also have to insist on being God-Emperor of Arrakis (Dune) if I had to be a worm.

  8. Remains to be seen if we can make use of what the avians are using (even domesticated peacocks live 40-50 years).

    Among mammals, we are pretty much top of the lifespan pyramid, even not allowing for size, with the exception of bowhead whales, that we now know can live at least 200 years. Some of them can probably remember whalers in wooden ships when whaling was at its peak in the 1840s and 50s.

    But they are MUCH larger than we are and they live exclusive in extremely cold arctic water which probably slows down their aging process considerably.

    Humans might accept being that big, but none of us want to spend 200 years soaking in freezing water.

  9. Generally, animals that live in trees have a longer lifespan than other comparable critters. This probably has less to do with the trees and more to do with the fact they get eaten less.

    Mice, for example, have a very short lifespan because chances are they will have been eaten before it is even over, so there is no evolutionary advantage to living longer in their niche and, instead, they are evolved for accelerated reproduction.

    Humans were recently discovered to have a genetic “footprint” that indicates we are evolved for about a 38 year lifespan.

    Domesticating an animal also tends to double its lifespan and modern humans are domesticated by definition.

    Given that most folks are gone by sometime in their 80’s, and only an incredibly minute number of people make it past 110 to maybe 120, they can be treated as outliers, probably on a bell curve (I haven’t looked) and, to balance that, there are people as young as 32 that die of “natural causes,” even though our instinct is to declare that to be unnatural.

    So, if we were non-arboreal, figure evolution probably setting us at about 19 (longer than a wolf, not as long as a horse). Instead we get double that for the arboreal origin, then double again to 76 for being domesticated, in the center of a bell curve extending 44 years in each direction.

    Let’s hear it for science. Eventually, with no bodily aging, the half-life of a human population (without births) will likely be around 1,000 years, or more.

  10. This can also be interpreted as an unintended side effect. The genes are selected for because of their early-life benefits, but cause problems later in life. The problems are not selected against (or not as strongly), because they tend to appear post-reproduction.

    I think programmed death would be more likely in species that evolved under strong resource strain. Then there’s selective pressure to free up resources for the offspring. That would improve their chances of survival.

    If resources are more abundant, then evolution should favor a longer reproductive lifespan (more offspring).

  11. As others have also noted, these genetic modifications in short-lived species like nematodes are often already being utilized in long-lived species like us, evolution has already picked the low-hanging fruit.
    Parrots are more interesting for research: giant Macaws can live at least to human lifespan (70-80 years) and exceptionally even to about 100 years, with a relatively small body mass and high metabolism, and low cancer incidence.

  12. Cells will actively send over their mitochondria to other cells when they get chemical signals that they’re struggling

  13. Mitochondrial GE will definitely be an important tool in biology.
    Unfortunately we still have a way to go in building tools to target them. It’s a bit tricky with current tech. (I was just reading up on it yesterday actually. Project to get express nitrogenase in plant mitochondria.)

  14. The conclusion of the paper supports the programmed theory of aging, to quote —

    “Through genome-wide translational state analysis and genetic screens, we identified 24 negative regulators of longevity from the 115 genes that are translationally downregulated in the daf-2 rsks-1 mutant. One observation was that the lifespan determinants are enriched with developmentally essential genes (71%). Inhibition of these genes during development causes larval arrest, whereas RNAi knockdown only during adulthood leads to significant lifespan extension (Table S2). These results support the antagonistic pleiotropy theory of aging, which proposes that aging is adaptive, because natural selection favors genes that confer benefits during development but cause deleterious effects later in life (Williams, 1957). Thus, inhibition of developmentally essential genes during adulthood might extend lifespan”

  15. Good point – and they’ve recently discovered why mammals don’t regenerate like cold blooded animals do even though they have the machinery. Turns out the thyroid shuts it down (the main organ for keeping warm body temperature regulation). A hibernative “cold blooded” interval might be part of it. Bats hibernate and birds go into what’s called torpor (105F to 85F temperature change).

  16. Mitochondria look like a relatively easy area for intervention, because quite a bit of aging seems to be due to their malfunctions, and you can actually replace mitochondria in vivo with some success just by flooding a tissue with mitochondria extracted from cultured cells.

    And with mitochondria having to some extent their own genes, this becomes a feasible route for genetic engineering, too.

  17. It is unclear why birds live longer than they should by metabolic rate. Bats do too. If you are only going to survive if you can fly…that is certanly going to have intence selection impact. There are probably less genetic errors passed down. Perhaps, better reduction in making errors as well.
    They are not the same temperature all the time. They tend to cool down at the part of the day they are inactive/sleeping. I suspect there is a very good repaire and cleanup system getting them up and ready to go the next day.

  18. I was going to say that short lived species are lousy for life extension research, because interventions usually just wind up duplicating something our biology already does. But the synergism between different interventions is interesting, if it proves to be a general trend.

  19. If you cripple IGF-1 in humans, you get dwarfism (same thing in mice). And that usually has health effects…because the body was never designed to stay that size. You end up with too much bone mass relative to overall size and consequent joint issues. Actually, ironically very similar to what happens in pituitary gigantism…where the bones and joints grow too large.
    You can temporarily reduce IGF-1 which allows your body to do housecleaning…removing senescent cells and such…if you go on periodic fasts (or near fasts with very low protein).
    5 days eating, 2 fasting, or nearly so, is one way (every week). The original calorie restriction research was one day with food the next day no food. It wasn’t just a little every day. Funding was cut, so he did not have enough to feed all his rats. So half had to settle with eating every other day.
    There is some reason to think that the “Mediterranean diet” is partly misunderstood…that many of these people are good Catholics and do all the fasts…and that is the real reason they are living longer…not olive oil and wine.
    I think all this complicated kinase stuff is just trying to get at m-TOR genetically rather than using rapamycin.

  20. Birds and bats live 5x longer than “expected” probably due to superior mitochondrial design and pathways required for sustained flight. Easy migration also means they have less chance of competing with their own offspring and frustrating the path of evolution so that’s another reason to preserve those genes. This may be the way to try to copy that in other animals.

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