Gary Ruvkun was awarded the Nobel Prize in Medicine today for establishing the importance of RNA as a signal molecule, independent of its role in transcribing nuclear DNA.
Before he worked on RNA, Ruvkun made important contributions to theoretical understanding of aging in lab worms, C. elegans. In 1993, Cynthia Kenyon had found that incapacitating the DAF-2 gene doubled the worms’ lifespan. This was extraordinary — only the second life extension from a single gene. The worms were not getting any new ability, but merely disabling a gene that they already had. This indicated that DAF-2 was a life-shortening gene. Darwinian theorists didn’t think this was possible.
Kenyon identified DAF-2 as the worm’s only insulin receptor. We think of insulin as regulating blood sugar, but worms have no blood and no blood sugar level. Long before vertebrates developed a role for insulin in regulating blood sugar, insulin was a life regulating hormone.
We already knew that when the worm senses food, lifespan was shorter than when food was scarce. Kenyon established that insulin was the signal that mediated this effect.
This brings us to Ruvkun’s contribution. Working in his Harvard lab a few years after Kenyon’s discovery, he created chimeric worms with different genomes in different tissues. He was able to disable DAF-2 just in the digestive system, or just in the muscles, or just in the nervous system.
Are you guessing yet?
DAF-2 in the digestive system had no effect on lifespan.
DAF-2 in muscle tissue had no effect on lifespan.
All of the lifespan-shortening effect of DAF-2 was accomplished through the nervous system.
The message was clear in neon lights — the caloric restriction effect isn’t about a metabolic trade-off. It’s something decided through signal processing. When there is plenty of food, the nerves make a calculation that it would be better to die sooner; and when food is scare, the worm decides to live longer.
Lifespan is not imposed on animals by physical limits or physiological tradeoffs. Lifespan is regulated, and, what is more, there is a conserved mechanism regulating lifespan in diverse species, inherited throughout the animal kingdom.
“Despite…vast differences in life-span, shared features of aging in diverse species support the existence of a common mechanism for life-span determination.”
Pleiotropy, re-imagined
In subsequent years, Ruvkun’s lab screened for other genes that shorten lifespan. He found 64 of them. Most of these genes are active in development, but they are re-purposed late in life to regulate lifespan. All eukaryotes have extensive networks of transcription factors that determine when and where genes are activated. It would be easy for the worm to de-activate these genes later in life, but instead, the worm keeps them active, with the effect of shortening lifespan.
Once again, he was able to trace the role of these same genes in different animals. Lifespan-shortening functions of the same genes are widely conserved across the animal kingdom.
Discover more from Josh Mitteldorf
Subscribe to get the latest posts sent to your email.
‘When there is plenty of food, the nerves make a calculation that it would be better to die sooner; and when food is scare, the worm decides to live longer.’ – the ‘calculation’ is likely derived via evolutionary selection; perhaps something like worms that die sooner are ‘living quicker’ having more offspring, and/or worms that die later are hanging around for better breeding conditions. It could be simulated with an agent based model I expect.
Yes — this is exactly what evolutionary theory predicts. Theory says that aging is all about tradeoffs. But the worms haven’t read the theory books. The aging genes are not coupled to longevity. Back in the 1990s, Michael Rose sought to validate the tradeoff theory by breeding fruit flies for longevity. He predicted that they would lay less eggs the longer they lived, and that eventually his experiment would end when the longest-living flies didn’t lay any eggs at all. Instead, what he found was that he succeeded in breeding flies that lived 3x as long as the wild type, and they laid more eggs every day of their lives, compared to wild type.
Has anyone tried to create transgenic worms with all of those 64 genes being able to be disabled later in life to see how long they live if, upon reaching adulthood, all of those genes are turned off?
I found this fascinating. Thanks Josh!
Now a question: If insulin is a life regulating hormone, what does that mean (if anything) for a person with very low levels of insulin (but not diabetic)?
Great post as always. Question: are you aware of high dose Melatonin’s benefits. Melatonin production is made 95% in the mitochondria. Only 5 % in the pineal gland. It works alongside ATP. Protecting it. Incredible information Doris Loh has some peer reviewed papers. I know you would like. Glad to see your back from that accident.
– warm regards
Since the worms didn’t manage to read the theory of aging and still able to live 3X longer than their peers it’s sufficient to point out that there’s no need for that theory either.
What they were fed and how much, besides fasting, may exist a clue there.
So, I am assuming that the presence of insulin stimulates the insulin receptor (in humans), which stimulates the daff-2 receptor.
This might balance out populations and keep the greedy eaters which could threaten the population numbers and the gene diversity of any given specie.
I probably have been told other philosophical reasons but either I forgot, or the reasons don’t quite fit everything and click. Else, the explanation was more mechanistic and less philosophical wider specie benefit. (For example, if every internal biological function is slowed, the individual will be better able to wait out famine periods, slowing the life cycle, and allowing more time between a generation span, and better odds of specie survival.)
I am so old and hungry, forgive me my need to brush up on the mechanisms. 😅
Humans don’t have a DAF-2 gene.
Question 1: Does higher DAF-2 have benefits in terms of number of offspring that survive?
Question 2: If so, does this occur independent of lifespan?
Great post. Thank you.
If somewhere in the body, say the central nervous system, a decision is made to live shorter or longer, this decision can probably be influenced by the human mind. That’s an encouraging thought. Even the very possibility of being healthy after living for 100 years may make people live longer….
Even within the “normal” range of attitudes and temperaments, psychological factors are already one of the largest components in longevity.
By similar reasoning, should not be that sensing the presence of reproduction mates, or actually mating, also shorten lifespan? Have there been found respective genes to block and extend lifespan?
Yes, classical evolutionary theory has made predictions about tradeoffs with mating, with fertility, with fecundity in different versions of the theory. All such claims have failed to pan out. For example, https://link.springer.com/article/10.1007/s11357-009-9116-1