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.
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‘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.
Another research paper on aging. It seems that there are “bursts” of aging, not a steady linear trend. See Nature Aging paper https://www.nature.com/articles/s43587-024-00692-2 For those who was just a gloss of the paper – https://med.stanford.edu/news/all-news/2024/08/massive-biomolecular-shifts-occur-in-our-40s-and-60s–stanford-m.html
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
The exceptions to the free radical theory of aging were explained away by the membrane pacemaker theory of aging. One of if not the main mechanism controlling the pace of aging or lack thereof is the peroxidation index of membranes and accompanying protective molecules that reduce damage to membranes.
Interventions that lengthen lifespan like calorie restriction one of the things they do is alter membrane peroxidation index to make membranes more resistant to damage. In organisms like clams, it is also seen that the longer lived a species is there is accompanying exponential decrease in peroxidation index of mitochondrial membranes. This is also seen in insects where queen membrane peroxidation index is exponentially lower, and queens live exponentially longer than workers.
Already in animals’ neurons can outlive host organism by over twice the lifespan, and it is believed the neurons could last indefinitely potentially for centuries in the right host. So, it is likely the body has altered mitochondrial peroxidation index to the extreme in some tissues like nervous tissue but chooses or is programmed not to do the same in other tissues, limiting organism lifespan.
An interesting finding from the ITP studies, was that astaxanthin was seen as providing one of the biggest life increases seen 12%. Yet according to some sources the blood levels achieved in animals were akin to those a human would get from a low 24mg to 48mg dose. Astaxanthin becomes embedded in membranes and protects them from damage. It might be a way to bypass the programmed susceptibility to damage that the body allows. More studies are needed to see what the optimal dose is. If we’re lucky it won’t be toxic at far higher doses, nor will it interfere with reactive molecule signaling. If that were to be the case, I believe it is even conceivable it could allow for negligible senescence at high enough doses.
No effect on females。
Females have higher fat in their bodies, it is possible this may have diluted it given it’s fat soluble.
Any case the blood levels achieved are said to be equivalent to those achieved in humans with a few 10s of mg. So it is a rather very small dose that was absorbed. It will be interesting to see what happens if far higher doses are tested and if we’ll still see no effects in females.
Astaxanthin is indeed an interesting compound, although it also inhibits mTOR, so lifespan extension in mice could be due to that. I also found it thinned my hair, which I didn’t like.
YOUTH AND OLD AGE – FOR THE FIRST TIME IN WORLD PRACTICE
It is better to analyze the state of youth and old age if the main indicators of the body are known. There are millions of indicators, let’s take nine main ones, which are determined by the information space diagnostics ICD from a person’s photo.
1. The starting point of youth is 16 years, when the human body is already formed. In youth, the thickness of the heart wall is 1 millimeter, with age, the wall thickness decreases to 0.1 mm and ruptures, then the heart does not work.
2. With age, the vessels become clogged with slags. With 59% slagging of the vessels, the blood flow is close to stopping and can completely block in the vessel.
3. The elasticity of the vessels decreases with age and at 78% elasticity, the vessels can rupture the vessel under strong blood pressure, and at 33% elasticity, the vessels are destroyed en masse.
4. Age contributes to the decrease of mitochondrial energy and at 11% of the norm of such energy a person dies, the cells become inoperative.
5. With age, telomeres characterize the state of the organism and when the relative length of telomeres decreases to 0.145% a person dies.
6. At 16 years old the number of nerve cells is 1000 million, with age the number of nerve cells decreases, at 80 years old there are 500 million cells, and at 100 years old 200 million.
7. Memory depends on many factors. In the Soul of a person information enters Consciousness, then from Consciousness to the Subconscious. When remembering for the first time information passes from the Subconscious to Consciousness. During such transitions some information is lost. The degree of information loss during transitions between Consciousness and Subconsciousness determines memory. The best memory is at 6 years old, when there is no memory loss, at 16 years old, memory loss is 16% in one transition, at 80 years old – 25%, at 100 years old – 50%. This does not take into account the state of the human body, which depends on the disease.
8. Y-chromosomes in blood cells at 16 years old are 100% of the norm, at 50 years old they are 50% on average, at 80 years old they are 20% and by the end of life they are absent. With age, cells become clogged and disintegrate due to a decrease in the magnetic field strength of hydrogen atoms in cells. To cleanse cells and restore them, it is necessary to increase the magnetic field strength of hydrogen atoms to the optimum.
9. With aging, the weight of bone and muscle tissue, hearing, strength, number of teeth, hair, skin thickness, vascular lumen decrease …
Is it possible to stop the aging process of a person? The processes in the human body depend on the main indicator – the magnetic field strength of hydrogen atoms in nerve cells. If you stop the decline in magnetic field intensity, the aging process will stop, and if you increase the magnetic field intensity, the rejuvenation process will be turned on in the Soul. Switching the magnetic field intensity of hydrogen atoms in nerve cells is possible through a control command in the information field of the Universe. To do this, it is necessary to increase the magnetic field intensity of hydrogen atoms in the substance to the required intensity. Such a substance can be malic acid YAKS44, water, that is, substances that contain hydrogen and easily penetrate the blood. In the blood, hydrogen-containing molecules are carried to all cells and contribute to a change in the magnetic field intensity of hydrogen atoms in nerve cells, which changes the control commands in the body for rejuvenation. However, such substances must be taken daily, for example, it is enough to take 0.1 grams of YAKS44 per day. It turns out that YAKS44 also helps remove poisons, nitrates, harmful drugs, radionuclides, heavy metals, cancerous tumors, the effects of vaccines, cleanse blood vessels, remove dioxins and many other harmful substances. Complete rejuvenation takes 365 days + the time when a person is in an unfavorable condition for his body and during this time rejuvenation is suspended, for example, in case of cancer, increased magnetic field strength on Earth above 4 A/m, the presence of poisons in the body… After complete rejuvenation, all parameters of the human body at 35-90 years old are restored to the level of 16 years old.
Dear Josh Mitteldorf
Considering your interest in aging, I suggest you take my course of rejuvenation of your body, so that you can evaluate this technology on yourself. You just need to give me consent – say I want to take a course of rejuvenation. Then I pronounce the command to your Soul in my own words in one sentence and it increases the intensity of the magnetic field of hydrogen atoms in nerve cells and this launches the control command of rejuvenation of your body.