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Longevity Linked to Proteins That Calm Overexcited Neurons (quantamagazine.org)
243 points by tiagom87 10 days ago | hide | past | web | favorite | 51 comments

> In their new study, Yankner and his colleagues report that the brains of long-lived humans have unusually low levels of proteins involved in excitation, at least in comparison with the brains of people who died much younger. This finding suggests that the exceptionally old people probably had less neural firing. To investigate this association in more detail, Yankner’s team turned to C. elegans. They compared neural activity in the splendidly long-lived daf-2 mutants with that of normal worms and saw that firing levels in the daf-2 animals were indeed very different.

> “They were almost silent. They had very low neural activity compared to normal worms,” Yankner said, noting that neural activity usually increases with age in worms. “This was very interesting, and sort of parallels the gene expression pattern we saw in the extremely old humans.”

Does the low neural activity correlate with a less active experience of the world? Are you experiencing your state with the mute button on? I'm no neurosurgeon, but if this is the trade-off, perhaps living longer by using this REST gene might result in a less rich, dynamic, and textured experience? Might it mean living a life like this is less 'fun'?

Depends on the nature of activity. Pure stress will activate your brain but experience is mostly degraded.

What if stressful existance pushes for shorter lifespan with the effect of quickening the turnover of generations.

So stressful environment would speed up the evolutionary iteration of generations. While less stressful existance that has adopted to the environment would persist longer.

This analogy happens in some animals for sure. At the zoo they place the antelope near the cheetahs so that they breed more.

And having everything firing at once is a seizure. But somewhere between that and normal is unclear.

It's also possible the association is in the other direction - people with neurons that fire less might be less stressed in general (almost by definition), and maybe the effect of stress on longevity takes place elsewhere entirely.

> Does the low neural activity correlate with a less active experience of the world?

From the fine article:

> "Neuronal overactivity may not feel like anything in particular from the viewpoint of the worm, mouse or human, unless it gets bad enough to provoke seizures. But perhaps over time it may damage neurons."


> Neural activity refers to the constant flicker of electrical currents and transmissions in the brain. Excessive activity, or excitation, could manifest in numerous ways, from a muscle twitch to a change in mood or thought, the authors said.

> It’s not yet clear from the study whether or how a person’s thoughts, personality, or behavior affect his or her longevity.


Does this relate in any way to the anti-aging drug cocktail that we saw a few months ago?

IIRC that one related to genetic aging markers, and stress can affect mitosis.

It seems like immortality has a lot of building blocks, and the research isn't far enough to combine them yet.

Here is the Nature article with a link to the study in the footnotes.


This blog post has commentary on the study. If you are interested in the topic, consider suspending disbelief until after reading the post. It does a great job of clarifying what the evidence actually shows, and outlines one way to contextualize this intervention.


Anyone have a link to that? Sounds interesting.

You should watch Joe Rogan speak with David Sinclair, who researches aging at Harvard, about the latest developments in his field https://youtu.be/ZGLL77wYxe8

Aside from multivitamins and idiosyncratic drugs, Sinclair takes the following supplements every day:

- Resveratrol – 1g in the morning (this is synergistic with NMN)

- Nicotinamide Mononucleotide (NMN) – 1g in the morning

- Metformin (prescription drug) – 1g in the evening – except on days when exercising, since metformin reduces muscle growth after exercising

(As an aside, he also engages in intermittent fasting, to reduce his total feeding hours. There’s a theory that intermittent fasting triggers a beneficial stress response whereby your body becomes more “efficient” in a way that prolongs life. Intermittent fasting has been shown to prolong lifespan in mice. Interestingly, resveratrol is expressed in plants as a defense mechanism akin to what intermittent fasting does in humans, and that’s one of the supplements that Sinclair recommends.)

Sinclair is very careful not to recommend that cocktail for anyone, since anti-aging research is still very preliminary. The relevant human trials are underway. However, NMN in particular has had astonishing effects on mice. Mice that took NMN lived significantly longer than other mice. Old mice that took it ran for so long that the measuring device on their running wheel timed out, because they weren’t expected to ever run that long.

In old age, the NMN mice were conspicuously stronger, had more hair, saw better, and were more mentally intact. In short, NMN might reverse the underlying epigenetic causes of aging. Sinclair subscribes to the information theory of aging, where, over time, your epigenome accumulates damage and errors, and protective mechanisms die out. It’s like scratches on an overplayed analog vinyl disc which slowly declines in function and eventually stops playing altogether. You lose a majority of your NAD+ as you get older (NAD+ is fed by NMN), which is problematic because NAD+ feeds biological mechanisms which mitigate informational damage. That’s why supplementing with NMN is theorized to have anti-aging effects.

Sinclair wrote a great book synthesizing aging research if you want to read more about it. https://www.amazon.com/dp/1501191977/ref=cm_sw_em_r_mt_awdo_...

Re reservatol:

The jury is out in terms of its efficacy, or lack thereof. [1,2]

[1] https://www.health.harvard.edu/blog/resveratrol-the-hype-con...

[2] https://www.health.harvard.edu/blog/diet-rich-resveratrol-of...

Re. David Sinclair [3]:

"Despite his enthusiasm, published scientific research has not yet demonstrated the molecule works in humans as it does in mice. Sinclair, however, has a considerable financial stake in his claims being proven correct, and has lent his scientific prowess to commercializing possible life extension products such as molecules known as “NAD boosters.”

His financial interests include being listed as an inventor on a patent licensed to Elysium Health, a supplement company that sells a NAD booster in pills for $60 a bottle. He’s also an investor in InsideTracker, the company that he says measured his age."

[3] https://khn.org/news/a-fountain-of-youth-pill-sure-if-youre-...

Yep, resveratrol on its own doesn’t seem to do much, which is puzzling given its effect on mice. That’s why I added Sinclair’s claim that it is a synergistic part of his drug cocktail. Let’s hope NMN is different. As for Elysium, Sinclair is not affiliated with them and he said he doesn’t make any money off of supplement sales.

hopefully it doesn't turn out like the book of that sleep guy, matthew walker


Walker seems to have made some claims without empirical backing. Sinclair on the other hand refers to miracle research in mice and says that they might or might not translate into humans. However, he does explain, at length, how it may work to extend longevity in humans just like it does in mice.

He also gave the aforementioned drug cocktail to his elderly dad and said it seems to have rejuvenated him. His dad is hiking all around Australia, just like he did as a young man. I paid little attention to that particular claim since it is an n=1 anecdote.

I’d like to read as well.

> The results may help explain the observation that some drugs used for epilepsy extend life span in lab animals.

It would be interesting to find out if CBD (seizure control, calming effect) might be beneficial in increasing levels of REST and calming neural activity.

Purely speculating, but perhaps this would place a positive evolutionary pressure on migraines, since they are associated with cortical spreading depression[1] which globally decreases neuronal activity for up to days at a time.

Could this be related to the generally shorter lifespans of males?

Life expectancy was the same for both genders in 1900 (in Europe at least).

We’ve just made continually more progress for women than for men. Nowadays for example: lots of research on female cancer (twice more funding than male cancers, for the same incidence and mortality) and domestic violence, little budgets on suicide. Lots of money for equality at work where women are fewer, little money for boys massively dropping at school. Practically no help if you are a man facing a male-specific issue, which is why a lot of them engage in the army or in Daesh (depending which side they tilt towards), and practically all killers you know are boys victims of harassment, absent father syndrome and on the spectrum of autism, with no help from the social fabric.

Men live shorter not because it is nature, but because we’ve made less progress for them.

Please don't take HN threads into gender flamewar. Last thing we need here.


You are driving a thesis here but using only data which supports that thesis. There are many other reasons why, at least in the culture I'm familiar with (the USA) men have tended to live shorter. These are all stated in past tense, though many are still true today:

- men smoked at higher rates than women

- men were more likely to drink heavily

- men were more likely to engage in dangerous work (construction vs nursing)

- men were more likely to drive aggressively and/or drive motorcycles

- men were far more likely to say "watch this!" and do something like, oh, jumping off the roof of a house an into a pool

Lets take this from a perspective of stress. Stress is highly correlated with life length, with those who has good stress management having longer lifer. What is good stress management? Among other things good social support. Bad stress management is things like substance abuse.

So why do men have worse social support than women? First we can look at is how society reward men who focus their time on social networking compared to a focus on career and higher income. On average, how do society react if a man choose a high social job such as nursing vs a high income job such as construction, and then compare that average for women.

The second thing we can look at is a more obvious one. On average men are more likely to be childless than women. It should surprise no one that having one or more children does increase the probability of a social support network at old age.

The third thing is suicide which is the single largest cause of death for men until age of 65 (if I remember right). Suicide is highly correlated with untreated depression, a illness where it is well know that men is in the receive end of discrimination. Very few culture has any tolerance for men with mental illness, and this again is correlated to social support and in the long run stress management. Men with mental illness run higher risk of handling it alone compared to women.

It should be noted here that for the age groups where "drive aggressively and/or drive motorcycles" is relevant, suicide is still more common cause of death. I will also include the age groups of people who say "watch this".

Exploration vs exploitation at work. Teenage men are way more biased towards exploration, whether it's good or bad. Sometimes some of them figure out something great that improves civilization. Without that risk taking we all would be dead or in zombie mode.

There are some interesting challenges to your premise, even though some of it very clearly plays a role in the gap.

There is a six year gap (81 vs 87 as of 2018-2019) between men and women in Japan. Arguably none of that gap is properly explained by the issues you've raised. The Japanese are the healthiest, longest living people of any large cohort on the planet and yet the gap persists.

Further, roughly twice as many girls (50.5%) born in 2019 in Japan will live to 90 as boys (26.5%).

None of that is explained by things like rates of cancer (low in Japan), school drop-out rates, domestic violence, murder rates, prison, crime, work equality, army / Daesh matters, or suicide rates. Japan's male suicide rate for example is below that of the US, Finland and only a few points above France.

Yet the life expectancy gap between men and women is smaller in the US than in Japan, which makes little sense if your raised issues were the leading cause agents.

There’s a theory that longevity is lower in men because they need to be stronger in order to survive in a conflict. It’s a trade off. Physical strength is the result of growth, but some of the same pathways for increased growth are also theorized to be the root cause of aging. Note that this is independent of strength training; it’s the ability to get stronger, rather than actually getting stronger (among other related characteristics), that may affect longevity. Your intuition that accidental death and smoking do not explain the entirety of the gender gap in longevity is spot on. It’s not all bad news for men though. If you manage to avoid obesity and diabetes, your increased strength and bone density may impart greater quality of life in old age, and that may be worth the 3 lost years at the end of life. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3034172/

The big killer among modern elderly people is the massive muscle wasting that accompanies most inpatient hospital procedures. Having a solid foundation of muscle can insulate a person from the dreaded point of no return after which it would be impossible to build one's body back after a procedure.

Even without being bedridden for days after an inpatient procedure, we have an epidemic of frailty among elderly people. This commonly causes serious falls and fractures, and after an incident like that most people fall into a rapid downward spiral. As a matter of public health policy we should be prescribing weight training and higher protein diets for elderly people.

More muscles are correlated with lower incidence of cancer (and inflammation), so that goes against strength preference being a reason of aging.

Scientists are finding that aging is a discrete disease that catalyzes other secondary diseases, like cancer and dementia. They are also finding that it is highly likely that men’s cellular aging is slightly accelerated compared to women, albeit with the trade off described above. The anti-inflammatory benefits of muscle are overwhelmed by the avalanche of diseases caused by aging. If you’re 80 years old and you use drugs to stave off one disease, you’re likely to die from another disease soon thereafter. It’s like playing wack-a-mole, because we’re not addressing the primary disease: aging. That may change soon since more research is being done into aging as a disease.

> None of that is explained by things like rates of cancer (low in Japan),

??? Not for Stomach cancer or CRC.

CRC: High in Japan vs most other countries, and significantly more prevalent with men: https://www.wcrf.org/dietandcancer/cancer-trends/colorectal-...

Stomach: https://www.wcrf.org/dietandcancer/cancer-trends/stomach-can... men get is almost 3x more than women in Japan and Japan is the top 3 worldwide in incidence.

And overall death rates by cancer for men in Japan are quite a lot higher than for females: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4929724/figure/...

For suicides in Japan it's predominantly men who commit suicide, with a ratio of 2.53 vs female: https://en.wikipedia.org/wiki/List_of_countries_by_suicide_r...

Before making blanket statements you may want to check the data...

The Japan difference for life expectancy could just be because Japanese men work themselves to death more often than not. Women do as well, but there's also lots of pressure to get them out of the workforce.

>Life expectancy was the same for both genders in 1900 (in Europe at least).

Probably because other factors that would kill early both men and women much sooner dominated. Like trying to measure the performance of a program when the disk is too slow and ending up measuring the disk...

This seems like it could be true, but is against my intuition. It could be that in 1900 things that killed people killed them before brain activity was significant to have an effect. But as health results improved, brain activity ended up being a bigger factor on when someone died because they weren't busy dying from typhoid 25 years prior.

I'm personally of the hypothesis that in most cultures men undertake activities that end up killing them earlier in aggregate than women.

Do you have a citation for the formerly same life expectancy in men and women. I cannot find any.

According to the UK government [1] there's been a gap back to at least the 1850s, which was growing worse until 1970, and has since been getting better, but remains considerably higher than in 1850.

1: https://www.ons.gov.uk/peoplepopulationandcommunity/birthsde...

Historically women likely had to deal with high death in child birth rates.

Sad facts.


Please don't take HN threads further into gender flamewar. Last thing we need here.


Raise men as girls? What good parent doesnt try and raise there sons do have care and empathy and to be reasonable? Are there any positive traits that you think men possess? You are only taking the negative side of mens tendency for risk taking. Willingness to take risks has many positive benefits like getting to the top management spots you mentioned.

A few points:

- Here's a recent example[1] of a father who doesn't seem to raise his sons with empathy and reason as his core value. He explicitly state that this is in opposition of "raising boys like girls"[2]. It's an over-the-top example, but of course every time an adult encourage a boy to bottle up his emotions, to be stronger than the other boys, to go and force-kiss a little girl, etc. they reinforce this construct a bit.

[1] https://twitter.com/aubrey_huff/status/1199200986658553857 [2] https://twitter.com/aubrey_huff/status/1200543836700889090

- Women contribute vastly more than men to the fundamental care that keep society going via mostly invisible, unpaid but constant and demanding work (see the documentary "Who's Counting? Marilyn Waring on Sex, Lies and Global Economics" for an accessible intro to that [3]. Example are child rearing, elderly care, domestic chores, generally taking care of social organizing... Men mostly opt out of this work, and we should not let them. We should teach boys to take an active part in this. That's another way to raise boys as girls.

[3] https://www.onf.ca/film/whos_counting/

- Are you sure that dangerous behaviors like drunk driving or bar fights are a necessary component of learning how to become a brilliant top manager? I have my doubts. In any case, it's a cultural decision: do we continue to encourage young men to be reckless and let them die more often than women of violent death, because being reckless will also help them steal all the good spots? If this kind of risk taking is so beneficial, do we encourage girls to be reckless too? Or do we encourage a more peaceful culture for boys?

(Anyway, your point about risk taking is conflating different kind of risks. Launching a startup or managing a big co has nothing to do with jumping off of a bridge because your friends dare you to do it.)

- Do I find some traditionally male traits desirable? Yes, a few of the less toxic. I think girls should be raised and socially accepted to be much less self-diminishing. To easily talk in public with confidence. To recognize their own physical force as it is and not less. To assert their own desires and to not default to fulfill the desires of their partners as a priority.

So I'm one of these persons who think that erasing the gender lines as much as possible would be beneficial for our societies :-)

Im not sure what your first point is attempting to accomplish. I said good parents and you are always going to be able to find one off exceptions and people who have seemingly wonky ideas about child rearing. A good parent on average will try and instill those good characteristics you mentioned in all their children whether boys or girls.

If your trying to say that the home care that more traditional or conservative women engage in is fundamental to society than I agree. So why do you want to push women to less fundamental roles in society?

You seem to only few attributes that are traditionally ascribed to men in a negative light. I dont think that bar fights or any other negative activity are necessary that is why men should use their natural tendencies in a good and productive manner as well as should women.

All of the 'positive' traits that you listed have an underlying negative connotation. Assert their own desires, Easily talk in public are not fundamental traits. Im not sure what you mean by 'use their own physical force'. It looks like you view men as mostly toxic.

So you think that men and women should be as indistinguishable from one another as possible? I am one of those people who celebrate diversity by realizing that the differences among genders and cultures ect.. are what makes life interesting.

By erasing gender lines you seem to mean erasing men and making them women. Wouldn't it be healthier for both genders to express their natural attributes in a positive way?

“The flame that burns Twice as bright burns half as long.” ― Lao Tzu, Te Tao Ching

Pretty sure that's from Blade Runner not Dao De Jing.

Why not both?

Yay! Responsible journalism that includes debunks of obvious theories. More like this, please.

Is this the norm for Quanta Magazine? If so, I'll subscribe.

I’m suspicious of the bacronym REST. Was it created to push the idea? I’d rather they coined a neutral acronym. This one reeks of marketing.

Everyone knows you come up with the cool acronym first and then figure out what the letters mean to fit the cool acronym.

That's a rather strong accusation...

In the article it says REST was studied previously in contexts that have nothing to do with aging.

I'm sure it wasn't an accident, but I think it was just meant to be a convenient association with it having an inhibitory effect.

At least it's not as overloaded as SAD.

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