comment on aging video by youtuber siimland

 

comment 1: The exceptions to the oxidative stress theory of aging (basically the evolved rate of living or free radical theory of aging) were explained by the membrane pacemaker theory of aging, whose own exceptions as pertains aging rate can be explained by the presence of antioxidant mechanisms such as the presence of plasmalogen molecules that act as sacrificial antioxidants.

Damage to membranes creates an autocatalytic chain reaction of damaging molecules that can bypass both lipid and aquatic sections of the cell damaging all components throughout the cell.   Species with high metabolic rate and high lifespan, achieve this by altering membrane peroxidation index or otherwise altering membranes to make them more resistant to damage, particularly the mitochondrial membrane.

The neuron of mice when transplanted into rats' lives twice as long as mice do.  It is believed that if transplanted into even longer-lived animals it'd live just as long as the host.  Even in humans' neurons last over 110 years longer than the average lifespan, and again it too might live as long as a longer-lived host if transplanted into such.

So at the cellular level a near agelessness was achieved in neurons.  Despite sustaining extensive genetic damage throughout the lifespan most seem to keep on working fine.  The fact humans age despite having ageless cells, and even mice too, is due to planned obsolescence.  Evolution optimizes lifespan to maximize evolvability, the rate of evolution for a particular species.

What can be done? Well look at insects despite the workers sharing same genome as queen, the lifespan difference can be up to dozens of times, iirc up to 100-fold difference in lifespan has been seen with different gene expression patterns.  It may be that we can take the anti-aging mechanisms used by neurons, perhaps even a fraction of these, and express them throughout the body by altering gene expression to increase membrane resistance to damage.

comment 2: resveratrol failed due to fast liver clearance, in animals without fast liver clearance above 50% life extension is achieved, including in vertebrates.   At very high dose it achieved over 20% life extension in primates albeit the group was too small to reach statistical significance.  New formulations of resveratrol such as JOTROL shows good promise, and is now undergoing clinical trials for some conditions.

Video on longevity and immortality

 

Comment

we don't need brain emulation; we only need central nervous system regeneration. The neurons of mice can live over twice as long as mice and are believed could live indefinitely in a new host. Same likely applies to humans, if the body didn't age most neurons could last for centuries, and they could be slowly replaced with regeneration. Backups could assist regeneration, and the brain tissue could be genetically extremophile hardened to withstand prolonged blood or oxygen deprivation so as to survive extreme accidents while awaiting regeneration of body.

Walk This Way to Live Longer (Backed by New Science)

Even under 8k steps might still have notable benefits.  It is convenient to walk more than 15 minutes at a time to reduce all cause mortality.

Dr. Sinclair's Protocol Updates In 2025

Comment

I take taurine, nmn, pqq, ergothioneine, urolithin a, spirulina, omega 3, magnesium, vitd+k2, hydroxytyrosol. Recently started taking nugevia resveratrol, which is best taken on a fasted empty stomach, iirc. Nugevia uses micellar resveratrol which is being tested as a resveratrol drug called Jotrol. 500mg Jotrol is said can exceed blood levels of 5g micronized resveratrol, nearly doubling them, that is it approaches levels that would take nearly 10g of expensive micronized resveratrol.

10g micronized is not just expensive but overloads system with metabolic byproducts, Jotrol can achieve the benefits of this at far lower dose without the side effects or issues of such high dose micronized.

In lemur primates, it was seen that high dose resveratrol was able to extend median lifespan over 20 percent, albeit too few primates were used to reach statistical significance in the study, and thus it was dismissed.

In fish which don't have the fast liver clearance issue seen in primates and rodents, resveratrol lengthened lifespan over 50 percent. The likely reason mice failed to show lifespan extension on resveratrol is due to fast liver clearance of resveratrol. But newer formulations promise to alleviate this issue somewhat and allow higher blood levels albeit temporarily.

If We Escape All Major Diseases, Neurodegeneration And Respiratory Failu...

Comment

Neurons were transplanted from mice to rats, and the mice neuron lived twice as long as the mice. The researchers believed that if transplanted into even longer lived animals they'd live even longer potentially indefinitely. Likely same for human. But the loss of respiratory reflex as cause of death in elderly was found in animals, and likely applies to humans too.

That is if vascular and support glia cells for neurons were kept youthful it is likely this would reduce rate of neuron death, and might allow for far longer neuron average lifespan potentially extending into two centuries or more.

That said it is true that for a real solution we do need central nervous system regeneration stem cells.

We'll Pay $101 Million If You Prove You Can Reverse Aging

Comment.

The exceptions to wear and tear, free radical oxidative stress theory of aging were explained by the membrane pacemaker theory of aging. And the exceptions to membrane pacemaker can be explained by presence of molecules such as plasmalogens that are not normally taken into account when calculating Peroxidation index. It is conceivable lowering membrane damage sufficiently would allow repair mechanisms to outclass rate of damage accumulation

Telomere Biology: The Ultimate Biohack

Interestingly in this presentation, the degree of telomerase activation from the ingredients of telo vital one of the strongest telomerase activating supplements is discussed.   All animals that have indefinite lifespans have some mechanism to lengthen telomeres.

IS AGING PROGRAMMED? Aubrey de Grey vs. Yuri Deigin debate at Vitalist B...

comment: one thing is that parasites, diseases, germline mutations accumulate with age, fighting all of these is easiest by killing organism, that is in addition to increased evolvability. Also, the exceptions to the free radical theory of aging were explained away with the membrane pacemaker theory of aging, wherein membrane resilience determines rate of damage accumulation. Evolution determines membrane composition, during Calorie Restriction and similar interventions organism even alters membrane composition in a controlled manner increasing lifespan drastically.

In organisms like insects same genome different epigenetic regulation allows 10x--100x lifespan difference between queen and workers. But even here, it was believed queens of some species might be immortal, but for whatever reason it was found that sequential replacement with clones was easier for nature than actual immortality, the longest lasting queens last like 30 years ageless iirc, with extreme reproduction.

Aubrey de Grey Reveals SECRET to Aging

Comment

While I like membrane pacemaker damage theory of aging, there is issues such as neurons being able to live twice as long as animals they come from, and repeated cloning being possible both without signs of aging. There is also the claim telomere lengthening rejuvenates cell and tissue level phenotype from old to young. I suspect that the damage is causing some internal clock or clocks to move and age us. Given again single cells like neurons can live twice as long as the animal and some believe can live more than ten times as long without genetic change. If repeated cloning shows dividing cells can yield youthful tissue far beyond animal lifespan and same is true for nondividing cells the body seems able to handle damage fine bar some aging clock or program interfering.

This 64-Year-Old Grandma Was Beating Bryan Johnson

64 year old woman beat multimillionaire at longevity benchmarks with low cost approach.   This is highly promising for the average person knowing they can achieve similar results without having to resort to extraordinary measures.

RESVERATROL - The Truth Will SHOCK You! (only on this channel!)

The benefits of the promising longevity molecule resveratrol are discussed.  Resveratrol is very promising but part of its benefits are limited in humans due to its fast clearance through the liver.  Newer formulations appear might offer promise of increasing its benefits.

Joe Rogan Experience #1432 - Aubrey de Grey

Comment: My problem with Aubrey is that he thinks solving aging is an engineering issue. But I think when handling the high metabolism nondividing neurons design, nature essentially solved aging at the cellular level. A mouse neuron transplanted to a rat lives twice as long as a mouse, just as long as a rat, and could potentially live even longer in an even longer lived species.

After essentially having a solution to aging baked in, nature had to adjust organism lifespan to their niche.

Michael Fossel, iirc, claims that many of the maintenance mechanisms are downregulated in an age related manner. And it is this downregulation of maintenance that leads to all the issues we see.

It was discovered that the rate of telomere shortening predicts species lifespan.

Researchers discover that the rate of telomere shortening predicts species lifespan. A flamingo lives 40 years and a human being lives 90 years; a mouse lives two years and an elephant lives 60.J What counts is not their length, but the rate at which they shorten | A better predictor than body size or heart rate https://phys.org/news/2019-07-telomere-shortening-species-lifespan.html

Would telomere lengthening work against aging? Maybe it wouldn't solve everything, but such therapies sound highly promising.

I think Aubrey's ideas might work but they seem like overengineering. We have seen that we had a mammal ancestor with mice like lifespan to reach our human lifespan nature did not need to transfer more genes from the mitochondria to the nucleus, nor did it abolish telomeres, etc. Even longer lived mammals, iirc, have not transfered additional mito genes to the nucleus.

We know there are superagers with brain functioning akin to 20 year olds. The brain functions at ultra high metabolism for decades, but when aging affects the support system and garbage clearance mechanisms, issues start to arise.

I think just like glymphatic systems helps transport garbage out of the brain, the lymphatic system does similar across the body. But aging compromises it too.

edit: Regards the idea that there's a trade off between cancer and aging. Mice engineered to have extra long telomeres had extended lifespan and did not have additional cancer rates.

Importantly, mice with hyper-long telomeres show an increased longevity and develop less tumors associated with aging. Together, these findings demonstrate that longer telomeres than normal show beneficial effects in mice, delaying metabolic aging and cancer, and resulting in longer lifespans. https://www.nature.com/articles/s41467-019-12664-x

edit2:There's also the fact that some mice appear cancer immune and a fraction of the human population might as well be( lifelong heavy smoker centenarians for example.). I think the additional copies of anticancer genes in extremely large animals are to protect against cancer during embryonic development, but theoretically the immune system might be sufficient at least in a fraction of the population.

IMHO, it is likely the body already has the capability for significantly longer lifespan. Rather than look for trying to redesign fundamental biological components past what nature has done, I think, in the short term, the search for small molecules that can restore epigenetic age and telomere length sounds more promising.

Interesting longevity finding regarding astaxanthin.

An Astaxanthin compound has been found to switch on the FOX03 'Longevity Gene' in a study using mice. Researchers measured a nearly 90% increase in the activation of the gene in the animals' heart tissue. Life sciences company Cardax, Inc. looks forward to further confirmation in human clinical trials of Astanxanthin's potential role as an anti-aging therapy. -link

Interesting finding.   The fact that astaxanthin increases lifespan in some species, and also appears to protect cell membranes, make it very promising.

AHS18 Michael Rose - Evolutionary Biology of Diet, Aging, and Mismatch.

Michael Rose speaks about antiaging,aging and evolution.  He is a researches who took flies and evolved a group of them to have extraordinary longevity through multiple rounds of selective breeding.  The key intervention was causing them to reproduce later and later by destroying the early eggs if I recall correctly.

Overtime a series of changes occurred that allowed the insects to live longer and longer while remaining healthy and youthful.

Longevity can be predicted by number of cortical neurons in an animal or so it seems.
https://onlinelibrary.wiley.com/doi/full/10.1002/cne.24564

Crucially, the finding that no correlation between
maximal longevity and metabolic rate remains after accounting for
variation in numbers of cortical neurons argues strongly against
the common notion that damages accumulate at rates that scale
across species depending on metabolism (West et al., 1997).-Herculano Houzel (2018)

Interesting snippet as well as the following

While this new possibility has yet to be investigated, it
leads to one clear prediction: those species with the largest number
of cells in the relevant organ(s) will live longer before succumbing
to physiological breakdown and disintegration and,
consequently, death.-Herculano Houzel (2018)

And yet another related snippet from the news

"The data suggest that warm-blooded species accumulate damages at the same rate as they age. But what curtails life are damages to the cerebral cortex, not the rest of the body; the more cortical neurons you have, the longer you will still have enough to keep your body functional,” said Herculano-Houzel.-source 

But it seems to me that if this were the case you'd see massive lifespan reductions in indivduals with half a brain, which does occur in humans.   Otherwise this would seem to suggest aging may very well be programmed.

Comment on CR mimetic drugs and nutraceuticals potential

From what I understand, iirc, CR works even outside the parameters that can ever be found in nature.   That is IIRC, even up to 65% restriction resulted in 65% increase in lifespan in mice.   It is extremely unlikely, virtually impossible, that on 65% restriction on a famine you will find extraordinarily micronutrient fortified food with minimal effort(as large effort will also result in death from excessive calorie burning from activity) as provided in the lab.
   
I've also heard that on CR started on adult organisms, the transition into CR needs to be gradual and not sudden to actually confer benefits.   The food also has to be fortified to provide sufficient micronutrients.   Again it would seem to be that famines might occur quite sudden and drastic, and may reduce micronutrient availability.

Even in the lab it may be that the mechanism could even go further if not for the low calories compromising vital functions.    On higher lifeforms like man the minimal calories necessary to not jeopardize function may be even higher(I've heard of some severe calorie restriction individuals losing bone integrity), but the genetic expression flexibility may still remain.

What will tell the true limits of these pathways are the physical limits in terms of gene expression that they can ever reach with interventions such as drugs or nutraceuticals.  Which may be reached at 65% CR or could be higher had it been physically possible to survive on even less calories.   CR mimetics stimulate the pathways without jeopardizing function from insufficient calories.

We now know that things like NAD+ drop with age in some organisms which may be behind why resveratrol failed on healthy organism with longer lifespans of a few years after succeeding in many organisms of lower lifespans such as yeast, c. elegans, fruit flies, and some short lived fishes.   Sirtuin dependence on NAD+ would obviously be compromised if NAD+ levels fall too low.Since resveratrol works in part through sirtuins it's effects would be adversely affected through such age associated changes.  But ways to increase NAD+ are now known, some readily available some on the horizon.

source Josh Mitteldorf scienceblog comment

Comment on sulforaphane and sprouts

Sulforaphane has a lot of benefits, as seen in the following link

39 Sulforaphane Benefits, Foods, Supplements + Broccoli Sprouts - self hacked link

Sprouts are a source with greater content.

POST AT LONGECITY

Not sure if previously posted

Quote

"As scientists, we learned that sulforaphane is maximized when broccoli has been heated 10 minutes at 140 degrees Fahrenheit," said Jeffery. "For the consumer, who cannot readily hold the temperature as low as 140 degrees, that means the best way to prepare broccoli is to steam it lightly about 3 or 4 minutes--until the broccoli is tough-tender."-https://www.sciencedaily.com/releases/2005/03/050326114810.htm

 

4 cups of sprouts supposedly might be enough to reach max safe dose.

If steaming for 3 to 4 min or the 10 min thing increases 3 to 4 fold sulforaphane maybe one cup might be near limit.   Add to that that I couldn't refind the reference, but I heard putting it in a blender drastically increased sulforaphane after being let sit for 30+ min, iirc[edit, put reference to blender article at bottom].

What I do is steam for 3 minutes, put in room temperature water, and add a bit of ground mustard powder and blend for 30 seconds and let sit for 30 minutes.

edit

Quote

“You want to cut it into very small pieces and even blend it,” she told Newsweek. One cancer-fighting way to consume the food is by making broccoli soup. However, you’ll want to add blended raw broccoli first and let it sit for 30 minutes before adding to your soup base.  

Chopping and exposing broccoli to the air allows it to activate the enzyme to promote sulforaphanes. In this study, researchers advise letting the broccoli sit for 90 minutes after chopping and Sherzaia said others have recommended at least 40 minutes.-http://www.newsweek.com/best-nutrition-chop-broccoli-small-pieces-cooking-study-finds-801712

I'm not sure, but considering there's a competing enzyme inactivated by cooking I think blending should occur after cooking.   You could cut it or blend it raw and let it sit for 90 min prior to cooking as a lot of sulforaphane would have been created and appears heat resistant.  But the dose should be lower than if you blend after steaming for 3 mins or doing the 10 min thing, as that will inactivate the competing enzyme.

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