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.

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.

NMN Anti-aging, disease, illness, fertility

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.

a response in Josh Mitteldorf's blog

 
Regards Telomeres:
while I'm not sure if the measurements are reflective of increases throughout, say stem cells, it has been claimed that a vegetarian diet combined with even modest low intensity exercise can increase the length of telomeres in humans by a noticeable amount.

Regards Thymus:
I've heard that some doses of melatonin are able to reverse thymic involution in nonhuman animals.

Regards natural substances, we have to remember that some can interact with regulatory proteins and alter gene expression.

For example I believe that CR is at least in  part  probably an artefact of metabolic regulatory networks and not a primarily evolved survival mechanism, it works up to around 65% restriction in some animals but requires optimal nutrition unlikely in any natural environment at that level of restriction.   If you can mess directly with the signaling pathways there's no telling what the limits are, as you wouldn't be bound by minimum survival necessary caloric intake limits, and multiple substances are emerging that appear to affect the signalling directly such as nicotinamide riboside, and the various partial cr-mimetics(resveratrol, fisetin, pterostilbene,etc).  There's also probable dietary means of also activating these signaling pathways such as low methionine diets, which can be combined with the substances and probably yield additive effect.

update:
The telomere study wasn't large but iirc, it took measures after five years, which should give time for changes to accumulate,  between comparison groups and had noticeable differences

"The group that made the lifestyle changes experienced a “significant” increase in telomere length of approximately 10 percent. Further, the more people changed their behavior by adhering to the recommended lifestyle program, the more dramatic their improvements in telomere length, the scientists learned.

By contrast, the men in the control group who were not asked to alter their lifestyle had measurably shorter telomeres – nearly 3 percent shorter – when the five-year study ended. Telomere length usually decreases over time."-http://www.ucsf.edu/news/2013/09/108886/lifestyle-changes-may-lengthen-telomeres-measure-cell-aging

"I believe CR is an evolved mechanism for population regulation. Think of it as aging extra fast when there is a temporary plentitude of food, so overpopulation is a risk. The idea that CR life extension only works with optimal nutrition has become part of the biological lore, but it has never really been tested. At the very least, there are big exceptions, as when insufficient protein and methionine help to ENHANCE life extension from CR."

While I don't remember the source I've also heard it must be gradually undertaken or else no lifespan benefits are seen if it is  introduced all of a sudden in adult organisms, in nature it seems sudden famine is more likely.  Also it seems to work up to about 65% in some animals, even if we were to assume no supplementation is necessary in more mild calorie restriction, it is unlikely there wouldn't be serious malnutrition at such extreme levels, yet it keeps on working past what would seem like natural environment nutrient limits.  
Regards methionine, iirc, it's believed to be one of the key signals of nutrient availability which is used by the mechanisms of cr, but it cannot be reduced beyond a certain point without severe side effects.

As for testing malnutrition CR I would imagine you consider CR not effective in humans or else some of the poorest on earth would be breaking records, which they're not and would serve as a test if it is effective in humans.

CR an artifact?

The most widely accepted theory is that this effect evolved to improve survival during times of famine. "But we think that lifespan extension from dietary restriction is more likely to be a laboratory artefact,"
  says Dr Adler.

Lifespan extension is unlikely to occur in the wild, because dietary restriction compromises the immune system's ability to fight off disease and reduces the muscle strength necessary to flee a predator.-link 

I would also add that since the calorie restriction is done with dense nutrient enriched optimal nutrition, this is unlikely to occur in the wild.  Without optimal nutrition calorie restriction is said to fail to extend life, small amounts of nonenriched foodsource as found in the wild is in my opinion unlikely to provide optimal nutrition required for extension. edit: especially at levels that cr can work in some animals like 60+%, at 60% deprivation not only would the nutrient density likely be insufficient, but in an environment lacking resources the small amount of calories would be insufficient for exploration, cr appears to work and extend life even in calorie amounts beyond what would be sustainable in the wild.