Delaying or Reversing Aging. Hype or the Future?

I recently noted that Dr David Sinclair, a somewhat famous longevity researcher at Harvard, who I respect a lot, is taking some drugs/chemicals to make himself younger and healthier.[3]

This is something that I see changing - aging researchers admitting that they are taking things now. In the past, serious researchers were reluctant to admit that they take anything to delay aging, to avoid being grouped with the many snake oil salesmen out there pushing cosmetics or useless herbs and vitamins. MDs and pHDs used to recommend diet and exercise which are well known to help people age better, but now are admitting to doing again interventions like fasting, and taking drugs like metformin.

Dr Sinclair is targetting 3 gene signaling networks AMPK, mTOR, and SIRT6, and this makes sense because there are tonnes of peer-reviewed papers that support those genes or networks as being key factors to aging.

I have asked AIs similar questions and gotten similar lists of genes, just as you would by reading hundreds of research papers on the subject. (which I have done)

 

Why do I care?

So you may wonder why you would care what genes are involved if there is no gene therapy available. The reason is that genes can sometimes be activated or regulated downwards by taking small-molecule drugs. And while this would not be as effective or permanent as gene therapy, it would also not be as expensive or as risky. Gene therapy can cost a million dollars or more. That sounds high, but in theory, it would be a one-time treatment and you are done. However, gene therapies today are risky, as well as expensive, and not available yet for aging.

However, drugs like rapamycin or metformin are well studied and used for diseases of old age, like diabetes, and seem to have definite effects on health and lifespan in animals. They are prescription drugs for humans with known safety profiles [1] [2] [3]

Rapamycin targets mTOR and has been shown to increase animal lifespan. In one study metformin[2]

Metformin may not increase lifespan in some tests, but makes test animals healthy for longer. And in some experiments, it did increase the lifespan of lab animals. [4]

When combined with other drugs like rapamycin, the effect was increased. [1]

Many other drugs show promise. Too many. Acarbose has had some promise. Acarbose reduces inflammation via the nuclear factor kappa B (NF-κB) inflammatory pathway, blocks carbohydrate absorption, and possibly affects insulin-like growth factor-1 (IGF-1). When combined with the mTOR inhibitor rapamycin, it resulted in a significant increase in lifespan. I might be worried about the safety of this. I’m not doing it. [2]

Some chemicals appear to affect lifespan or health span, which are not prescription drugs. The list is long and the safety profiles of these, or combinations of these are not known. Here is a partial list:

Spermidine, Berberine, Quercetin, Fisetin, phenformin, Goats Rue, valproic acid, 

Klotho upregulators (cycloastrogenol Troglitazone pioglitazone Losartan Fosinopril ), 

Trehalose, Melatonin, pterostilbene, curcumin, Tumeric, lenalidomide, vitamin D, 

Alpha-ketoglutarate (AKG) or α-ketoglutarate

Does this make sense to take these?

I have taken AKG, Quercetin, Fisetin, cycloastrogenol, trehalose, melatonin, and a raft of others, and at some point, my kitchen counter was covered with bottles of pills, so I stopped this. At some point, it reaches a ridiculous level, and you have to ask, “Does this make sense? Is it worth the cost?” Are all of these together, as good as say Rapamycin or Metformin? And how can you know which of these might be worth taking or reading more about?

Well in a reference mentioned earlier, you can read about the National Institute on Aging Interventions Testing Program (ITP). “This was designed to be the most exhaustive testing framework and system to evaluate whether longevity molecules extend longevity in mice and understand the underlying mechanisms leading to those benefits.” [2]

This study appears

to be suggesting the following chemicals and reasons. [2][5-10]

Acarbose: Reduces digestion and absorption of carbs, lowers the risk of cardiovascular
disease, reducing IGF-1 hormone which likely helps with cancer and is a known target of
aging studies. 

Rapamycin: Slows growth (a good thing) via mTOR signaling and increases mouse lifespan. 

Rapamycin and Acarbose: increase mouse lifespan 28% to 34%

Well, that is good news, since I have seen a lot of researchers (reluctantly) admit that they take Metformin or Rapamycin.

 

Rejuvenation.

One last thing should be mentioned. The drugs that I have mentioned so far merely delay aging, or make the animal healthier until they die. None of them have made lab animals exceed the normal maximum lifespan for the species. They have made more animals reach that maximum lifespan, and perhaps they are aging at a slower rate.

However other experiments are going on, where a mouse or human cells in culture have had aging reversed. Yes reversed.

In some experiments, old grey-haired mice were rejuvenated to a state with brown hair, and stronger muscle strength, and other measures of age returned to youthful measures. [11] These are examples where it appears that the animal has not just had aging slowed, but reversed. And it has been repeated and verified many times by different researchers.

And it can be done in multiple ways. Parabiosis [16], senolytic drugs, young blood factors (likely exosomes full of youthful RNA, proteins, hormones, etc) , and Yamanaka gene factors are 4 of the common methods where researchers are turning back the clock for lab animals, but there are about 8 ways to rejuvenate a rat at this point.

Dr. Shinya Yamanaka won the Nobel Prize in Physiology or Medicine in 2012 for his work in this rejuvenation area, using 4 genes that were seen reseting the epigenetic clock in fertilized eggs. And that lends some credibility to the rejuvenation research work, as well as giving researchers a useful way to reset the epigenetic clock for further experiments. [14] He has been hired by Altos Labs to pursue this.

Some of these rejuvenation experiments have succeeded in human cells in culture, so it is not expected that these methods only work in rodents.

And some of these methods are being done by self-experimentation by billionaires, or pHD researchers like Dr Katcher. [12] [13]

Futures.

Obviously, with this promising research done, billions are now being sunk into this research area, with the hopes of making trillions. [15]

So until we finally find the fountain of youth, it’s going to get more and more complicated, and I expect the news and social media to be full of misinformation and hype! Enjoy!

 

Errata.

This is complicated, so probably raised a few questions in your mind, and I will try to answer the most common ones that I hear.

Why mice?

The astute reader may be asking a question at this point. Why mice and not humans? The answer is that mice do not live very long and research can be complete in a few years, whereas the same type of study on humans might take 100 years to complete. Also, mice are mammals like us and are commonly used for testing drugs for humans.

Why gene therapy?

Gene therapy is a permanent fix. If you fix a broken gene or upregulate it where it has dropped in function during aging, you have to potential of fixing it forever. Unlike drugs which have to be taken constantly, a gene fix is once-and-done ideally.

Why not gene therapy?

Unfortunately, gene therapies are also risky and expensive today, even when the gene to fix is known, and there is no one or two genes that we know would fix aging. You may have heard about the OKSM (Yamanaka factors) that rejuvenated rats, but this is a genetic trick that is not currently safe in humans, due to the fear of a Teratoma type of cancer that it can cause. So-called “partial reprogramming” may be a way around that risk - stay tuned.

Rejuvenation versus slowing it down?

Current methods seem to slow down aging, and at most you might get more people achieving the 100-year mark. But Calico, Altos Labs, and other billion-dollar companies are trying to find ways to rejuvenate humans safely, expecting this to be a Trillion-dollar industry. I expect that they are right, but we will see.

 

References:

[1]Experimental Gerontology Volume 104, April 2018, Pages 35-42 A brief history of modern aging research https://doi.org/10.1016/j.exger.2018.01.018 

[2] https://gethealthspan.com/blog/articles/acarbose-and-rapamycin-longevity/4wxxj7itxktmmnrxuwmulj/ 

[3] www.youtube.com/watch?v=3i5GwlxVk7Y 

[4] Martin-Montalvo, A., Mercken, E., Mitchell, S. et al. Metformin improves healthspan and lifespan in mice. Nat Commun 4, 2192 (2013). https://doi.org/10.1038/ncomms3192 References from the ITP 

[5] Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition 

[6] Acarbose improves health and lifespan in aging HET3 mice 

[7] Drugs that slow aging in mice 

[8] Changes in the gut microbiome and fermentation products concurrent with enhanced longevity in acarbose-treated mice 

[9] The role of GLP-1 in the postprandial effects of acarbose in type 2 diabetes 

[10] Acarbose, lente carbohydrate, and prebiotics promote metabolic health and longevity by stimulating intestinal production of GLP-1 

[11] https://www.aging-us.com/article/203966 

[12] www.youtube.com/watch?v=YCSn7CjqYVk 

[13] https://fortune.com/well/2023/02/01/will-bryan-johnson-reverse-aging-regimen-extend-his-life/ 

[14] www.nobelprize.org/prizes/medicine/2012/yamanaka/facts/ 

[15]https://www.nature.com/articles/d41587-022-00002-4

[16]https://www.nature.com/articles/s43587-023-00452-8 

Images by craiyon.com AI

How to save the Post Office?

 

“On a U.S. generally accepted accounting principles basis, the Postal Service had a net loss of $4.9 billion for 2021, compared to a net loss of $9.2 billion for 2020.” [1] Yay! Let’s celebrate that it only lost 4 billion. But I think we can do better.

In their planning, the post office mentions that “compensation and benefits expenses increased $1.4 billion, or 2.8 percent, from the prior year” [1]. So we can see that one large expense is the workers. Add to that retirement expenses, worker’s compensation, etc. I will summarize: revenue is down and expenses are up.

So given that one major expense for the Post Office is people, gasoline, and machines, why not have a portal where people can schedule pickups, instead of assuming daily pickups for every house on every day? This is a waste in many cases You don’t have to run every route, on every day.

If we only picked up when people said they had mail to pick up, and we knew which addresses had a delivery in the next few days, then a computer could print out an optimized route that skips many streets. This would save manpower and gasoline and wear on vehicles.

“Ah”, you say. But what about Grandma? She doesn’t know how to use the internet. She needs to mail in her water bill. Well, you could still have a once or twice-a-week schedule that would hit every box, once or twice a week. Given that more and more business is going online, and the post office is becoming less relevant, except for packages, what I have outlined can be scaled down, as more payments go online, but still gives Grandma a safety net plan.

You could also have the local pickup agents be bad at their job, and lose mail every so often. This would encourage people to take their outgoing mail to the post office, drive their water bill to the water company, or go to electronic payments. That idea is working for my local post office.

[1] https://about.usps.com/newsroom/national-releases/2021/1110-usps-reports-fiscal-year-2021-results.htm

 

A safer way to colonize Mars?

If I were going to colonise Mars, there are 2 important questions, that I have not heard good answers for yet. 

 Will there be enough food, water, and a place to chillaxe?
 Will there be beer?

These are important questions, and if you don't think so, just remember what you do every day after work. You want dinner. You want to rest a bit. And if possible, you want a beer.

Discussing this over beers, led to the following very serious discussion.

 

So you're going to Mars.

If you were going to Mars, wouldn’t it be comforting to know that when you got there, you would have a habitat, a large supply of water and oxygen, and maybe some extra rocket fuel, as well as some solar panels and charged batteries? And since we are wishing, how about a cold beer too?

Step 1. Habitat and Radiation Shield.

Well, before you do anything else, you will want a place to get away from the radiation.

Fortunately, there is apparently a large 82-kilometre-wide crater full of ice on Mars, that would be very useful as a starting place for settling Mars. This is about 2000 cubic km of ice. [1] 

So what if you send up some tiny rovers years ahead of time? They could melt tunnels in this ice for a habitat that would shelter you from radiation and could be filled with air to breathe. You could do this years before sending any humans, so when they arrive there could be a very large habitat, ready to move into. 

And perhaps more importantly, if things went badly with this, you would know BEFORE you send people there. If you happen to be one of those people, this is an important point.

Step 2. Water.

In the melting of these tunnels, the rover robots would end up with melted water, H2O. This is important because you can only go a few days without water.

This melted ice could be purified and put into large plastic bags, or allowed to freeze into blocks of frozen pure drinking water. This crater has about 500,000,000 gallons of water, so your drinking water issue just went away.

Step 3. Air, Fuel.

The water in these bags, or pools, could be hydrolyzed into Hydrogen (rocket fuel), and Oxygen with a simple electric current powered by solar panels or whatever electricity you have available.

I don't need to tell you that breathable air is pretty important, and you won't last long without it.

Oxygen is breathable and is also a big part of rocket fuel. The H2 is rocket fuel, or you could just let it go. So when the humans arrive they would also have lots of drinkable water and purified ice, and the habitat would be full of Oxygen. Just add some Nitrogen and move in.

So now you have rocket fuel, oxygen, drinking water, and a habitat, before you even send anyone there. So you have proactively reduced several risks for the arriving humans. And you can test things out and phone home, so you know the situation before you go.

This could be done by robots; it’s simple enough. And it could be ongoing, long before colonists arrive, to build up a supply of air (just add nitrogen), water.

Step 4. Power.

Also, these robots could store power as well, either from solar collected in batteries or by storing Hydrogen in liquid form, fuel cells, or some other form. You could store power as compressed air in some non-habitat tunnels if you have enough lead time, but that requires knowledge about the nature of the ice.

When humans arrive, they could find a lot of stored power, ready and waiting for them to use. Of course they could also bring a nuclear power plant with them, but when help is far far away, it doesn't hurt to have backups.

Step 5. Food.

So what else would a colonist want to be staged for their arrival? Food maybe? That is possible also. If you take some large plastic bags and nutrient powder with you, you could fill them with water and some yeast or algae or yogurt bacteria, and store them in these habitats. Since the habitats will be at a reasonable temperature, you will end up with large volumes of edible yogurt, beer, etc. Add flavors too. You know you will want that.

But "wait a minute", the gourmet in you objects! I don't want to eat yogurt and yeast crackers forever.

Of course not, but you can deal with the gourmet aspects, once you have dealt with the "not dying" aspects of this trip.

Step 6. Beer and yeast.

If you choose a separate tunnel for the yeast bags, you will have an added benefit. The CO2 from the fermenting yeast gradually vented from the growth bags, will create a CO2 atmosphere in that separate tunnel, which green plants could then use to grow. So you’d end up with a greenhouse tunnel, ready for use. And beer for the gardeners. Sign me up as a gardener.

Details.

If you like the basic idea of sending robots to build things out using local materials, BEFORE you go there, then there are lots of improvements that could be made to that basic idea.

I won’t go into them all. (because I don't know them all)

For example, how do you vent the CO2 from the greenhouse-type growth bags - some one-way valve maybe? I don't know.

Will the yeast that is produced this way be tasty? Will the yogurt be good? Maybe you should bring some flavorings with you? That's up to you, but I would bring strawberry and banana.

Tweeks Questions Etc.

I could think up many tweaks to this idea. I’ll bet you can too. For example, you could bring some liquid nitrogen (aka LN2), so you could normalize these oxygenated tunnels from the LN2 *, and heat it to earth-normal once you have a few tunnels, so the colonists would arrive in a fully breathable habitat. You could have several separate tunnels just as a safety buffer. Or the LN2 could come later. You could cool some H2 and O2 from hydrolysis to liquid to create a rocket fuel supply. Or you could use Methane from your fermentations instead of H2. You could bring a few LEDs for light for a greenhouse; they are lightweight and handy to have.

Here is some recent research that might help a bit. An AI found a catalyst to make Oxygen from an ore found on Mars, and you can make the catalyst on Mars, so maybe you don’t have to use a crater full of water to have Oxygen. Of course, you would have to dig soil to process instead. That would give you a wider range to choose a good site. There are other good ideas like MOXIE for making Oxygen on Mars. [2]

To put this in context, there will no doubt be many other good ideas to make Oxygen, Water, Food, Power, Fuel, and shelter on Mars. I have just outlined one method that is easy and could be done today.

References.

[1] https://www.techdigest.tv/2018/12/winter-wonderland-giant-ice-filled-crater-on-mars-photographed-by-esa.html

Graphics from text-to-image AI at https://www.craiyon.com/

[2] https://www.nature.com/articles/d41586-023-03522-4?utm_source=Live+Audience&utm_campaign=5ab7d28551-briefing-dy-20231114&utm_medium=email&utm_term=0_b27a691814-5ab7d28551-49258243

* Breathing air on earth is about 78 percent nitrogen, 21 percent oxygen, and water vapor.

If I have an AI Chip in my Brain...

 

If I have an AI embedded in a computer chip, in my brain, and it’s internet-connected, is it cheating to use that during a test?

What if this chip can chat with my friends or with a much larger internet-based AI? What if it has memory capacity and the whole textbook is uploaded and searchable in its memory store? Is it cheating then?

And what if I have lived a long time, getting first a knee replacement, then a leg, then an arm, until eventually, only my brain is still organic? (except for the AI chip) Am I still a human? I want to say “Yes” since I see my brain and mind as “Me”.

But now it gets harder.

Now suppose that I have gotten much older, and I have gotten nanotech implants that mirror each organic neuron, with each synthetic neuron learning what is normal for that organic neuron, and then mimicking that work, when the organic neuron dies. Like a neural prosthetic. If this were just cerebellum cells, for walking and balance, it seems like any other prosthetic, like a very fancy cane or walker.

But imagine that this is also the frontal lob and white matter cells, which are very much “Me”. And imagine that after years of this, many of my organic neurons have died, and much of my brain functions are now done by these prosthetic nanobots.

And someday, maybe the last organic neuron dies, and I am 100% synthetic. I act the same and feel the same, but I’m not organic at all.

Am I a robot or a human? Does it matter?

Do I have rights, or will they divide my wealth among my heirs, because I am now finally, legally, dead?

Beware the Walnut Tree My Son...

 

As I was blow drying the roof with my leaf blower again, and sweeping oak leaves off the deck AGAIN, I had a realization.

This wasn’t just some tree getting rid of old used-up photosynthesis mechanisms. Those fallen leaves have a darker purpose for the tree.

They mess with the competition. If you leave them alone, those leaves build up a thick layer that other plants have trouble getting through, leaving all of those yummy resources for the tree. After all, an Oak can’t hunt around for things, it’s stuck in place. But leaves make favorable conditions for helpful fungi, and fertilizer, and block out other competitive plants.

Of course, the Black Walnut does all of this and also has another weapon - poison. [1] Surprised? You can eat the nuts or picnic under the shade, but for plants, this tree is a Jabberwock. The Juglone toxin can extend 50 to 80 feet from the base of the tree and can kill off or suppress many of your vegetables and ornamentals. You can do that experiment in your backyard if you have such a tree. Just plant various things under the tree canopy and in other places that have similar light and water, but no Black Walnut and observe the results.

Trees are not totally passive individuals. They grow tall to block sunlight from the competition. They coat the ground with leaves, sometimes acidic leaves, as with Pines. They may make thorns. They create toxins in some cases to discourage herbivores (or you) or other plants from eating them. [3] I might even speculate that crashing down hard and breaking nearby trees, may be a sort of competitive action, by big trees, that rewards their seedlings and punishes the smaller competition (just my speculation). But there is no doubt that trees actively compete - and they might surprise you with some of those methods.

Beware the Walnut Tree my Son, and the frumious Shagbark Hickory!

References

[1] https://hort.extension.wisc.edu/articles/black-walnut-toxicity/

[2] By Lewis Carroll.

“Beware the Jabberwock, my son! 

The jaws that bite, the claws that catch!

Beware the Jubjub bird, and

shun The frumious Bandersnatch!”

[3] https://en.wikipedia.org/wiki/List_of_poisonous_plants

Images from text-to-image AI at craiyon.com

Give to My Cute Kitties PAC

 

I get a lot of phone calls wanting me to give to Firefighters-PAC, or CuteDoggyPAC, or StarvingChildrenPAC. Ok, I like Firefighters and Puppies and want to help them.

But, I made the mistake of Googling what the PAC stands for, and it’s not good. It basically means that I have NOT been giving my hard-earned monopoly money to Charities for cute puppies. I have been giving it to Political Action Committees. PACs. [1] What the hell is a PAC you might ask?

Google it. Ask bard.google.com, and it gets worse. One AI told me,

“PACs are less accountable and transparent than charities because they are not subject to the same level of oversight. This means that PACs are more likely to engage in activities that are not in the public interest.”

Great. Not only did I not help any puppies, but my money may have been used against the public interest. A sort of Anti-Charity, disguised as a charity.

But this rabbit hole gets deeper. There are also Scam-PACs [2] that “gather money for a candidate or cause and then pocket the cash instead of giving it to the cause or the candidate.”

I’m fairly sure that is illegal. But if not, maybe I should start a PAC to help all of those stray cats that we keep adopting. I could call it the “Rescue Poor Kitties PAC”.

Ring. Ring. Ring.

“Mr Smith?”

“Yes.”

“Hi, we are from the Rescue Poor Kitties PAhemmmhemm, and We are collecting money to elect more people who help kitties, not those haters in office now.”

“What? Oh kitties? Well, yes. Great idea! Let’s get you some money then!” …. “So, did you say PAC? What the hell is a PAC anyway?”

 

[1] https://en.wikipedia.org/wiki/Political_action_committee

[2] https://www.brennancenter.org/our-work/analysis-opinion/beware-scam-pacs-and-pacs-scam

 

Where's the Coffee after Zombie Apocalypse?

Every now and then, I get into serious discussions like "Where will we get coffee after Zombie Apocalypse?" 

It's an important question. I live in the US and there are no native coffee plants there. 

So, naturally I’m a bit worried that the coffee will run out fast, and then things would get bad. After all, you are going to have to stay alert in a situation like that.

So I’ve done some research, and it turns out there is a Holly bush that produces caffeine, and was used by Native Americans. It’s called Yaupon. The official name is Ilex Vomitoria if you want to buy it. So you can all relax. There will be coffee after Zombie Apocalypse. Sort of.