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.

Swiss Water® Process, link to article about decaff benefits, and comment

What follows is a quote from an article on decaff benefits. ,more info at link

"It's the end of the day and you've neglected to consume the recommended amount of coffee to prevent Parkinson's and Alzheimer's disease, prostate cancer or Type II diabetes.  Maybe it's time to settle down with a cup of decaffeinated coffee.  However, does decaffeinated coffee offer the same health benefits as caffeinated coffee?  The answer is a qualified yes.  Fortunately, with or without the caffeine, coffee is rich in biologically active substances that contribute to its aroma, taste and color. Some of these have been investigated to determine which components of the drink are responsible for its well-documented health benefits."-psychologytoday source

Given that coffee was associated with longer telomeres, despite caffeine being associated with telomere shortening, that suggests that either some activity, diet, or action correlated with coffee consumption improved telomeres or something in coffee can not only counter the negative effects of caffeine on telomeres but actually move things in the opposite direction resulting in longer telomeres.

Caffeine itself has benefits, and thus some moderate amount of caffeinated coffee sounds reasonable.   But additional coffee if it can be as good as 99.9% caffeine free and maintain beneficial substances might be of complementary use.    It seems coffee in excess can adversely affect cholesterol, so one'd have to monitor cholesterol levels and see what level of coffee consumption is compatible with one's diet and physiology.    But combined with other substances that have been hinted to possibly mildly enhance telomerase activity, it might prove synergistic.

Comment on fightaging telomerase article

"Contrast that with the SENS hypothesis that aging is molecular and cellular damage that the body cannot repair at any reasonable cost."

If that were the case, we should see SENS like approaches being implemented by nature in negligible Senescence species. If all they've is mostly the same genes and differing expression patterns, then existing mechanisms are sufficient if ramped up. We have over 98% genetic similarity with our closest relative yet over twice the lifespan.

What approach doubled species lifespan?

If we were bonobos with 40year lifespans and we asked SENS proponents. They'd say most of the [easy] longevity changes were already implemented by nature in achieving this lifespan and they'd propose the SENS solutions as a way to lengthen lifespan.

If like me you believed existing mechanisms are mostly sufficient for vast lifespan increase, then you'd suggest mostly gene expression changes with high conservation of the genome. What did nature do? AFAIK, it simply mostly tweaked gene expression and presto triple lifespan.

If you ask me, it is likely that similar tweaks could very likely carry us all the way up to negligible senescence.

 Let's see what we find from the genetic sequences of negligible senescence organisms.

"Indeed; it's not like there aren't plenty of species whose telomeres don't shorten with age, in fact there's a species of bird whose telomeres get -longer- with increasing age, and it ages quite normally."

I've not looked into it deeply, but according to Dr. Bill Andrews, it is only a few species who have significant aging contribution from short telomeres.

"The same thing should happen if you were to repair all the cellular and molecular damage of aging that suppresses stem cell activity."

And it also as mentioned seems to slightly begin to occur with lifestyle changes that increase telomeres.-Darian S in Fightaging

"Curing Aging through Telomere Biology."

"Curing Aging through Telomere Biology." From the Independent Pharmacy Business Growth Conference, February 23, 2012 in Orlando, FL.

Telomerase comments

 Many species of protozoans do not express telomerase during mitosis (but only during conjugation), so their telomeres shorten with each reproduction, leading to a limit of a few hundred reproductions per cell line.  This mechanism is the precursor to telomeric aging that exists to the present day in humans and many other higher animals. ...

Therefore, any cell lineage that does not conjugate will die out after a few hundred generations. This prevents cell colonies from becoming too homogeneous. -link

Snippet from a post josh mitteldorf's blog. The article delves on the promising science of telomerase and its underfunding. I agree that telomerase research should be better funded and sounds quite promising.  I too agree that the need for genetic diversity may be a reason for the existence of an aging process.

Genes that promote variability or diversity in a population will be more likely to be successful than those that don't.  In the absence of aging, populations are subject to the older organisms competing with the younger less mature ones for limited resources and the fittest organisms would be the least likeliest to die in a population barring aging.

EDIT

Reply from topic

 "Josh, yes telomeres are an ancient clock, the even occur in paramecial macronuclear DNA – but there -they don’t shorten. So that’s paramecia, they’re weird in any case – but the same is true of mice – their telomeres don’t shorten with aging – and in case the readership doesn’t know, mice last two to three years (I’ve heard of four)."-Harold Katcher

Mice have other reasons for being short lived.  In fact some say they die mostly from cancer so their long telomeres and telomerase may be a mechanism to cause them to die on time . 

"Anyway the important thing is to get to the cause of aging – attack each arm of the octopus or hydra; amyloid accumulation, DNA damage accumulation, lipofuscin accumulation, ROS production, mitochondrial dysfunction etc."-Harold Katcher

We would have to look at what exactly is being implemented in negligible senescence organisms to see if all of those need to be addressed.  

We know that even smoking 60 cigarettes a day which should surely increase all forms of damage, doesn't impede a human from reaching 100 in good health.

We also know that mechanisms must already exist or be present that allow one of the most metabolically active cells in mammals to live extraordinary long lives far in excess of pretty much any other cells.  Neurons live over a century in humans, in other mammals transplant of neurons showed they could live twice as long as original host without genetic modification, it may be the case that human neurons too could live twice as long for all we know.   What changes needed implementation to go from 2-3 years to 120+ years in neurons within mammals?
  That would be interesting to know.

One might say lots of changes or things had to be addressed, but the cells from shorter lived rodents were transplanted unmodified and exceeded twice the lifespan of the original host organism.   IF there truly was a serious change needed, at least in these cells, one wouldn't expect them to live twice as long as the host(and it is believed they could've lived even longer).without necessary modification.