Comment on aging regards Gene expression vs more radical changes as pertains lifespan increases.

At least at the cellular level, it seems altering gene expression makes old cells indistinguishable from young cells in the lab under a microscope.   If you go by what Bill Andrews and Michael Fossel comment, iirc.

Some of them(Fossel, iirc) seem to believe that if gene expression is changed, the body will clear the garbage out.    The inability to process garbage locally shouldn't be too concerning, as systems like the brain have the glymphatic system that routinely exports molecular garbage out(when it malfunctions you get neurodegeneration diseases, when not you get superagers with 20 year old brain function.).   It is likely, imho, in young animals the lymphatic system plays a similar role and exports molecular garbage out of tissues.   But with aging it is compromised, and along with increased garbage production, garbage starts  to accumulate.

In human society houses don't process all of their garbage, they merely export it out for disposal or recycling, wouldn't surprise if nature does similar.   Look at the brain for example, an extremely high metabolism organ, neurons have similar metabolic costs between species, yet we live 3 times as long as bonobos who share 98% of our genes.  Our common ancestor likely had similar short lifespan, but to increase the lifespan, even tripling it, even of organs like the brain, it was mostly gene expression changes that allowed it, not novel radical mechanisms.-link to source

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.

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.

Fermi Paradox Solutions

Comment: I like 4G Ascension

It is said the ultimate possible computer might be a blackhole. The issues that exist with blackholes are blackhole evaporation, and whether blackhole computation can be meaningfully used without external systems interacting with it. Even if blackhole evaporation couldn't somehow be dealt with, a suitably large enough blackhole would last a very very long time so that might not be a significant issue. Whether a blackhole can be used in a computational sense without devices externally interacting with it is agood question. But if a civilization can effectively miniaturize computation to the max and actually live as simulated entities within a blackhole, this might be the ultimate level. Perhaps turning into a blackhole and sending it in motion towards the center of the galaxy increasing its mass and converging with other blackhole class civilzations.

UPDATE: 

 “Maybe in a highly advanced civilisation, physicists could create a black hole that didn’t evaporate,” he told New Scientist. “It would be exquisitely difficult, but mathematically you can do it.”-source new scientist

Ah, interesting. let's hope it is indeed possible.  If it is possible and if it is possible to ensure a blackhole performs the useful desired computations, then you've effectively found a way for immortality, true immortality.

Was disappointed with heat death and the showing that time crystals might be unviable, but this may potentially be a way towards man's dream, the final conquest of death

UPDATE 2:
The earth might or might not be hit by mini blackholes about every 1000 years, as they're one of the hypothetical possible dark matter candidates.    The idea of containing blackholes has been suggested, perhaps using opposite charge to contain black holes carrying charge.   Don't know how feasible it is, given that if these exist they'd be relatively fast, but there may be someway to slow and capture such black holes, speculatively speaking.

It is said that a micro blackhole would take countless billions of years to assimilate the earth, so even if containment of such was compromised it wouldn't apparently be a significant hazard.    The frequency of black hole collisions is in part informed by the idea of evaporation of even smaller black holes, but even though difficult, if  it is indeed true that black holes can be made eternal, perhaps the initial conditions might have allowed for a decent number to form naturally.  

Given smaller size they should be easier to contain, if they do exist, and easier to stop if it is at all possible, assuming eternal black holes can have or be given charge.

If,  and this is wild speculation, if the rate of micro black holes hitting the earth(as a result of potentially eternal micro holes occurring) was higher, say once per decade, year, day, etc.    If that was so and they could be captured they might prove useful.

Though some say eternal black hole papers tend to have errors, and be wrong.  So all this would depend on several things being just so(decent hit rate, eternal, stoppable, etc).

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.

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

Increasing membrane unsaturation with aging and longevity

It has now been documented that there is an age-associated increase in membrane PI and lipoxidation-derived molecular damage (see Table ​Table1).1). In general, PI increases during aging in an organ-dependent way.  -http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865700/

As seen on the above quote it seems that membranes peroxidation index tends to become less favorable with the passage of time, at least in some organisms.   Given that differences in membrane peroxidation index have been associated with differences in lifespan between species and within species this suggest it may be causal.

In the following we see further evidence:

The results showed significantly lower PI and lipoxidation-derived protein damage in brain and spleen from exceptionally old animals when compared to old specimens, and in a range analogous to adult animals. Therefore, low susceptibility to lipid peroxidation and maintenance of adult-like molecular lipoxidative damage could be key factors for longevity achievement.-http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865700/

 The animals that exhibited most vigorous long term survival seemed to have lower PI similar to younger adults.   While the authors suggest it may be a key to longevity, I would say it may also be a key to indefinite longevity.   It may or may not be the case that if PI is lowered enough the existing biological maintenance and repair mechanisms may be enough to grant negligible senescence.   I would predict that organisms showing negligible senescence would show such peroxidation resistance, that is they would have a lower PI and it may even be significantly lower(depending on threshold or break even point for indefinite homeostatic balance/maintenance), and a quick wikipedia search shows just that in at least one organism

 Abstract:
Summary: The deleterious reactive carbonyls released upon oxidation of polyunsaturated fatty acids in biological membranes are believed to foster cellular aging. Comparative studies in mammals and birds have shown that the susceptibility to peroxidation of membrane lipids peroxidation index (PI) is negatively correlated with longevity. Long-living marine molluscs are increasingly studied as longevity models, and the presence of different types of lipids in the membranes of these organisms raises questions on the existence of a PI-longevity relationship. We address this question by comparing the longest living metazoan species, the mud clam Arctica islandica (maximum reported longevity = 507 year) to four other sympatric bivalve molluscs greatly differing in longevity (28, 37, 92, and 106 year). We contrasted the acyl and alkenyl chain composition of phospholipids from the mitochondrial membranes of these species. The analysis was reproduced in parallel for a mix of other cell membranes to investigate whether a different PI-longevity relationship would be found. The mitochondrial membrane PI was found to have an exponential decrease with increasing longevity among species and is significantly lower for A. islandica. The PI of other cell membranes showed a linear decrease with increasing longevity among species and was also significantly lower for A. islandica. These results clearly demonstrate that the PI also decreases with increasing longevity in marine bivalves and that it decreases faster in the mitochondrial membrane than in other membranes in general. Furthermore, the particularly low PI values for A. islandica can partly explain this species' extreme longevity.

^ Munro, D., and Blier P.U. (2012). The extreme longevity of Arctica islandica is associated with increased peroxidation resistance in mitochondrial membranes. Ageing Cell 11(5): 845-55. doi: 10.1111/j.1474-9726.2012.00847.x. Epub 2012 Jul 25.-wikipedia
 

Century breakthroughs comment

The 3 most important breakthroughs that can happen, AI, VR, Immortality are likely to take place this century. I'm confident the human survival curve can be squared by lifestyle, nutraceuticals and drugs. We will know what works and what doesn't in the coming decades but if the curve is squared that would mean most can reach 100-110 that's ignoring more radical breakthroughs.

For example it may be possible to analyze telomeres, dna, and genome wide gene expression on a large group and check on them in 5 to 10 years determining mortality over that period and increases, decreases, etc. Some centenarians can eat red meat like abaddon, others smoke dozens of cigarettes a day for decades others don't exercise often yet some remain independent dementia free surgery free cancer free. That's 100+years. Exercise gives about 5 years(and helps square survival too), but if we knew the expression pattern of such centenarians and used drugs, lifestyle or nutrients to replicate it we could very well obtain 20+ years over the average lifespan... that's happening in the coming decades, so I think adding 20~years over average lifespan is safe bet(which should buy plenty of time for radical breakthroughs in case they arrive somewhat later than expected).

UPDATE:

Regards immortality, our ability to analyze and modify genes, will allow us to perfect the naturally occurring phenomena of negligible senescence.   It will be applied to our bodies through organ and cellular transplants, cells and organs massively genetically modified, our immune systems will also be modified to be compatible with any novel protein produced by these new tissues.    This is the power of advanced synthetic biology, applied to the design and operation of human cells, tissues, and organs.  The creation of super cells, tissues and organs.   Muscles and bones for example could be designed to synthesize and utilize novel molecular structures such as carbon nanotubes in novel ways, greatly enhancing strength, and potentially speed.

As for AI, true AI, it will allow for full automation, and the ability to accelerate the rate of progress beyond anything that's ever been seen.  If digital physics is true, then eventually the perfection of the science of mind design, will allow for the summoning of  the 'true' individuals from any time period or location real or fictional, past, present, or future.   Effectively, it will be like teleportation or time travel of minds, such that minds distant in time or space can be brought near.   And if all is digital, this will be the exact truly the same individuals, a true version of them instantiated.   

VR, or advanced VR-AR(virtual reality - augmented reality), will occur with the advent of advanced brain computer interfaces.  This will allow for any sensation to be experienced at any time, and the perfect recall of any experience or sensation, including those which could be shared by others from their personal lives(say how a traumatic experience felt, vividly and perhaps indistinguishably from one having lived it, so as to relate more).    This will allow for collective shared mass multisensory 'hallucination', in essence the brain will become partially divorced from the physical world and will become subject to the mental world manifesting in ways indistinguishable from physical reality.   Man's art, dreams, will permeate experience, and it will be collectively shared.