A Damage-Based View of Aging, Offering the Hope of Rejuvenation through Repair

This paper, published earlier in the year, is a reaffirmation of the consensus position that aging is caused by the accumulation of cell and tissue damage, made at a time in which programmed aging theories are becoming more popular. Initiatives such as those of Turn.bio and other groups, in which cells are at least partially reprogrammed towards a pluripotent state in living animals, have spurred greater interest in the characteristic epigenetic changes that take place with aging. That reversing those epigenetic changes produces rejuvenation by many measures is interesting and promising, but it isn't clear that it can be taken as evidence that epigenetic programs of change are at the root of aging. We might look instead at the evidence for detrimental epigenetic change in cells throughout the body to be an unfortunate consequence of the processes of DNA double strand break repair, for example. If confirmed, that puts age-related epigenetic change firmly in the category of damage, not a program that exists independently of damage as a root cause of aging.

Aging is an irreversible process, and most organisms can never escape the diversity and accumulation of damage that their own functions generate. To reduce damage, species with a simple organization may opt to discard some damage with a part of the cytoplasm, but this mechanism needs to be investigated in more complex species. Interventions such as parabiosis may partially restore aged organ functions through transfusion of young blood to an old organism. This may be considered as a damage dilution process, where the old blood is diluted by the less damaged young blood. It was shown that, following hematopoietic stem cell transfer, the blood of the recipient follows the epigenomic age of the donor, suggesting a possibility to consistently generate younger blood than the actual age of the organism, if the source of hematopoietic stem cells is a young donor. It is important to emphasize that the transition to a younger age, based on one or more tissues being younger than the rest and younger than the chronological age, does not necessarily mean a longer lifespan for the subject, particularly if the lifespan is limited by a particular dysfunction or disorder that causes death.

Although somatic aging appears at first sight irreversible, we cannot bypass the fact that it is successfully reset to zero from generation to generation, suggesting that, during germline development, embryonic development, or some other phases of life there is a process that rewinds the aging clock. Somatic cell nuclear transfer shows that this rewinding process can be also induced in differentiated cell nuclei. These mechanisms of dilution or repair of damage are currently unclear, although evidence suggests that they may involve a combination of cell division, cell selection, epigenetic remodeling, and global activation of genes, especially those genes for controlling DNA damage. These mechanisms allow cells to dilute even the scarcest molecular species such as functionally abnormal RNA, proteins, harmful metabolites, and those that would not be sensed by a cell. Thus, a combination of cell growth, selection, and proliferation dilutes mild damage, in addition to the removal of damage through specialized detoxification, repair, excretion, preemption, and other approaches. These mechanisms together allow the cells to keep the damage in control.

It should be noted that division and dilution are not necessarily related in the context of proliferation of differentiated somatic cells, as, unlike germ cells or stem cells, these cells may undergo senescence or tumor transformation when proliferating in culture. This suggests that there is a particular relationship between cell division and damage dilution, whose mechanism is not yet understood. We think that this relationship is reflected, for instance, in the differences between early embryonic and aged cells, partially due to their different differentiation states. The former may stay in quiescent stage to avoid further damage or proliferate to select the cells with less damage. Compared to adult cells, embryonic cells specifically experience two waves of global demethylation and re-methylation, establishing the same DNA methylation pattern for every generation. These differences suggest a possibility that certain embryonic cells and somatic cells have different modes and rate of damage accumulation and dilution through proliferation. From the damage perspective, the proliferation of cells with more specialized functions bears higher damage, as more specialized molecules are produced, allowing more side-products to be generated. Furthermore, adult stem cells may overcome the proliferation limit when exposed to a mixed pro-stemness signal. This shows that the combined effect of niche pathways that promote the stemness of the adult stem cells may act similarly to reprogramming. Thus, the difference in the damage accumulation between somatic cells and stem cells may lie, at least in part, in the cell matrix environment in which cells reside. Moreover, the environment may undergo a transition to sacrifice stemness for specific biological functions.

To visualize this stage-shifting concept, we advance a weight-scale metaphor, which we call a "stemness-function" model. We designate the two states as "pro-stemness" and "pro-function" based on the balance between damage production and its removal by proliferation and apoptosis. During early life, organisms remain in a "pro-stemness" state, encouraging cells to proliferate and grow so that the damage is unchecked and does not cause cell cycle arrest. In that state, although stem cells exhibit a limited intrinsic immune function, the function to recognize "self" and "nonself" is not yet fully developed, allowing a lower level of inflammation and an increased potential for regeneration. In contrast, in somatic cells, the damage generation can be sensed easier, triggering the reactions such as the DNA damage repair process, growth arrest, apoptosis, and immune responses. Therefore, organisms must undergo a transition from the "pro-stemness" to "pro-function" states, wherein differentiation and specification of cells are supported. Following this transition, the cells enhance their function in reproduction, damage sensing and apoptosis pathway, complete the immune function, and increase fitness by generating specific biological products related to their functions, while adult stem cells at this stage undergo gradual exhaustion. At this stage, damage accumulation is spontaneous while damage dilution via proliferation is not supported in most cell types. During the process of fertilization or before/after it, this damage gets thoroughly checked, cleared and diluted by the transition to the "pro-stemness" state.

What perturbations might then be expected to delay or reverse aging? If a mild "pro-function" feature is induced in the cells with the "pro-stemness" state, it may extend lifespan as we learn from mild overexpression of certain tumor suppressors. Similarly, the weakened immune system upon rapamycin treatment provides an example that the opposite may also work. On the other hand, if a specific function (supported by a certain gene) that shifts the system toward the "pro-function" state is introduced, it may lead to death or premature aging, caused by a sudden increase in function and damage. This might be the case when tumor-suppressor Tp53 is overexpressed in mice, and the animals show a significantly shorter lifespan. It should be noted, however, that similar cases of Tp53 overexpression in mouse models show an indistinguishable lifespan. Nevertheless, considering that cancer-related deaths are more common in lab mice than in humans and that these risks are limited in these cancer-resistant mouse models, there is still a possibility that the overexpression accelerates aging. Conversely, if a "pro-stemness" signal introduced to cells in the "pro-function" state, it may also cause deleterious effects, resulting in cell death or aberrant immortality. For instance, forcing cell proliferation by expressing oncogenes in fibroblasts promotes tumor transformation.

Link: https://doi.org/10.1002/ggn2.10025

Comments

I have focused lately on viruses and retroelements being the main source of aging. As you have noted here many times, cytomegalovirus infects about 100% of centenarians. And that is just one virus. IMO the successful reprogramming that has been done by the Conboy's and Katcher is great but I think will not give a durable age resetting because the viral (and microbial) burden is still present. When George Church perfects their viral editing that they are able to do without strand breaks we will know how much viruses affect aging.

I have been trying various pharmaceuticals and dietary interventions targeting viruses and will retest my DNAm age in the future to see if there is an improvement.

"HCMV can inflict site-specific chromosomal damage in a form of DSBs. Disruption of DSB repair system often leads to more intensive viral infection"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4429022/

"Human cytomegalovirus inhibits a DNA damage response by mislocalizing checkpoint proteins"
https://www.pnas.org/content/103/8/2821

Posted by: Lee at September 10th, 2020 6:26 AM

This is such a tired, circular topic that is in many ways is useless to the ultimate goal

The truth is it's going to be much easier and more practical to actually find interventions that reverse aging and THEN figure out why they work

The pharma industry has created trillions of $$ of wealth over the past century doing exactly this and even in 2020 we understand a very small % of mechanisms-of-action and WHY any of those products work as they do.

Forget all these papers arguing the cause of aging

If you can't address it, they are worthless - see recent Samumed, Unity and ResTORbio clinical failures, as well as the billions of $$ gone with b-amyloid drugs - all supported by great MOA data but worthless in the clinic

Focus all energy on seeing what works in humans

Figure out why later

Posted by: devon mcradle at September 10th, 2020 8:46 AM

Hi guys,

Off topic, but maybe someone will chime in. For the layperson reader, how are things looking these days, generally speaking? Are the more scientifically literate readers of Fight Aging optimistic about near terms success?

I keep hearing Sinclair and DeGrey make ever more optimistic sounding predictions. If DeGrey is right that the cultural tipping point for all this is just three to five years away that's very significant. If he's also right that LEV could be seventeen years away, then presumably smaller but nonetheless profound victories are significantly closer?

Do people here generally share this optimism?

Posted by: Ben at September 10th, 2020 8:25 PM

@Ben

Scientifically optimistic

Translationaly - Very pessimistic - see recent Samumed, Unity and ResTORbio clinical failures, as well as the billions of $$ gone the last couple years from b-amyloid drugs -

Also see Brain Kennedy's recent views on this - https://www.longevity.technology/longevity-trials-time-to-change-the-approach/

At ARDD (http://agingpharma.org/program) Jim Mellon summed it up as (paraphrasing) - "If we don't start seeing clinical successes, the money will dry up fast"

Posted by: devon mcradle at September 11th, 2020 3:47 AM

@Ben
Real Anti-Aging, Rejuvenation, Younging.... all just around the corner...
Demethylating H3K27me2/3 with JMJD3 and waiting for a couple of years for the effects to kick in, done.
There're just a few tiny details to figure out. ;)

https://www.anti-agingfirewalls.com/2020/08/15/younging1-the-emerging-aging-reversal-strategy/
https://www.anti-agingfirewalls.com/2020/09/02/introduction-to-the-younging-series-emerging-aging-reversal-strategies-and-treatments/

Posted by: Jones at September 11th, 2020 5:01 AM

"If we don't start seeing clinical successes"
The huge problem with all this is measuring success in terms of life expectancy.
Reversing fribrosis in one organ or lessening inflammation in another won't register if people keep dying on schedule, which they will if the approach is piecemeal.
Either way, the only way to prove life expectancy gains in the near future, barring a major breakthrough with epigenetic clocks, is by running combination therapy trials on thousands of 90 year olds.
I can't see this happening, if for no other reason that when you use multiple agents without having investigated the effect of each one first you don't know which is doing what. Not good for profits.
And of course no regulatory agency will ever approve such an approach.
The only way to see results within a couple of decades is probably pay-to-play trials, even though with a million dollar price tag for one treatment (see Libella) you'll never get the numbers required for meaningful data.
Bottom line is, young people and middle aged people programmed to become centenarians may have reached LEV already (LEV is not a blanket population concept), but aging will "end" only for a few of us, depending on our current life expectancy, choices we'll make in the future, and sheer luck. Someone gambling on new treatments overseas may end up living 50 years longer (and thus perhaps indefinitely thereafter) than someone of the same chronological age who only maintains a healthy lifestyle, but this will only be evident decades after the money for bringing those cutting edge treatments to the wider market is required.
Catch 22.
LEV is like menopause in that it can only be "diagnosed" retrospectively. Only, the wait time in this case is not 12 months but decades.
It would be different if we were mice but we live too long. The irony.

Posted by: Barbara T. at September 11th, 2020 5:06 AM

@Ben
Telomerase extension (TAM818 and/or brahmic acid) and senolytics (fisetin+dasatinib) combined, and we crossed LEV in 2019.

Posted by: SilverSeeker at September 11th, 2020 5:38 AM

@Ben

I lately swing between optimism and pessimism. The biggest change is in the startup camp, where a lot of new companies focused on antiaging, including SENS-style antiaging, are emerging. OTOH, big pharma is still behaving as always, pursuing poor approaches (the few projects focused in some aspect of aging are slow and unambitious); and academia's antiaging research is moving faster than before but not at an impressive speed (still most of it is calorie restriction and the like).

The most depressing part is certainly big pharma. The slow response to the pandemics (including, but not limited to, the total disinterest in DRACO) is another sign that they are slow, inefficient dinosaurs. We need an Elon Musk in the biotech arena (and Jim Mellon isn't it).

Posted by: Antonio at September 11th, 2020 6:41 AM

@All
the scientific progress is real but we are not near LEV, not anytime soon. Look for example in gene therapies, which had scientific success 20 years ago but failed clinically. E-ink technology was expected to replace all paper labels by 2010 and be too cheap to care about. Organ printing in late 90s-early 2000s was just around the corner. Electric cars were tried in 70s and failed for financial reasons. All those examples had good proof-of-concept prototypes or basic science backing. With anti-aging we are barely at the phase that the basic science starts to show promising results. It seems we have a few low-hanging fruits like good old calorie restriction (nothing new, really), Senolytics, rapamycine, NAD+ supplements and such. Even those have immense costs to do proper clinical trials to get the right protocols. So I would tone down my expectations. Eventually the humanity will be there but we are not near LEV. In 50 years for sure, 40 quite likely , 30 quite possible, 20 possible, 10 unlikely, 5y - only in the case of a lucky discovery happening right now coupled with a "space race" and a sputnik moment.

Posted by: cuberat at September 11th, 2020 7:40 AM

"the scientific progress is real but we are not near LEV"
There won't be any LEV for humanity as a whole, at least not for centuries.
It doesn't make sense to say "we." The prospects for a 20 year old are not the same as those for a 50 year old or an 80 year old.
Someone may or may not have reached negligible senescence already, but we won't know it for many decades to come. Think of a 15 year old. If he lives to be 80 and by then aging is under control - an outcome that will happen progressively - he could be considered to have reached LEV today, even if nobody knows it yet. That's the reasoning behind people like Kurzweil claiming to have reached their own personal LEV.
The only way to find out within a couple of decades where we stand is by running trials on very many very old people. If their mortality rate starts decreasing (as opposed to remaining the same given that the death rate of an 80 year old on a wash-rinse-repeat cycle kills people quickly), then you would have an indication that death from aging is no longer a foregone conclusion. But such an experiment would require political and economic conditions that don't exist.
The problem is that people here and everywhere on anti-aging fora want a guarantee that they will "make it to LEV", meaning that they will never die form old age, but nothing short of an amazing epigenetic clock or a large scale experiment like the one I mentioned will ever be able to give them the peace of mind they seek.
As things stand, we will know what we want to know now only long after it has happened.
For the moment, the way we soothe ourselves when faced with uncertainty is not dissimilar from how a Catholic who frets about dying seeks reassurance from a priest about the existence of an afterlife.
I really, truly think that this idea of "LEV" has taken on a life of its own, one not intended by its designers and one that creates a lot of misunderstandings and frustration.
It was a good model to introduce the impact of progressive gains and exponential growth when it was floated almost two decades ago, but we need to move on from that because models are not real life.

Posted by: Barbara T. at September 11th, 2020 8:33 AM

@Barbara said:

"Someone may or may not have reached negligible senescence already, but we won't know it for many decades to come. Think of a 15 year old. If he lives to be 80 and by then aging is under control - an outcome that will happen progressively - he could be considered to have reached LEV today"

Nope. Firstly, LEV is based on life expectancy, which is based on mortality rates, so it's a population variable, not an individual variable. But more importantly, LEV is when life expectancy grows by one year in one year. So, if today there is no technology that has "aging under control", then there is no LEV today, no matter how young you are.

"The problem is that people here and everywhere on anti-aging fora want a guarantee that they will "make it to LEV", meaning that they will never die form old age, but nothing short of an amazing epigenetic clock or a large scale experiment like the one I mentioned will ever be able to give them the peace of mind they seek."

Well, if, say, senolytics and glucosepane breakers become commonplace in 2030, and we see life expectancy national statistics to skyrocket in 2031 and 2032, then we in 2033 can have a pretty good idea about whether we are at LEV or near it.

Luckily, all SENS therapy categories have applications for named diseases apart from "aging", so they could reach the market independently of what the general public thinks about aging or whether they wish life extension.

Posted by: Antonio at September 11th, 2020 9:34 AM

Disagree with your understanding of LEV since it is not how most people in the field interpret it (I may be wrong but I think it was David Gobel who explained it on this very forum a couple of years ago), but to avoid sterile polemics I am just going to say that if you are waiting to see even a semblance of population based LEV with LEV being as you interpret it, I hope you live well into the 22nd century.

"if today there is no technology that has "aging under control", then there is no LEV today, no matter how young you are."

Well, actually as per the current definition of LEV we have reached it already.

CASE 1:
Botswana got its LEV many times over when they rolled out anti-retrovirals in the early 2000s and life expectancy shot up by almost two decades in 5 years.
Did they beat aging? Of course not.

EXAMPLE 2:
If LEV means gaining more than one year of life every year that goes by; AND life expectancy can be measured by epigenetic clocks; AND you are looking at reducing mortality in relatively old people (as opposed to young Botswanans) THEN The Thymus Regeneration, Immunorestoration and Insulin Mitigation (TRIIM) trial has already given a bunch of people their LEV...

... for a few months.

LEV is not absolute and stable in time, so you will never be in the clear.
You will reach LEV and then lose it again, unless you find a magic pill that turns you into a teenager at once. And even then, you don't know how long it will last. For a few of years you may age, then de-age for a couple more, then fall behind and die of something that still hasn't got a perfect cure rate.

"if, say, senolytics and glucosepane breakers become commonplace in 2030, and we see life expectancy national statistics to skyrocket in 2031 and 2032, then we in 2033 can have a pretty good idea about whether we are at LEV or near it."

Apart from the fact that it is unreasonable to expect senolytics and glucosepane breakers to lengthen the life of any one person to a significant level (even assuming that by decreasing inflammation these therapies will somewhat lower the incidence of cancer and Alzheimer's), expecting to see an impact at population level in 10 years time is cray cray.
Immunotherapy has been proven in the clinic for as long (whereas glucosepane breakers aren't even in mice yet) and we are barely seeing a tiny dent in cancer survival.

Anti-aging therapies are not like antibiotics where with a pin prick you are suddenly saving millions of young people from dying, and by doing so you give them potential decades of extra life. That's what pushes life expectancy up. It's easy because you remove one killer disease from a cohort that will likely not get another killer disease for many more years.
The situation is VERY different when you are trying to extend the lives of old people.
You are not going to reduce the mortality of the majority of the 80+ year olds in any one country four-folds (you would need to delay many killer diseases at once by at least 15 years to convince people that we are on the right track) with those two therapies. Or even with four.
Wishful thinking, sorry.

Even if by 2030 safe treatments to reduce age-specific mortality to a decent degree existed - for example a combination of strong immunotherapy + effective senolytics + glucosepane breakers + OSKM factors + some targeted gene therapy for specific issues - you'll have to take a massive leap of faith, travel to multiple low regulation countries, and fork out hundreds of thousands to get a suit of therapies that may or may not give you a couple of decades of extra life.

You think a whole "population" will be able to do this?

I share in the hope, but any prediction of when "we will reverse aging" (itself an ill-defined aim), including estimates by de Grey et al. is just guessing. Pure and simple.
The world doesn't work like the lab. Even the lab doesn't always work like the lab technician wants it to.

To recap, the idea of LEV as some holy grail that will deliver humanity from death is grossly flawed.
It's a model that served its purpose 20 years ago during the first stages of anti-aging advocacy and nothing more.
It is not to be taken literally.
Time to move on to new constructs.

Posted by: Barbara T. at September 11th, 2020 11:31 AM

It looks like I am being censored for some reason.

Let's see if a shorter version works:

"LEV is when life expectancy grows by one year in one year. "

According to this definition, many African countries reached LEV when they rolled out anti-retrovirals in the early 2000s.

If you want to look at older people only, The Thymus Regeneration, Immunorestoration and Insulin Mitigation (TRIIM) trial has already given a bunch of 51-65 year olds their LEV.... for two years or so.

Bottom line: LEV is ill-defined, and as it stands pretty misleading.

Posted by: Barbara T. at September 11th, 2020 11:43 AM

"According to this definition, many African countries reached LEV when they rolled out anti-retrovirals in the early 2000s."

Which countries?

"If you want to look at older people only, The Thymus Regeneration, Immunorestoration and Insulin Mitigation (TRIIM) trial has already given a bunch of 51-65 year olds their LEV.... for two years or so."

Where is the life expectancy data?

"Bottom line: LEV is ill-defined, and as it stands pretty misleading."

It's perfectly well defined.

Posted by: Antonio at September 11th, 2020 12:25 PM

"Which countries?"

1. Botswana amongst many others. Life expectancy shot up by 20 years within half a decade once HIV was under control. That's your definition of LEV.

"Where is the life expectancy data?"

2. You are making my point. Unless you want to wait 50 years or run trials in nonagenarians as per my suggestion, you need to use a proxy like an epigenetic clock.
Or, as I said earlier, don't expect to see data for decades.

On this point: given the snail pace of running trials and gaining regulatory approval for mass marketing, you won't have most 80+ people in any population taking senolytics and glucosepane breakers by 2030. And even if they did, they wouldn't live much longer because one of the many diseases little impacted by these two treatments (one of which hasn't even be proven to work in mice) would kill them soon enough to leave the public unimpressed with the magnitude of the gains.
It's the very people you quote who say that gains in the very old will be very small, and if you want to see meaningful life expectancy data as given by mortality rates as early as 2030, it is only the very old that can provide that.

"It's perfectly well defined."

3. No it isn't. See point 1.

It would be better if it said: "LEV occurs when for every year that goes by, life expectancy increases by one year in the 80+ cohort."
But as it happens, this is not its current definition.

Also, the current definition of LEV implies that once you've reached it you will be young in perpetuity. It is not so, because you can reach LEV today and lose it tomorrow, depending on what happens with both science and society.

The idea of LEV as some holy grail that will deliver humanity from death is grossly flawed.
It's a model that served its purpose 20 years ago during the first stages of anti-aging advocacy but
it is not to be taken literally.

Time to think of new constructs.
It would be nice if we could use fightaging as platform for throwing out new ideas and moving forward rather than trying to fit a square peg into a round hole.

Posted by: Barbara T. at September 11th, 2020 1:18 PM

1. Yes, Botswana reached LEV. So what's the problem? For our countries (yours, mine, other readers's), with the life tables we had for the last 100 years or so, LEV implies a good control of aging.

"2. You are making my point. Unless you want to wait 50 years or run trials in nonagenarians as per my suggestion, you need to use a proxy like an epigenetic clock.
Or, as I said earlier, don't expect to see data for decades."

Huh? What of what I said implies that? I'm starting to think you don't know the definition of life expectancy. It's not lifespan.

"you won't have most 80+ people in any population taking senolytics and glucosepane breakers by 2030"

That's not my point. You said "nothing short of an amazing epigenetic clock or a large scale experiment like the one I mentioned will ever be able to give them the peace of mind they seek". I showed another way to know we reached LEV in a short time. I didn't mean that those 2 therapies will be widely used for sure by 2030. It was only a number for the sake of example

'It would be better if it said: "LEV occurs when for every year that goes by, life expectancy increases by one year in the 80+ cohort."'

Nope. Life expectancy is not defined that way. I think you are misunderstanding the definition for lifespan. Life expectancy is not a longitudinal variable defined for cohorts, its a cross sectional variable defined for populations for a short period of time (usually a year).

https://learning.closer.ac.uk/introduction/types-of-longitudinal-research/longitudinal-versus-cross-sectional-studies/

Posted by: Antonio at September 11th, 2020 2:11 PM

"Also, the current definition of LEV implies that once you've reached it you will be young in perpetuity."

No, it doesn't imply that at all. It's LEV reached through SENS which implies that. It's explained in the first paper about LEV by Aubrey and many other papers about SENS. It's based on the ideas that: (1) aging is caused by damage accumulation and (2) there is only a limited number of types of therapies that are needed for eliminating those damages (7 for our currently known damages and probably not much more in the future).

Posted by: Antonio at September 11th, 2020 2:24 PM

HI all, LEV is longevity escape velocity as in maximum species lifespan, not life expectancy escape velocity. It's based on the current hard limit of 120ish years. In mice we are already in the neighborhood of 35% maximum life span extension with current interventions that can be had in humans (rapamycin, metformin etc.) and with senolytics and RNA reprogramming we should get another "jump". LEV will first be choppy, then smooth, then obvious, then boring.

Posted by: David Gobel at September 11th, 2020 2:45 PM

Hi, David Gobel. So your definition is different from Aubrey's, which clearly defines it in terms of life expectancy:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC423155/

(The paragraph that begins with "The second oversight made both by the contributors".)

Posted by: Antonio at September 11th, 2020 3:05 PM

Thanks for the clarification. This makes much more sense than "LEV is when life expectancy grows by one year in one year" or any definition along those lines. Life expectancy escape velocity has been already reached and lost many times in many different parts of the world.

Posted by: Barbara T. at September 11th, 2020 3:05 PM

About this article:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC423155/

I remember reading a longer and more detailed paper on the subject, co-authored by de Grey with someone else. I haven't been able to find it: anyone remember the title or name of the second author?

Posted by: Barbara T. at September 11th, 2020 3:10 PM

@Barbara: Is it the second one I linked above?

Posted by: Antonio at September 11th, 2020 3:12 PM

@Barbara: By the "second one" I meant the long one. I posted a couple of papers above in one comment.

Posted by: Antonio at September 11th, 2020 3:19 PM

Yes, there should be a longer one with lots of charts and I seem to remember also a co-author. I think I linked it on this forum years ago, so I will try and do a quick search.

EDIT: I couldn't find it, so I either dreamed it or downloaded it onto my old laptop instead of posting it.

EDIT: ah yes, it was the one he wrote with Chris Phoenix.

Posted by: Barbara T. at September 11th, 2020 3:23 PM

Wow. My question has certainly led to some debate.

Some encouraging and not so encouraging responses, and a range of different issues and potential complications have been discussed. I'm not sure I'm any closer to being able to reliably predict the future on this topic, but I thank you all for your thoughtful replies.

Posted by: Ben at September 11th, 2020 6:53 PM

@devon

I'm wondering what Samumed trial was a failure? I see 8 active trials, 2 of which are Phase III...?

@all
How encouraged are people feeling about "right to try", when it comes to allowing older persons to directly experiment with valid potential medicines? Could that not be very valuable information, no matter the outcome, if people are encouraged to give these a shot?

thanks!
Eugene

Posted by: Eugene at September 12th, 2020 10:45 AM

Hey there! Just a 2 cents. TL DR: I hope LEV happens quicker/than later. optimistic but not lulling myself.

In my view, the senolytics and rapamycin/metformin, are overrated, they are bettehr than nothing though. If mice get 35% increase in maximum lifespan with them, I don't see that as translatable 1:1; I would divide that number a bit (since we ahve seen so many times 'potent' mice stuff do jacksh in humans or barely much), simply because humans are already ultra-optimized for hyperlongevity; unlike a mouse/short-live animals who get big gains. It's even more apparent with C.elegans getting 800% lifespan extension, same with flies...all of them barely live a few months or years. Calorie restriction is the strongest one right now (of course, combining it with these can boost a little bit; not all that much; because CR is redudant pathways with metformin/methioneine restriction/IGF/DAF/SIR pathways that rely on HK histones/chromosome activation of NRF2/redox maintenance and insulin signaling. I would wager (just a guess) that CR in human would give 5 years or so extra; possibly 10-15 in certain humans who really benefit from it. Doubtful above 20 years much. Metformin though does improve insuling signaling (my fathr takes it for his T2D...it does not help only 'maintain' somewhat normal levels), the diabetes still continues its course and the glucose ends up rising anyway over the years (with metforming). Same for HBaC (glycated hemoglobin). plus, there have been studies on mice with metformin where they saw neuron death/problems by it. So metformin is not a cure-all. It is certain that like CR, metformin ends up affecting insulin signaling (lkie rapamycin too) and thus affect IGF/IGF-R/DAF...thus it helps for longevity since CR works on calories/blood glucose levels (which rise with age). And we know that maintain blood glucose levels over decades is crucial for longevity.
Centenarians don't have diabetes or if they did, it was short bout and they maintain normal/low post-prandial/fasting/blood glucose.

RNA reprogramming, splicing reprogramming, transcirption and epigenetic reprogramming are the ones that could break the 120-hard like limit. It may end up that reprogramming is really our only saving graces; because damage repair is just too hard/playing catch up (but if we comvbine all these therapies we would start to see some serious gains), but as others said, all this will a privilege for the rich for a long time price won't go down for a while; so to say LEV is for the next 17 years is very exaggerated/overoptimiztic simply because of how ridiculuolsly long everything takes to happen (due to lacking funds and bodies (FDA, health canada) and so forth, so it'S like; it's an illusion lots of stuff hapenning but what is 'becomeing tangible' as a therapy 'Available' 'made and done'...for that, it Always takes decades. Not 2 3 years. thus, illusion/mirage 'almost almost almost....close/in reach'. Almost, is not good enough. It's like trying to hold flowing water current in your hands; it's night impossible. It always slips by/eludes you.

We need a naked mole rat - in a mouse; they day a mouse live as long as nake mole rat I will be condvincend. Also, if we don't see reversal all of lipofuscin (in lysosomes) or telomeres reconstrunction/lengngthening 'enough' it will be 'catch up/playing catch up'...we must 'resest' the body to a yougn state and only then is LEV even a thought. The 'we deage 2 years and then we age 1 year..so we gain 1 year each 1 year...' is something is strive but we don't know how much it is feasible; I mean if we see in the epigenetic clock and teloemres, I guess then we could say indeed we reached LEV; but until then don't hold your breath. It's why medical scientist just talk of breawking the 120 and even just getting over that is nearly impossible. The 'repair damages' and do it perpetually so you should 'reverse 2 year of aging' each year you age so you youthen 1 year each year (LEV)...is still nebulous.

On paper it should happen, in real, that'S hard to say. Hopefully it is possible; what is certain the earlier we get it the faster we can start (I think these therapies 'all combined' will take 20 years at least to be available to mass and that is very optimistic; less so is more like 30-35 years (hopefully not). I remember 20 years ago we talked about anti-aging, what says in another 15-20 we are basically same point... (we discovered plenty...but what has 'become'/tangible.. (as in available to the mass public) thing still same) things could happen that way; very possible/likely. Until more funds are put towards rejufenation it is to temper your hopes; the well may dry up (financially) and like COVID did not help, it threw a 'wrench' in the fig. cogwheels. FDA should be as fast as they are with COVID - but with antiaging/rejuvenation...they are not. It's the ultimate error; to be safe/certain a therapy works is understandable but it makes 'low yield' efforts
(CR/metformin...), thankfully AdG and Mrs. Parrish understood that only them will change thginfs; outside of a few endeavors, not many people decided to tackle aging the way they do (like, we building therapies and making them avail). Having to go through body gauntlet (FDA) is why slow to a crawl (except when in COVID pandemy). Rich people only can look forward to LEV (For the next 20 years if more). the rest of poor people in thrird world countries will be able to reach LEV due to cost or until it becomes avail to all; like COVID 'vaccin' 'sent to all' by 8000 cargo Boeing 737 airplanes 'spreading the vaccine' in one huge 'operation' of 'delivering it to ALLL'' arodn the world affected by COVID;
All affected by COVID... ''but COVID is more important/people dying''...yes...but aging is still ALSO important and people dy by the thousands of aging..it's just saying :''well we will pull miracles because (understansably) a virus threathens the immediacy of survival of people''; true, but the immediacy of aging is quite important too (aging is bottom of the list).

All affected by aging..only COVID gets treatment. Find error. If we had the same fervor that this pandemia did - but for rejuvenation, things would progress real faster. In fact, because of COVID, people in medical science should wake up and force those bodies/FDA to become faster. FDA regulatory bodies should Always be in 'covid' 'speedy' mode, or if not, dismantled for a new body.
As for people that would say: ''but there is danger/clinical safety...ewe have to be careful''; absolutely, but 'when push comes to shove'...it,S why people like Mrs. Parrish endu p in Colombia doing telomerase on herself - f...that/she SKipped the whole body (wow); that,S what we need. 'but too dangerous - must go thruogh FAD'...no. Life too short, must take some minimal risks or else nothing happening. Big Pharman want ts to make cash from your dying body, and FHDA is just one more wall/hindrance to making LEV; to wish to protect citizens by 'making sure/clinical trials...on and on'...is understandable for safety; but if it's too slow ? Something needs to give,

Just a 2 cents. (sorry for length)

Posted by: CANanonymity at September 12th, 2020 3:04 PM

Even if the low hanging fruits don't extend the life expectancy by much they for sure will improve the healthspan. That will would be huge. If we have squire cruces of age morbidity it would be still a big improvement ovwr what we currently have.

For example, I am in my mid 40s ; for me the healthspan matters much more than reaching an age over 125. Of course, if 90s become new 60s I would prefer not to just drop dead if I am otherwise healthy

Posted by: Cuberat at September 12th, 2020 11:01 PM

I've not posted a comment here for a while, but this seems like a good meta discussion to do so.

On the matter of results, funding and low hanging fruit.

There is no low hanging fruit capable of extending the lifespan or even the healthspan of humans available or even possible - and I'm actually prepared to bet money on this argument.
And my logic is pretty simple, but also mostly bulletproof - Everyone says they don't care about aging or getting old - yet - I've not met a single person who hasn't tried some sort of concoction, exercise regiment or drug to prevent aging. Once they go over a certain age, everyone does it.

So even if we look at something supposedly exotic like senolytics - first of all, there are natural compounds which absolutely have senolytic properties, and even if we disregard those there are compounds with general cytotoxicity like curcumin and those are in wide use in quack natural medicine. And yet no results.

If we look at medical experimentation which goes on in professional sports. Loss of fitness seems to be the first and most easily detectable sign of aging an based on the results it is not preventable currently.

That leads to a terrifying but unfortunately also undeniable conclusion - there is no therapy which can show any sort of measurable success when it comes to combating aging. As of now.

Reversing disease states in the old once they are beyond a certain age might be nearly impossible anyway. That's a different discussion and a theory I've had for a long time - the damage barrier - it is completely possible a person at certain ages has accumulated so many types of damage and so much damage in general, you can't possibly hope to see any sort of success when it comes to their health from administering a single drug or therapy. Or even a cocktail of drugs. People over certain levels of decay might not be treatable with the current paradigm of medicine at all. It is possible to increase their lifespan by a couple of years maybe, but their health - less pain, more mobility, less loss of strength, a better immune system, etc. - that's out of the question.

Getting funding in this area in the near future will become harder. I fully expect a second "dark age" of aging research, if you can even call the last 5 years much of an enlightenment period at all.

Unfortunately if you're financially invested in the sector currently you're faced with two options - retool your product for a different market or stick with your guns and hope for a miracle. Breakthroughs happen but they are not the norm.

Posted by: Anonymoose at September 13th, 2020 9:30 AM

"there is no therapy which can show any sort of measurable success when it comes to combating aging. As of now."

"People over certain levels of decay might not be treatable with the current paradigm of medicine at all."

Sure. I agree with all of the above: there is nothing apart from exercise etc. currently on the market.

But no one here hopes to see anything of notice within the current paradigm...
So, what's your point?

Tricks like epigenetic reprogramming and tissue regeneration, just to use two examples, are not within the current paradigm, and we simply have no idea how much they will yield. Could be little, could be a lot.
We don't have a frame of reference to do more than guessing, in either direction.

Posted by: Barbara T. at September 13th, 2020 4:22 PM

PS: I mean might sound pessimistic (am too I know- but when you experience near death (atherosclerosis) it kinds of makes pessimistic about life/death)/but COVID made us alll a lil bit more pessimistic even if we say 'but we are stronger - because of COVID, so we are most optimistic'...let's be real, COVID = depression for many/recession/debts = cynicism/pessimism (as you say the 2nd *Dark age of aging...won't be 'anti-aging'...but just ..aging. In other worsd it won't be the 2nd Coming of The Christ, but more like not showing up to the party) etc not 'we flow in money, we flow in progress'..COVID Halted a bit the process/we put more Ardeur/ardor..but we burning candles by both ends (hard burn out).... I think the message that AdG was saying is that 'FULL' 100% damage repair/reversable is nearly/quasi impossible; and so...his saying was that since we can't get 100% of it (nearly sure of that), could we get 50% maybe?...he said 'Enough'...that's the key word...could we repair a car 'enough' to thus 'reverse aging 2 years each year you ago so you have a net negative of 1 year aging/you are deaging by 1 year biologically - each 1 chronological real-time year that passed''.

Thus, I think 'Partial' rejuvenation, enough, robust enough, but not enough for 100% reversal...would matter; 100% reverseal/repair would Not matter then; I mean we suppose that 100% reversal is crucial for LEV...but AdG said no, it's Enough of It would be enough for LEV; so let's say 75% reversal/repair...maybe it could indeed be more than enough - Because, we would do it Ad Vitam Eternam/Repeated/Perpetually in a Loop-d-Loop....-d-loop-d-loo....
Again this analogy of repairing the 'car just enough' to matter and thus 'getting away with it'...and reversal would then 'nullify' aging 'enough' that we would Indeed be continuoulsy Deaging Or Frozen in age; like if you are 50 years old...and you deaged to 40....you will later be 50 again...but doesn't matter..you will AGAIN be 40 later once more...so indeed that is Frozen Aging/Stopping Aging, simply because we continuously reverse it and it thus stays in 'a standstill'. The analogy is not bulltet proof but we hope it is and that this car's windows Are bullet proof. For now, we Think that if you do reverset it enough you would then reach LEV. It remains to be seen (if yes or not we need 100% of reversal/repairing damages...or can get away with partial 25-50% reparation...I don't tihnk below 50 it's possible, but at over 50% it might be; because our body Can live with Some damage...but it will be a 'clocks' problem, our clocks may have a slight with that; so we need to erase/reverse our clocks to 'let more damage in' and we'll repair it Again. and again, ...it is optimistic maybe gullible that it would work but it 'might just work who knows - we've seen people step on the moon, invent electricity and make stuff that should not have happened; 'by miracle' it happened (I'm not saying we should hold our breaths/pour our hopes on miracles; it's why I think your assessment is more realistic neutral normal and could end up the truth too, we'll see in time (if we are still alive then))).

Just a 2 cents.

Posted by: CANanonymity at September 13th, 2020 4:38 PM

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.