Signs of the Spreading Interest in Cellular Senescence as a Cause of Aging

In just a few short years, the study of cellular senescence has grown enormously. It has become an area of intense interest and funding in comparison to its prior status as a thin sideline of cancer research and a yet another of the backwaters of aging research. Sadly, aging research considered as a whole is still a neglected, poorly funded field of medical science in comparison to its importance to all of our futures, but this will hopefully change soon. The 2011 demonstration of a slowing of degeneration in an accelerated aging lineage of mice via removal of senescent cells opened a great many eyes. A growing number of studies since then have shown reversal of many specific aspects of aging through clearance of senescent cells, and the potential for removal of senescent cells to form the basis for the effective treatment of many age-related diseases. These studies are accompanied by varied approaches to the selective destruction of these unwanted, harmful cells in aged tissues, including several classes of drug compound, gene therapies, and antibody therapies. This is an important transition for the study of aging as a medical condition: the first legitimate, working rejuvenation therapies now exist in their earliest stages. They have become a reality. From here the field will only become ever more promising.

The July issue of EBioMedicine gathers together papers from recent months to focus on aging and metabolism. Prominent in this collection are papers on the biology of senescent cells, the contribution of senescent cells to aging, and methods of selectively destroying senescent cells. I pointed out a few of these when they were first published online earlier this year, but I think it worth looking through the collection as it is presented here. This is the future: the stream that will become a flood, a huge new industry of medicine. It is impossible to work in the medical life sciences without having heard something of this newly important area of research and development. Senolytic therapies capable of safely clearing a large fraction of the burden of senescent cells in old individuals may well do more for health in later life than all of the heralded advances of the past thirty years, statins and early stem cell therapies included. These are exciting times that we live in - and then, I would hope, not too many years from now, we'll be able to say all of this again as glucosepane cross-link breakers become a reality as well, another line of rejuvenation research that should be just as influential, at the very least for cardiovascular health.

Aging and Metabolism: Two Sides of the Same Coin

The mounting challenges healthcare systems face with an aging population are largely due to increased prevalence of noncommunicable diseases (NCDs). In 2015, NCDs accounted for 70% of all deaths globally. 80% of NCD-related deaths are attributed to cardiovascular disease, cancer, respiratory diseases, and diabetes. In this issue find a series of articles discussing diverse aspects of geroscience - the relatively new field of understanding the biology of aging and age-related disease. At the core of geroscience research is the dogma that aging is not simply an immutable outcome of life, but that its biological underpinnings, once understood, can be manipulated to improve health. From the series of pieces presented in this issue, it becomes apparent that aging and age-related disease are intimately entangled with metabolic function, both at the molecular/cellular and organismal levels. The etiology of cardiovascular disease, cancer, lung, liver, and kidney dysfunction, and diabetes can be at least in part attributed to metabolic defects associated with increasing age.

Cellular senescence describes the phenomenon where somatic cells cease to divide, become resistant to apoptosis, and develop a senescence-associated secretory phenotype (SASP) that can have deleterious effects on surrounding tissues and throughout the body. One article discusses the role of mitochondrial dysfunction in cellular senescence and how breakdown of mitochondrial components (mitophagy) is likely involved in senescence and aging. How telomeres - irrespective of length, contrary to the previous notion that shortened telomeres were simply a readout of a cell's age - can both protect against and effect cellular senescence programs is discussed in another article. Translational approaches to targeting the biological basis of aging is a rapidly-developing field. A third article discusses targeting cellular senescence programs to improve fitness. Among these approaches are so-called senolytic agents, which selectively clear senescent cells and relieve the associated pathophysiology they confer.

Telomeres and Cell Senescence - Size Matters Not

So far, the best explanation for replicative senescence is the shortening of telomeres, regions composed of DNA repeats associated with proteins, found at the ends of chromosomes. In the 1990s, it was shown that telomere regions gradually shorten with cell division and that this correlates with the induction of cellular senescence. Importantly, it was demonstrated that ectopic expression of the enzyme telomerase, which is capable of elongating telomeres, counteracts telomere shortening driven by cell division and bypasses the senescence arrest. This experiment demonstrated that telomere length was the limiting factor in the senescence arrest and therefore played a causal role in the process. Since then, great advances have been made in the understanding of how telomeres are able to signal the senescence arrest. These mechanisms are of particular importance in the field of ageing, since cellular senescence, driven by telomere dysfunction, has been shown to be a causal driver of ageing and age-related pathology.

In recent years, important conceptual advances have been made in terms of our understanding of the role of senescent cells in vivo. It is now clear that the impact of senescence in vivo is not restricted to the loss of proliferative capacity. Apart from the cell-cycle arrest, senescent cells have been shown to experience dramatic changes in terms of gene expression, metabolism, epigenome and importantly, have been shown to have a distinct secretome profile, known as the Senescence-Associated Secretory Phenotype (SASP), which mediates the interactions between senescent and neighboring cells. The SASP includes pro-inflammatory cytokines as well as growth factors and extracellular matrix degrading proteins and is thought to have evolved as a way for senescent cells to communicate with the immune system (potentially to facilitate their own clearance), but also as an extracellular signal to promote the regeneration of tissues through the stimulation of nearby progenitor cells. Nonetheless, it has been shown that a "chronic" SASP is able to induce senescence in adjacent young cells, contributing to tissue dysfunction.

Recent data indicates that senescent cells play a variety of beneficial roles during processes such as embryonic development, tumor suppression, wound healing and tissue repair. On the other hand, senescent cells have been detected in multiple age-related diseases and in a variety of different tissues during ageing. The positive and negative effects of senescence in different physiological contexts may be a reflection of the ability of the immune system to effectively clear senescent cells. It has been speculated that an "acute" type of senescence plays generally beneficial roles in processes such as embryonic development and wound-healing, while a "chronic" type of senescence may contribute to ageing and age-related disease. The role of telomeres in the induction of these two types of senescence is still unclear. In this review, we will first describe evidence suggesting a key role for senescence in the ageing process and elaborate on some of the mechanisms by which telomeres can induce cellular senescence. Furthermore, we will present multiple lines of evidence suggesting that telomeres can act as sensors of both intrinsic and extrinsic stress as well as recent data indicating that telomere-induced senescence may occur irrespectively of the length of telomeres.

Mitochondria in cell senescence: Is mitophagy the weakest link?

Cell senescence is increasingly recognized as a major contributor to the loss of health and fitness associated with aging. Senescent cells accumulate dysfunctional mitochondria; oxidative phosphorylation efficiency is decreased and reactive oxygen species production is increased. In this review we will discuss how the turnover of mitochondria (a term referred to as mitophagy) is perturbed in senescence contributing to mitochondrial accumulation and Senescence-Associated Mitochondrial Dysfunction (SAMD). We will further explore the subsequent cellular consequences; in particular SAMD appears to be necessary for at least part of the specific Senescence-Associated Secretory Phenotype (SASP) and may be responsible for tissue-level metabolic dysfunction that is associated with aging and obesity. Understanding the complex interplay between these major senescence-associated phenotypes will help to select and improve interventions that prolong healthy life in humans.

Cellular Senescence: A Translational Perspective

There is a possibility that senolytics and SASP inhibitors could be transformative, substantially benefiting the large numbers on patients with chronic diseases and enhancing healthspan. That said, as this is a very new treatment paradigm, there are many obstacles to overcome. At least one reassuring advantage of targeting cellular senescence is the conservation of fundamental aging mechanisms such as senescence across mammalian species, however, reducing the risk of results in mice failing to translate to humans. Furthermore, unlike the situation for developing drugs to eliminate infectious agents or cancer cells, not every senescent cell needs to be eliminated to have beneficial effects. Unlike microbes or cancer cells, senescent cells do not divide, decreasing risk of developing drug resistance and, possibly, speed of recurrence. With respect to risk of side-effects, single or intermittent doses of senolytics appear to alleviate at least some age- or senescence-related conditions in mice. This suggests that intermittent treatment may eventually be feasible in humans, perhaps given during periods of good health. If so, this would reduce risk of side-effects. Progression from the discovery of the first senolytics to being at the point of initiating proof-of-concept clinical trials has been remarkably fast. With sustained effort and a lot of luck, these agents could be transformative.

Comments

Is there any research that correlates the effects seen in parabiosis with senescent cells? In other words, is it possible that the positive effects, or a substantial part of the effects, seen in parabiosis are a result of diluting the SASP of the older animal.

Posted by: RickD at July 21st, 2017 7:09 PM

I think there is unfortunately an important difference between the field of removing senescent cells and the field of removing glucosepane. With senescent cells the Mayo researchers were able to use germline genetic engineering to remove senescent cells, and demonstrate comprehensive effects in an animal model. Setting up a race to replicate this with therapy that could work in adult animals. With glucosepane you'd probably have to go straight to a demonstration of a removal technology that could work in adult animals.

On the other hand if a technology for demonstrating removal of glucosepane in adult mice/rats is achieved then there might be another rush to create a treatment as with senescent cells.

Perhaps another problem is that a good animal model (mice) exist for the negative effects of senescent cells. Such a model where a treatment can exhibit positive effects on an animals health doesn't exist for glucosepane as far as I know. Are there any short lived animals that suffer from the effects of accumulating glucosepane? Can we use biomarkers/synthetic endpoints such as cartilage elasticity/ or blood vessel elasticity to demonstrated benefits in longer lived primate models?

Posted by: Jim at July 21st, 2017 10:23 PM

If the glucosepane breaker molecule is small enough and non-toxic (tested on rodents) you could probably put it into a cream and test it directly on skin. Cosmetic products don't need approval, just registration. In fact you find a lot of slightly toxic stuff in cosmetics (formaledhyde, toluol, acetone, hydrogen peroxide, etc.). If you show some positive effect on skin you will see them rushing to the labs.

Posted by: Matthias F at July 21st, 2017 11:52 PM

@Matthias - given that senescent cells probably have a role in making skin look older, how come there are no senescent cell removal creams available?

Posted by: Jim at July 21st, 2017 11:58 PM

You can buy some with quercetin. But it may be that the connection of quercetin to senescence is not well established. So they don't know why it works.

Posted by: Matthias F at July 22nd, 2017 12:05 AM

Well I hope that the SENS RF have some rights to whatever AGE breaker comes out of the Yale lab and make a huge amount of money from "SENS Skin Cream" which they can plough back into research.

Posted by: Jim at July 22nd, 2017 1:36 AM

A couple months ago Mr. Reason posted an excellent paper by Dr. Javier Menendez and Dr. Tomás Alarcón that no one commented on at all:

https://www.fightaging.org/archives/2017/05/a-view-of-how-senescent-cells-disrupt-tissue-regeneration/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418360/

This is a very important paper to digest.

We need to quickly go beyond this one dimensional thinking that we pull out these chronic SASP cells and everything will revert to normal and be OK - things are going to get much more complicated in the "real world" of human biology

I fear we will end up with these first generation approaches of failing in human studies to have any meaningful effect and will be asking all the same questions as we have been doing for decades in cancer research - "Well, we cure the mice. I wonder what happened??"

Posted by: Jorge Bonilla at July 22nd, 2017 6:06 AM

I'm sorry but this subject of senescent cell removal begins to look like either a highly marginal benefit - or just plain BS.

If effective apoptosis inducing agents are already available, then we should be able to see solid anecdotes of benefit coming from the self experimentation folks - similar to that which occurred in mice. If not, it's another dead end. Prove me wrong (please, that's what I prefer here !)

Posted by: Chris Zell at July 22nd, 2017 11:18 AM

@Chris Zell: No self-experimenters are presently both (a) running tests that would determine degree of results, (b) using compounds that are definitely senolytic to a significant degree. Your argument could be used to suggest that fisetin and quercertin are not particularly senolytic, but that is about it.

Posted by: Reason at July 22nd, 2017 11:56 AM

I find it amusing that people expect to take quercetin and to experience rejuvenation of every and any ailment they imagine they have.

I remember one hilarious guy from Longecity back from when I used to visit those forums, so he was taking a bunch of quercetin, right? And the funny thing is, he was expecting his liver spots to go away...

Now that is quite funny because liver spots are lipofuscin loaded bodies currently considered to be indigestible - so even if quercetin was a senolytic agent, something which has been questioned in the last 3 years - those liver spots would remain unchanged, If not even growing in size from the release of even more lipofuscin in the ECM.

Long story short, most self experimenters are ... shall we say not quite bright enough to know what to look for even if they got the drugs and the dose right - which most of them didn't back when I was still paying attention to them.
Have the monkeys grown brains in the last year or two? I doubt it. They've been at it for a decade and are still doing it wrong.

Posted by: Anonymoose at July 22nd, 2017 1:05 PM

@anonymoose: your comment lacks empathy. This is the sort of complacency and selfrighteousness that makes people turn away from donating to SENSE.

Posted by: PeterB at July 22nd, 2017 1:42 PM

@Jorge Bonilla

As far as I know, it is planned not to remove all senescent cells but just enough that the SASP is reduced significantly but the remaining senescent cells could still produce their positive effects in the body. I shall say I'm not an expert on the topic and I don't know if this is what you meant and If i understand everyxthing correctly.

Posted by: C at July 22nd, 2017 2:07 PM

@Jorge Bonilla - The Fightaging blog post and paper you link to are about how the build up of senescent cells could inhibit tissue repair. Periodically removing senescent cells should therefore enhance tissue repair in aged animals.

"Compared with young tissues containing few senescent cells where transient creation of senescent cells might cause temporary reprogramming and differentiation/proliferation to replenish cells, the prolonged accumulation of senescent cells in tissues that are old or under high levels of stress (e.g., following medical procedures such as chemotherapy) might be accompanied by a defective clearance of damaged, senescent cells, which can promote further SASP accumulation. A situation of chronic SASP secretion might not only counter the continued regenerative stimuli by promoting cell-intrinsic senescence arrest in single damaged cells but also paradoxically impose a permanent, locked gain of stem cell-like cellular states with blocked differentiation capabilities in surrounding cells."

I don't see any logical link from this to your conclusion that "I fear we will end up with these first generation approaches of failing in human studies to have any meaningful effect ".

And this is based on what exactly? Your opinion? If you are presenting your negative opinion as fact then you are veering into troll like behaviour.

Posted by: Jim at July 22nd, 2017 2:19 PM

Empathy only goes so far.
After spending a good year or two telling self experimenters what they're doing is stupid, meaningless and dangerous at some point you start seeing this problem for what it is:

A bunch of crazy people popping pills grasping for the next placebo. It's more or less a drug addiction. A lot of the self experimenting crowd have a history in body building and juicing as well.

It's like trying to help a person with an eating disorder. You can tell them what their problem is, but it will only make their addiction stronger.

Posted by: Anonymoose at July 22nd, 2017 2:23 PM

@Anonymoose - Michael Rae has pointed out to me in the past the liver spots/age spots are not actually due to lipofuscin:

"in many people, the dark pigment melanin that normally darkens our skin to give us an even tan clumps together into concentrated deposits known as "age spots" (often mistakenly attributed to lipofuscin in the anti-aging community, propagating an error first introduced by Pearson and Shaw)".

Yes it is a small point, but it was something I was interested to learn. Either way senescent cell removal won't get rid of liver/age spots.

Posted by: Jim at July 22nd, 2017 2:30 PM

Chris Zell wrote: "Prove me wrong"

Nope. First you must try to prove you right. You can't start a discussion by asking people to do what you don't bother to do yourself. That's unpolite.

There are lots of information in this blog about senolytics. If you think they are a wrong therapy, the very least you should do is to point out what is the problem with senolytics, why they will fail in humans, where the errors in the papers are or what data the researchers have misinterpreted.

Posted by: Antonio at July 22nd, 2017 2:33 PM

@Jim As far as I know we don't know for sure how they form, so he might be right, or he might not be completely right.

Whether the bodies are made up of lipofuscin or melanin, the problem is more or less the same. Granted melanin has a significantly shorter half-life in it's pure form, but since these clumps of pigment don't seem to be well studied currently I wouldn't wager that they're easier to digest than lipofuscin inclusions.

Posted by: Anonymoose at July 22nd, 2017 2:57 PM

@anonymoose LOL! too funny, as long as it says rejuvenate
https://www.amazon.com/Life-Extension-Bioflavonoid-Cream-Ounce/dp/B008S02D7C/ref=sr_1_6_a_it?ie=UTF8&qid=1500756815&sr=8-6&keywords=quercetin+cream

but really, study the mitochondriolus folks, its optimized for making respiratory subunits, allotopic expression is folly because the mitochondrion is a metagenic hybrid that exploits two differentand uniquely optimized translation systems working in tandem on opposite sides of the membrane, is it reallythat hard to see how mitos are built folks???

The Mitochondriolus: assembling mitoribosomes http://mbi-umiami.org/wp-content/uploads/2016/06/Barrientos-A.-Mitochondriolus-assembling-ribosomes-Oncotarget-2015.pdf

Posted by: john hewitt at July 22nd, 2017 3:58 PM

http://foxo4dri.com/summary/

I'm judging that the jury is still out on this topic. I think the quercetin (and combo) are probably ineffective. The photo of the hair looks very interesting in the foxo4 case.

Posted by: Chris Zell at July 22nd, 2017 7:51 PM

If you (and the idiots popping random pills) bothered to read the papers by Peter de Kaizer - you know, the guy who designed the peptide and first used it in a lab setting - you'd see that in the experiments even though the peptide worked, it pointed his research team to the conclusion that even if senescent cells are cleared, there's still enough of them left behind in an old organism to impair regeneration.

So it might be a problem with his own peptide or stem cell lock might be a legitimate side effect of senescence and in need of treatment as well. We don't know yet.

http://linkinghub.elsevier.com/retrieve/pii/S1471491416301721
https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(17)30246-5

Posted by: Anonymoose at July 23rd, 2017 9:44 AM

I wish someone could give me a clue of how to reduce the number and size of my age spots. I have tried some methods over the last 20 years, but have not had any success with getting rid on even one age spot. I am thinking that excess sunlight exposure is the main cause by killing off stem cells in the skin or resulting miss folding of proteins. Perhaps CR or reduction of protein intake would help. I grew up on a farm on a diet high in protein, dairy products, potatoes, and field work.

Posted by: Biotechy at July 23rd, 2017 2:58 PM

Is it really that hard to determine the nature of age spots or has it just not been tried hard enough to figure out? I mean can't you biopsy that part of the skin and analyze its composition?

Posted by: K. at July 23rd, 2017 3:16 PM

@Jim - existing models to study cell clearance do nothing to validate / address the downstream issues highlighted in the literature by Menendez, Alarcón, and for that matter de Kaizer.

Very similar to how xenograft models have failed in translational oncology

Posted by: Jorge Bonilla at July 23rd, 2017 3:36 PM

Jorge: to what kind of issues do you refer? This quite recent article by Menendez and Alarcón highlights the pleitropic effects of senescent cells in resolution of tissue repair in the short term vs. the long-term effects of the chronic accumulation of SC - but while that would be an objection to therapeutic approaches based on inhibition of senescent cell formation, it's not really an objection to periodically ablating them when present at high levels due to age-related accumulation (aside from the need to be cautious not to administer senolytic therapies in people who have recently been injured or who are about to undergo surgery).

Also, Baker et alet al did look at this in their study of senescent cell clearance throughout adult life and found that even after having undergone regular rounds of extremely thorough SC ablation (much more thorough than are going to be achieved with currently-forthcoming senolytic therapies), "mice repaired cutaneous wounds when [treatment] was suspended during healing (Extended Data Fig. 10a-c). When [treatment] was administered during wound closure, healing was delayed with similar kinetics as [very young adult] or [early]-old ATTAC mice without previous [senolygic] treatment, indicating that acute senescence mechanisms are preserved with ageing and ot influenced by constitutive clearance of senescent cellsn. Furthermore, 18-month-old [long-term-senolytic]-treated mice showed no evidence of increased fibrosis in skin and other tissues, despite a role for senescent cells in limiting fibrosis during tissue repair."

As far as any analogy to xenograft models: well, those are quite artificial systems that don't reflect the underlying biology of tumor initiation, progression, or metastasis, and have the additional problem of the differing reasons for tumor lethality in mice vs. humans; most of the studies with senolytic therapies to date (including all of Oisín Biotechnology's work) has been in normally-aging mice, or in mice only modified by the introduction of the senolytic-senovisualization tech (INK-ATTAC, p16-3MR). I don't see any good reason to expect the biology of these natually-forming cells to be profoundly different between mouse and human - do you?

As regards age spots: this is somewhat contentious, but no one actually working in the field suggests that they are the result of lipofuscin accumulation any more. The main schools of thought are that it is the result of (a) melanin clumping together instead of being spread evenly across the skin, or being produced in particularly high local concentrations; and/or (b) a local excess of melanocytes, the melanin-producing cells.

Posted by: Michael at July 23rd, 2017 4:37 PM

@Michael So how do they distinguish aging spots from moles?

Posted by: Anonymoose at July 23rd, 2017 5:59 PM

With regard to the stem cell lock issue but in the context of the broader question of robust mouse rejuvenation: I wonder whether technologically we may be there already without knowing it, since the same batch of mice has never been given all of the treatments that in isolation produce some degree of life extension.

So perhaps feeding mice NMN and Yamanaka factors (even if they'd have to be transgenic mice at this stage) as well as clearing their senescent cells and treating whatever cancer they get, already extends their remaining lifespan enough to qualify them for the prize.

I understand this wouldn't translate to humans in the same way, but as far as good publicity goes, a mouse whose years in his cage have been doubled would certainly get the funding flowing.

Posted by: Barbara T. at July 23rd, 2017 6:10 PM

@Anonymoose: I am not a dermatologist ;) , but AFAIK the most obvious difference is that moles are usually distinct bumps, while age spots are flat or slightly elevated and sometimes clustered. See this from the American Academy of Dermatology.

@Barbara T: why this specific combination? That sounds like an awfully expensive and time-consuming grab-bag crapshoot to me. We don't yet know even the medium-term consequences of the cyclic Yamanaka factor protocol, and this combination wouldn't do anything about extra- or intracellular aggregates, crosslinks, most cell loss, etc. And saying "treating whatever cancer they get" is no small task - particularly if repeated rounds of cyclic Yamanaka factors caused more cancers, which is highly plausible.

Posted by: Michael at July 23rd, 2017 10:23 PM

@ Biotechy

Just scrape 'em off! Age spots are right on the surface (epidermis), where there aren't any nerves, so it won't hurt (much). The skin that replaces it will be normal colour.

They are almost certainly just melanin; just look at the colour and compare them to a freckle.

Posted by: Mark at July 24th, 2017 3:26 AM

This particular combination or any other. I mentioned those treatments, with the disclaimer "perhaps", because they are aimed at four of the issues that SENS sees as causative of degenerative aging rather than at metabolism modification.

However, I am not talking biospecifics as clearly I am not a scientist. I am a medical anthropologist though, so my interest, amongst other things, lies in understanding what sort of messaging would work best to nudge people as a cultural entity (the masses in the anglo-saxon world are a cultural entity, billionaires are another etc.) towards supporting radical life extension, or at least life extension to 150, which seems to be the magical number here - also interestingly.

So mine was a broad question of method, predicated on the reasonable assumption that combination therapies would work better than standalone ones. Then what it is that would be best to combine in terms of risks, synergies, and cost to achieve a median life extension of more than 25% I certainly don't know.

Posted by: Barbara T. at July 24th, 2017 3:37 AM

Thanks Michael, I'll try that. Actually, I have only 2 age spots, both on the backside of my left hand. Being nearly 77, I guess I am fortunate I do not have more brown spots.

Posted by: Biotechy at July 24th, 2017 2:22 PM

Hi Barbara,

''So perhaps feeding mice NMN and Yamanaka factors (even if they'd have to be transgenic mice at this stage) as well as clearing their senescent cells and treating whatever cancer they get, already extends their remaining lifespan enough to qualify them for the prize.

I understand this wouldn't translate to humans in the same way, but as far as good publicity goes, a mouse whose years in his cage have been doubled would certainly get the funding flowing...

Then what it is that would be best to combine in terms of risks synergies, and cost to achieve a median life extension of more than 25% I certainly don't know''

Just my 2c ents,

I think that currently the only decent thing is CR (calorie restriciton) and even then, it's not a magic bullet. It's been shown to increase avg lifespan a bit and healthspan. In humans, these effects are quite weak but still it does help as one study had shown that mortality increased depending on the number of calories consumed daily, that 600 calories what is the exact number you needed (which is low but technically, you only need 200 calories per meal). Above 600 calories there was clear 'sharp' increase in mortality for people of nearly all ages (it was a bell curve, where 600 cal what the magic number with the least mortality).
Below 600 calories is dangerous, and mortality rises (this is akin to famine/starvation).
This 600 could spread, like people whom do 'fasting' days' and then feed quite a lot to make up for those days. In any case, you can'Tfast for more than a few days (30 days, water fast above that is death and you will lose a tremendous amount of weight/start to look anorexic/ghastly skeleton weighting about 90 lbs; and for people (like me or my father) whom suffer from debilitation diseases (atherosclerosis me (have a genetic allele mutation for hypercholestermia, I'm 36 tunring 37 in a week) and him, diabetes type II, he turned 70) doing CR can kill you Much faster, because if you mess with your insulin levels and glucose levels (which CR does that) it can be Worse and very dangerous for your health, You absolutely need to have your calories but excess calories is The Point to correct). For example, CR switches from glucose to fat burning metabolism for energy (you become ketotic/ketones acid bodies production for enegy), in my case, that's dangerous because my body relies on more glucose than fat (and I'm Very thin, so it's dangerous, since I have little fat mass, I tried to gain weight but I lose it so fast it's scary (unlike obese people whom can't lose it), because my metabolism is so fast it burns everything - I have to double the glucose just to keep my glucose high enough and have enough energy/ATP production in my cells mitochondria; so I'm suffreing from a sort of 'CR' atherosclerosis, which makes me have to play yoyo on my glucose jkust like diabetes have to also; that's because without glucose the body cannot truly survive the ischemic attacks as well (loss of O2 from narrowed arteries/cholesterol plaque) and as such cannot activate important ischemia protectors (that insulin activates upon glucose rise) such HIF-1 (Hypoxia-Inducible Factor 1) my levels are so low that lack of O2 is deadly to me because my HIF-1 is too low from bad arteries not producing enough Nitric oxide (vasodilation) and HIF-1 for ischemic control))). As such I would recommend CR only to peple whom are in perfect shape/health and 'have this under caerful control'.

I think currently there is (near) absolutely nothing that can give over 25% extension in human over long time,
Only if started young (if your are over 50 it will be hard) below 40 years old it will work.
Over 50 is too late, the slope is too low (unless you are Biologically Younger than your age, let'S say 42 years old Biologically and 50 years old Chronologically, which is what centenarians were (they were 8 years bio/epigeneticaly youger than others at all times in their lives).

CR can give life extension (in mice or flies at least, not much in humans) because it alters the metabolism many cross-road signals (IGF, insulin, glucose, calorie, energy, damage accrual, oxidative stress and So forth, senescence, it's a 'total package'),
so that's wht I still hold certain doubt that even with 4 or more therapies (like SENS) it will do better than CR does; because CR touches on SO many genes and variables - and it does also so much; why would we think it would be SO much better. I think that combination is the only way.

I still hold that Redox change is probably the most powerful thing there is for like CR it affects everything down the line, including metabolism, senescence entry, proteasome gating and damage accrual speed...

NMN Nicotinamide mononucleotide is decent like Nicotinamide dinucleotide phosphate NAD+ NADP for it increase NAD levels indirectly through conversion NMN to NAD. IT does improve health and the redox (for it is a redox electron donor - just not the actual oxidative stress caretaker (that's the GSH/GST/SOD/TXRedoxin (activated by NRF2 ARE nuclear-translocated stress sensor) and other enzymes, it is only a fuel for the redox). Studies with NAD have increased mice lifespan/healthspan a bit so that's a good thing. As said, Yamanaka factors must increase cell division and 'stem cell-like quality' : Oct, NAnog, Sox and so forth are highly 'stem-cellish' factors that are found in embryonic signals (which cancer cells mimic by highjacking these factors for themselves when they become very 'stem-cell' like). As such, these factors increase mutation possibility and cancer formation/stem cell cancer formation/accelrate cell division/proliferation. It's what they used to reprogramm like iPSCs and so forth, they need this special cocktail of 'embryonic/fetal/'child's cells'' like factors to make any sort of reprogramming/rejuvenation but the danger is cancer high-jacking it/Human cancers tumor formation from excess cell division proliferation. Stem cells must keep quiescent or they can form tumors if overly differentiating.

I know... one more stumbling block. I'm curious to see how the SENS will play out and if they will have strong impact or little impact. I guessed that all of them gave the chance to make humans at least reach their MLSP; but even that is not certain; and LEV, is evenly less certain or feasible altogether. I think we must concentrate on improving health because the message is now longevity extension is continously seeing 'new' problems that make it an ever ending 'non-reachable' goal (kind of life a mirage..you get closer it...and it goes a little farther...smore more closer...still far...it continously 'goes back' as you 'approach it').

Just a 2 cent.

PS: I guessed but now I realize even people at/over 77 years old read fighintg, it's incredible and it shows elders are 'getting on internet' and want to take care of their health. The message is 'cure diseases of age' like Alxheimers, Diabetes, Atherosclerosis (I have it I'm so far from 70, so it's like not good looking...Heart Attacks, CAncers (mother died of that at 56 years old. So people whom are over 60-70, yes you are lucky to be alive; for many are dead at that age)) (and longevity will be something that happens, just not talk about it too much).

Posted by: CANanonymity at July 24th, 2017 7:54 PM

Hi CANanonymity!

The thing with CR is that it just slows everything down (including damage accrual). But who wants to be 90lb and only half alive?

The SENS therapies are actually aiming to remove a whole chunk of damage (years and years worth) in one go, and so can aim for a much bigger effect on lifespan than CR.

I don't think we'll get any max lifespan extension from Senescent Cell clearance alone, and I think Aubrey would probably agree with that. You also need the proliferating cells to replace them. There is evidence from the regeneration of mice that removal of stem cell does encourage this replacement, but without telomere extension either directly or via fresh, working stem cell infusions, senescent cell clearance is actually making you use up your reserves faster (although you will be healthier in the short term).

So yes, we definitely need a combination of therapies for the majority of people to benefit in a really big way. You might get some genetically gifted people breaking the world record (122 years) with just one or two therapies though.

Personally I think we might have made a mistake concentrating so many efforts on the lifespan effects on mice. The dominant aging mechanisms might not even be the same as humans. As Jim says, they don't suffer from glucosepane (too short lived). They also don't come up against replicative senescence (as far as I know), though they get senescent cells due to other stressors. Nevertheless if we could demonstrate RMR I'd go for it, just for the publicity and extra funding it would draw in.

Posted by: Mark at July 25th, 2017 3:51 AM

@Michael @Barbara T

I asked the same question to Michael, Aubrey, & Reason last month, but it got lost in other strands of conversation and never answered. If we are at the point where 3 or more SENS areas have treatments ready for human trials after having been published effective in mice (as indicated by Reason's recent SENS update posts and LEAF's "where are we now"), and given that mouse trials are so much cheaper & faster than human trials, then: Have there been *any* mouse studies testing any combination of 2 different SENS related interventions from 2 different SENS areas? (Or in any short-lived model species for that matter.) If not, why not?

Even if significant life-/health-span extension really requires all SENS areas, the fact that there is any utility to a single SENS treatment in humans, as there must be for all the excitement to get single-SENS-treatments into humans, then even better health outcomes must come from treating multiple SENS areas. Science showing monotonically better health in multiple areas and against multiple diseases from increasing numbers of SENS treatments would galvanize funding, scientific interest, and possibly regulatory change too.

Is the problem that there is no particular return-on-investment so no one with incentive to fund combination studies? But surely it would be a great use for charitable or government money.

Posted by: Karl Pfleger at July 25th, 2017 12:11 PM

Hi Karl,

There seems to have been a miscommunication: I understood you to have answered your own question ;) . The main reason, as you say, is that no one has any commercial interest in doing so; teh challenges are discussed further here. As is discussed here, there was a serious move on to make it easier to do early testing of combination therapies for neurodegenerative diseases of aging a few years ago, but unfortunately, the initial guidance that came out of that was vastly watered-down from what advocates thought they were working toward, and no further progress has been made to my knowledge.

In the specific case of mouse studies, an additional problem is that although mice and other model organisms age in ways analogous to the way we age, relatively few of their specific aging pathologies are the same at the molecular or clinical level as ours (aside from ones that would best be addressed by tissue engineering and bona fide cell replacement therapy). Wild-type mice do not develop atherosclerosis, or Alzheimers (they develop neither beta-amyloid nor aberrant tau), nor Parkinson's (no alpha-synuclein aggregates, only modest loss of dopaminergic neurons), etc; they seem to suffer a different range of extracellular matrix glycation crosslinks; heck, even their cancers are clinically different from humans' in important ways.

So tests in mice of single rej bios often entail engineering mice to develop lesions that are similar at the molecular level to humans'. Those all have their limits, of course, and none of them are good for the mice. Neither is subjecting them to regular injections, even if the thing with which one is injecting them is good for them. So to do a good test of combination therapies in mice, you will often have to develop a very complicated and artificial model, that might be sufficiently abnormal as to be too short-lived or frail to be useful for testing, and therapies that rescue them would be subject in many cases to additional skepticism.

Additionally, there is understandable hesitance to spend a lot of time and money testing the effects of therapies that have been shown to be beneficial to mice (or to engineered mouse models), but that still haven't individually been shown to benefit human health.

And, it's more of a priority for individual scientists to develop new therapies than to test combinations of them - and arguably more of a scientific priority as well.

As to it being a great use for charitable or government money: well, there is an awful lot of medical research that would be a great use for charitable or government money ...

Posted by: Michael at July 25th, 2017 6:29 PM

Doesn't this invalidate the whole RMR project? If not, how would that be different?

Posted by: Barbara T. at July 25th, 2017 7:16 PM

@Barbara T.: No, it just means that we shouldn't expect many of the entities involved in development to take any steps towards testing combinations, largely as a result of the regulatory rules and costs involved, I think. Combinational testing is going to have to be funded by philanthropy, or will have to wait until a couple of SENS technologies are quite mature. Look at how long it took to, for example, get to the polypill concept involving statins in mainstream pharmacology.

Posted by: Reason at July 25th, 2017 7:33 PM

@Barbara - I think RMR is still valid. The lesions that kill old mice may not be the same at the molecular level as those that kill humans, but then the seven types of SENS damage are just categories of molecular damage that can be resolved with the same technology. Using enzymes to remove oxidised cholersterol from marcophages in blood vessels and then to remove other damaged or built up proteins in retinal cells could be extended to remove whatever lysosomal protein aggregates kill mice. The damage is species specific in many cases, but the technology used to repair the damage is species agnostic.

We can probably use other species for technology demonstrations where lesions in mice differ from those in humans. For example in cancer research there is now a shift to testing treatments on dogs with cancer that occurred naturally rather than mouse models with transplanted human cancers.

RMR would technically be a bit more work, but it could be a massive PR win.

Posted by: Jim at July 25th, 2017 7:40 PM

Thanks!

Posted by: Barbara T. at July 25th, 2017 8:02 PM

Try Alexandrite laser for age spots.

Posted by: JohnD at July 25th, 2017 9:09 PM

@Barbara: I think we will probably not see RMR ever. Individual therapies will be tested in mice and then translated to humans. Some day we will see therapies for all the seven categories be used in humans, but I don't think it will happen for mice. Unless the life-extension community does that (and it seems to be expensive for them) I don't see why an university or company that has just developed, say, a glucosepane breaker in mice, would test it in mice again with senolytics, A-beta breakers and whatelse instead of going straight to human trials.

Posted by: Antonio at July 26th, 2017 4:21 AM

@Antonio

"I don't see why an university or company that has just developed, say, a glucosepane breaker in mice, would test it in mice again with senolytics, A-beta breakers and whatelse instead of going straight to human trials."

Because of safety (who knows how these therapies interact?), cost and time? I'm all for human trials as fast as possible but I think at least a subset of combinations should be tested in mice to exclude unexpected side effects, although logically beneficial effects should be enhanced. But you know, the body is complex and in some way unpredictable. Just my opinion.

Posted by: K. at July 26th, 2017 8:14 AM

Clinical trials are expensive enough to require that a new drug must be tested also for interactions with other drugs. Companies aren't required to do that. That's only done in phase IV.

Posted by: Antonio at July 26th, 2017 9:37 AM

@Michael Thanks for the links & explaining how mouse aging damage differs from humans. I understand the issue better now. I wish there were a table of all the different types of aging damage for each important model species (yeast, worms, flies, etc. maybe dogs or some of the fish too) not just the SENS list for humans only.

Despite different damage types across species, all these species have more than one important type of damage. Humans are the most expensive, slowest species to advance the science, so it still seems absolutely crazy to me for *all* the science that involves combining rejuvenation therapies for more than one aging damage type to happen *only* in humans.

I don't think combine-only-in-humans would even make sense in a world where 90+% of NIH budget went to aging and 90+% of that went to SENS style research. It makes even less sense when there is still an urgent need to convince others of the strategy. Aubrey's 2013 editorial that you linked to directly explains one of the main reasons why other scientists aren't yet convinced: "biogerontologists, by and large, do not believe that [multiple SENS style] interventions will ever be comprehensive enough to work, because aging is just too complex".

If the SENS advocates only wait to convince them by combining everything in humans, that's equivalent to saying that they are just going to go it alone with tiny slivers of the budgets & scientists on-board until it's done. That will take a lot longer.

Posted by: Karl Pfleger at July 26th, 2017 1:12 PM

In a 2014 Quora answer on RMR timeframe, Aubrey said we were progressing but slower than if there was more money, but it sounded back then like RMR was still a goal.

Have things changed in the thinking? Michael's explanation made clear that RMR might take some science that isn't directly useful in humans, and thus could be seen as slowing down human progress. Reasonable people can have different estimates of how long RMR would take and how much money and opinion it would sway. Do Aubrey and SRF no longer see it as an intermediary goal?

Posted by: Karl Pfleger at July 26th, 2017 1:18 PM

What I took from Michael Rae's comment was that RMR in a mouse that has been engineered to have all the aging lesions that humans experience is unlikely, not least because engineering such a mouse without it dying before birth is probably impossible.

But wild type mice still die from lesions in the seven SENS categories. These lesions are often different from the human ones at the molecular level, but once a technology has been demonstrated in a mouse model with human style molecular damage for that particular SENS class of damage, the heavy lifting has been done. It should be relatively straightforward to then adapt the treatment to remove the specific molecular damage that wild type mice experience in that class of SENS damage. This is actually the underlying premise of SENS. If every individual type of damage was its own independent research project with no reduction in work required from increased knowledge when another type of damage in its class was successfully removed, then implementing SENS would take near forever.

So RMR (fixing the damage that wild type mice die from) will probably happen some time before all the technologies have made it through clinical trials. And it would be worth doing for the PR.

Posted by: Jim at July 26th, 2017 7:25 PM

Post a comment; thoughtful, considered opinions are valued. 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.