A Popular Science Article on Calorie Restriction Mimetic Development
This popular science piece covers some of the major themes of recent years in the development of calorie restriction mimetic drugs, pharmaceuticals intended to recreate at least a little of the beneficial metabolic response to lowered calorie intake. The article is a cut above the average in terms of quality, but I remain bothered that this line of work receives so much attention in comparison to far better approaches to the treatment of aging, such as the SENS portfolio of therapies based on repair of the molecular damage that causes aging.
Calorie restriction mimetics cannot produce rejuvenation, and cannot do more than slightly slow aging. They are enormously challenging and expensive to develop, as illustrated by the past fifteen years of investment and failure: there is still no viable, reliable, useful choice if you want to take a calorie restriction mimetic drug, and there is still no full accounting of the cellular biochemistry of the calorie restriction response. The drug candidates on the table such as metformin, mTOR inhibitors, and autophagy enhancers are all some combination of only marginally effective, possessed of unreliable data from animal studies, or producing undesirable side-effects. None come close to the reliability and benefits of calorie restriction itself, but even that buys little in humans, considered in context of the bigger picture of what is possible via the SENS approach of damage repair. People taking a hypothetical perfect calorie restriction mimetic would still age and die on much the same schedule as their untreated peers, gaining only modest benefits. We can do better than this.
Soon to be 50, the respected head of an Australian medical institute is contemplating the latest offering from the anti-ageing industry. It's a product that tops up the levels of nicotinamide adenine dinucleotide (NAD+), a commonplace chemical made by our bodies that is crucial for our metabolism. He's not alone. Leonard Guarente has been taking NAD+ boosters for years; and in 2015 started a company, Elysium, to market them. There are likely thousands of users by now. Something has changed in the anti-ageing field. Eccentrics and gullible-types have always availed themselves of anti-ageing remedies. Dubious supplements feed a mushrooming $30 billion industry. But when evidence-clamouring scientists start popping a pill, you sit up and take notice. Like the soon-to-be-50 Australian professor, most aren't aiming to extend their lifespan; they are aiming to extend their "health span" - the period of time before the diseases of ageing catch up with them.
The rough rule of thumb in nematode worms is: restrict calorie intake by 30% and see up to a 30% increase in lifespan. The effects are smaller in mice and even smaller in primates. Not many people have the willpower to adhere to a lifelong diet, though occasional "fasting mimicking diets" seem to have beneficial effects. Nevertheless the holy grail has been to find a drug that could mimic fasting. Calorie restriction flips a metabolic switch from "abundance" to "austerity". Like when you get a big salary cut, you don't go adding extensions to the house; you hunker down, live modestly, recycle your old things and delay your plans to have babies. Somehow responding to this stress also lengthens lifespan. These days researchers think autophagy plays a big part in the lengthening. For instance, recent studies on mice and humans shows that fasting accelerates the refurbishing of tissues, clearing away damaged "senescent cells" while turning on renewing stem cells.
You might think with all the epiphanies of the past 30 years, surely we know enough about ageing to go full speed ahead with interventions? All the candidate compounds, so far, seem to hack into the same pathway triggered by calorie restriction. Well, yes - but this rabbit hole goes very deep. Over the years, one compelling theory has been that it controls the integrity of mitochondria, the engines of our cells which clearly degenerate as we age. According to the theory, the corrosive by-products of cellular combustion - free radicals - cause ongoing damage as an inevitable consequence of being alive. But numerous recent experiments show that slowing the generation of free radicals in mice or flies doesn't actually slow the ageing process. In fact, it seems to have the opposite effect. Nowadays the paradigm shift is that stress signals like those from free radicals, fasting, or exercise trigger an adaptive anti-ageing response. It doesn't mean past theories are entirely wrong. It's just that there is a lot of other stuff going on in ageing as well.
None of this means the era of anti-ageing medicine has to wait for us to explore every blind alley of the rabbit hole. Indeed, most of the researchers I spoke with passionately believe they are more than ready to start testing the plethora of promising new compounds in their pipelines. What's needed is the faucet at the end - the regulatory framework that will incorporate "ageing" as a medical indication.
Link: https://cosmosmagazine.com/biology/time-to-pop-an-anti-ageing-pill
"the regulatory framework that will incorporate "ageing" as a medical indication."
This is the important part. If we get that, it's a win - I have my doubts we're getting to that point in regulation any time soon though.
Anti-aging treatments need to be started early.
Before pathology. Otherwise they will not work.
Pathological states are fueled by innumerable feedback loops.
As for SENS - any treatment which can go from theoretical to real will have it's chance if the regulation allows for it.
"This is the important part. If we get that, it's a win - I have my doubts we're getting to that point in regulation any time soon though."
This is my fear. I'd like to think it'll happen soon, otherwise all these companies are probably spinning their wheels. Unless, for example, companies working on something like senolytics will make them for different targeted parts of the body, since aging isn't a general indication yet.
@Ham
That is what they are doing right now.
Preparing trials for single indications.
I'm not sure how successful they will be moving forward with senolytics. I suspect not very. But I expect the trials to have groups with people in different stages and severity of symptoms so it will be made obvious that these types of treatments work best when started as early as possible.
I have hope for senolytics. Not as a be all, end all treatment, but as a solid first step to get the ball rolling. That said, I don't know how much hope I have for single indications that are only going to treat a specific part of your body. We'll see I guess.
The big wild card IMHO is regulatory. Well, the good news is that this NEEDS to happen. There is a lot of hand-wringing over "Will they or won't they?". I think they will, and I'll explain why.
Alex posted a great follow up to my inquiry. Hop on over and have another peek...
https://www.fightaging.org/archives/2017/07/considering-juvenescence/
This is probably the most important thing we can get across to EVERYONE. Every policy maker, every layman, every single person on the planet. Remember this going forward. Repeat it. It should be the topic of every dinner conversation, business pitch, and it should be printed on every roll of toilet paper so everyone knows...
"Aging is very bad for the global economy and productive longevity will be the main source of economic growth in the future." - Alex Zhavoronkov at August 5th, 2017 10:27 PM
The long and short of it, if we don't fix aging, we will be BROKE. We have far too many people, and not enough younglings to cover their expense. If you want to have a good look at what will happen to society, have a look at Greece. I know what you are saying "Greece's problems weren't caused by aging". Not entirely, no, but legacy pension costs are CERTAINLY economically tied to aging.
That issue is coming to a G7 country near you in the next 10 years. Especially with dementia. The coming wave of AD sufferers alone will break the backs of every healthcare budget in the G7. Just that disease alone. Never mind Cancer, Heart disease, etc etc etc. We all know the massive boatload of treatment failures for AD. Its starting to creep into collective wisdom that perhaps the whole approach is flawed. Without a treatment for the underlying cause of AD (Aging), we are sunk.
A lot of old and decrepit people, few younglings, collapsed pensions, higher taxes, rationed healthcare. Its going to be a MESS.
There are two solutions.
1) Soylent Green the elderly. This is not going to fly as Theresa May recently tried it by capping payments for dementia and it cost her a Majority in the election. Don't kid yourself, it cost her EVERYTHING. She will be PM, but the knives are out in her own party. The "Dementia Tax" really crippled her election results. They will not be turning us into soylent (Although I'm sure that in smokey back rooms, they talked about it and some even wished for it).
https://www.theguardian.com/society/2017/may/22/theresa-may-u-turn-on-dementia-tax-cap-social-care-conservative-manifesto
2) Keep the elderly healthy, productive and working longer. It won't happen without better technology. You can't make a 70 year old man become a longshoreman if he's a typical 70 year old. Can a 70 year old with SENS 1.0 become a labourer again? Probably! SENS 1.0 can probably make him biologically 45-50 again. (We won't get into the whole jobs/AI talk at this point, that's a different can of corn).
Right now, the 1% are becoming aware that we will be living longer and that perhaps killing us off would be a bad business move. They are starting to come around to the idea that society will need to change in EVERY WAY to accommodate this, and they can make a LOT of money going forward.
Have a look at a panel that our new ally Jim Mellon is hosting here at the Milken Institute. Make no mistake, this is the 1%, and what I see in this room are a lot of HNWIs starting to lick their chops at the opportunity this is presenting. Watch it... and LISTEN... listen CLOSELY.
https://www.youtube.com/watch?v=qv2K-QmCDDs&t=1400s
Here we are beginning to see what Reason described after Senolytics are rolls out. "The rest of this century will be a grand adventure. The course of a human life is no longer planned and plotted and set in stone as it was for your grandparents."
This is EXACTLY what they are talking about, and the 1% wants in. They recognize this as an opportunity PLUS they don't want to die. And they are looking to start marketing this to the world so they know its coming. They WANT to get everyone on-board. They WANT to make this happen.
They also know that in order for this to come about regulation is going to need to change. And when the 1% wants something, they aggressively lobby for it. Next phase... start looking for the lobbying.
In fact, Aubrey himself has started to push the demographic angle. Check out his new talk. Yup.. Aubrey has new material... check it out. Its important to note not only what he is saying here, but WHO he is saying it too. Aubrey is on-board with the plan.
https://www.youtube.com/watch?v=t_mAnkdVKsM
The talk is mostly a wonkish walk thru of calculating maximum natural life span. His main point at the end is "Your models are going to be blown out of the water, sooner than you think. Policy based on the old models is doomed to failure with catastrophic results".
This tells me we have moved on from the "Here's what I propose and here's how we intend to do it", talk he's given for the last decade or so. He's moving on to "This is coming, please come and talk to me about it so we can start preparing for a whole new world.".
I'm seeing a push now. Don't kid yourself, this has all the markers of a push to educate the public and get them on board. Public pressure = policy change. Combine that with lobbying and you see the tactics forming.
As I said on Reddit... Welcome to level 2.
@Mark: "Aging is very bad for the global economy and productive longevity will be the main source of economic growth in the future." - Alex Zhavoronkov at August 5th, 2017 10:27 PM
Sinclair have stated that his R&D will produce a fifth generation. I dont understand why not more people understand that if we were 4 generations to pay for the baby boomer generations things would be easier.
@Mark: Oh, didn't know that Aubrey came to Spain again for that talk. Thanks for the link!
@Antonio: I see he does a lot of talks in Spain. Do we have a stronger support base there? A lot of good science is coming out of Spain right now as well....
Hi there ! interesting article, just my 2 cents on article,
''Calorie restriction flips a metabolic switch from "abundance" to "austerity".''
Exactly. (with time I am noticing that science magz (especially ones not medical ones, but general science oneS) are trying their best to be truthful and not shy away from telling like it is; people can understand and are not foolish. There might be some mumbo jumbo but the more learn/hear about it, the more it becomes standard stuff everybody knows. I guess it is down to education and learning (but that means 'Believing in it' oftenyly, which many hard headed people don'T want to (believe in or care about ; as I said before, you can handed it on a free silver plater 'IMMORTALITY TM/Inc.' makes no difference they won't eat it).
''Somehow responding to this stress also lengthens lifespan. These days researchers think autophagy plays a big part in the lengthening.''
CR; is abundance (not CR) to austerity (CR) metab switch because you are now officially in 'survival' mode. Evolution favors survival of individuals and species (cause obviously without them there is no evolution). Species continuation depend of the survival of theirs, when nutrients/calories drop so does life (DNA synthesis can't work anymore when there is not enough
nutrient'blocks' getting in to build it), this means it puts the specie/individual in jeopardy. But why then would CR increase lifespan if undernutrition is dangerous to life - because producing energy (ATP)/DNA requires these nutrients (along with Oxygen for OXPHOS) and to maintain blodo glucose levels/many biological activities - but CR uses clever tactics to circumvent the shortcomings. As said, metabolis switching towards ketone production and fat burning instead of relying on dwindwling glucose (liver produces whatever is needed to maintain levels but for oh so long until it is dangerous, you can't just fuel on fat/fatty acids or protein and that's because the Pentose phosphate Shunt pathway relies mainly on glucose - not fat to produce the necessary (G6PD/fructokinase etc)). Not only that, CR activates a plethora of little tricks that make it liveable (for a while 'survival'),
evolution compensates you - you live longer because you are Surviving -when food gets scarce, thus Increasing the Odds of Specie Survival/increase Reproduction Possibility (because you're alive and kicking/can make babies (altough half-fed it will be harder, for even reproduction is Glucose rich endaveor/demanding lots nutrients which CR does not provide.)) = Compensation = Individual Lifespan Increase.
So it's Inabundance vs Abundance nutrient thing. More Resources = More Possibility to Create Energy (in fact one study showed that pigeons with the highest nutrient level intake and the slowest telomere attrition, while starved one were dying quicker (becoming frail and undernourrished/lacing energy))
It's middle ground there, is Overfed, Fed, CR, Underfed, Starved and Starved to Death. CR is in that sweet spot where it is not enough below a certain threshold to create extreme frailty and kill you (but over time it may, if your body as difficulty addapting to this, especially at the start and later on as you continuously do this and body adapts (or tries), not one person reacts the same to CR)
And they are absolutely right - CR is a Stress, purely. It increases dysfunction because nutrients-in drop. Why, later on, it reduces dynsfunction is because as they said it activates autophagy, which is capable of eliminating the small-enough senescing effete. Without autophagy, CR would kill you assuredly. And that's because CR is a stress, like heat or cold, or ROS production - in fact All of these stresses work in the exact same way as CR : they activate autophagy. CR also works its magic by activating a compensatory 'hormetic response ('mild stress'ed-out')' from UCPs and NRF2/ARE response (translocation into nucleus and then activation of Antioxidative Response), this akin
to endoplasmic reticulum stress activating longevity genes.
''Nowadays the paradigm shift is that stress signals like those from free radicals, fasting, or exercise trigger an adaptive anti-ageing response. It doesn't mean past theories are entirely wrong.''
Totally, stress signals are more complicated than we thought. And many of these stresses work in the Exact same way, which is they target the autophagosome. Any of these stress signals 'longevity enhancements' are Nullified if autophagy is gone. Because, all these stresses compromise DNA and damage it, damage the chromosomes,
which bad news -> straight to autophagy process/proteasome. And espeically, damage the Proteins that are crucial to maintain function. When these proteins become Unfolded, they only salvage
is the Chaperons and others (HSPs) that can refold them, otherwise it is irreversible protein unfolding that contributes to aging.
Now you might ask which proteins, they are not the DNA's or RNA's but rather the redox's.
Fatty acid/protein thiols regulate aging. It is now crystal clear :
Autophagy is a 'Background' process (macrophagy, also mitophagy, microphagy), it is like garbage collector, you need one - to function - but it is Not the Cause of Maximum Lifespan
between animals. It is a 'part' of the process for a lifespan - it can make animal life last 30 days or 300 years, it's just there to make life 'happen' it doesn,t control its lengthspan.
Autophagy (and proteasomes) is Only activated by stress and 'insults' - it is a 'compensatory' 'feedback' mechanism that responds when there is damage done - and only when there is damage done, otherwise it's dormant. Its job is to collect the crap that is coming to it (as damaged crap/'stressed-out' molecules) and 'desintegrate it' to smitheereens, at the same time it is supported by special 'folding' proteins/enzymes that refold crapped=out (dysnfunctional) 'unfolded' proteins to their (functional) 'folded-form'. Why would that be so important (over DNA or what have you), because DNA and what have you is dependent, not the autophagosome annd proteasome to dispose of garbages (it is dependent on that but not for lifespan elongation);
but is dependent - To Be Protected, in the First place - to Not accumulate such crap. Remeber the 'it's better to Avoid Damage Altogether, than try to repair it or slow accumulation', ww always lose at that repair game.
And, as said many time, only when start Young do you see real results, any stuff started old, is not helping for damages have clogged the autophagosome (along with lipofuscion increasing lysosomal mass), and that's very bad news because it means you will accumulate
more crap and it will, soon, clogg you to death (for, remember, you need your garbage collector/disposor (functional, that is), if you lose it (because it's so jam-packed of detritus), you're done).
Tink of it like Windows, when Windows accumulates Lots of junk, it starts to slow down and you curse at it - you need a disk defrag or partition erasure (call the garbage disposer 'software', even Windows very own software 'clean the desktop of piled sh*t' is better than nothing).
But what's even more crystal clear is that this autophagy system works with the Guardian of DNA/Telomeres/enzymes/other proteins/etc : The Redox. One study showed that redox protein thiols are the major resason we age, when they become damaged this alters the mV in the cell and has dramatic
consequence on the capability to keep it functioning. Without redox power, cell dies immediately. This study showed that, why is it that certain studies Increase ROS production and there is life extension (because of the hormetic response compensating for the ROS increase and quenching
it) but it was not really that - ROS increase had very little bearing on the lifespan - what did, instead was IF the protein thiols were damaged by these same ROS through some 'end-product' conversion. If not, they were unconsequential -even if they damaged the mitochondria (if the ATP output is kept mitochondrias are a secondary element behind chromosome/nucleus, the mitochondrias are responsible for ATP and are important, but them too rely on Redox, GSH is in every subcompartment of mitochondrias (and outside in cytosol and extra-cellularly), without it they senescene immediately (one study
showed that cell redox was dependent on two systems, GSH/GST/GSX and TRX (thioredoxin), one relieved the other if the other was compromised - they are
in balance and need each other), these systems rely on specific protein thiols and when they are ocmpromised they become unfolded/oxidized (
disulfides), they have catastrophic consequence, the cells just have no more protection (from these said ROS whom damage these thiols through chemical reaction (akin to crosslinking formation)).
Why I am saying all of this, is that I sort of had an epyphany (again), I now link Autophagy with Lifespan, but not the Cause of ITs Length, just a REquirement for it to 'happen', not a 'driver of its aging/why you die at 100 year and a blowfly at a 100 days. Autophagy (as seen in CR, which is 'stress' that damages you, and activates Autophagy 'as a compensatory' mechanism : Austerity/Frailty/Starvation/famine/Undernutrien (CR) -> Autophagy response to 'relieve' austerity 'crap' accumulation (remember CR 'damages' because you are underfed/lower nutrients or lets' just enough, but not enough to make 'more' and this can manifest as damage somewhere. The fact that it activates Autphagy is a proof that it is damaging, autophagy only activated by damaging accrual : easy to understand, its job to Stop/destroy DNA junk that will come from this incurred damage - so it needs cell to 'be damaged' in the first place, hence only activated by damage).
Why I link it to lifespan, is because many animals Show Stellar Autophagy, especially the ones that live LONG. (Naked MOle Rats, Little Brown Bats, Humans, etc...many studies showed they have
enhanced/maintained (functional) proteostatis for a very long time - it's not a consequence of living a long life, it is a COntribution To a Long Life - but not The Cause ultimate.
You need it, yo live a long life, without it you're doomed. That's why mice die in 2 years, there autophagy system is filled up and it's game over.
And that's why, a nake mole rat 'mice-like' rodent live 35 years and maintains a very 'active' proteasome and autophagic system. Any crap it accumulates it's disposed of Quickly and ask very little bearing on its life (hence living 35 years). But, as said, autophagy is not the Cause of why the NMR can live 35 year, it is 'partly' a helping contribution to Allowing it to reach 35 years. For you NEed a Proteasom3Autophagosome/lysosome (functionning) to Live...
What is far more the Cause of this, is this intricate talk - between the Autophagosome and the Redox. (Redox -> Protect from damage happening, Autophagy -> Remove junkcrap if damage happens and makes junk),
ONe recent study demonstrated that clams and ultra long-lived sharks (Groenland skarks living in the deep frigid waters whom are metabolically dead), maintain powerful autophagy if Ever needed (their autophagic systems are DORMANT, and just waitttting for Anything, like Anything, but..no, nothing comes,,no crap accumulate in them, thus autophagy goes to sleep), not only that, it showed that they maintain pristine tiols, confirming the clear relation between autopahy and antioxidative redox mechanisms - to certain fatty acid/prot ein thiol (such as cystein residues) that protect the entire mitochondrial ETC, mtDNA, nDNA, RNA, cytosol, extra-cellular, ECM) and demonstrating, Why, these animals can live 500 years, while a Mouse - has Telomerase with Huge Telomeres - and dies in 2 years. So much for telomerase... Protecting from damage is far more crucial than we thought to lifespan, but this damage can be pinpointed and then, said as the major contributory limit/'intrinsic aging' to why a human has a maximum lifespan of 122-130 years and not 500 years like that greenland shark or clam.
PS: stem cells are NOt the sole decider, they help tremendously when damage happens to repair tissues (and perhaps continous replacement of the niche could solve this), doubtful though, even stem cell injection will not help to make much go over MLSP.
PPS: Last weekend, with family and all, I sort 'confronted' (gently) my family about life extension and talking about death. ....I felt like david against Goliath. You know, like when you are the little man in the corner against a Huge Gang whom will Gang on You to SChool You. It's kind of hard to defend yourself, but Defend Myself, I did. And took them All On (a few of them - intense table speech with voice raising a little bit), alone. It may me remember that debate with Aubrey in front of the Pro-deathists and the crowd not too sure. Me and Against All Them. I feel scared. So anyways, I told them : ''Look...LOOOOKKK....seriously, why could not it not be such a thing as living Longer, you know...like...not dying...not hurting...uknow''. Then it came : ''Because the palent will be OVerpopulated, we will Suffer, and the planet will ExplodE''. I told them, we have thought of all of that and have the solutions - and we will find the solutions, we have no choice, we will MAKE them. But they thought, nahhh, it's science-fiction that stuff, like star trek, 'immortality..seriouslly..',
I told them : 'Rejuvenation...it's real, and it's not some Bullsh*t, we are at tthe crossroad of a revolution and a change, we could make it a SCIENCE, not SCIENCE_FICTION', like a real thing. I told them, how would you like to live to 120...but they said, i will hurt and be sick and want to die, or be bored out of my mind. I replied, that is all in Your Head, you have to Build Mental Strength and tell yourself you Have Reasons to Continue To Live, You want TO Find Reasons, And You Will. They said, but you should accept it humans have always died and we die (period). I said Think Farther, out of the box, let's say, LETS' SAY, we can live HEALTHY and LONG and CONTRIBUTE TO SOCIETY and reduce the burden on hospitals (no one is sick anymore and '''AGING'''' IS GONE (so is the BIG PHARMA WE WANT TO GIVE A PILL FOR YOUR ILL AND KEEP YOU SICK UNTIL YOU DIE), bmy dad said : ''scientifics are trying to stop aging and you can now genetically remove stuff from like in your parents to not give it to the child (to avoid giving dna defects you carry to your child/not compromise your child's life through genetic editing), and then the doctors are saying we will Increase Your Health - Healthspan, so that you can live long..you son, will live to a 100 years old''. I told him, probably not (seeing mother died at 56).
But, I said, I hope to, I believe in REjuvenation, Biorejuvenation, it is our future is WRIITEN in the stars. ITs so crystal clear, more clear than that, you die (well technically, now you won'T since rejuvenation will save you so it can be even CleaRER). My sis told me : 'But YOU...you..what do YOU want TO LIVE FOR...or what would do if you just had 100 days left'...I told her, look twinsis (I'm a twin), I just wish we can live long life, for everyone and remove our diseases that kill us before we reach our maximum lifespan as humans as we age. But what I really want to live for, is FOR MY life...I know hat sounds a bit selfifsh, I only have 1 Life, so do you. Protect it. Death is VERYYYYY long, compared to life. It's infintely long. A 100 years, is but a finite micro-thing. I feel that is unfair and I could have a choice on whether I Want To COntinue to Live or To End It. It is a personal choice, like for everyone's body and life. Also, they said, you will be tired, or sad, people will die around you while you are 'immortal'...I said, yes, that true, there cab be sadness when you are outliving others, but remeber, life was never going to be easy and there are good and bad times (and it's how you deal and ADAPT to it) - if you feel you can't takn aynmore 'Had Enough' and 'accepts it' who am I to tell you otherwise; I can only convince you with what I'm saying but that's just fluff. It'S your decision if you wish to pull the plug. That is why I said, if someone watns to live to 70 years only or if they wish to reach 120; I support them BOTH. I sure wish that person whom wants to leave at 70 would decide to stay a bit longer but what can I say, that's life c'est la vie (or in this case, c'est la mort (it is death).
@Mark: I don't know much people of the LE community in Spain. From the few I knew in the last summit, it seems that SENS is not their favourite approach. Some favour nanotechnology/AI (Kurzweil style), some like telomere elongation, others like the regular use of Yamanaka factors, others are rapamycin fans, etc.
"Have a look at a panel that our new ally Jim Mellon is hosting here at the Milken Institute. Make no mistake, this is the 1%, and what I see in this room are a lot of HNWIs starting to lick their chops at the opportunity this is presenting. Watch it... and LISTEN... listen CLOSELY."
Very interesting talk, mostly because of the kind of people who are talking about LE, even if they have some gross misunderstandings like this one: "a new risk which societies never really had before, which is 'I get incapacited at fifty but I live to a hundred'." Tithonus strikes again...
No, calorie restriction mimetic are not enormously expensive. Polyphenols (resveratrol, quercetin, catechin, curcumin, cinnamon, others) mimic CR and are inexpensive. Yes, CR mimetics that chelate metals like calcium, iron and copper address the drivers of aging and do induce endogenous stem cell survival and therefore do regenerate tissues. The over mineralization theory of aging stands without dismissal. It is the only explanation why humans have birthdays but do not biologically age (intracellularly experience dysfunction of lysosomes, accumulate lipofuscin) in the growth years (up to age 18 or so) when they need calcium to build new bone, iron to make red cells and copper to make connective tissue. Women do not age as fast as men as they menstruate, dispose of iron in the blood loss (akin to blood letting) and don't begin to age till the onset of menopause (cessation of menstruation). There is virtually no biological aging in the growth years, accelerated aging beginning first in males after full growth is achieved and in women with the onset of menopause, and then a flattened rate of aging late in life as the body has reached a steady state of minerals. Women who undergo early hysterectomy age like males. There is no other explanation for these 3 speeds of aging other than mineralization. Genes control aging but what controls genes? Gene expression is involved and the minerals controls the genes. Tissue destruction emanates from the iron-copper induced oxidation (creating the dreaded hydroxyl radical). An over- responsive immune system releases unbound iron from macrophages worsening the problem. If anyone else has an explanation for the three speeds of human aging, I would like to hear it.
@Bill Sardi: the research and development process is expensive, not the current marginal drug candidates. Look at Sirtris, for example. Three quarters of a billion dollars and nothing of any practical use resulted from it.
We know what happens when people take these compounds: essentially nothing. Small, unreliable changes in biomarkers. Recent history is replete with people who consumed larger than usual amounts of these items and who didn't make it to their 80s.
These things are not worth paying a moment of attention to, not when senolytics exist.