Fight Aging!

"at the benefit of an extremely rare long-lived phenotype supported by a specific lifestyle and chance"

Supported by a specific lifestyle?? Jeanne Calment smoked from the age of 21 to 117, and often ate chocolate, even 1 kg per week in her old age.

The burden of proof is on us I think.
The mainstream won't change their opinion based on discourse unfortunately.

Nope, proof will be in the pudding so to speak. However, we all know it is coming, and coming soon. Aubrey and Jim wouldn't be out there pounding the pavement of policy makers if they didn't have some meat to serve.

Hi there, just my 2 cents, (TL DR : there is just a transparent limit, it is not impermeable; if going at the slowest rate of centenarians, that limits is pretty much there; but that will change later. Jeanne Calment had some help but her lifespan is nearly entirely attributed to family-inherited genetics)

For humans above 60-70 years old, the limit of 120 or so will probably stand (because of irreverisble damages in them). But for people under 60 today, this could be a soft limit and is permeable. Because of the less damage accumulated so far in these younger people; they have a chance of 'keeping their young self' until full rejuvenation happens. In a sense, they can prolong their neotenous period (neoteny features). Because that is the problem with old people, the irreversibility of certain things/damages/etc. Complete Replacement of that old human to a biologically younger human (total replacement/tissue/cells..) seems the only solution. Otherwise it seems there is no solution for already old people today. You need to be young in the first place, that'S the crux of it of 'rejuvenation' - you can wait tops 50-60 but not much more (unless you are biologically younger than other 50-60 years old).

I think Jeanne Calment is a paradox and evidence at the same time. Paradoxal because as said she smoked for a century and evidence because she lived this long while smoking. She would lather her food with extra virgin olive oil and drank red wine. The benefits she got :
- High ORAC from eating dark chocolate 99% cocoa solids, high cocoa bean polyphenols (1 kg a week makes for a lot of antioxidants intake, dark chocolate (of the darkest kind) is top of the list in ORAC/FRAP/TAC power in foods. She was gifted with protection from atherosclerosis - these cocoa polyphenols helped to mop atherosclerosis ROS - but they were not the cause of her protection (she was gifted with inherited family-longevity genetics, her siblings lived long lives too; thus, proving it is not the stuff she took it is her genetics at at least 70% responsible the reason for why she attained 122). She was protected from atherosclerosis by having higher HDL levels right off the bat (centenarian's offsprings display this feature) and lower LDL. Because in my case dark chocolate (and I consumed Tons of it) nearly killed me (that is due to the cocoa butter in chocolate, it is full of saturated fats (saturated fats protect you from oxidation of lipids (from being saturated by missing double kinks in the carbon chain) but they also contribute to dramatic cholesterol synthesis and to 'viscosity' of membrane (losing fluidity offered by the polyUnsaturates which is catastrophic for important reactions and the mitochondrial kinetics); which accumulate in arteries and the atherogenic nature of dark chocolate if without its polyphenols, by its saturates it activates LDL cholesterol and triglycerides formation in liver which is death nail if you are atherosclerosis prone. While the polyphenols work by reducing LDL rate formation and allowing HDL species to be made over LDL; or they literally block cholesterol production enzyme activity altogether (which is the case with beta-glucans or plant sterols or statins). This is why in some cases it can help with HDL but in other case it can be detrimental by raising LDL (because certain people, like me, have defects in LDL specie inhibition (make too much LDL), for more HDL species (lack enough of HDL). To mitigate that, she drank red wine and was getting tons of Resveratrol/senolytic compounds from wine drinking. She also ate cheeses and other produce (mostly the French gastronomy produce, she came from a rich family and could 'afford' buying all this foodstuff). But she did not 'help' herself with smoking a pack a week or so. Paradoxically, it may have helped her (and she was 'immune enough' to it that it did not matter enough to kill her) :

Some studies showed that 'light' smoking can be beneficial; that is the toxicants of smoke act as oxidative stress resistance 'stress response mounting' aka hormesis. One study showed that smoking could increase GSH by forcing the body to respond to the oxidative insults from cigarette carninogens; in tern, this increase 'oxidative stress resistance' : when a small stress becomes benefitial (hormesis). Whereas in other people they can't mount (enough) response (NRF2/ARE/EpRE/Phase II detoxification enzymes/HSPs/Chaperones/HO-1/SOD/CAT...) to counter the damages from cigarette's toxic elements (which many studies showed damage DNA/oxidizes; one single puff is all that is needed to see cell lesions appear)).
Also the olive oil she took was full of monounsaturates, thus she had a double whammy in lipid protection : saturates (dark chocolate cocoa butter, palmitic acid (16:0) and stearic acid (18:0))), monounsaturates (MUFAs (monounsatured fatty acids), in olive oil); extravirgin olive oil is rich in polyphenols (again the ORAC of olive leaf/xtra virgin oil is very high) and the monounsatures (16:1 (palmitoleic acid), 18:1 (oleic acid, the name coming from olive oil))) end up in mitochondrial phospholipids as incorporated fatty acids in the mitochondrial membranes (reducing the ROS lesions), this would protect against lipid peroxidation of highly unsaturated ones (PUFAs) and thus protect mtDNA closeby/more ATP production, longer.

Yet, as said, some people ate All of these and Never reached 122 either. THus, it is a combination of family 'genetic luck' + support (the things she ate/diet/did/environment); about 70% former and 30% or less latter.

The fact that she had siblings that lived long is a demonstration that 'centenarian' genetics obtained (at birth and its importance with advanced age) is a huge reason why people reach 120.
They start young, look young and live longer (Jeanne looked very young at 40 years old, if looking at old pics of her; thus she had high collagen levels (closer to that a woman of 30 or 20 years old; yet she was 40 years old chronologically. She aging in slow-mode and had longer telomeres in young age (thus more 'telomere' left down the road to worth with/postponed replicative senescence - matching the results of a 115 year old woman whom had 2-3kb telomere length left in her leukocytes and was 'at the limit'/the replicative senescence limit).

Moral of the story: you either got it or don't (that is why I believe in CRISP or other techs, they will gave that possibility to people who have 'short-lived' family members and that is not a very good precursor for you if you come from a family that all die at 55.

Just my 2 cents.

PS: I recently found that one of the biggest contributor to aging (is of course telomere-replicative senesnce but besides that) is protein aggregation (SDS-insolube proteins); and it correlates very well with replicative senesnce and telomeres. For example, in NMRs they live 35 years but have very slow accumulation of insoluble protein aggregates (theirs are soluble). Mice have rapide accumulation of protein aggregates. It seems aggregation is incompatible with lifespan, not just 'Average lifespan' but Maximal lifespan. Proteins must be kept Folded, (UPR) uncoupled protein response), when they become unfolded or damaged; they try to refold them (in the proteasome 20/26S, by LAMP, HSF-1, small and large HSPs chaperones), to reuse them (if they can't it is irreversible 'unfolded' state and they are vowed for degradation inthe proteasome); that is why long-lived animals are capable of such long lives they keep proteins unaggregated. Vitamin D3 is capable of lifespan extension or health extension because it works by blocking protein aggregation. A recent study showed that protein aggregation is present not only in all diseases but in intrinsic aging. Alzheimer's, Parkinson's and Huntington diseases show protein aggregations/aggregates as Beta-sheet Beta-amyloids/tau filler - all agreggate cause by excessive oxidative stress. Oxidized/denatured proteins and enzymes become inactive once in this unfolded state; only refolding them can somewhat restore function (and it is why humans live this long, they keep proteostasis of the proteins/enzymes themselves). Studies in NMRs, Little Brown bats (who live 40 years), and other long-lived creatures showed dramatic delaying of protein aggregation and maintained proteostasis (not necessarily More proteasome activity - but just maintenance of it and also inhibiting aggregation in the first place). I think the next 'jackpot' is aroudn there somewhere. One study showed a Positive correlation between HSF/HSPs/NRF2 levels and MLSP, in certain tissues of 17 rodents from mice to NMRs (2 to 35 years). This was also visible in another study using mammals from pig, deer, cow (which reach 50 years old MLSP)...to mice. It seems that protein aggregation and protein errors are fatal (one recent study showed that humans have lower protein errors than many other mammals). HSPs protein chaperones are capable of refolding unfolded proteins and that is a god sent it seems for extreme lonvegity. This was also showed in long-lived clams from Iceland (A.Islandica, 500 years old), they can mount a UPR much easierly and maintain pristine 'unfolded' folded proteins aka no protein aggregates depot accumulation. What is also interesting is that this connects/ties directly with the Redox. HSPs work their magic by activating GR/GPRx/TRX, this in turn protects the cysteine amino-residue of all proteins (which becomes oxidized with age and contributes to protein aggregation). Cancer highjack HSPs and the redox to make an inflammatory environment that is safe-enough for its own survival yet harmful enough to kill surrounding cells (SASP).

PPS: typo. UPR ((unfolded* protein response).

Thanks for the excellent comments on limits to Human Longevity. Of note, Calment also ate lots of tomato paste, which provides a concentrated amount of beta-carotenes, a strong antioxidant, that is not as available in fresh tomatoes. So she really practiced good nutrition. She had a brother who lived to 96. Men in general have a 5 year shorter lifespan than women, so 115 is really the maximum lifespan for men, and 120 for women.

Nope. See the last comment here: https://www.fightaging.org/archives/2016/09/use-of-a-mitochondrially-targeted-antioxidant-fails-to-reduce-sarcopenia/

And see also this paper linked there, that shows that tobacco + beta-carotene is worse for lung cancer than tobacco alone: https://academic.oup.com/jnci/article/91/1/7/2549283/Lung-Cancer-Promotion-by-Carotene-and-Tobacco

Antonio, what exactly do you mean by 'nope'? You reference Michael's explanation of mitochondrial anti oxidants, but without further elaboration. Having less saturated lipids making up the mitochondrial membrane is one thing which is probably of benefit- are you objecting to this point? Or are you claiming anti oxidants are not helpful at all; clearly this is not true, particularly if you consider those endogeneousky generated via NRF2 for example, (although admittedly not generating ROS is always better). And remember the mice with mitochondrially targeted catalase did live longer.

PPPS: I think it is true that antioxidant can be detrimental, as Michael explained it deeply, yet from the same token they are beneficial Too. But has he specified it depended on a host of circumstances (like where (if it is in the mitochondrial ETC to quench ROS at COmplex I and III; if not well it may not be doing its job and as he said, certain antioxidants become Prooxidants; I know I suffered this when I was in my earliest bout of my disease, certain antioxidants made me worse and increased the athoeroscleosis rather than reduce it. As he specified, such Vitamin E, Ascorbate, Selenium, GSH or other important antioxidants could turn 'bad' and produce new forms of the antioxidant - which are oxidizing instead of antioxidizing. It is why certain could not see improvements from antioxidants; they could behave 2-faced/double-edge sword depending on where/when/how much (dose)/context (diseased or not?)...etc)). ANother problem with them is that they could quench ROS Too much and this affected the precious ROS/Quenched ROS balance - ROS are signals that are crucial for function - Too Little - Very Bad - Too Much - Very Bad too. Thus, there is a sort of middle ground where the mitochondrias use UCPs (uncouplin proteins) to uncouple mitochondrial membrane potential and ETC aTP production; this reduces ROS production to a level that is not enough to be absent either yet high enough that there are still ROS, thus the signaling is not lost.

It is also why endogenous antioxidative enzymes and other antioxidatives (SOD, CAT) do a better job when it is the body that regulates this (endogenously) rather than intake of SOD/CAT (exogenously)). And as Michael said, sometimes these antioxidants never reach their intended target (like mitochondria ETC), they just linger aroudn and become Prooxidant.

About the beta-carotene he said it was converted to a type of oxidizing version...

Studies showed that centenarians have higher beta-carotene, lutein, lycopene, astaxanthin and cryptoxanthin in the brain fluids. Demonstrating that they are powerful ROS quenchers that boost cognitive function (which is necessary for long lifespan and stopping Alzheimer'S/dementia/cognitivie decline (cognitive decline is correlated lifespan))), especially tomato red pigement lutein, lycopene. But, as said, it is double-edge sword, in certain instances this can be prooxidizing. It really is confusing.

''In brain, lutein and -carotene were related to cognition with lutein being consistently associated with a range of measures.''

Relationship between Serum and Brain Carotenoids, -Tocopherol, and Retinol Concentrations and Cognitive Performance in the Oldest Old from the Georgia Centenarian Study

1.https://www.hindawi.com/journals/jar/2013/951786/

@Mark

OK, I will quote the relevant part in both links:

"It would depend, first, on whether such agents actually acted as antioxidants in situ: with the exception of spin traps like PBN, antioxidants almost never truly "quench" a free radical, but rather donate an electron to complete the unpaired valence electron in the reactive species and then themselves adopt a pro-oxidant form (such as conversion of GSH and NAC into thiyl radicals, vitamin E to tocoperoxyl radical, beta-carotene to beta-apo-carotenals, etc). What makes a given molecule an "antioxidant" in meaningful terms is that its radicalized form is less toxic than the original radical species in the biological context in which it occurs"

"Several large-scale intervention studies were then designed to test the ability of β-carotene alone or combined with α-tocopherol or retinyl palmitate to prevent lung cancer (6-10). Unexpectedly, these studies failed to demonstrate prevention of lung cancer. Furthermore, both the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study conducted in Finland (6, 7) and the β-Carotene and Retinol Efficacy Trial study conducted in the United States (8, 9) demonstrated a higher incidence of lung cancer in current smokers, alcohol drinkers, and individuals exposed to asbestos who received β-carotene."

From the first quote, beta-carotene doesn't seem the be an antioxidant.

From the second quote, beta-carotene seems to worsen the effects of tobacco, not preventing them as Biotechy suggests.

I just googled some health benefits of tomato paste, and found that tomatoes contain a synergistic mixture of all four carotinoids, including alpha and beta carotene, lycopene, and lutein. Lycopene is the most abundant and strongest antioxidant regarding tomatoes. One study found that tomato paste reduced LDL levels somewhat, and improved the dynamics of the blood vessel endothelium. I was aware of some of these other benefits and nutritional components of tomatoes, but did not give it much thought in my original comment.

@Biotechy: Size of effect matters. If eating tomatoes made enough of a difference to matter, that would have been noted in antiquity. Everyone who ate a lot of tomatoes still died on just about the same schedule as all of their close peers who didn't eat quite so many tomatoes.

It drives me to distraction that so much of this community would rather scrabble around in the dirt and try to age to death five minutes after their neighbors rather than strive for something radically, massively better.

If tomato paste is affecting blood vessel endothelium then it might not be a direct anti oxidant effect, but possibly to do with the angiotensin pathway. This is related to both relaxation of blood vessels and maintenance of mitochondria via mitophagy. Mice with genetically inhibited angiotensin lived 25% longer, I believe, which is pretty substantial - and touches on the important point again: maintenance of mitophagy results in lower production of ROS. This is far better than trying to intercept the effect of ROS, as explained my Michael and repeated above.

I think there is real benefit to be had now for humans if we can maintain our mitochondria with lower long term ROS. CR does this already, but maybe we can better that with a more direct intervention.

Well Reason, when SENS or others provide something that beats CR/ other current interventions we can all stop messing about with this stuff!

Reason Tomato benefits would not have been found in any case in ancient times, because it was only brought to Europe in post Columbus times. Clement was the longest living person, so it is of interest why she lived so long. I am simply suggesting that her eating a lot of tomato paste was good for her longevity, as was eating chocolate, another post Columbian discovery. Some of us are trying to live long enough on conventional medical knowledge and food nutrition until the real life-extending therapies come on board. I am 77 so I can't rely simply on the life extending therapies that start to come on line 20 years from now.

It's even more difficult to find the benefits when you a priori decide that it's beneficial and then search for proof of the imagined benefits.

You started by saying that Calment lived so long, despite her bad habits like smoking, because tomato has beta carotene, that is a strong antioxidant. When I pointed out that beta carotene, nor is an antioxidant nor prevents the bad effects of smoking, then you present a different mechanism for the alleged benefits of tomato, again with no solid proof. That's just the opposite of how science works.

Antonio, Perhaps the best answer I can give you is CANanonymity's last comment above where he found studies where Centenarians had high levels of beta-carotene, lycopene, and lutein in their brains along with some other important carotinoids. They lived a long time, perhaps more than most of us will live, so maybe Clement, who ate a lot of tomato paste benefitted her longevity by having it in her diet. Various authors have stated that greater benefits occur when several carotinoids work synergistically to provide healthspan benefits.

That doesn't prove that ingesting beta carotene extends lifespan.

Some people don't get lung cancer even if they smoke. Lots going on here, all we can say for sure is that Calment won the lottery genetically many times over.

@Mark - you assumed that genes determined the outcome of Calment living to 120+. However aging is stochastic damage. Her long life probably wasn't much to do with her genes at all, she just won the lottery on how much damage she accrued several times in her life. Put another way, if you cloned calment 1000 times, none of those clones would live to 120+. They might even just have a slightly higher than life expectancy over all.

As Reason has pointed out many times, looking for longevity genes can be a bit of a waste of time and money.

I disagree Jim, I think her age would have been impossible to reach without her genes and none of us could do it no matter how many times we lived our lives over (without using intervention unavailable to her).

She just had the genes to accrue damage more slowly, and/or live on in spite of that damage.

I look forward to the time when we can all remove that damage and live to her age and beyond in real, non decrepit, health.

There are many papers measuring the influence of lifestyle and genetics in aging. Generally, genetics is more important in late life. See for example: https://www.fightaging.org/archives/2016/04/influences-on-longevity-genetics-or-lifestyle/

And see also: https://www.youtube.com/watch?v=I1hlLM-LTmU (last half)

PPPS: I believe that since one of her siblings did live long too, it helps to solidy genetic component - it is not the be all end all, of course and not all her siblings lived as long. But, as said, she did harmful things (smoke cigarettes pack for a 100 years basically) that kill other people (how many people survive smoking a 100 years). She was protected by that (both by genetically and food she took) and as said earlier, I think there may been a paradox-effect for her - smoking increased NRF2 response because of Hormesis 'small-stress' response (also the French Paradox (French eat fatty saturated foods (game meat, blue cheese, fat livers, fatty duck..etc) and would be dead of atherosclerosis (like me when I ate this stuff and nearly died of it)) but they are not, they are protected; first by enough genes for a 'normal lifespan' - but by drinking red wine or compensating with dark chocolate cocoa polyphenols or olive oil polyphenols/MUFAs intake - they are getting sufficient TAC/FRAP/ORAC to improve oxidative stress caused by certain foods or smoking cigarttes like she did for so long. Thus are somewhat spared. Humans need about 3000 ORAC units a day in blood ORAC to combat oxidative stress; you get that when you ingest antioxidant rich/nutrient dense foods. In her case, most of this damage from smoking is 'curbed' because she ate those things - but it was not the totality why she reached 122. As said, other people lathered in olive oil/chocolate/red wine and Never lived to 122 either. That 'extra component' is that genetic she was gifted with. Her brother lived to 97 years old, ok not all her siblings and he might have also eaten tomatoes/chocolate/red wine for sure; but it means it is a combination of both.
About 60-70% (genes at birth, and especially 'later on' in life where genetic is larger factor if you make it pass 100 or not) + 30-40% (the rest/lifestyle/diet/environment). Also, it is not one or the other, genes affect damage rate (NRF2/ARE and others which mitigate ROS damages) and damages affect gene activation/genome fidelity and transcription too (epigenetic (de)methylation/epigenetic DNA clock become deregulated/dysfunctional). Also, it's true that carotenoid will not stop everything. High brain carotenoid levesl is mostly Correlative to long lifespan, but as Michael said, it can be oxidative (2-face antioxidants). It's not one-size-fits-all with antioxidants; that is why you must verify when taking them; how your body responds because it could actually be detrimental and produce oxidizing condition instead of 'helping' as 'Anti-oxidant'. Bottom line: test it and see what works/or not - there seems to be More Positive (outweighing the Negative) to take food antioxidants than Not take them (take into accoutn your current health and other factors); they May behave as Oxidants in your current health state, only you will find out. I had to stop certain antioxidants - such as high selenium because it was too dramatic and caused oxidative lesions/ischemia (selenium raised GSTs, glutathione s transferase and other seleno enzymes of the redox, which are detoxifying enzymes. They are great but in diseased state they turn 2-face and can Accelerate a disease because they are akin to 'immune' cytokines that are part of the 'inflamattory' respons Compensation (IL-6, TNF-a, Interferon-G, all are helpful in immunity yet can kill you also; especially TNF who raises ROS production to kill cancer cells and increases p53/p16/p21/cell cycle arrest/senescence by major ROS production. Well, certain antioxidants are not Alwways Antioxidants (depending if exogenous or endogenous) and have Dual Role - can be Oxidants if Needed or Become oxidants by chemical reactions changing/Turning 'its state' (2-faced nature antioxidants depending on biological context)). Also, some of the marketed stuff as antioxidant is not really in its antioxidinz form...like certain Omega-3s or L-cysteine that can be exposed to oxygen and go 'rancid/oxidized form'; which basically becomes 'poison' (that is why it is better to consume foods that contain them naturally 'in natural balance' with others, rather than by separate synthetic ones). In any case, apply judgment and don'T over do it/go slow, pace/dose and see how body responds. It took me 2 years tostabilize atherosclerosis and without any SENS. You become so so so aware of your body, it's like you're not living 'out there/out of your body' in the world; your living Inside, in your body, that'S it; what happens outside is no concern for there could be not more 'inside' soon if you don'T fix it. Just a 2 cent.

CANanonymity: Dr. Micozzi just published an article in Insider' Cures on Nov. 17. 2017, where he discusses the longevity benefits of the carotenoid astaxanthin, that you listed in an earlier post above as being found in higher than normal levels in the brains of Centenarians. He cites a study from Hawaii that recently found that animals that received the highest amounts of this carotenoid showed a 90% increase in the activation of FOXO3A longevity gene in their heart cells. About a third of humans have the longevity allele G of the FOXO3A SNP. I happen to be homozygous GG for this SNP and at least 12 other FOXO3A SNP's. Astaxanthin is found in salmon, crill oil and a number of other food products.

Hi Biotechy !

Thanks for that. Just a 2 cent. Astaxanthin is one of the most potent carotenoid, along with lycopene. Beta-carotene is most abundant. They have strong antioxidative activity (in certain cases) because they quench/are incorporated in the inner mitochondrial membrane; thus they mitigate Complex I ROS. And then again at the same time, could be bad in certain context (such as the studies showing that certain carotenoids could accelerate cancer and like beta-carotene converted to beta-apo-carotenal oxidized version which is toxic). There is an old saying, too much of a good thing is just as bad as too little. Moderation is key. Also, as you said, some carotenoid act far more than just antioxidant (or oxidant in certain cases), they activate many genes that contribute to longevity (as the FOXO3A from the study you mentioned); plus the study I mentioned questioned the 'antioxidative' power of such carotenoids; alpha-tocopherol could possibly quench radicals even more - yet centenarians had higher brain carotenoids. This means, that carotenoids act through other pathways that affect longevity genes (such as FOXO3A), which alpha-tocopherol does not act through (they have more tricks up their sleeve than just 'antioxidation'). I believe one of the other pathways they work on is retinol/retinoic acid pathway - very related to Vitamin A; which correlate carotenoids. Retinoic acid pathway can induce rejuvenation/remodelling/bone remodelling; and I am positive neuronal remodelling/BDNF/neuronal synthesis, this can explain why the centenarians with high carotenoids had better cognitive function. plus, as I said in previous posts; certain vitamins stop protein aggregation (vit D for example, strangely a Sun-vitamin; while vit. A is skin pigment vitaminl they reach other half-way; Vit D/A are crucial for stopping protein aggregation and solid neuronal protection (D is also good for immunity and improving redox as well as stop LDL specie for HDL species. Disease states show oftenly low D or A; and also low Carotenoids. Carotenoids are part of the blood ORAC/TAC/FRAP; they circulate in it and mop ROS (and in some instances they don'T as some studies showed that they could be detrimental if in a state of disease (such as cancer)))). It thus becomes the question : better to take them or not ? it depends how you are now/health wise. There seems to be more good from them than bad Overall. But if you are in a disease state, it could 'reverse' and they could be harmful (any doctor would say about such and you would have to stop them/adjust/adapt your antioxidants regimen))). Because there are so many 'types' of genes and so many people with different phenotypes/gene types...it's very hard to say one thing Will Work in someone and in an another too; it may not work in the next person simply because of the immense diversity of SNPs/genetic types; no single person is the same or responds 'Exactly' the same. Some food may kill me but for others, they can eat day and night; and will never have a problem. Genetics are so complex. Again, moderation/middle ground is the key.