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[Mechanism]

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[paula]

Reset the genome with chemicals.  https://www.nytimes.com/2016/12/15/science/scientists-say-they-can-reset-clock-of-aging-for-mice-at-least.html?rref=collection%2Fspotlightcollection%2Ftimes-tips&action=click&contentCollection=topics&region=stream&module=stream_unit&version=latest&contentPlacement=18&pgtype=collection&_r=0

[TomBAvoider]

So, the idea is that the two labs reconciled their results? Highly unusual. One wonders about their methodology. If the conclusions hold - a BIG if - then this should be pretty momentous news for CRONies everywhere, n'est-ce pas? Where is Michael R. who did such a detailed analysis when the NIH monkey research cratered the hopes of so many? Seems this should be fertile ground for him - and we await his sage commentary... anyone there?

[Gordo]

I see nothing new in this article, and some of the statements are dubious.  "Caloric restriction (CR) without malnutrition extends lifespan and delays the onset of age-related disorders in most species" except for most subtypes of mice, mammals larger than a rat, or anything already long lived (like people)! You have to compare CR to a junk food diet, or being overweight, for it to look good (and didn't everyone already know junk food diets and being overweight weren't good?).  You may also have to be locked in a cage where osteoporosis and infectious disease won't hurt you to benefit from CR.  The primate studies were a big disappointment to CR enthusiasts, most of whom have moved on to other more promising pathways to better health and longevity (such as intermittent fasting, plant based whole food diets, large quantities of phytonutrients from diverse sources, restricting IGF-1 boosting foods, avoiding blood sugar spikes, reducing advanced glycation end products, cold exposure, heart rate variability optimization, etc.) But at the end of the day, none of these things will make an enormous difference, perhaps 5-10 years of extra life. The real gains will only come from future technological discoveries, the more we can all promote investment in, and contribute intellectually toward that end, the better.

[Matt]

I've posted this at longecity, but will expand slightly on what I said over there.

 

Although it still stands that both studies have some flaws. To me, it seems that calorie intake does have a significant impact on health and survival, although one could wish that the results were more clearer. Whether or not CR works in in humans is still not settled. As you said, lifespan can be affected in one strain of mice and not another. There were some issues in both studies; as well as inconsistencies with how the monkeys responded to CR (Humans still seem to respond better to CR and more consistently than rhesus monkeys). And certain things which may have compromised the studies' results, some of which they talk about in the paper. UW wasn't great in that it lost quite a few monkeys to preventable and uncommon causes of death: gastric bloat, anesthesia and others. A high number of female monkeys at NIA died from complications of endometriosis. In one of the papers from UW, you'll remember the researchers separating age-related mortality from all causes of mortality, and showing a much more significant result. Personally, and perhaps because i just want to believe! I don't see how gastric bloat from overcooked food tells us anything useful about CR and aging/mortality in primates, so could be excluded in both groups. 

 

The NIA old onset CR and controls showed some impressive survival results though! The control group ate fewer calories relative to the UW male monkeys. However, body weight of the NIA control and CR old onset was not different during much of the study, and as we know, many of the health indicators didn't significantly differ either. (I've written about that in my review of the studies). That being said, estimated survival up to 35-37y relative to 34y in the controls. Perhaps if the CR group was restricted further, and from an earlier age (like UW) with the same nutrition as NIA, we might've seen an even better result (pure speculation of course). But still, the average lifespan being around 26 years for a rhesus monkey, up to 11 years INCREASE is quite a difference, which corresponds to about 33 human years? It's thought that rhesus monkeys at at 3x the rate of humans. So 26 rhesus monkey years would be 78 years for a human

 

Six of the twenty original rhesus monkeys have lived beyond 40 years of age. That is very old for a rhesus monkey! The oldest is on CR and is still alive at 43 years old, breaking all records. 

 

One result which is quite impressive as well is below:

 

"All males and females from the NIA old-onset groups consumed fewer calories than their counterpart controls from UW, instead both control and CR were closely aligned with food intake values of UW CR. Importantly, the median survival estimates for old-onset males were very high, similar to what has been reported previously as the 90th percentile for this species (∼35 years of age). Six of the original 20 monkeys have lived beyond 40 years of age, the previous maximal lifespan recorded, and one old-onset CR male monkey is currently 43 years old, which is a longevity record for this species. Median survival estimates for old-onset females, ∼27 and ∼28 for controls and CR respectively, were also greater than national median lifespan estimates, with one remaining female currently 38 years of age. The clear benefit in survival estimates for monkeys within the old-onset cohort compared to UW controls suggests that food intake can and does influence survival. The lack of difference between control and CR old-onset monkeys suggests that a reduction in food intake beyond that of the controls brings no further advantage."

 

 

If we estimate that many of us could get to around 85-88 or so on a reasonably healthy diet; something like seventh day adventists (average BMI 24-25?), then many of us would see our 100th birthday and beyond with CR. I don't think a 15 year increase in lifespan is a stretch given the evidence of how well CR works in humans and how it more closely matches the CR response we typically would see in rodents. 

[mccoy]

A possibility which deserves some thought, I believe, is that all of these methods are effective inasmuch as they are able to effectively and optimally downregulate the mTOR pathway, which purportedly rules the basic metabolic setup of mammals.

It may be that CR with too high a  protein and carbs quota fails to downregulate mTOR in some subjects. Conversely, a zero or very moderate CR with restriction of protein and carbs may be successful in downregulating this metabolic masterswitch.

[Gordo]

A possibility which deserves some thought, I believe, is that all of these methods are effective inasmuch as they are able to effectively and optimally downregulate the mTOR pathway, which purportedly rules the basic metabolic setup of mammals.

It may be that CR with too high a  protein and carbs quota fails to downregulate mTOR in some subjects. Conversely, a zero or very moderate CR with restriction of protein and carbs may be successful in downregulating this metabolic masterswitch.

This was basically the heart of the whole low IGF-1 debate and Dr. Greger's video comparing CR to a plant based diet.  CR in and of itself does not lower IGF-1, but a plant based diet generally does, no CR required (just avoid more than 3 servings of soy per day and you are good to go).  Again, what are you comparing CR to?  The general population on standard american diet?  Sure, it will look good. This was what the CALERIE study did, much to the annoyance of anyone looking for "real" science on CR in humans.

[Gordo]

Matt, you are all over the board here.  You say "estimated survival up to 35-37y relative to 34y in the controls" but even that is cherry picked.  And then somehow you jump to an 11 year advantage?  I don't think so.  Here are the survival curves:

 

 

UW=high sugar diet.

Even if you pull a 3 year advantage for CR out of this which is questionable, and multiply that by 3 for "human years", that's a 9 year advantage.  Life expectancy in the USA is around  78.8  That means a typical American might live to 87.8 on CR.  This essentially matches the gains expected from a healthy diet and lifestyle (vegetarian, nut eating, exercising, non-smoker, not overweight).  It sounds like you want to take all of the gains from a healthy diet and lifestyle (+10 years) and then add that to the gains from CR (+9) to get +19.  That is seriously flawed thinking.  If anything, the combination results in lower life expectancy compared to healthy diet and lifestyle alone (we pretty much know this based on the Okinawan vs. Adventists).  Dean did a pretty detailed post on this, and Dr. Greger did a video, see:

 

Okinawans vs. Adventists - Is it the Low Calories or Vegetarian Diet?

 

https://youtu.be/mryzkO5QWWY

(go to 3 minutes in to get straight to the point)

 

And what do you mean by "Humans still seem to respond better to CR and more consistently"?  Again I have to ask, "compared to what"?  It seems biomarkers of health are fantastic for people on a plant based diet who aren't overweight, what does CR add other than osteoporosis and lower white blood cell counts (which might end up killing you if you get an infection or fall and break a bone)?

[Matt]

"In the UW adult-onset study, the estimated survival of UW control animals was close to that of the average recorded for monkeys in captivity (∼26 years of age)"

 

I'm saying that the UW study represents more what the ad lib population which we could compare ourselves.. The NIA study's control group were themselves were restricted, and not ad lib. And I was comparing median survival across studies. 

 

"Although an impact of CR on survival was not detected within the NIA old-onset cohort, comparison to the UW study shows that bodyweight was significantly lower in both control and CR groups of males and females than in their UW control counterparts, and was largely equivalent to that of UW CR. All males and females from the NIA old-onset groups consumed fewer calories than their counterpart controls from UW, instead both control and CR were closely aligned with food intake values of UW CR"

 

We do see a trend towards lower calories = better health and longevity across studies (UW > NIA) and within the same study (NIA) looking at morbidity - although clearly, nutrition seems to play a big role. But given the lack of effect on the NIA old onset, in terms of biomarkers and weight (for most of the study), why would the survival curves be that different? We don't know now what would've happened if the CR monkeys were restricted more relative to the *restricted* controls.

 

Median estimated survival is 37 in the NIA. Researchers say that monkeys age 3x faster than humans, so is this like a human reaching 111? I guess it isn't an exact science and just estimates. Monkeys develop /mature between 3-4 times faster than humans, so I guess they factor in this. Also aging of the eye in rhesus monkeys is 3 times faster than humans. So with 6 out of 20 of the original NIA monkeys reaching 40, did we see 6 jean calments? :| or perhaps the extrapolation of the rate of aging is wrong. 43 year old monkey is the oldest on record. And just to quote something again to see why I think this is a big deal. 

"Researchers analysed data on lifespan of 3264 rhesus monkeys, and only two 40-year old monkeys has ever been documented."
 

Hmm okay, so if you compare seventh day adventists to people on CRON, you will see a big difference in biomarkers.  I haven't really looked into this for years, but I believe that people on CRON display far better results across the board from blood pressure, glucose, cholesterol, inflammation etc.. And seventh day adventists live between 85-88 or something depending on if they are vegetarian or not? But perhaps there would be no difference even if these people do CR and improved their health markers even further. I guess it's possible... it's complex, as we see with U-curves on mortality risk from various things - which sometimes can be explained easily, and others not so.

 

People on CR also display much better health markers than offspring of centenarians (they often have a high chance of reaching 100 compared to general population), and although centenarians offspring's biomarkers trend in a CR-like direction, CR seems to have a more powerful effect.

I've read the Okinawan books, and some of the studies, and I know that caloric intake gradually increased over the decades. It was 1500 k/cal or so, and increased substantially. 

 

Hope I've made sense.. super tired! I should be sleeping. Lack of sleep is bad for health. :P 

[Burak]

The traditional Okinawan Diet that surveyed in 1949 was a pinnacle of calorie and protein restriction. Just 39 grams of protein and mostly from plant sources especially sweet potatoes. I think this the lowest we can get from humans and the result is lots of centenarians today who practiced this dietary regime for most of their times due to what was presented at that moment. Furthermore, their diet was also deficient for some of the vitamins and minerals. They were also very high on carbs which I believe as long as it is from natural unrefined sources it should not negatively affect lifespan. 

[Saul]

Thanks Matt, for your careful analysis of the data of the two studies.

 

My opinion of the two studies:  As noted by Matt (and one of the speakers at the last CR Conference, in answer to a question of mine), both studies were seriously flawed -- so, IMO, no valid conclusions can be drawn from either of them.

 

However, Matt does make the interesting point that several of the NIAA monkeys, that were in the "restricted" category -- did have extraordinarily long lifespans -- one of them having the laongest lifespan ever recorded for a Rhesus monkey.

 

I think that any CR pessimism (Gordo? Dean?) based on the two flawed studies is unwarranted.

 

  --  Saul

[Gordo]

I appreciate you guys' optimistic point of view, but I'm still not convinced.  The record long lifespan though is certainly noteworthy and I was not previously aware of that so thanks for pointing it out.