Path to Longevity (new book) by Luigi Fontana

[Dean Pomerleau]

1 hour ago, Matt said:

Low LDL-C and mortality from cancer, and all-cause mortality has been discussed so many times around here and on the CR email lists.

Yes Matt. We have talked previously about the likely reverse causality in the relationship between low LDL and mortality risk in elderly. In other words, underlying pathologies and poor health (perhaps early stage cancer) reduce cholesterol levels, often long before the acute illness or death. Here is an article [1] (pdf) I hadn't seen before providing evidence that the relationship is mediated by interleukin 6 (IL-6). 

Here is the gist of the article:

Hence, it seems reasonable to postulate that, when low LDL-C points to increased non-cardiovascular mortality, it is simply serving as a marker for incipient pathologies, associated with inflammatory elevation of IL-6, which are driving the increase in mortality risk...

Importantly, meta-analysis has now confirmed that increased plasma IL-6 in the elderly is associated with a notable increase in all-cause and cardiovascular mortality; an increase in non-cardiovascular mortality can also be inferred from the data. Hence, it is proposed that when low LDL-C in the elderly predicts increased non-cardiovascular mortality, this low LDL-C is serving as a marker for inflammation-linked incipient pathologies, entailing increased production of IL-6, which are responsible for this increased mortality.

In other words, IL-6 causes both inflammation and reduces LDL-C, and it is the inflammatory state (not the low LDL) that is undermines health and longevity.

Here is a figure from the paper illustrating the relationship:

"Prodromal" means something like "precursor".

--Dean

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[1] DiNicolantonio JJ, McCarty MF. Is interleukin-6 the link between low LDL cholesterol and increased non-cardiovascular mortality in the elderly?. Open Heart. 2018;5(1):e000789. Published 2018 Apr 13. doi:10.1136/openhrt-2018-000789

 

[Mike41]

I too think Matt nailed it. IAC, a Cochrane review of PCKS 9 inhibitors showed higher mortality among people who HAD HEART DISEASE! 
 

strange that even though they have significant positive effects on cardio mortality Lowering cardio mortality by 25%. BUT overall mortality was not better than placebo among people who already had vascular heart disease and took these drugs. My guess is it’s side effects of the drug WHICH MUST BE AWFUL FOR THIS RESULT!  But still perhaps a very low ldl is not a good thing and that is the cause. That seems very doubtful though as statins improve overall mortality.
Also the studies should have been longer for a more reliable conclusion.

Over short-term to medium-term follow-up, PCSK9 inhibitors reduced LDL-C. Studies with medium-term follow-up time (longest median follow-up recorded was 26 months) reported that PCSK9 inhibitors (compared with placebo) decreased CVD risk but may have increased the risk of any adverse events (driven by SPIRE-1 and -2 trials). Available evidence suggests that PCSK9 inhibitor use probably leads to little or no difference in mortality. Evidence on relative efficacy and safety when PCSK9 inhibitors were compared with active treatments was of low to very low quality (GRADE); follow-up times were short and events were few. Large trials with longer follow-up are needed to evaluate PCSK9 inhibitors versus active treatments as well as placebo. Owing to the predominant inclusion of high-risk patients in these studies, applicability of results to primary prevention is limited. Finally, estimated risk differences indicate that PCSK9 inhibitors only modestly change absolute risks (often to less than 1%

Edited July 6, 2020 by Mike41

[AlexB]

What do you all think of the vegetable fast concept Fontana talked about in this book? Seems similar to Valter Longo's FMD but just veggies and evoo, and done 1 or two days each week. He said that doing this twice a week would be roughly a 20% calories restriction. I like the idea of regular 1-day fasts instead of 5 days fasts, which can be more grueling and harder to be consistent with.

[mccoy]

On 7/19/2020 at 11:52 PM, AlexB said:

I like the idea of regular 1-day fasts instead of 5 days fasts, which can be more grueling and harder to be consistent with.

I agree that Fontana's brief fasts are surely useful, but the overall result, in terms of metabolic signals, is not the same. A 1-day restriction on vegetables and EVO cannot provide the same regenerative benefits of a 5 days restriction which has been experimented on rats and humans. 

[Ron Put]

6 hours ago, mccoy said:

I agree that Fontana's brief fasts are surely useful, but the overall result, in terms of metabolic signals, is not the same. A 1-day restriction on vegetables and EVO cannot provide the same regenerative benefits of a 5 days restriction which has been experimented on rats and humans. 

I agree.  But I wonder if fasting has much additional benefit for those already on moderate CR?

Also, doesn't Longo argue that his fasting-mimicking regimen ameliorates some of the problems with fasting? 

[mccoy]

4 hours ago, Ron Put said:

I agree.  But I wonder if fasting has much additional benefit for those already on moderate CR?

That's debated, there has been some discussion about it in the past. Of course, a chronic restriction is conceptually and probably biologically different from acute restriction, but I don't have an answer, people on moderate CR in this board have tried more severe fasts than the FMD, like a zero-calories 5 days fast, or a 7-days FMD plus another 7 days at 250 kCals, or others. The benefits are not immediately visible since there are no lab tests for autophagy. 

4 hours ago, Ron Put said:

Also, doesn't Longo argue that his fasting-mimicking regimen ameliorates some of the problems with fasting? 

Sure, His FMD is the result of optimization and an FMD is not as grueling and hard as AlexB thinks. He optimized for various variables, such as neurological signals (hunger, tiredness), glucose signal, amminoacids signal, psychological and even social considerations (5 days can be done during a working week , refeeding on the weekend).

The result in my case sure ameliorated the situation. I once went thru a 5-days, zero calories fast but it was pretty hard, I lost 11 pounds, was very tired and could not reach my target of seven days because I was not even able to study for my university exams.

With the FMD, which according to Longo yields similar metabolic results to a zero fasting, I have no such problems and am presently finishing my 12th FMD.

In this perspective, it's a huge breakthrough in the field of health and longevity.

Last, Longo's optimization has been designed for the general public. We might benefit from another optimization. One step further, for example, which I'm experimenting now, is the low-carbs FMD, which decreases the glucose signal and triggers a stronger pathway of autophagy. A keto FMD would be another kind of optimization which probably approximates more a zero calorie fast, but probably not fit for everyone like those having some gluconeogenesis problems. Longo has hinted at these concepts in some of his podcasts.

[Ron Put]

15 hours ago, mccoy said:

Of course, a chronic restriction is conceptually and probably biologically different from acute restriction, but I don't have an answer, people on moderate CR in this board have tried more severe fasts than the FMD, like a zero-calories 5 days fast, or a 7-days FMD plus another 7 days at 250 kCals, or others. The benefits are not immediately visible since there are no lab tests for autophagy

I did three-day water-only fast last year, but at BMI between 18.5 and 19, I am thinking there is little chance of any great benefit.  I do daily intermittent fasting, usually about 15-19 hours without any food. 

I do drink coffee in the morning, as from what I've read it actually facilitates autophagy.  I am also a fast caffeine metabolizer.

[Mike41]

Ron wrt coffee do you recall where you read that. I generally do 14 -16 hour fasts. I was not certain wrt coffee which I love first thing if it would break the fast. I drink it black

[Ron Put]

4 hours ago, Mike41 said:

Ron wrt coffee do you recall where you read that. I generally do 14 -16 hour fasts. I was not certain wrt coffee which I love first thing if it would break the fast. I drink it black

As long as it's black, drink it up, Mike 🙂  That's what I do.

Coffee induces autophagy in vivo

The data presented in this paper unequivocally demonstrate that coffee is a potent, rapid inducer of autophagy in multiple tissues in vivo in mice. This effect is independent of caffeine content. Although caffeine has been shown to inhibit mTORC1 and to induce autophagy in hepatocytes in vivo, thereby reducing intrahepatic lipid content and stimulating β-oxidation, as well as counteracting hepatosteatosis,³⁴ caffeine is apparently not required for coffee-induced autophagy. Rather, other coffee components that are not eliminated during the decaffeination process, presumably polyphenols, must be responsible for these effects. Autophagy induced by coffee is accompanied by the inhibition of mTORC1, which represses autophagy in conditions of nutrient availability (particularly amino acids and lipids).

[mccoy]

The conclusions fo that article are pretty strong and should be confirmed elsewhere. We've discussed pretty much about the typical compounds found in coffee, the diterpenes cafestol and Kafewhol, they might have a role in that, although they are also told to have an adverse effect on blood lipids (higher LDL), which is debated. The presence of diterpenes is relating to the filtering process used or the lack of it.

Again, when such a report comes up, it needs to be confirmed by others, simply because it seems too good to be true!

 

The Harvard site has a good summary of the properties of coffee, didn't see the autophagy effect though.

Quote

 

Coffee drinkers concerned about cholesterol weren't happy about some early study results showing that coffee seems to increase cholesterol levels, and "bad" LDL cholesterol levels in particular. But upon closer inspection, the bad news turned out to be not so bad, because the cholesterol-raising effect seems to be limited to coffee that hasn't been filtered, which includes Turkish coffee, coffee brewed in a French press, and the boiled coffee consumed in Scandinavia.

The cholesterol-raising ingredients in coffee are oily substances called diterpenes, and the two main types in coffee are cafestol (pronounced CAF-es-tol) and kahweol (pronounced KAH-we-awl). They are present either as oily droplets or in the grounds floating in the coffee. But a paper filter traps most of the cafestol and kahweol, so coffee that's been filtered probably has little, if any, effect on cholesterol levels.

The best evidence is for paper filters, but an interesting study published in 2011 showed that filtering methods used in Singapore (the so-called sock method, which uses a cotton-nylon cloth) and India (metal mesh) were also effective at trapping cafestol.

Espresso contains more cafestol and kahweol than paper-filtered coffee, but because it is consumed in smaller amounts, it may not have much of an effect on people's LDL level.

There is a twist to this aspect of the coffee story, because cafestol and kahweol may also have some health benefits that are lost when they're filtered out. The research is in the preliminary stages, but cafestol and kahweol could have some anticancer effects and be good for the liver.

 

 

[AlexB]

On 7/22/2020 at 4:03 PM, mccoy said:

I agree that Fontana's brief fasts are surely useful, but the overall result, in terms of metabolic signals, is not the same. A 1-day restriction on vegetables and EVO cannot provide the same regenerative benefits of a 5 days restriction which has been experimented on rats and humans. 

I think I'll undulate my fasting.

1-day veggie fasts on a weekly basis.

5-day FMD quarterly.

Thanks for all of your input on this thread.

[TomBAvoider]

I too think Matt nailed it. IAC, a Cochrane review of PCKS 9 inhibitors showed higher mortality among people who HAD HEART DISEASE! 
 

strange that even though they have significant positive effects on cardio mortality Lowering cardio mortality by 25%. BUT overall mortality was not better than placebo among people who already had vascular heart disease and took these drugs. My guess is it’s side effects of the drug WHICH MUST BE AWFUL FOR THIS RESULT!  But still perhaps a very low ldl is not a good thing and that is the cause. That seems very doubtful though as statins improve overall mortality.

But PCKS 9 and statins do not act the same way in the body, so it's unreasonable to expect the same outcomes. PCKS 9 inhibitors cut LDL production very narrowly. But statins have much broader action in the body, and in fact there is a lot of speculation that the benefits from statins are not tied to the lowering of cholesterol, but due to their incidental anti-inflammatory effects and impact on the endothielial tissue. If that is so, then there is no surprise really that PCKS 9, which lowers LDL does not have the same life extending effects that statins do, which have a ton of other effects.

That said, I don't find this study compelling. I think there is a lot more to the PCKS 9 inhibitors.

As I've stated before, I'm on a statin - atorvostatin 10mg daily - due to high LDL that I am unable to control despite heroic lifestyle/diet interventions. The statin brings it down very nicely to low 70's. Obviously, I was concerned about taking a statin, but on balance, I will continue. Meanwhile, my triglycerides have always been reasonable (50's).

[Mike41]

TomB said: That said, I don't find this study compelling. I think there is a lot more to the PCKS 9 inhibitors
 

why is that??

Ron Putt said:

s long as it's black, drink it up, Mike 🙂  That's what I do.

Coffee induces autophagy in vivo

The data presented in this paper unequivocally demonstrate that coffee is a potent, rapid inducer of autophagy in multiple tissues in vivo in mice. This effect is independent of caffeine content. Although caffeine has been shown to inhibit mTORC1 and to induce autophagy in hepatocytes in vivo, thereby reducing intrahepatic lipid content and stimulating β-oxidation, as well as counteracting hepatosteatosis,³⁴ caffeine is apparently not required for coffee-induced autophagy. Rather, other coffee components that are not eliminated during the decaffeination process, presumably polyphenols, must be responsible for these effects. Autophagy induced by coffee is accompanied by the inhibition of mTORC1, which represses autophagy in conditions of nutrient availability (particularly amino acids and lipids
 

thank you Ron! Now McCoys post has got me wondering? Should I filter it? I cannot afford to allow my cholesterol to climb. My ldl is 105 and that is with 40 mg. Of Crestor!!, the highest dose and the most potent statin. I am also on a Dean Ornish 12% fat plant based diet. Geez, Damn genes! Ldl is over 200 on a low fat plant based diet without statins. 

 

 

[Dean Pomerleau]

1 minute ago, Mike41 said:

Should I filter it? 

Yes, with a paper filter. See this discussion between me and Michael:

--Dean 

[Mike41]

Thanks Dean, I will continue to paper filter my pour overs.

[Ron Put]

28 minutes ago, Mike41 said:

I am also on a Dean Ornish 12% fat plant based diet.

Mike, do you use olive oil (EVOO)?  I am just curious since my one-person experiment has dropped my cholesterol dramatically, from almost 200 five or so years ago, before I started my sort of a CR regimen, after which it dropped to the mid 160s. 

Since I drastically cut EVOO a year and a little ago, it has dropped further to the high 130s, with HDL staying in the low 60s, VLDL at 6, and triglycerides at 28.  All my 30% fat intake nowadays is from flax, avocado, cacao nibs, and nuts.  The weird part is that I have a hodgepodge of genes that supposedly affect this, but a bunch appear to predispose me to high LDL, like  rs599839(AA).

I attribute it to the elimination of EVOO since this is what I set out to specifically do, after reading a bit about it, but of course, it may be just a coincidence.

[mccoy]

On 7/24/2020 at 5:57 PM, AlexB said:

I think I'll undulate my fasting.

1-day veggie fasts on a weekly basis.

5-day FMD quarterly.

Thanks for all of your input on this thread.

Good strategy!

[Mike41]

22 hours ago, Ron Put said:

Mike, do you use olive oil (EVOO)?  I am just curious since my one-person experiment has dropped my cholesterol dramatically, from almost 200 five or so years ago, before I started my sort of a CR regimen, after which it dropped to the mid 160s. 

Since I drastically cut EVOO a year and a little ago, it has dropped further to the high 130s, with HDL staying in the low 60s, VLDL at 6, and triglycerides at 28.  All my 30% fat intake nowadays is from flax, avocado, cacao nibs, and nuts.  The weird part is that I have a hodgepodge of genes that supposedly affect this, but a bunch appear to predispose me to high LDL, like  rs599839(AA).

I attribute it to the elimination of EVOO since this is what I set out to specifically do, after reading a bit about it, but of course, it may be just a coincidence.

Ron it literally doesn’t matter what I eat WRT LDL. I have familial hypercholesterolemia. High fat, low fat the liver over produces it either way. Diet has zero effect.

[Mike41]

2 hours ago, mccoy said:

Good strategy!

Wrt to Longo And his FMD all I can say is the plan is  a bit off putting. I mean seriously one size fits all! Makes no sense what so ever. Again it’s easier to sell it, but that don’t make it right.

[mccoy]

3 hours ago, Mike41 said:

Wrt to Longo And his FMD all I can say is the plan is  a bit off putting. I mean seriously one size fits all! Makes no sense what so ever. Again it’s easier to sell it, but that don’t make it right.

Mike, as I wrote the FMD is the result of an optimization, that's why it tends to be one size fits all.

Besides, Longo is clear that the frequency can be adjusted, from once, twice a year for ultra fit persons to once per month for obese individuals.

Moreover, as already discussed, we may adjust the macros, fine-tuning the glucose signal according to our individual response, with the possibility to choose a ketogenic FMD.

Last, we can adjust the length, some people in this forum already did longer FMDs or FMDs plus a more rigorous fast.

[TomBAvoider]

Mike, sorry to be asking all these questions - I too have high LDL which I'm completely unable to control without medication - but I'm still curious. Do you know what effect fasting has on your LDL? When I fasted water only for 8 days, my LDL dropped a little, but not nearly as much as with a statin (I went off the statin when I was fasting).

The reason I ask, is because fasting primes catabolism, so any function that is anabolic or that "builds", should theoretically go down drastically. I would therefore think that when you fast, the body gets the signal "don't produce as much LDL (or anything else for that matter)". Fasting spurs autophagy as the body searches for all materials to break down in the absence of nutrients. This would lead me to think that LDL production would collapse as well. What is your experience? TIA!

[Mike41]

19 hours ago, TomBAvoider said:

Mike, sorry to be asking all these questions - I too have high LDL which I'm completely unable to control without medication - but I'm still curious. Do you know what effect fasting has on your LDL? When I fasted water only for 8 days, my LDL dropped a little, but not nearly as much as with a statin (I went off the statin when I was fasting).

The reason I ask, is because fasting primes catabolism, so any function that is anabolic or that "builds", should theoretically go down drastically. I would therefore think that when you fast, the body gets the signal "don't produce as much LDL (or anything else for that matter)". Fasting spurs autophagy as the body searches for all materials to break down in the absence of nutrients. This would lead me to think that LDL production would collapse as well. What is your experience? TIA!

Well Tom Generally I try to fast 14 hours most days and this has no effect whatsoever. The fasting your talking about I’ve never done. Not clear why it would matter anyways because the moment you go back to relatively normal eating the ldl would shoot right back up.

[Mike41]

20 hours ago, mccoy said:

Mike, as I wrote the FMD is the result of an optimization, that's why it tends to be one size fits all.

Besides, Longo is clear that the frequency can be adjusted, from once, twice a year for ultra fit persons to once per month for obese individuals.

Moreover, as already discussed, we may adjust the macros, fine-tuning the glucose signal according to our individual response, with the possibility to choose a ketogenic FMD.

Last, we can adjust the length, some people in this forum already did longer FMDs or FMDs plus a more rigorous fast.

My point is a 6’3’ muscular active guy vs. a 5 foot 90 pound inactive woman. How can one size FMD make any sense in that comparison. It simply does not. A FMD needs to be tailored to each individual right?

[Saul]

On 7/25/2020 at 6:23 PM, Mike41 said:

Wrt to Longo And his FMD all I can say is the plan is  a bit off putting. I mean seriously one size fits all! Makes no sense what so ever. Again it’s easier to sell it, but that don’t make it right.

i agree.

  --  Saul

[Ron Put]

On 7/26/2020 at 4:00 PM, Mike41 said:

My point is a 6’3’ muscular active guy vs. a 5 foot 90 pound inactive woman. How can one size FMD make any sense in that comparison. It simply does not. A FMD needs to be tailored to each individual right?

This is from the Prolon FAQ:

ProLon^® has been studied in a wide range of individuals with different caloric needs and found to be safe. The overall meal program was effective at inducing a fasting state in people with a wide range of body mass index (BMI), and the L-Drink is dosed per individual body weight to provide just enough glycerin to support fasting mode.