149 replies to this topic

[TheFountain]

It is interesting to me how a ketogenic diet decreases IGF-1 formation.

According to the paper titled Genetic determinants of exceptional human longevity: insights from the Okinawa Centenarian Study, one of the benefits provided by caloric restriction is due to:

"The extended longevity of these mutants is thought to result from lower insulin and IGF-1 levels, higher insulin sensitivity, metabolic changes in carbohydrate and lipid metabolism."

Since a caloric-restricted diet would by vitrue restrict total dietary carbohydrate intake, it makes sense that IGF-1 and insulin sensitivity would be improved. However, if one goes a ketogenic diet providing sufficient calories to meet or exceed BMR, IGF-1 sensitivity continues to improve.

Growth dependence on insulin-like growth factor-1 during the ketogenic diet.

"CONCLUSIONS: Height velocity was most affected in those with pronounced ketosis, which implies that, in clinical practice, the level of ketosis should be related to outcomes in seizure response and growth. Our data indicate that growth disturbances and the decreased sensitivity of growth to similar IGF-I levels during KD are independent of seizure reduction. The metabolic status induced by KD may be the mechanism underlying both alterations of linear growth and seizure reduction."

Carbohydrate restriction, prostate cancer growth, and the insulin-like growth factor axis.

"CONCLUSIONS: In this xenograft model, despite consuming more calories, NCKD-fed mice had significantly reduced tumor growth and prolonged survival relative to Western mice and was associated with favorable changes in serum insulin and IGF axis hormones relative to low-fat or Western diet. © 2007 Wiley-Liss, Inc."

If longevity can be linked to IGF-1 reduction, it makes me question whether a ketogenic diet (or modified carbohydrate restricted diet) might also be good for longevity.

I don't think it's as simple as carbs because the study referenced earlier showed no specific correlation between the moderate carb vegan whole food diet and IGF-1 levels, in fact it showed a trend toward increased IGF-1 reduction. You can try to blame carbs as much as you want for this one but I think meat and other animal products and protein biproducts (such as casein) are the real culprit and you need to face that. I know you like your diet because it helps you maintain muscle, but that doesn't make it the best for longevity.

[JLL]

Well, a reduction in IGF-1 is clearly not what CR folks are trying to do. Fontana criticized them for not doing this, but Michael and others commented that IGF-1 reduction in humans is not the key to lifespan extension. So, I think the paper you posted may be correct in stating "whole vegetarian foods decrease IGF-1", but do they have evidence that "a reduction IGF-1 will extend lifespan" in mammals?

Besides the eloquent post from our friend above, even if in the most ridiculous hypothetical example IGF-1 reduction didn't extend life on a cellular level (and again, this just a hypothetical 'what if') it still seems to curtail the development of the primary diseases of aging, one of the most feared being diabetes. This means that your chances of dying prematurely of one of these age-related diseases is a fair bit lower on a diet conducive to IGF-1 restriction. I understand you like your extremely high fat Paleo meat diet but you need to look at these findings and stop looking for unwarranted reasons to discard them.

What are you rambling on about? What ridiculous hypothesis?

Do you have evidence that lower IGF-1 extends lifespan in humans?

By "CR folks are clearly not trying to lower IGF-1" I mean that if you go to the CR society list, you will see that most of them are not lowering their protein intake and their IGF-1. I assume they know IGF-1 reductions increase lifespan in other species, so there must be a reason why their CR diets are the way they are.

[tunt01]

What are you rambling on about? What ridiculous hypothesis?

Do you have evidence that lower IGF-1 extends lifespan in humans?

By "CR folks are clearly not trying to lower IGF-1" I mean that if you go to the CR society list, you will see that most of them are not lowering their protein intake and their IGF-1. I assume they know IGF-1 reductions increase lifespan in other species, so there must be a reason why their CR diets are the way they are.

We all know the Fontana comments on IGF-1 and studies which show animals w/ lower IGF-1 have extended lifespans. To say it doesn't translate into similar results in humans, seems a real stretch to me.

Some CR practitioners do eat for lower IGF-1.

This one CR guy's diet and meal (click on his meal link) is the most intriguing to me. He basically spends $30 a day on eating a near-veggie diet.

http://deanpomerleau.tripod.com/

His supplements and exercise routine are posted there as well. I think for a CR diet, that restricts protein intake for lower IGF, Pomerleau's approach seems pretty sensible to me.

In fact, his regimen, is probably the most sensible regimen I've seen in totality. He has not updated his bloodwork in a while (hopefully he's not dead... !)

Edited by prophets, 29 September 2009 - 05:30 PM.

[TheFountain]

Well, a reduction in IGF-1 is clearly not what CR folks are trying to do. Fontana criticized them for not doing this, but Michael and others commented that IGF-1 reduction in humans is not the key to lifespan extension. So, I think the paper you posted may be correct in stating "whole vegetarian foods decrease IGF-1", but do they have evidence that "a reduction IGF-1 will extend lifespan" in mammals?

Besides the eloquent post from our friend above, even if in the most ridiculous hypothetical example IGF-1 reduction didn't extend life on a cellular level (and again, this just a hypothetical 'what if') it still seems to curtail the development of the primary diseases of aging, one of the most feared being diabetes. This means that your chances of dying prematurely of one of these age-related diseases is a fair bit lower on a diet conducive to IGF-1 restriction. I understand you like your extremely high fat Paleo meat diet but you need to look at these findings and stop looking for unwarranted reasons to discard them.

What are you rambling on about? What ridiculous hypothesis?

Do you have evidence that lower IGF-1 extends lifespan in humans?

By "CR folks are clearly not trying to lower IGF-1" I mean that if you go to the CR society list, you will see that most of them are not lowering their protein intake and their IGF-1. I assume they know IGF-1 reductions increase lifespan in other species, so there must be a reason why their CR diets are the way they are.

You're just talking unsubstantiated crap. And it is obvious if you need to ask how IGF-1 reduction could extend life you just haven't read the posts or you're being a knucklehead for no apparent reason.

Edited by TheFountain, 29 September 2009 - 05:41 PM.

[JLL]

Right, I'm talking unsubstantiated crap because I'm asking questions. I don't know whether IGF-1 increases or decreases longevity in humans, that's why I'm asking. But it's clear you don't have the answer either.

ScienceDaily (May 28, 2008) — Elderly men with higher activity of the hormone IGF-1--or insulin-growth factor 1--appear to have greater life expectancy and reduced cardiovascular risk, according to a new study.

http://www.scienceda...80527084252.htm

Although dwarf mice with defective growth hormone or IGF-1 signaling also have significantly increased lifespan, humans with defects in growth hormone signaling tend to develop diseases that shorten their lifespan.

http://www.biocarta....vityPathway.asp

IGF1 null mice show growth deficiency and usually are not viable, though some can reach adulthood [0965]. Mutations that lower IGF1 levels in mice retard growth and extend lifespan [0287], even if a definitive causative relation between IGF1 and ageing has not been demonstrated. Genotype combinations in the human PIK3CB and IGF1R genes have been related to plasma IGF1 levels and longevity [0141]. Cardiac specific overexpression of IGF1 results in a 23% increase in median lifespan, though no increase in maximum lifespan [1902]. In humans, IGF1 levels have been associated with several pathologies. High levels of IGF1 have been found to be associated with risk of breast cancer [0993]. On the other hand, low levels of IGF1 have been associated with osteoporosis [1923]. Despite being a putative regulator of ageing, IGF1's exact influence on human ageing is not known.

http://genomics.sene...y.php?hgnc=IGF1

[Blue]

There is no doubt that lower igf-1 increases lifespan in various short-lived animals. If in doubt, read this article:
http://www.plosbiolo...al.pbio.0060254

Now in the long-lived humans the situation is more complex. There has been numerous studies looking at igf-1 and binding proteins and mortality and morbidity. The results are all over the place. JLL cites some pro-igf-1 results. I will cite some anti:

" functionally relevant IGF receptor (IGF-1R) mutations have recently been discovered in centenarians [17], and conditions of low IGF-I, PI3K, IRS1, GH, and GHRH correlate with prolonged lifespan [18,19]. "

"Van Heemst et al. [19] investigated the relationship between somatotropic function, adult height, and longevity in humans, and found that in women, genetically determined low GH and IGF-I signaling was beneficial for old age survival. Recently, functionally relevant IGF-1R mutations were isolated from human centenarians [17]. Persisting high GH in acromegalic patients after surgical treatment is predictive of premature death [46], and elevated IGF-I in elderly individuals correlates with increased mortality [47]. Furthermore, the average lifespan of people with pituitary gigantism (mean height 236 cm, n = 28) is only 44 y, roughly 20 y below the corresponding historical adult life expectancy. It would be extremely valuable to measure the consequences of somatotropic tone for human health and longevity in a variety of contexts to clarify these important issues."
http://www.plosbiolo...al.pbio.0060254

Part of the problem is that likely short-term IGF-1 as an anabolic hormone is beneficial. It will increase bone and muscle mass and maybe generally improve various organs and even survival short-term. The problems may come more long-term from problems such as increased cancer and the growth of pathologic masses such as in alzheimers plaques or in atheriosclerosis.

Edited by Blue, 29 September 2009 - 06:09 PM.

[JLL]

I have one specific thread in mind where I asked why aren't people trying to reduce their IGF-1 (and got an answer) but I can't find it. Meanwhile:

http://www.crsociety...3992#msg-183992

http://www.imminst.o...-CR-t24531.html

It initially sounds
reasonable to argume that if high-protein diets raise IGF-1, and if
genetically-low IGF-1 may slow down aging, then one ought to reduce
protein intake. But as I've documented repeatedly in the past, despite
this surface plausibility, when one actually looks prospectively at real
health outcomes, higher-protein diets in either a CR or an AL context,
considered on an isocaloric baasis, lead to LONGER lifespans, LOWER
disease burden, and REDUCED risk factors.

http://www.crsociety...8804#msg-188804

[JLL]

There is no doubt that lower igf-1 increases lifespan in various short-lived animals. If in doubt, read this article:
http://www.plosbiolo...al.pbio.0060254

I don't refute that. I'm interested in what it will do in humans.

I'm also not sure that lowering IGF-1 through dietary modification will increase lifespan in these animals. This also raises the question of whether we should be trying to increase or decrease IGF-1 through diet. Perhaps those who are born with genes that dictate lower IGF-1 levels will live longer; but can the rest of us really compensate by lowering IGF-1 through, say, limiting protein and fat intake? I think that's a stretch at this point.

[Blue]

I have one specific thread in mind where I asked why aren't people trying to reduce their IGF-1 (and got an answer) but I can't find it. Meanwhile:

http://www.crsociety...3992#msg-183992

http://www.imminst.o...-CR-t24531.html

It initially sounds
reasonable to argume that if high-protein diets raise IGF-1, and if
genetically-low IGF-1 may slow down aging, then one ought to reduce
protein intake. But as I've documented repeatedly in the past, despite
this surface plausibility, when one actually looks prospectively at real
health outcomes, higher-protein diets in either a CR or an AL context,
considered on an isocaloric baasis, lead to LONGER lifespans, LOWER
disease burden, and REDUCED risk factors.

http://www.crsociety...8804#msg-188804

The rodent studies cited does not say much regarding humans because rodent CR reduces their IGF-1 regardless of they restrict their protein intake or not. Furthermore, normal rodent chow likely have a protein intake corresponding to their RDAs, so if they decrease it they will of course fare badly, while western humans consume much, much more than the human protein RDAs so a very severe protein reduction will only bring it down the to RDAs.

Edited by Blue, 29 September 2009 - 06:22 PM.

[TheFountain]

reasonable to argume that if high-protein diets raise IGF-1, and if
genetically-low IGF-1 may slow down aging, then one ought to reduce
protein intake. But as I've documented repeatedly in the past, despite
this surface plausibility, when one actually looks prospectively at real
health outcomes, higher-protein diets in either a CR or an AL context,
considered on an isocaloric baasis, lead to LONGER lifespans, LOWER
disease burden, and REDUCED risk factors.

That's just someones opinion. More studies correlate positively with IGF-1 reduction=slower aging and potentially increased life span. Your argument is ideological not scientific. You are arguing in favor of todays benefits, not tomorrows. While it may be true that a high fat paleo diet is better for impressing people with an ability to do 50 pull ups in queue and to drag ones knuckles across a floor it does not mean anything in terms of longevity studies. There are studies indicating high fat intake is bad, but of course we all know those studies are horse manure because they weren't controlling for X-Y-Z or whatever right? Point of my sarcastic remark is that any findings that suggest vegetarianism or veganism are best for longevity or health people like you attack immediately because it doesn't suit your Paleo ideology. You simply have no argument on this one, sorry.

[Blue]

More studies correlate positively with IGF-1 reduction=slower aging and potentially increased life span.

Again, results are all over the place for humans.

[TheFountain]

More studies correlate positively with IGF-1 reduction=slower aging and potentially increased life span.

Again, results are all over the place for humans.

There is a difference between IGF-1 mutations and a lack of correlation in longevity. I mean the very fact that such a mutation exists in Centenarians shows that IGF-1 differentiation plays a role in longevity. Whether it's a reduction or a mutation is just semantics, some change in IGF-1 seems to be cited.

[JLL]

What are you rambling on about? What ridiculous hypothesis?

Do you have evidence that lower IGF-1 extends lifespan in humans?

By "CR folks are clearly not trying to lower IGF-1" I mean that if you go to the CR society list, you will see that most of them are not lowering their protein intake and their IGF-1. I assume they know IGF-1 reductions increase lifespan in other species, so there must be a reason why their CR diets are the way they are.

We all know the Fontana comments on IGF-1 and studies which show animals w/ lower IGF-1 have extended lifespans. To say it doesn't translate into similar results in humans, seems a real stretch to me.

Some CR practitioners do eat for lower IGF-1.

This one CR guy's diet and meal (click on his meal link) is the most intriguing to me. He basically spends $30 a day on eating a near-veggie diet.

http://deanpomerleau.tripod.com/

His supplements and exercise routine are posted there as well. I think for a CR diet, that restricts protein intake for lower IGF, Pomerleau's approach seems pretty sensible to me.

In fact, his regimen, is probably the most sensible regimen I've seen in totality. He has not updated his bloodwork in a while (hopefully he's not dead... !)

He's eating 2000 kcal per day... I wouldn't call that CR.

[tunt01]

He's eating 2000 kcal per day... I wouldn't call that CR.

yea but look at his workout routine. you have to deduct calories burned...

[Blue]

"Recently, we have shown that compared to controls, long‐lived familial nonagenarians (mean age: 93.4 years)
from the Leiden Longevity Study displayed a lower mortality rate, and their middle‐aged offspring displayed a lower
prevalence of cardio‐metabolic diseases, including diabetes mellitus. The evolutionarily conserved insulin/IGF‐1 signaling (IIS) pathway has been implicated in longevity in model organisms, but its relevance for human longevity has generated much controversy. Here, we show that compared to their partners, the offspring of familial nonagenarians displayed similar non‐fasted serum levels of IGF‐1, IGFBP3 and insulin but lower non‐fasted serum levels of glucose, indicating that familial longevity is associated with differences in insulin sensitivity."

"Interestingly, the hallmark phenotype of all long-lived mouse models containing mutations that induce GH/IGF-1 deficiency or resistance, is their enhanced insulin sensitivity."

"Other data also support a link between preserved insulin sensitivity and human longevity. While insulin sensitivity generally declines with age in humans, sporadic long-lived centenarians have been shown to exhibit an exquisite insulin sensitivity, comparable to that of young adults."
http://www.impactagi.../pdf/100071.pdf

Edited by Blue, 29 September 2009 - 08:34 PM.

[Skötkonung]

Interesting. Has there been any animal lifespan studies using healthy animals on a ketogenic diet? This study is not it but suggests that at least rats on a high-fat diet does not fare well:
http://cat.inist.fr/...cpsidt=14939299

Regarding diet, mice have sufficiently diverged via evolution from humans to a point where a ketogenic diet is not sufficient to maintain health. Most species of mice instinctively collect and eat seeds and plant material, where as humans (and other hominids) have occasionally relied exclusively on large amount of animal products throughout our evolutionary history. As such, our bodies may be better accustomed to prolonged or intermittent ketosis.

One interesting study I found in the Journal of Biological Chemistry indicates that ketones stimulate CMA:
Ketone Bodies Stimulate Chaperone-mediated Autophagy

Ketosis is one of the signs of long term starvation. Ketones are produced throughout the day and are perfectly normal, but sustained ketosis takes place during starvation and sends a message that the body needs to conserve both glucose and protein. The body begins to conserve glucose by signaling to many of the organs and tissues to start using ketones for energy instead of glucose. The body conserves protein by decreasing its use of glucose because in the absence of dietary carbohydrate (as in starvation) the body makes glucose out of protein. Conserving glucose by switching to ketones allows the body can preserve its protein stores. The other thing the body can do is to make sure that the protein it does break down to use for glucose formation comes from non-essential sources. What more non-essential source can we have than useless junk proteins floating around in the cells? The ketones themselves stimulate the process of CMA to salvage all the junk protein to be used for glucose conversion.

Now, all we have to do to slow the aging process is to stay in some degree of ketosis most of the time and let nature take her course and clean all the junk out of our cellular attics.

[Skötkonung]

I don't think it's as simple as carbs because the study referenced earlier showed no specific correlation between the moderate carb vegan whole food diet and IGF-1 levels, in fact it showed a trend toward increased IGF-1 reduction. You can try to blame carbs as much as you want for this one but I think meat and other animal products and protein biproducts (such as casein) are the real culprit and you need to face that. I know you like your diet because it helps you maintain muscle, but that doesn't make it the best for longevity.

You're right about casein, and I personally (through my own diet, which is not ketogenic) try to raise IGF-1 levels to maintain and build muscle. So I tried to prove you wrong by unequivaclly linking carbohydrate via glucose to IGF-1 production and surprised myself with what I learned.

It does appear that IGF-1 stimulation is dependent on glucose levels, and glucose production occurs mostly when consuming carbohydrate. When in on a ketogenic diet, IGF-1 levels fall as do glucose levels. However, this may be caused by to switch of the metabolism to depend on ketone bodies instead of glucose, and not an absence of glucose itself.

The reason I say this is that all of the studies I have found seem to show no rise in IGF-1 when glucose is spiked. Paradoxically, glucose is often lowered by glucose levels.

Glucose regulates ghrelin, neuropeptide Y, and the GH/IGF-I axis in the tilapia, Oreochromis mossambicus.
"Glucose significantly reduced plasma IGF-I levels."

The circulating IGF system and its relationship with 24-h glucose regulation and insulin sensitivity in healthy subjects
"We found no evidence that the circulating IGF system is involved in meal-related blood glucose regulation or that it reflects short-term changes in insulin sensitivity in healthy, nonobese subjects. However, we cannot preclude that the observed changes in circulating IGFBP-1 may affect the glucose-lowering effect of IGF-I and -II at the local tissue level."

Interestingly, this study had volunteers switch milk consumption for cola consumption:
Short-term effects of replacing milk with cola beverages on insulin-like growth factor-I and insulin-glucose metabolism: a 10 d interventional study in young men.
"No effects of treatment were observed on IGFBP-3, IGF-I:IGFBP-3, insulin, glucose, insulin resistance or beta-cell function. The present study demonstrates that high intake of cola over a 10 d period decreases total IGF-I compared with a high intake of milk, with no effect on glucose-insulin metabolism in adult men. It is unknown whether this is a transient phenomenon or whether it has long-term consequences."

I'm not sure what this means? Perhaps someone could elaborate for me:
High glucose concentration decreases insulin-like growth factor type 1-mediated mitogen-activated protein kinase activation in bovine retinal endothelial cells
"Furthermore, the presence of IGF-1 appears to exert a protective effect on the cells in high glucose concentration by preventing progression through the cell cycle."

At any rate, it appears that the following is true:
Very Low Carb (Ketogenic Diet) > Low IGF-1
Moderate - Low Carb > High IGF-1
High Carb > Low IGF-1

But the question remains, is either high or low IGF-1 best for longevity? In this study, IGF-1 helps with glucose utilization by the brain and can post-pone age related mental decline:
Insulin-like growth factor-1 selectively increases glucose utilization in brains of aged animals.

[Skötkonung]

I thought this was a interesting excerpt on the relationship between IGF-1 and FoxO Transcription Factors:

But that's just the beginning of the similarity. Both IGF-1 and insulin affect metabolism. In fact, IGF-1 can bind to the same receptor that insulin does, although a lot less strongly. That, and the not coincidental structural similarity to insulin suggest that perhaps, sometime far back in evolution, the same gene may have coded for some ancestor of both insulin and IGF-1.

If you take into account a striking fact about the IGF-1 receptor, this hypothesis of a common origin for insulin and IGF-1 becomes even more intriguing. The fact is that the (gene for the) IGF-1 receptor is a homologue of the daf-2 gene of the nematode Caenorhabditis elegans (as is the gene for the insulin receptor also). In fact, DAF-2 (the protein product of daf-2) is the only insulin-like receptor in nematodes, so biologists now regard daf-2 as the ancestor of the mammalian receptors for IGF-1 and insulin.

I first mentioned this relationship back here, and went into more detail here, in connection with understanding the effect of sirtuin proteins on aging and longevity of C. elegans.

But the "coincidences" don't stop there. The important function of a receptor is the effect it has, when activated, upon signaling downstream inside the cell. All of the receptors we're talking about here are of the sort called tyrosine kinase receptors. Let's unbundle that term. Tyrosine is one of the 20 amino acids that make up proteins. A kinase is a type of protein enzyme whose function is to attach phosphate groups to specific kinds of amino acids in other proteins. This process is called phosphorylation. When another protein of the right sort is phosphorylated, it becomes able to act as a tyrosine kinase itself, and go on to affect yet other proteins.

This whole process is called signal transduction. The process begins (in the case here) with a receptor tyrosine kinase, which is a cell surface receptor protein that is also a tyrosine kinase – for example DAF-2, and the receptors for IGF-1 and insulin. There may be a number of intermediate steps, but the eventual result is the phosphorylation of a transcription factor, which enters the cell nucleus and facilitates the transcription of certain genes in order to produce new proteins.

In C. elegans, DAF-16 is the transcription factor that is activated by signaling mediated by DAF-2. We discussed DAF-16 in the aforementioned posts here and here. DAF-16 belongs to a family of transcription factors called forkhead box proteins. We have discussed these before too, or rather the subclass called FoxO transcription factors.

http://scienceandrea...ercise-and.html

[Skötkonung]

More studies correlate positively with IGF-1 reduction=slower aging and potentially increased life span.

Again, results are all over the place for humans.

From this blog:
http://ouroboros.wor...ation-by-igf-i/

Piper et al. have a nice comprehensive review on IGF-I signaling and genetic control of longevity. The authors are especially interested in moving beyond the genetic phenomenology and drilling down into the mechanistic details of how single-gene mutations can radically influence lifespan in widely separated species:

Separating cause from effect: how does insulin/IGF signaling control lifespan in worms, flies and mice?
"Ageing research has been revolutionized by the use of model organisms to discover genetic alterations that can extend lifespan. In the last 5 years alone, it has become apparent that single gene mutations in the insulin and insulin-like growth-factor signaling pathways can lengthen lifespan in worms, flies and mice, implying evolutionary conservation of mechanisms. Importantly, this research has also shown that these mutations can keep the animals healthy and disease-free for longer and can alleviate specific ageing-related pathologies. These findings are striking in view of the negative effects that disruption of these signaling pathways can also produce. Here, we summarize the body of work that has lead to these discoveries and point out areas of interest for future work in characterizing the genetic, molecular and biochemical details of the mechanisms to achieving a longer and healthier life."

The underscored passage brings up an issue that we’ve discussed here previously: Why is it that IGF-I pathway mutations can confer long healthy lives on organisms, even though supplementation with IGF-I is often quite beneficial, and depletion of IGF-I is often bad for individual organ systems? Indeed, according to another recent study, low doses of IGF-I appear to protect the mitochondria in aging rodents — why then do completely IGF-I-deficient animals enjoy extended and healthy lives?

It’s a mystery, and not one that this review answers — but it’s well worth thinking about, especially as we begin to consider pharmaceutical intervention in the aging process itself. When choosing between alternatives that might alter lifespan by 20-50%, it would be a damn shame to get the sign wrong.

[Blue]

Interesting. Has there been any animal lifespan studies using healthy animals on a ketogenic diet? This study is not it but suggests that at least rats on a high-fat diet does not fare well:
http://cat.inist.fr/...cpsidt=14939299

Regarding diet, mice have sufficiently diverged via evolution from humans to a point where a ketogenic diet is not sufficient to maintain health. Most species of mice instinctively collect and eat seeds and plant material, where as humans (and other hominids) have occasionally relied exclusively on large amount of animal products throughout our evolutionary history. As such, our bodies may be better accustomed to prolonged or intermittent ketosis.

One interesting study I found in the Journal of Biological Chemistry indicates that ketones stimulate CMA:
Ketone Bodies Stimulate Chaperone-mediated Autophagy

Ketosis is one of the signs of long term starvation. Ketones are produced throughout the day and are perfectly normal, but sustained ketosis takes place during starvation and sends a message that the body needs to conserve both glucose and protein. The body begins to conserve glucose by signaling to many of the organs and tissues to start using ketones for energy instead of glucose. The body conserves protein by decreasing its use of glucose because in the absence of dietary carbohydrate (as in starvation) the body makes glucose out of protein. Conserving glucose by switching to ketones allows the body can preserve its protein stores. The other thing the body can do is to make sure that the protein it does break down to use for glucose formation comes from non-essential sources. What more non-essential source can we have than useless junk proteins floating around in the cells? The ketones themselves stimulate the process of CMA to salvage all the junk protein to be used for glucose conversion.

Now, all we have to do to slow the aging process is to stay in some degree of ketosis most of the time and let nature take her course and clean all the junk out of our cellular attics.

Regarding your first point, no one really knows what the diet was for homo sapiens sapiens during most part of their existence. Even if we knew, this does not mean that homo sapiens sapiens had had time to adapt to their environment. Even if they had, this would be adaption for maximum gene transmission, not longevity, which would be gladly sacrificed if the surviving number of offspring increased.

Rodents are not humans but that ketogenic diet does not work for them certainly does not strengthen the theory. Is there any animal model showing increased longevity for a ketogenic diet?

Regarding your second point, the study cited is not even an animal study but a cell study. If one is arguing that protein degradation is important, then restricting protein intake to RDA levels and avoiding anabolic substances would seem to be logical step.

Edited by Blue, 03 October 2009 - 05:34 PM.

[Blue]

I don't think it's as simple as carbs because the study referenced earlier showed no specific correlation between the moderate carb vegan whole food diet and IGF-1 levels, in fact it showed a trend toward increased IGF-1 reduction. You can try to blame carbs as much as you want for this one but I think meat and other animal products and protein biproducts (such as casein) are the real culprit and you need to face that. I know you like your diet because it helps you maintain muscle, but that doesn't make it the best for longevity.

You're right about casein, and I personally (through my own diet, which is not ketogenic) try to raise IGF-1 levels to maintain and build muscle. So I tried to prove you wrong by unequivaclly linking carbohydrate via glucose to IGF-1 production and surprised myself with what I learned.

It does appear that IGF-1 stimulation is dependent on glucose levels, and glucose production occurs mostly when consuming carbohydrate. When in on a ketogenic diet, IGF-1 levels fall as do glucose levels. However, this may be caused by to switch of the metabolism to depend on ketone bodies instead of glucose, and not an absence of glucose itself.

The reason I say this is that all of the studies I have found seem to show no rise in IGF-1 when glucose is spiked. Paradoxically, glucose is often lowered by glucose levels.

Glucose regulates ghrelin, neuropeptide Y, and the GH/IGF-I axis in the tilapia, Oreochromis mossambicus.
"Glucose significantly reduced plasma IGF-I levels."

The circulating IGF system and its relationship with 24-h glucose regulation and insulin sensitivity in healthy subjects
"We found no evidence that the circulating IGF system is involved in meal-related blood glucose regulation or that it reflects short-term changes in insulin sensitivity in healthy, nonobese subjects. However, we cannot preclude that the observed changes in circulating IGFBP-1 may affect the glucose-lowering effect of IGF-I and -II at the local tissue level."

Interestingly, this study had volunteers switch milk consumption for cola consumption:
Short-term effects of replacing milk with cola beverages on insulin-like growth factor-I and insulin-glucose metabolism: a 10 d interventional study in young men.
"No effects of treatment were observed on IGFBP-3, IGF-I:IGFBP-3, insulin, glucose, insulin resistance or beta-cell function. The present study demonstrates that high intake of cola over a 10 d period decreases total IGF-I compared with a high intake of milk, with no effect on glucose-insulin metabolism in adult men. It is unknown whether this is a transient phenomenon or whether it has long-term consequences."

I'm not sure what this means? Perhaps someone could elaborate for me:
High glucose concentration decreases insulin-like growth factor type 1-mediated mitogen-activated protein kinase activation in bovine retinal endothelial cells
"Furthermore, the presence of IGF-1 appears to exert a protective effect on the cells in high glucose concentration by preventing progression through the cell cycle."

At any rate, it appears that the following is true:
Very Low Carb (Ketogenic Diet) > Low IGF-1
Moderate - Low Carb > High IGF-1
High Carb > Low IGF-1

But the question remains, is either high or low IGF-1 best for longevity? In this study, IGF-1 helps with glucose utilization by the brain and can post-pone age related mental decline:
Insulin-like growth factor-1 selectively increases glucose utilization in brains of aged animals.

Unfortunately a ketogenic diet and CR are often combined in studies. Are there studies showing that a ketogenic diet without CR reduces IGF-1? Regarding the effects of IGF-1, like all anabolic hormones, I think you can find at least short-term good effects in most organs including the brain. Which is why for example growth hormone and sex hormones were seen as miracle drugs for aging some time ago. The question is the long-term consequences which are much more uncertain or shown to be sometimes dangerous for GH and sex hormones which are therefore no longer seen as only positive miracle cures that everyone should have as they age.

Edited by Blue, 03 October 2009 - 05:26 PM.

[TheFountain]

If one is arguing that protein degradation is important, then restricting protein intake to RDA levels and avoiding anabolic substances would seem to be logical step.

And vegetarian calorie restriction does just that!

[Skötkonung]

Regarding your first point, no one really knows what the diet was for homo sapiens sapiens during most part of their existence. Even if we knew, this does not mean that homo sapiens sapiens had had time to adapt to their environment. Even if they had, this would be adaption for maximum gene transmission, not longevity, which would be gladly sacrificed if the surviving number of offspring increased.

Rodents are not humans but that ketogenic diet does not work for them certainly does not strengthen the theory. Is there any animal model showing increased longevity for a ketogenic diet?

Regarding your second point, the study cited is not even an animal study but a cell study. If one is arguing that protein degradation is important, then restricting protein intake to RDA levels and avoiding anabolic substances would seem to be logical step.

We do know what hominids ate for most of their evolutionary history by analyzing their teeth and wear patterns. Regarding humans in their current form, we can analyze the carbon signature of the collagen fibers in their bones and compare it to that of different plant and animal species. These techniques, combined with archeological evidence, paints a fairly complete picture of what homo sapiens and their distant ancestors such as homo erectus and homo heidelbergensis ate. Note that 600,000 years ago, when heidelbergensis was thriving across the European and Asian continents, they were eating primarily meat, and likely lived in ketosis for part if not the majority of their lives.

Cut marks found on wild deer, elephants, rhinoceroses and horses demonstrate that they were butchered. Some of the animals weighed as much as 700 kg (1,500 lb) or possibly larger. During this era, now-extinct wild animals such as mammoths, European lions and Irish elk roamed the European continent.

Moreover, a number of 400,000-year-old wooden projectile spears were found at Schöningen in northern Germany. These are thought to have been made by H. erectus or H. heidelbergensis. Generally, projectile weapons are more commonly associated with H. sapiens. The lack of projectile weaponry is an indication of different sustenance methods, rather than inferior technology or abilities. The situation is identical to that of native New Zealand Maori, modern H. sapiens, who also rarely threw objects, but used spears and clubs instead.^[5]


But that is besides the point; what hominids ate a several million years ago (when we ate largely fruits and other vegetation) is likely not pertinent to us in our current form. The reason for this is because evolution cannot go backwards. As our biology adapted to an animal tissue based diet between the upper and lower paleolithic, we have lost our ability to function optimally on a completely plant (or largely carbohydrate) based diet. Very little divergent evolution has occurred since the upper paleolithic.

Since ketosis was certainly a regular condition for paleolithic humans and likely their ancestors, it would make sense that we too could thrive on such a diet. However, mice have never shared this evolutionary path. In fact, mice are strictly herbivores. We are using herbivores, which have a different reaction to dietary fat, to judge what is best for human beings, which are omnivores and are most likely non-obligate carnivores because our digestive tracts, enzyme production, etc. are closer to that of dogs than to that of sheep or rabbits or cattle (or mice). Does nobody see what's wrong with this?

From Wikipedia:
In nature, mice are herbivores, consuming any kind of fruit or grain from plants.^[5] Due to this, mice adapt well to urban areas and are known for eating most all types of food scraps, especially cheese. In captivity, mice are commonly fed commercial pelleted mouse diet. These diets are nutritionally complete, but they still need a large variety of vegetables. Food intake is approximately 15 g (0.53 oz) per 100 g (3.5 oz) of body weight per day; water intake is approximately 15 ml (0.53 imp fl oz; 0.51 US fl oz) per 100 g of body weight per day.^[4]

With all the studies you dig up and post to these threads, I'm honestly surprised you couldn't be bothered to dig up a book on comparative anatomy.

And regarding your last point:
Any obligate carnivore will function better on a ketogenic diet than one with carbohydrate. Consider a domestic cat, which is a obligate carnivore. They can eat carbohydrate, but when wild, will live almost exclusively on meat. Without the ability to synthesize taurine, their diet must be supplement to mimic a meat based diet or it must contain acutal meat. Hypercarnivores of course function only in ketosis. A carbohydrate based diet would kill them.

[Skötkonung]

Unfortunately a ketogenic diet and CR are often combined in studies. Are there studies showing that a ketogenic diet without CR reduces IGF-1? Regarding the effects of IGF-1, like all anabolic hormones, I think you can find at least short-term good effects in most organs including the brain. Which is why for example growth hormone and sex hormones were seen as miracle drugs for aging some time ago. The question is the long-term consequences which are much more uncertain or shown to be sometimes dangerous for GH and sex hormones which are therefore no longer seen as only positive miracle cures that everyone should have as they age.

As a general rule, when insulin is high, glucagon levels are low. By the same token, if insulin levels decrease, glucagon will increase. The majority of the literature (especially as it pertains to ketone body formation) emphasizes the ratio of insulin to glucagon, called the insulin/glucagon ratio (I/G ratio), rather than absolute levels of either hormone.

This ratio is an important factor in the discussion of ketogenesis. While insulin and glucagon play the major roles in determining the anabolic or catabolic state of the body, there are several other hormones which play additional roles.

Growth hormone (GH) is another peptide hormone which has numerous effects on the body, both on tissue growth as well as fuel mobilization. GH is released in response to a variety of stressors the most important of which for our purposes are exercise, a decrease in blood glucose, and carbohydrate restriction or fasting. As its name suggests, GH is a growth promoting hormone, increasing protein synthesis in the muscle and liver. GH also tends to mobilize FFA from fat cells for energy.

In all likelihood, most of the anabolic actions of GH are mediated through a class of hormones called somatomedins, also called insulin-like growth factors (IGFs). The primary IGF in the human body is insulin like grow-1 (IGF-1) whith factorch has anabolic effects on most tissues of the body. GH stimulates the liver to produce IGF-1 but only in the presence of insulin. High GH levels along with high insulin levels (as would be seen with a protein and carbohydrate containing meal) will raise IGF-1 levels as well as increasing anabolic reactions in the body. To the contrary, high GH levels with low levels of insulin, as seen in fasting or carbohydrate restriction, will not cause an increase in IGF-1 levels. This is one of the reasons that ketogenic diets are not ideal for situations requiring tissue synthesis, such as muscle growth or recovery from certain injuries: the lack of insulin may compromise IGF-1 levels as well as affecting protein synthesis.

Edited by Skotkonung, 03 October 2009 - 08:56 PM.

[Blue]

Regarding your first point, no one really knows what the diet was for homo sapiens sapiens during most part of their existence. Even if we knew, this does not mean that homo sapiens sapiens had had time to adapt to their environment. Even if they had, this would be adaption for maximum gene transmission, not longevity, which would be gladly sacrificed if the surviving number of offspring increased.

Rodents are not humans but that ketogenic diet does not work for them certainly does not strengthen the theory. Is there any animal model showing increased longevity for a ketogenic diet?

Regarding your second point, the study cited is not even an animal study but a cell study. If one is arguing that protein degradation is important, then restricting protein intake to RDA levels and avoiding anabolic substances would seem to be logical step.

We do know what hominids ate for most of their evolutionary history by analyzing their teeth and wear patterns. Regarding humans in their current form, we can analyze the carbon signature of the collagen fibers in their bones and compare it to that of different plant and animal species. These techniques, combined with archeological evidence, paints a fairly complete picture of what homo sapiens and their distant ancestors such as homo erectus and homo heidelbergensis ate. Note that 600,000 years ago, when heidelbergensis was thriving across the European and Asian continents, they were eating primarily meat, and likely lived in ketosis for part if not the majority of their lives.

Cut marks found on wild deer, elephants, rhinoceroses and horses demonstrate that they were butchered. Some of the animals weighed as much as 700 kg (1,500 lb) or possibly larger. During this era, now-extinct wild animals such as mammoths, European lions and Irish elk roamed the European continent.

Moreover, a number of 400,000-year-old wooden projectile spears were found at Schöningen in northern Germany. These are thought to have been made by H. erectus or H. heidelbergensis. Generally, projectile weapons are more commonly associated with H. sapiens. The lack of projectile weaponry is an indication of different sustenance methods, rather than inferior technology or abilities. The situation is identical to that of native New Zealand Maori, modern H. sapiens, who also rarely threw objects, but used spears and clubs instead.^[5]


But that is besides the point; what hominids ate a several million years ago (when we ate largely fruits and other vegetation) is likely not pertinent to us in our current form. The reason for this is because evolution cannot go backwards. As our biology adapted to an animal tissue based diet between the upper and lower paleolithic, we have lost our ability to function optimally on a completely plant (or largely carbohydrate) based diet. Very little divergent evolution has occurred since the upper paleolithic.

Since ketosis was certainly a regular condition for paleolithic humans and likely their ancestors, it would make sense that we too could thrive on such a diet. However, mice have never shared this evolutionary path. In fact, mice are strictly herbivores. We are using herbivores, which have a different reaction to dietary fat, to judge what is best for human beings, which are omnivores and are most likely non-obligate carnivores because our digestive tracts, enzyme production, etc. are closer to that of dogs than to that of sheep or rabbits or cattle (or mice). Does nobody see what's wrong with this?

From Wikipedia:
In nature, mice are herbivores, consuming any kind of fruit or grain from plants.^[5] Due to this, mice adapt well to urban areas and are known for eating most all types of food scraps, especially cheese. In captivity, mice are commonly fed commercial pelleted mouse diet. These diets are nutritionally complete, but they still need a large variety of vegetables. Food intake is approximately 15 g (0.53 oz) per 100 g (3.5 oz) of body weight per day; water intake is approximately 15 ml (0.53 imp fl oz; 0.51 US fl oz) per 100 g of body weight per day.^[4]

With all the studies you dig up and post to these threads, I'm honestly surprised you couldn't be bothered to dig up a book on comparative anatomy.

And regarding your last point:
Any obligate carnivore will function better on a ketogenic diet than one with carbohydrate. Consider a domestic cat, which is a obligate carnivore. They can eat carbohydrate, but when wild, will live almost exclusively on meat. Without the ability to synthesize taurine, their diet must be supplement to mimic a meat based diet or it must contain acutal meat. Hypercarnivores of course function only in ketosis. A carbohydrate based diet would kill them.

What homo erectus and others may have eaten is irrelevant since homo sapiens sapiens is clearly different in many ways. Which limit the timespan to at most the last 200,000 years. That evolution may not have caused some adaptions to diet during, say, the last 10,000 years is very unlikely. A very different diet for agriculturists probably lead to a strong evolutionary pressure causing adapations to this diet.

No, it is not possible to say from bones what the micronutrient composition was and cerrtainly not that homo sapiens sapiens ever had a ketogenic diet even if they had a high meat intake. Source please if making this claim.

"Any obligate carnivore will function better on a ketogenic diet than one with carbohydrate." Source please. Remember, one for a ketogenic diet, not just a high meat diet.

Again, do you have any source for any animal living longer on a ketogenic diet?

[Blue]

Unfortunately a ketogenic diet and CR are often combined in studies. Are there studies showing that a ketogenic diet without CR reduces IGF-1? Regarding the effects of IGF-1, like all anabolic hormones, I think you can find at least short-term good effects in most organs including the brain. Which is why for example growth hormone and sex hormones were seen as miracle drugs for aging some time ago. The question is the long-term consequences which are much more uncertain or shown to be sometimes dangerous for GH and sex hormones which are therefore no longer seen as only positive miracle cures that everyone should have as they age.

As a general rule, when insulin is high, glucagon levels are low. By the same token, if insulin levels decrease, glucagon will increase. The majority of the literature (especially as it pertains to ketone body formation) emphasizes the ratio of insulin to glucagon, called the insulin/glucagon ratio (I/G ratio), rather than absolute levels of either hormone.

This ratio is an important factor in the discussion of ketogenesis. While insulin and glucagon play the major roles in determining the anabolic or catabolic state of the body, there are several other hormones which play additional roles.

Growth hormone (GH) is another peptide hormone which has numerous effects on the body, both on tissue growth as well as fuel mobilization. GH is released in response to a variety of stressors the most important of which for our purposes are exercise, a decrease in blood glucose, and carbohydrate restriction or fasting. As its name suggests, GH is a growth promoting hormone, increasing protein synthesis in the muscle and liver. GH also tends to mobilize FFA from fat cells for energy.

In all likelihood, most of the anabolic actions of GH are mediated through a class of hormones called somatomedins, also called insulin-like growth factors (IGFs). The primary IGF in the human body is insulin like grow-1 (IGF-1) whith factorch has anabolic effects on most tissues of the body. GH stimulates the liver to produce IGF-1 but only in the presence of insulin. High GH levels along with high insulin levels (as would be seen with a protein and carbohydrate containing meal) will raise IGF-1 levels as well as increasing anabolic reactions in the body. To the contrary, high GH levels with low levels of insulin, as seen in fasting or carbohydrate restriction, will not cause an increase in IGF-1 levels. This is one of the reasons that ketogenic diets are not ideal for situations requiring tissue synthesis, such as muscle growth or recovery from certain injuries: the lack of insulin may compromise IGF-1 levels as well as affecting protein synthesis.

Still waiting for a source stating that a ketogenic diet without CR reduces IGF-1. Is there one?

[Blue]

Unfortunately a ketogenic diet and CR are often combined in studies. Are there studies showing that a ketogenic diet without CR reduces IGF-1? Regarding the effects of IGF-1, like all anabolic hormones, I think you can find at least short-term good effects in most organs including the brain. Which is why for example growth hormone and sex hormones were seen as miracle drugs for aging some time ago. The question is the long-term consequences which are much more uncertain or shown to be sometimes dangerous for GH and sex hormones which are therefore no longer seen as only positive miracle cures that everyone should have as they age.

As a general rule, when insulin is high, glucagon levels are low. By the same token, if insulin levels decrease, glucagon will increase. The majority of the literature (especially as it pertains to ketone body formation) emphasizes the ratio of insulin to glucagon, called the insulin/glucagon ratio (I/G ratio), rather than absolute levels of either hormone.

This ratio is an important factor in the discussion of ketogenesis. While insulin and glucagon play the major roles in determining the anabolic or catabolic state of the body, there are several other hormones which play additional roles.

Growth hormone (GH) is another peptide hormone which has numerous effects on the body, both on tissue growth as well as fuel mobilization. GH is released in response to a variety of stressors the most important of which for our purposes are exercise, a decrease in blood glucose, and carbohydrate restriction or fasting. As its name suggests, GH is a growth promoting hormone, increasing protein synthesis in the muscle and liver. GH also tends to mobilize FFA from fat cells for energy.

In all likelihood, most of the anabolic actions of GH are mediated through a class of hormones called somatomedins, also called insulin-like growth factors (IGFs). The primary IGF in the human body is insulin like grow-1 (IGF-1) whith factorch has anabolic effects on most tissues of the body. GH stimulates the liver to produce IGF-1 but only in the presence of insulin. High GH levels along with high insulin levels (as would be seen with a protein and carbohydrate containing meal) will raise IGF-1 levels as well as increasing anabolic reactions in the body. To the contrary, high GH levels with low levels of insulin, as seen in fasting or carbohydrate restriction, will not cause an increase in IGF-1 levels. This is one of the reasons that ketogenic diets are not ideal for situations requiring tissue synthesis, such as muscle growth or recovery from certain injuries: the lack of insulin may compromise IGF-1 levels as well as affecting protein synthesis.

Still waiting for a source stating that a ketogenic diet without CR reduces IGF-1. Is there one?

Looked into this some more. The ketogenic diet for children with epilepsy does reduce IGF-1 and height. But this diet it is also a CR and PR diet so this is not surprising. Regarding rodents, in at least some studies the rodents seem to dislike the ketogenic diet intensly and must be quite starved and have a significant weight reduction before eating it. Thus also in effect achieving CR. Still looking if there a study with isocaloric, ketogenic diet showing IGF-1 reduction.

[kismet]

Blue, as a rule of thumb: your post should be no longer than the quote you include. Massive, redundant quotes clutter the thread.

@Skotkonung, are you sure that a moderate-low carb diet increases IGF-1? I'm pretty sure a moderate GL diet (which works out to carb moderation and low GI/GL carbs) reduces IGFBP-1 & IGF-1 is unchanged (see for instance PMID: 17448569).

Edited by kismet, 04 October 2009 - 05:09 PM.

[Skötkonung]

What homo erectus and others may have eaten is irrelevant since homo sapiens sapiens is clearly different in many ways. Which limit the timespan to at most the last 200,000 years. That evolution may not have caused some adaptions to diet during, say, the last 10,000 years is very unlikely. A very different diet for agriculturists probably lead to a strong evolutionary pressure causing adapations to this diet.

No, it is not possible to say from bones what the micronutrient composition was and cerrtainly not that homo sapiens sapiens ever had a ketogenic diet even if they had a high meat intake. Source please if making this claim.

"Any obligate carnivore will function better on a ketogenic diet than one with carbohydrate." Source please. Remember, one for a ketogenic diet, not just a high meat diet.

Again, do you have any source for any animal living longer on a ketogenic diet?

And what about more recent ancestors such as homo heidelbergensis or modern homo sapiens from the paleolithic? Or our own genome, where gluten intolerance genes (HLA-DQ2, HLA-DQ8, etc) run rampant, obviously elucidating the fact that many genetic adaptations have not occurred since the paleolithic. Source.

As for diet, I reiterate we can generate a realistic picture of what ancient humans ate based on isotope studies:
Isotopic evidence for the diets of European Neanderthals and early modern humans

"The isotope data agree well with results from faunal analyses. Studies of animal remains from Neanderthal sites in Europe have repeatedly shown that Neanderthals consistently hunted large herbivores (51, 52), including seasonal use of reindeer (53). Yet, there is little evidence for the use of small game such as birds or fish (4, 51, 54). Early modern humans also appear to have regularly hunted large herbivores (55–57), but there is also evidence for the use of small game, including fish at some of these sites (15, 16)."

Regarding the suitability of mice on a ketogenic diet:
Again I ask you to PLEASE look at a book of comparative anatomy and biology. If lions could live on fortified corn and soy, why don't Zoo's feed them these cheap foods instead of expensive meat? Do you think they would live longer on a diet of vegetable greens and seeds only?

Finally, regrading IGF-1 and carbohydrate. As far as I am aware, there are no isocaloric studies of that kind available. However, the two are correlated and I have described that relationship in detail in a previous post to this thread. If you are curious about those processes, I suggest you research using Pubmed. Given the lack of "evidence," this will be the way in which we will need to continue IGF-1 and carbohydrate debate. As a suggestion, you might start by looking at the relationship between glutamine and glycogen storage in skeletal muscle on IGF-1 stimulation.

Edited by Skotkonung, 05 October 2009 - 07:01 AM.

[Blue]

Other species clearly different from us in many ways are not interesting. Gluten intolerance does not "run rampant", even if paleo dieters for ideological reasons like to think so. Almost all people can eat wheat without problems.

Regarding you isotope study. The diet of the Neanderthals is not relevant, again, very different from ourselves. Regrding the method itself: "Isotopic analysis provides information about the sources of dietary protein over a number of years, even though it does not measure the caloric contributions of different foods. As the method only measures protein intake, many low-protein foods that may have been important to the diet (i.e., high caloric foods like honey, underground storage organs, and essential mineral and vitamin rich plant foods) are simply invisible to this method."

Now this study argues that in Europe 40,000 to 27,000 years ago most of the protein came from animal sources. That does not prove that diet was ketogenic. Furthermore, does not say anything of the time outside this period. Human are very good predators that have often when made many other species extinct when they move into a new area. Like many species made quickly extinct in the Americas when humans moved in. So this time period may only have been a brief period of feast when homo sapiens sapiens sapiens moved into Europe and hunted down all the big game animals. Furthermore, the study says nothing regarding the situation outside Europe.

You have furthermore argued that evolution have not had the time to adapt to recent diet changes. That is clearly wrong for example for lactose intolerance where a tolerance has occurred in populations having a diet including a lot of milk from cows.

Regarding a ketogenic diet, those advocating that there are benefits should cite the evidence. There seem to be no animal studies showing that it increases lifespan in any species. Since animal studies using a ketogenic diet have often included CR it is unclear what benefits a ketogenic diet, if any, provides. If there is no clear evidence of benefits, then there is no reason to advocate it.