A Look at the Laron Syndrome Population
Laron syndrome is a form of dwarfism that occurs in a small human population all descended from a single mutant ancestor. It is of interest to aging researchers because the mutation is on the growth hormone receptor, analogous to that approach used to engineer the present record holder for mouse longevity, the growth hormone receptor knockout (GHRKO) lineage. These dwarf mice live 60-70% longer than their peers. However, as is the case for the differences in the long-term outcome of calorie restriction between mice and humans, there is no sign that Laron syndrome produces any meaningful lengthening of life. Human longevity has evolved to be much less plastic than that of short-lived mammals in response to circumstances and changes - such as those involving growth hormone - that affect insulin metabolism, and Laron syndrome is one of the illustrations of that point.
In the remote villages of Ecuador, 100 very small people may hold the key to a huge medical breakthrough. They all suffer from Laron Syndrome, an incredibly rare genetic disorder that stops them from growing taller than 4 feet but also seems to protect them against cancer and diabetes and maybe even heart disease and Alzheimer's. "There's only one patient that has died of cancer among all of the subjects. And that is fascinating," said Dr. Jaime Guevara-Aguirre, who has been studying the Laron population for 30 years.The project has two goals: figuring out how to distill the anti-disease properties of Laron Syndrome into a medication that could be used to fight cancer, diabetes and other illnesses in the rest of the world, and getting treatment that could help young people with the syndrome grow to full size. "The complaint of these little people was, 'We're doing so much for you. What are science and the pharmaceutical companies, etc., doing for us?'" said Dr. Valter Longo, a longevity specialist.
Laron Syndrome was first identified in 1950 and there are only 350 people with it in the world, all descended from a single ancestor who introduced the mutated gene thousands of years ago. A third of them live in isolated communities in Ecuador, while others live in Spain. Unlike others with dwarfism, Laron patients don't lack growth hormone, but they have a defect in the receptor in the liver that is supposed to bind to the hormone and produce a substance called insulin-like growth factor 1. In Laron, there is no binding and no IGF-1 - and stunted growth as a result. But the absence of IGF-1 may also prevent the uncontrolled growth of cells that turn into cancer, and it creates extra sensitivity to insulin that serves as a shield against diabetes.
Longo duplicated Laron in lab rats. "The mice actually lived 50 percent longer and get a lot less diseases. It's very clear in the mice. Can it be true for people?'" His lab is testing drugs that would block IGF-1 in people, but the question is whether medicine will work as well as an actual mutation in humans. Longo said it will be at least a decade before they know the answer. Meanwhile, his team is also investigating its theory that Laron may be a defense against heart disease and Alzheimer's. Preliminary results show that at the very least, the little people don't have any higher risk of those conditions. The researchers say Laron patients tend to live just as long as their average-sized siblings.
What do they die of if they are resistant to cancer and diabetes, and might be partially protected against heart disease and alzheimer's? Shouldn't they live longer than non-Laron people?
It looks like 20% die from accidents vs 2% of their relatives, 17% from convulsive disorders and 13% from alcohol related deaths.
Also interesting is how low protien consumption lowers IGF-1 and the effect that has on the risk of death from diabetes and cancer in normal humans. A study found that people who ate 20% or more of their calories in protien had a 72 fold increase in death from diabetes and people who ate 10-19% of their calories from protien had a 23 fold increase in death from diabetes compared to people who are less than 10% of calories from protien. This was in people aged 50-65 followed for 18 years.
For cancer the 20+ protien group has a 4 fold higher rate of death by cancer and the 10-19% protien group had a 3 fold higher rate of death by cancer compared to the less than 10% protien group.
Low protien increases FGF21 which also decreases mortality rates so it is difficult to say how much of the benefit is from FGF21 and how much is from lower IGF-1. However for every 10ng/ml increase in IGF-1 there was a 9% increase in mortality from cancer.
http://stm.sciencemag.org/content/3/70/70ra13.full.html
The Ecuadorian Laron population studied by Longo "shows high mortality
from common diseases of childhood"; those that survive to age 30 "died much more frequently [than non-mutant relatives used as controls] from accidents, alcohol-related causes, and convulsive disorders [such as epilepsy]".
Also, being resistant to cancer, diabetes, and Alzheimer's doesn't mean being immune to them. And there's a mixture of oversimplification and some speculation in suggesting that there is protection against CVD: Laron "subjects may have elevated cardiac disease mortality [27% of subjects living beyond age 30, vs. 21% of related non-mutation-bearing controls], the mortality from vascular diseases (combining cardiac disease and stroke) appears to be similar to that of their relatives (33% of deaths in relatives versus 30% of deaths in GHRD subjects) [including 3% stroke vs. 12% stroke]. In agreement with studies of a human population with isolated GH deficiency, our data suggest that [Laron] does not increase overall vascular disease mortality."
It would be interesting to see if the kind of "cardiac disease" that kills some Laron patients is a different etiopathologiacal entity from that in the general population: is it possible that they have some protection against the usual atherosclerotic heart disease (as suggested by the low stroke mortality) but suffer from structural problems in the heart related to embryonic and early childhood development that contribute to congestive heart failure or other "cardiac disease" in old age?
And remember that this is a small (no pun intended) cohort (n=30), so we may just be leaping to conclusions and generating hypotheses from sampling errors. However, there are other human populations with blunted IGF-1 signaling (Ashkenazi Jewish centenarians and relatives , and a general-population nonagenerian cohort segregated by IGF-1 levels studied by Nir Barzilai and others) who should be studied for more information: they, too, have lower incidence of diabetes and cancer (and higher survival after a cancer diagnosis).
@Santi
Hi Santi !
'' Low protien increases FGF21 which also decreases mortality rates so it is difficult to say how much of the benefit is from FGF21 and how much is from lower IGF-1''
It is a IGF/GH-dependent effect that FGF21 acts upon.
Thus It really is from GH/IGF-1 that we largely derive all the main benefits of FGF21; because if IGF/GH is increased (see Ames dwarf mice injected with GH who live shorter lives equal to normal mice), then FGF21 won't be able to do anything to counter the damage accrual from accelerated growth by increased IGF and increased insulin signaling. Insulin (with IGF) is in direct correlation with glycemia; and glycemia is responsible for accelerated aging in diabetes by glycation/glycoxidation (AGEs and crosslink formation).
FGF21 acts on IGF and especially, on endocrinal brain GH production, reducing both cell growth/developmental organismal growth and GH/IGF/IGF-1R signaling in the brain. It's actually ironical, you would think FGF, being a GF, like IGF (both growth factors) would increase IGF-1; but it's the opposite that happens : one growth factor inhibiting another. Most likely a negative feedback/loop compensation 'on-off' mechanism that cancel each other out to maintain a controled self-regulating balance between developmental growth and resource conservation in nutrient starvation mode (and evolution strategy for specie survival). This representing higher nutrient access for sexual reproduction by accelerated 'adult' puberty sexual maturity (activating sexual endocrine production) vs limited nutrient availability (CR, and starvation 'stress (survival) period' reducing sexual endocrine and reordering growth/sexual resources to resource conservation for energy and DNA repair in time of nutrient deprivation. Basically the whole IGF/DAF-16/DAF-2/mTOR pathways in concert with the hormones Testosterone/Estrogen/HGH/pituitary hormones/pineal gland hormones). This is at the crossroad of endrocrine regulation of growth and aging.
'' FGF21 also blocks somatic growth by causing GH resistance, a phenomenon associated with starvation. Transgenic (Tg) mice overexpressing FGF21 are markedly smaller than wild-type mice and have a corresponding decrease in circulating IGF-1 concentrations despite having elevated growth hormone (GH) levels (Inagaki et al., 2008).
Conversely, FGF21-knockout mice grow more than wild-type mice under conditions of nutrient deprivation (Kubicky et al., 2012). In liver, FGF21 inhibits the GH signaling pathway by blocking JAK2-mediated phosphorylation and nuclear translocation of the transcription factor, STAT5. This suppresses the transcription of Igf1 and other GH/STAT5-regulated genes (Inagaki, et al., 2008).
Thus, FGF21-mediated repression of the GH/IGF-1 axis provides a mechanism for blocking growth and conserving energy under starvation conditions. ''
As for Laron Syndrome people, they are unique and as was mentioned they may have developmental phenotype problems during aging because of their small stature; if may create organ dysfunction problems later on in life.
Yet...they do show that evade most diseases of normal people. Meaning, overall, they have lower oxidative stress by reduced insulin signaling and most likely are normoglycemic or controlled border-hypoglycemic (humans that are hypothyroidal have reduced metabolism, reduced hormones (thyroid), sometimes they suffer from hypoglycemia; this is correlation with no hormones in these Laron people) same goes for centenarians with little hormones and reduced IGF-1 (little Ashkenazi and Japanese centenarian peoples; that are small stature and emulate the 'woman' body (smaller body lower IGF in women than men). This means IGF must be kept at 'low basal' (adequate) levels but not eradicated. IGF protects the neuron (neurogenesis/neuroarborisation by IGF-1 acting on IGF-1 receptors in brain such as cortex and hypothalamus) and It is a survival signal by increasing 'Growth' in times of deprivation/stress (such as CR). It is no surprise that centenarians have low IGF and are insulin sensitive; with maintained low blood glucose againt rising levels over decades (pre-diabetic).
What is far more interesting is a study that showed demented centenarians have lower IGF-1 than *non-demented* centenarians; dementia and Alzheimer's kill a human in less than 10 years. Thus, it means that the levels of IGF-1 were too low in certain centenarians and it reduced neurogenesis capability in them. Not enough to kill them, low levels were necessary to reach centenarian age. But to maintain cognitive capacity, you need 'some' brain IGF. And that's also why, Laron syndrome people puzzle me, I wonder what is going in their brain. I am guessing near-absence of IGF/GH is compatible with centenarian lifespan, Laron or not, but to a maximum - as shown with Demented centenarians who 'lose it' and have reduced brain IGF (and - die sooner - then centenarians with (slightly ?) higher brain IGF). As aging increases, it seems brain necessitates IGF even more to maintain neurogenesis in the face of brain involution over the years. What is sure, is that IGF, is endrocrine costly and increases oxidative stress by its cascade of damages during growth; which becomes a double-edged sword. CR seems the 'in between' just 'low-enough IGF' but not abrogation either.
Laron and short-centenarians seem to benefit from a 'form' of CR acting on IGF. One study showed centenarians have higher FOXO3a, which is directly linked to IGF/DAF-16, so the insulin pathway yet again; the nutrient pathway again; the glucose (glycation/diabetes AGEs) pathway again, CR again.
PS:
'' Low protien increases FGF21 which also decreases mortality rates so it is difficult to say how much of the benefit is from FGF21 and how much is from lower IGF-1''
And the effect of lowered protein is that there is a reduced intake of methionine (the most oxidation susceptible amino acid in the proteins). Methionine-restricted mice live longer, akin to FGF-21 overexpressing mice or
CR-fed mice. The smaller FGF-21 overexpressing mice, means reduced methionine accumulation/protein content mimicry. Since these FGF-21 mice are smaller in size, their total protein content is smaller too (smaller musculature frame means immediately smaller protein demand). Some studies stipulate, the CR longevity effect is dependent on methionine* protein-restriction (not so much the others, who have a role, but not as much as methionine who is responsible in the redox control of aging) rather than calorie-restriction per se. So it's not so much the calorie amount, it's the methionine amount, firstly, and total protein amount also.
PPS: incredible fact :
''There is also a disproportionate number of [Laron Syndrome] sufferers found in remote villages in the South American country of Ecuador who are descended from colonial-era Jewish-origin New Christian conversos (Sephardi Jews who themselves, or whose forebears, had been compelled to convert to Catholicism back in Spain) who had covertly migrated to Ecuador during the Spanish Conquest despite the Spanish Crown's prohibition of their immigration to its colonies and territories as a result of the Inquisition.[6][7]''
So, basically, these Laron people carry Jewish Ashkenazy genes because - they are in part Jewish genetically from Spanish-Jew Conquistador conquer of first nations aboriginals in Ecaduor in 16th century. Jewish European admixture backtraced to Israel. Now it makes a lot of sense and I'm guessing, Laron people, have it to the extreme 'form' of Ashkenazi Jews centenarians IGF/GH levels. So, if we were to put this on a scale of 0 to 10 in level of IGF. 10 is us normal shorter-lived people. 5 is Ashkenazi centenarians/offsprings 'in-between levels' and 0 is nearly no GH at all, creating Laron syndrome of Ecuadorian-mixJewish ancestry people.
It really shows that IGF-1 needs to be maintained on the 5 or less scale on 10. But not reach 0 either. 1 One would be the lowest, best, possible digit.
CANanonymity at February 16, 2016 4:20 PM: Some studies stipulate, the CR longevity effect is dependent on methionine* protein-restriction (not so much the others, who have a role, but not as much as methionine who is responsible in the redox control of aging) rather than calorie-restriction per se.
People keep repeating this, but it is very clearly not true. There are many, many CR studies (such as these) in which the percentage of protein in the chow fed to the CR rodents is increased in order to ensure that the absolute intake of protein (and, as a result, Met) is kept exactly the same between the CR and AL groups, and the CR works just fine (better, in fact, in adult-onset organisms). In fact, this is the standard CR protocol of the best labs.
Thanks for pointing that out Michael. I was one of those still under the impression that it was the methionine restriction doing the work.
@Michael
Hi Michael !
'' Life span can be extended in rodents by restricting food availability (caloric restriction [CR]) or by providing food low in methionine (Meth-R). Here, we show that a period of food restriction limited to the first 20 days of life, via a 50% enlargement of litter size, shows extended median and maximal life span relative to mice from normal sized litters and that a Meth-R diet initiated at 12 months of age also significantly increases longevity. **Furthermore, mice exposed to a CR diet show changes in liver messenger RNA patterns, in phosphorylation of Erk, Jnk2, and p38 kinases, and in phosphorylation of mammalian target of rapamycin and its substrate 4EBP1, HE-binding protein 1 that are not observed in liver from age-matched Meth-R mice.**
These results introduce new protocols that can increase maximal life span and suggest that the spectrum of metabolic changes induced by low-calorie and low-methionine diets may differ in instructive ways. ''
You are right, it seems CR is an independent metabolic and genetic effect from
Methionine-restriction. Although, both increase lifespan, in their own way..
I guess the best it to combine them both. CR + Meth-R could give slightly stronger effect than either alone; although it could be an average effect with redundancy of interdependent pathways (still this study shows that CR activates genes that Meth-R doesn't; so it is quite a different effect and so they could add together or maybe (most likely not) synergize).
Methionine restriction and CR affect both IGF-1, Thyroid hormones (T4 reduction means metabolism slowing), Insulin levels/Glucose levels (thus glycemia/AGEs/glycated hemoglobin/diabetes) and I'm guessing they are really The major instigators of their downstream longevity effects (CR is nutrient reduction, reducing AGEs formation and insulin production from reduced glucose levels; Meth-R does the same thing, reduces insulin and improves insulin sensitivity without reducing calorie count but only protein methionine intake...it seems definitely IGF/insulin/glucose pathway the true whole responsible (not in entirety but in greatly responsible for their effects, since IGF acts are basically everything from proteasome, growth, hormones, glucose control, nutrient sensing, hormesis, nutrient 'signals', oxidative stress and cell redox):
''
Hormone levels
Table 1 shows the results of serum hormone and fasting glucose levels measured at 16 months of age. Mice in the Meth-R group are significantly lower in serum IGF-I, and thyroxine (T4) levels. Serum insulin is approximately 25% of controls, and fasting glucose is reduced by about 50%. Differences between groups are significant at P < 0.01 for all four measures. Table 1. Hormone and glucose levels Measure Control Methionine-restricted IGF-I (ng mL−1) 397 ± 125 (12) 257 ± 66 (12) T4 (µg dL−1) 3.5 ± 1.1 (37) 2.7 ± 0.7 (30) Insulin (ng mL−1) 1.6 ± 1.1 (12) 0.4 ± 0.2 (11) Glucose (mg dL−1) 64.7 ± 22.6 (11) 32.9 ± 14.9 (12) Life-Span Extension in Mice by Preweaning Food Restriction and by Methionine Restriction in Middle Age 1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2691799/
Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance
2. http://onlinelibrary.wiley.com/doi/10.1111/j.1474-9726.2005.00152.x/full
Fascinating that this form of dwarfism only occurs in a small population descended from a common ancestor and that concentrated fragments of this population survive in remote villages.
@michael
CR with no methionine restriction increases healthspan. CR with equal amounts of lipid, protien, and carbohydrate restriction increases healthspan and maximum lifespan. Methionine restriction increases healthspan and maximum lifespan.
I pulled up the full text from all 4 studies that you referenced. 2 of the studies looked like straight CR, meaning 40% protien restricted as well as, 40% lipid, and 40% carbohydrate restricted. The other two studies were CR with nutrient enriched diet which was done so that the mice didn't die prematurely from malnutrition from the lack of vitamins or protien skewing the results. I think this is were you got confused. Nutrient enriched doesn't mean that they were at the normal level of protein intake as the control group. It just means it was less restricted than the amount of lipids and carbohydrates. It is the same in humans studies they don't normally restrict protien or vitamins to the point that it would be detrimental but if you look at the recent study on FGF21 in humans you do not have to restrict methionine to detrimental levels to increase FGF21.
Study on the topic
"Regarding the dietary factor responsible for the life extension effect of DR, **neither carbohydrate nor lipid restriction seem to modify maximum longevity.** However protein restriction (PR) and methionine restriction (at least 80% MetR) increase maximum lifespan in rats and mice. Interestingly, only 7 weeks of 40% PR (at least in liver) or 40% MetR (in all the studied organs, heart, brain, liver or kidney) are enough to decrease mtROSp and oxidative damage to mtDNA in rats, whereas **neither carbohydrate nor lipid restriction change these parameters.**"
https://www.fightaging.org/archives/2013/03/on-methionine-restriction.php
@Santi
I guess you are right too !
It' actually quite confusing, because the study I cited really shows that CR produces a metabolic and genetic signature in the liver than Meth-R does not; so they are different. But, the question is is it the carbohydrates ? The total protein content ? The type of protein (animal vs vegetal) ? The amino acid composition of proteins ? The methionine content, specifically ? The sulfur proteins (methionine, cysteine, homocysteine, s-adenosyl-methionine (SAM, ironically SAM reduces methionine during the methonine sulfuration pathway that is responsible for cell redox formation of GSH), s-adenosyl-homocysteine (SAH)) only which are responsible in the transulfuruation pathway ? The total calories count ? The fat intake ? The sodium intake ? The vitamins&mineral&food antioxidants/polyphenols ORAC/HORAC/TAC intake ? The total AGEs and toxins content in the food ? The fact, one study use BALB mice others use other types of mice ? Female vs male mice gender longevity cancelation effect ? It's hard to say. So many variables that can skew results and make bias.
The study I pointed earlier was capable of extending MLSP by CR and, also, by Meth-R started in middle age.
Yet, the genes liver organ signature was different after both intervention. Still, the end result was the same :
reduction of IGF-1, reduction of glucose and insulin levels (thus reduction of AGEs formation and reduction of pre-diabetes), reduction of thyroid hormones and GH too.
Here is one study that really goes with what you are saying :
'' Both caloric restriction (CR) and low-protein, high-carbohydrate (LPHC) ad-libitum-fed diets increase lifespan and improve metabolic parameters such as insulin, glucose, and blood lipids. Severe CR, however, is unsustainable for most people; therefore, it is important to determine whether manipulating macronutrient ratios in ad-libitum-fed conditions can generate similar health outcomes. We present the results of a short-term (8 week) dietary manipulation on metabolic outcomes in mice. We compared three diets varying in protein to carbohydrate ratio under both CR and ad libitum conditions.
***Ad libitum LPHC diets delivered similar benefits to CR in terms of levels of insulin, glucose, lipids, and HOMA, despite increased energy intake.***
***CR on LPHC diets did not provide additional benefits relative to ad libitum LPHC.***
We show that LPHC diets under ad-libitum-fed conditions generate the metabolic benefits of CR
***without a 40% reduction in total caloric intake.*** ''
''More recently, it has been demonstrated in studies using nutritional geometry that the balance of macronutrients has a profound impact on healthspan and lifespan in animals with ad libitum (AL) access to food (Lee et al., 2008, Piper et al., 2011 and Solon-Biet et al., 2014). ***In these studies, CR induced by dietary dilution did not increase lifespan (Solon-Biet et al., 2014).***
In AL-fed mice and Drosophila melanogaster,
***diets low in protein and high in carbohydrates (LPHC) maximized lifespan, while a reduction of total energy intake had no positive impact on longevity ( Lee et al., 2008 and Solon-Biet et al., 2014).***
Moreover in mice, LPHC diets were associated with improved late-life cardiometabolic health (Solon-Biet et al., 2014) and a younger immune profile (Le Couteur et al., 2014).
Low protein intake has also been associated with better health and reduced mortality in observational studies of humans (Levine et al., 2014), while
***high-protein, low-carbohydrate (HPLC) diets* are associated with higher mortality, cardiovascular disease, and diabetes mellitus*** ( Fontana and Partridge, 2015, Fung et al., 2010, Lagiou et al., 2012 and Simpson et al., 2015). ''
''Meanwhile, the second team of researchers found that a high-protein, low-carbohydrate diet led to a shorter lifespan in mice.'' That basically shows that High protein intake + CR - at the same time = Fail (of CR longevity effect).
***Thus, it is not CR the effector or calories count, but protein intake, and hence, methionine content.***
From these studies, carbs have no say or little, same for calories, they Act through Protein Metabolism for their effect, it seems, thus, this :
CR - *that increases MLSP* - Acts on Protein (somehow) -> *Creating a 'form' of Meth-R or TotalProteins-R* -> Creating Reduced IGF-1/Glucose/AGEs -> Creating Lifespan extension.
Dietary Protein to Carbohydrate Ratio and Caloric Restriction: Comparing Metabolic Outcomes in Mice
1. http://www.sciencedirect.com/science/article/pii/S2211124715005057
@Santi: You are, respectfully, just wrong about this. It would help if you had individually cited the PMIDs of the particular studies to which you refer. I'm guessing that you didn't look at the full texts of at least some of these, and in another case may have looked at the full text but not followed a key reference.
In PMID: 15059645, the authors say "An additional group of mice were 151 subjected to CR at 14 months of age (as detailed in [39]) to serve as a positive control." Their reference (39) is this study from the same authors, which says " The restricted diet was nearly isocaloric to the normal diet, but enriched in protein, vitamins, and minerals to avoid malnutrition." They cite back to an earlier "Methods" guideline of theirs (PMID 10537025, "Controlling caloric consumption: protocols for rodents and rhesus monkeys"), which says even more explicitly, "The protein (casein), minerals, and vitamins are enriched in the [CR] diet such that nearly identical amounts of these components are fed to both [AL and CR] animals after a reduction in diet." I cited PMID: 15059645, and not these other papers where their exact method is described, because the latter 2 are not lifespan studies.
In PMID: 15044709, a pivotal study (being the first successful CR study in truly aged mammals, and happily available in free full-text), "Control mice were fed 93 kcal per week of chemically defined control diet (AIN-93M, Diet No. F05312, Bioserv, Frenchtown, NJ). ... CR was introduced by reducing calories to 77 kcal per week of chemically defined CR diet for 2 weeks, followed by 52.2 kcal per week of CR diet thereafter (AIN-93M 40% Restricted, Diet No. F05314, Bioserv)." As is spelled out in the main investigators' own patent for "Methods of evaluating caloric restriction and identifying caloric restriction mimetics", "Mice on the control diet were fed 93 kcal per week fo the control diet (AIN-93M). Mice on the CR diets were fed 77 kcal per week of the CR diet or 52 kcal per week Of the CR diet (40% calorie restricted AIN-93M). ... Each mouse in the LT-CR [Long-Term CR] group 106 was subjected to a LT-CR dietary program with feeding of 52.2 kcal per week of a semi-purified CR diet (AIN-93M 40% Restricted, Diet No. F05314, BIO-SERV). The control diet program consist of about 14 gm/100 gm diet casein, about 0.2 gm/100 gm diet L-cysteine ... The CR diet consist of about 23.3 gm 100 gm diet casein, about 0.3 gm/100 gm diet cysteine ... Note that the 40% CR diet composition listed in Table 12 is for both the 52 kcal per week CR diet and the 77 kcal per week CR diet. The dietary composition for the diet in the reduction stage, where the diet includes a 77 kcal per week diet program, can be adjusted accordingly from the CR diet to obtain a 77 kcal per week diet. The CR diet was used for both 52 and 77 kcal per week CR diets." I'm sure you can do the math ;) .
I'll also leave it to you to dig more fully than you did previously into the other two citations, both of which are available in free full-text, but I assure you that my characterization is accurate.
I will also point you to two additional studies, both with free full-text. PMID 4351915 compared three groups each of AL and CR animals, with the three AL groups and the three CR groups getting chow fed at 10, 22, and 51% casein, but with the CR groups getting 33% of the chow daily as the AL group. As you can see from their Table 2, the 51% casein CR animals had the lowest mortality rates and highest mean and maximal lifespans.
Additionally, PMID 729159 fed the AL animals a 21% casein and .15% methionine chow; these were compared to two 40% CR groups, each getting chow suitably enriched in vitamins and minerals, but with one group maintained on 21% casein and .15% methionine (just like the AL, but less of it, leading to 40% less absolute protein) while the other received 35% casein and 0.25% Met (so that the absolute protein intake was the same as the AL group despite the lower total Calories). Both CR groups lived substantially longer mean and maximal LSs than the AL group, with the difference between the two CR groups being nonsignificant — but the actual numbers indicate that, if anything, the higher-casein, higher-Met chow resulted in slightly longer lives.
@CAN: "Dietary Protein to Carbohydrate Ratio and Caloric Restriction: Comparing Metabolic Outcomes in Mice" is not a strict CR study, but a study of lower-Calorie chow fed ad libitum. A lower Calorie intake resulted, but a strict control of Calories did not result. Unsurprisingly, if you dig into their different cohorts' actual individual outcomes, you see extremely wide variation for each despite the overall trend.
@Michael
How can we explain that diets with High Carbohydrates and Low Protein increase lifespan (in studies that matched calorie count). Paradoxal? While Diets, Low Carbohydrates and High(or much Higher) Protein do not ? This is where the CR argument of controlling kj calorie falters a lil, CR is acting on something, through its calorie reduction, and that pathway 'seems' to be of protein nature...because high carbs don't stop from lifespan extension - only when protein is reduced at the same time. Ad libitum or not - thus calorie restricted or full on calories, makes little difference. And so, render calories is the responsible one as more moot. It is 'part' of it as it energy (kJ) but study I showed said restricted energy (by calorie restriction) did not increase longevity when protein content was modified at the same time of CR. So in order of effect protein, it seems, has the final say over CR, it's not the inverse. Why is that the final effects of Meth-R or TotalProteins-R are so similar to CR (as in reduced IGF-1, reduced glucose, reduced thyroxine, reduced insulin final benefitial effects) ?
In any case, both on their own, increase lifespan but in the grand scheme of things have little value for us human except increasing healthspan slightly and maybe MLSP (very doubtful, was extends mice lifespan does nothing to humans). That is why, I can't wait to your great SENS therapies (must be in 50 years or less : ) otherwise us living will be too old to get any result (from accumulated damage, and the 7 SENS damage therapies do not stop the forms of ongoing oxidative stress inside mitochondria (such as complex I ROS damage); thus aging will continue despite taking all SENS, I did a last post that estimated all of them to make humans reach 122 years by healthspan extension. As for MLSP extension, it would have been 15 up to max 200% extension depending on interdependent redundancy pathways activation of the therapies (synergy/addition/substraction effect (or not)) and the age at start of the therapy). These were just layman very optimistic estimates (my estimates were very 'friendly/positively exaggerated' and it may end up much lower in longevity effect after combining the thearapies) based on countless CR studies results and everyone told i was making stuff up with not one shred of base (when I did base things on the very fact that CR - does -increase maximum lifespan (in mice at least), so it is a surrogate for all SENS endeavours). : D
https://www.fightaging.org/archives/2016/02/the-sens-rejuvenation-biotechnology-companies.php#comments
scroll down discussion to my post: February 7, 2016 at 1:12 AM
PS: From this study, we may now suppose rougly how much CR would increase lifespan in humans :
it shows the effect of Meth-R in human fibroblast replicative senescence.
So, from this study, it seems that humans on specific methionine restriction (and protein restriction with methionine out of the composition) would get about 20% extension of average and maximum lifespan. Human Fibroblast replicative lifespan potential that is left is a close correlate of chronological aging/donor age, because fibroblast replicative lifespan correlates to fibroblast telomere size (which reduces has replicative potential left reduces too).
58 Population doublings (PDs) -> 70 PDs.
'' Similar levels of MTR depletion (∼44%) in human MRC5-381 fibroblasts also accelerated their growth rate and extended their maximal lifespan (70 PD, MTR-KD; 58 PD, control) (Fig. 4H). As genetic Meth-R was initiated at PD46 in human cells, this represents a lifespan extension of 100%, or 21% when comparing overall lifespans. Interestingly, more moderate depletion of MTR transcripts in MRC5-383 cells also resulted in an accelerated growth rate and extension of replicative lifespan (65 PD, MTR-KD; 58 PD, control) (Fig. 4I), but not to the same extent as observed for MRC-381 fibroblasts. ''
Thus, since Meth-R is so close in final effects of CR, we can infer that CR, *in humans*, would increase their average median lifespan and maximum lifespan, by approximately 20%, using these human fibroblast as surrogate results for CR (since they are so similar in final longevity potential).
'' In addition, similar to yeast, the extended lifespan of methionine-restricted mammalian cells is associated with NFκB-mediated retrograde signaling''
And, it seems, that Meth-R, like CR, both activate the retrograde response which reduces NF-Kb pathway, reducing mTOR and, thus, IGF.
Plus, they reduce the cell pH (strange, although pH is crucial), as such the cell become more alkaline; and the acidity kills the yeast faster; there is correlation between acidity and cell death.
''To discriminate between these possibilities, we tested whether acid accumulation was affected in methionine-restricted cultures by measuring the pH of normally aged cultures (i.e., unbuffered) at varying intervals. We found that there was a direct correlation between age-related pH and lifespan, with cultures of long-lived cells genetically restricted for methionine (met15Δ) demonstrating higher pH values. Measurements of WT cultures revealed a pH of 3.5 after 13 days of aging, whereas met15Δ cultures were less acidic even 12 days later (Day 25, pH 3.75).''
And, also, it seems total protein is not so much important, it's rather methionine content that is. Because removal of other amino acids from total protein count does not increase lifespan. As such, the culprit is methionine.
''What is clear, however, is that amino acid availability can have profound consequences for the stationary phase survival of yeast. To determine whether the simple removal of any one amino acid was sufficient to extend chronological lifespan, we aged wild-type yeast in normal media, as well as four other media formulations, each lacking a randomly selected amino acid (lysine, valine, isoleucine or threonine). We observed no lifespan extension for cells aged under these conditions (Fig. S1A). In addition, we found that genetic restriction of lysine, through deletion of the LYS2 gene, was similarly incapable of extending chronological lifespan (Fig. S1B). These data therefore indicate that the mere limitation of any particular amino acid is insufficent to extend chronological lifespan. Rather, the Meth-R-responsive pathway(s) that confer extended lifespan in yeast do so in response to manipulations that specifically restrict methionine.''
Methionine Restriction Activates the Retrograde Response and Confers Both Stress Tolerance and Lifespan Extension to Yeast, Mouse and Human Cells
1. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0097729
@CANanonymity: I can assure you that there is no chance of a 20% life span effect from CR in humans. If an effect of that size was the case, it would have been pinned down and categorized centuries ago.
@Reason
Hi Reason !
'' During extra-uterine life, telomerase activity is largely repressed in somatic tissues, including in hematopoietic stem cells5, 6; hence TL varies across somatic tissues in proportion to replicative activity.''
''Relative telomerase activity for fibroblasts from the younger age group was significantly higher than that from the older age group; 69.7% higher for fresh isolates and 31.1% higher at P0 (p<0.05). No detectable telomerase activity was to be found at later subcultures for both age groups. Similarly for keratinocytes, telomerase activity in the younger age group was significantly higher (p<0.05) compared to that in the older age group; 507.7% at P0, 36.8% at P3 and the difference was no longer significant at P6. In conclusion, the study provided evidence that telomerase sustained the proliferation of keratinocytes but not fibroblasts. Telomerase activity is an important criterion for continued survival and replication of keratinocytes, hence its positive detection before transplantation is desirable. Inferring from our results, the use of keratinocytes from Passage 3 or lesser for construction of skin substitute or cell-based therapy is recommended owing to their sustained telomerase expression.''
There is a correlation between replicative life potential *left* (thus before cell replicative senescence pathway)
and TL (telomere length) in many somatic tissues depending on donor chronological age. Thus, here, the study above showed the methionine restriction (okay maybe not CR, since it did not test CR, but CR has the same final effects as Meth-R, which slow aging, that is :
reduced IGF-1, reduced GH production, and especially, reduced blood glucose and reduced insulin, both do that and both give about the same 'average' median effect in mice; thus, we can extrapolate, in part at least, the Meth-R human fibroblast datat to CR - CR and Meth-CR are translatable because of same final effect on important aging parameters).
Methionine restriction was capable of pushing back replicative senescence (intrinsic aging) by 14 PDs (20%), of course, this is just in that 'type' of fibroblast. But, Meth-R is a whole-system effect, so other fibroblasts will gain. And fibroblasts remaining replicative culture longevity is good indicator/emulator of human lifespan as it directly correlate with it - because as said, telomeres shortening (in replicative potential reduction) - is reduced when the replicative lifespan potential shortens (which have lower replicative PDs/population doublings left).
Telomeres lengh is a direct predictor of MLSP, thus by way of telomeres, we know that fibroblast telomeres from different age of donors - affects their replicative lifepan potential that is left to these cells. And thus, both telomere and replicative potential, are correlates to human MLSP.
I am guessing that history of CR accounts cannot detect 20 years or less of lifespan extension, it is too small and too vague; and too long enough (or care) to notice. It seems it is a very 'subtle' effect, and for people who did CR (like say Japanese people who eat 80%/8 parts out of 10), they were 'already' doing 'some form' of CR to get them to live longer - did people notice, no ? Not really..it seems , it is very recent that we 'detected' this CR effect and can actually 'see' it happening. Before, people didn't even know, besides saying : 'well, we saw them eat less...and feel better...they lived long lives....'...ok so how is that helping us ? It cannot quantify anything of CR. I think the most important studies are the ones of primates doing CR, which doesn't increase their lifespan but reduced their mortality and health problems. I think CR might not increase 20% MLSP, neither Meth-R, but they definitely increase healthspan 10-20% or so, as is shown from the Meth-R study on human fibroblasts. Anyways, all speculations, but this study, definitely shows that Meth-R delays replicative senescence onset and thus, would reduce oxidative stress, and improve lifespan, median or MLSP ? The study said MLSP of Meth-R fibroblast were increased...does this translate into a Human living a longer MLSP life, I'm not sure but these fibroblasts have been quite effective at determining the MLSP of humans (as shown from telomere studies in human fibroblasts of different donor age).
Telomeres shorten at equivalent rates in somatic tissues of adults
1. http://www.nature.com/ncomms/journal/v4/n3/full/ncomms2602.html
Correlation of donor age and telomerase activity with in vitro cell growth and replicative potential for dermal fibroblasts and keratinocytes
2. http://www.journaloftissueviability.com/article/S0965-206X(09)00034-5/abstract
@michael
While the experts are still not in agreement on mice I am going to have to agree with you that your point of view has merit for mice while mine has merit with humans.
Your statement makes sense for mice as CR without methionine restriction would decrease visceral fat in mice compared to AL mice. Visceral fat removal has been shown to increase median and maximum lifespan in mice making your statement true.
I admit that I am not an expert in mice and spend the vast majority of my research on humans. So I will restate what I said before and relate it to humans.
CR to the level possible in humans without methionine restriction doesn't hit the main pathways in mice that are believed responsible for maximum lifespan extention but does likely increase healthspan in humans.
While methionine restriction at a level possible in humans does hit the same main pathways believed to be responsible for maximum lifespan extention in mice and may increase both median and maximum lifespan in humans.
Hopefully we can now agree.
@CANanonymity
Good information as always. CR without methionine restriction won't work in humans as it does not decrease IGF-1/increase FGF21. I am not aware of any historical group that followed a healthy diet with methionine restriction for reference so it is hard to know what its effects would be but I agree I think that 10-20% average lifespan extention is possible.
It would be nice if someone did a study in a group of people and checked the rate of change in their epigenetic clock on their normal diet over a period of time and then put the group on a methionine restricted diet and later measured the change in their epigenetic clock to see if it slowed down compared to their normal diet.
As most people here know horvath's epigenetic clock is more accurate at predicting mortality risk than age so as far as I know it would be a better measure than anything else currently available to show if methionine restriction slows aging.
If someone knows of a lab in the Americas that can do a blood test and analyze it according to how Horvath does it or another similar epigenetic clock please let me know.
Here is the reference for no IGF-1 change in CRON followers:
"The CR Society members, who call themselves CRONies (Calorie Restriction with Optimal Nutrition), had been on a calorie-restriction diet for an average of seven years when Fontana did the measurements, but their IGF-1 levels were virtually identical to sedentary people who ate a standard, Western diet."
Differences Between People And Animals On Calorie Restriction
https://www.sciencedaily.com/releases/2008/09/080924151018.htm
@michael
We need an edit button on here like on reddit. I wrote that at 1am and it looks confusing.
Edit: to clarify I am speaking about CR and methionine restriction conducted by humans not mice
CR without methionine restriction in humans conducted at a level that can be sustained over time does not hit the same main pathways that are believed responsible for maximum lifespan extention found in CR mice but does likely increase healthspan in humans.
While methionine restriction in humans conducted at a level that can be sustained over time does hit the same main pathways that are believed responsible for maximum lifespan extention found in methionine restricted mice and may increase median and maximum lifespan in humans.
Hopefully that clears up what I was saying
Hello! My daughter has Laron syndrome. Do you know someone who has the same condition as her here in USA? She wants to make friends! Thank you.
I just got back genetic results confirming that I have a GHR mutation ( c.556C>T; p.Arg186cys ) that can cause Laron Syndrome.
I'm an Israeli Jew with only known Eastern European ancestry (Ukraine, Hungary, Slovakia, Poland). My wife's descendants are from Morocco and former Yugoslavia (She's pregnant and will soon get tested for the mutation).
I was wondering if the fact that I have the mutated gene proves that I'm a descendant of the spanish inquisition? Are there any genealogical studies that show the spread and distribution of people who are only carriers of the mutation?