Ghrelin Knockout Mice Eat Less But Fail to Live Longer as a Result

One of the many interesting but unresolved questions relating to calorie restriction and its beneficial effects on health and longevity is the role played by ghrelin. This hormone regulates appetite, but also has a range of other effects on metabolism. For example, it appears to be involved in immune function and inflammation. This sort of observation raises the question of the degree to which the full physiological experience of hunger is a necessary part of the benefits produced by calorie restriction. Researchers here take a first step in the exploration of this topic with a study of mice genetically engineered to lack ghrelin. The interesting portion of the data is that mice without ghrelin eat less, at least while young, but did not live longer, as is reliably the case in normal mice with a reduced calorie intake. I think that the authors head off in the wrong direction with a focus on AMPK, rather than exploring calorie restriction as an explanation for much of what they observed. There is no real discussion of why it might be that life span was not increased in ghrelin knockout mice, which seems to me the real question here.

In line with what is seen in humans during aging, here we show that old wild-type (WT) mice show an increase in body weight and fat mass, along with a significant decrease in muscle strength and endurance. Although ghrelin deletion (KO) in young animals on regular diet was previously shown not to have a significant effect on food intake, energy expenditure, or body weight, we show for the first time that ghrelin deletion significantly prevented body weight and fat mass gain in older mice while maintaining lean mass and muscle function when compared to wild-type age-matched animals.

As body weight gain develops as a result of energy imbalance, food intake and energy expenditure were studied in detail. Aging was associated with a decline in food intake, but also in spontaneous locomotor activity and total energy expenditure. Ghrelin deletion decreased food intake in young animals and partially prevented the decrease in energy expenditure seen with aging in WT mice. Given that the decrease in locomotor activity seen with aging was similar in WT and KO mice, we postulate that the difference in total energy expenditure between genotypes was primarily due to changes in resting energy expenditure. The data also suggest that a decrease in energy expenditure due to decrease locomotor activity and, perhaps also in resting energy expenditure, is the main variable driving the energy imbalance during aging in mice.

We found no differences in muscle mass or whole body lean mass between genotypes. Nevertheless, the decline in endurance and grip strength seen with aging in WT mice was also partially prevented by ghrelin deletion. In this study, we also show a significant increase in type IIa (fatigue resistant, more oxidative) fiber content with aging in KO compared to WT mice that is likely to be responsible for the increased endurance seen in KO aged animals. We postulate that this increase in type IIa, fatigue-resistant, oxidative fibers could have contributed to the increased energy expenditure and subsequently decreased fat mass seen in aged KO mice as skeletal muscle fibers are major contributors to resting energy expenditure.

At the molecular level, the age-related decreases in endurance and muscle strength were associated with downregulation of phospho-AMPK and its downstream mediators. These changes were partially prevented by ghrelin deletion. Previous studies have shown the importance of the AMPK pathway on improving endurance, and this finding suggests that AMPK modulation by ghrelin could contribute to the phenotype seen in our model of increased endurance and muscle strength. The interplay between ghrelin and AMPK is not well-understood, however. There are no previous reports of chronic effects of ghrelin or ghrelin blockade on AMPK activation; however, it is known that AMPK target genes are key to mitochondrial biogenesis, fatty acid oxidation, and energy expenditure. Taken together, the data are consistent with the hypothesis that AMPK modulation by ghrelin may contribute to ghrelin's effects on muscle function, fat accumulation, and energy expenditure.

Link: https://doi.org/10.1111/acel.12618

Comments

I wanted to ask a question about Cooked Food. I've read that among the main glycosylation residues that cells have difficulty breaking down and expelling, are Maillard-reaction products. If eating Cooked Food is a significant contributor to our exposure to Maillard-reaction products, then does that mean the invention of Cooking has helped contribute to age-related dysfunction? Would avoiding/minimizing consumption of Maillard-reacted foods then help reduce age-related dysfunction?

Posted by: sanman at June 13th, 2017 2:17 AM

@sanman

Hi sanman ! Just my 2 cents :

In one word. Yes. And in more words, it depends on the type of food, nutrient in it (for example certain beans, which contain lectins and other poisons can be deadly eaten raw; you must cook them; once cooked these elements are lost or destroyed/oxidized/rendered harmless during the exposure to heat stress - the AGEs (advanced glycation end products) load is thus minimal; but, even there there is still some; when you expose a food to a oxidizing-stress (such a intense heat); this can chemicallly transform the food of being unedible anymore (unless you want to eat toxic poison full of aldehydes (MDA/TBARS), carbonyls and AGEs.. - there is also a point (such as charring/burning the food) when the food is completely oxidized and the nutrients are fully lost - there is intense destruction of food DNA, cell and mitochondrias (the membranes rupture); when you leave to food to be cooked for hours on end. At a certain point, there is 'smoking' 'browning/tanning' (Maillard) AGEs, charring, until its ash etc..

Avoid cooking (only for food that needs it to remove dangerous elements in that food), cooking is also important for removing/destroying pathogens and bacterias in foods - again, you kill them - because you expose them to an Oxidizing (heat) temperature stress - as such, you destroy them but can destroy the food too (for all of these elements are 'organic' and when 'stressed'by an oxidative stress - it damages the DNA of these elements; thus, the food is not necessarily more protected (it has antioxidative content such as polyphenols and redox elements, but they can be burned quick and then the food is 'naked' and the oxidative stress will make that food 'spoil' (accumulate DNA fragmenation, MDA/TBARS, nutrient loss, AGEs, carbonyls, protein misfolding - just like in human flesh same thing, it's 'lively/organic'...).

On your second question :
Yes- absolutely. I noticed it myself too, since cutting out sugarycrap food, my intake of AGEs and my accumulation of AGEs by excess glucose/sucrose/etc..reduces diabetes and HbA1C...it's the CR (calorie restriction) with avoiding AGEs dense-food for more 'Whole'foods that contain the fiber; and as such, to avoid excessive hemoglobin glycoxidation from 'sweet junk foods'.
These sweets accelerate Maillard reactions Dramatically - Especially - Fructose, that's the worse of the worse (one experiment showed that Fructose made 10x more AGEs maillard reaction and crosslinks - than other sugars, such as glucose, lactose, amylose, sucrose (even sucrose), dextrose, etc (it's funny because fructose has a lower GI (glycemic index) and they advise you to eat fruits rather than sweets/as fructose could impact less the insulin response - just for a little while than the problems come (intense AGEs formation from whatever fructose intakem this would increase spontaneous senescence of cells))...Fructose is utter poison (in large dose) and contributes - dramatically - to diabetes onset, eating fruits-filled with fructose is bad, eat low-fructose fruits or avoid fruits altogether. The fact is most of it converted inside G6P (glucose6phosphate pathway/fructokinase, the body uses fructose converts it vice versa depending on the needs and enzyme) hexokinase and fructose-1-phosphate kinase. Glucose-6-phosphate (G6P) to Fructose-6-phosphate (F6P). It's done inside, so it's better to let it convert it (from the glucose you get) than intake excess fructose from eating too many fructose-rich fruits. Also avoid : High-Fructose Corn Syrup, a strong Diabetes accelerator.

As for the argument taht 'fruits are full of antioxidants - even fructose rich ones' yes, but it's not enough. All the antioxidants cannot stop the damage caused by excessive fructose exposure. As for people whom say 'but some people ate blueberries and live a 100' yes, they are micro-percentage. You can live a long life consuming these fruits, most of them are in the lower fructose levels; but trust me, if you have problems - eating these fruits will not magically heal everything; like diabetes for example, they will slow it but like in anything, there is 'pluses' and 'minuses' from whatever you eat.

Also, In this paper the reason why the mice (I feel) did not live longer is tied to CR itself
and what happens with muscle increase. This is because mTOR is at the center of this -
mTOR is regulator of senescence entry and a regulator of Growth/Muscle Growth to be precise.

mTOR is a gate-keeper double-edged sword, it's meant for survival and specie reproduction goal.
Here the mice improved in 'fitness' - (at the cost) of 'same life' or having the chance to at least reach maximal lifespas, no extension they kept their health and improved/maintained muscle mass (stopped sarcopenia); but, this muscle improvement has a cost - mTOR activation (muscle fibers depend on that and the whole IGF/mTOR/Nutrient/Amino-intake insulin growth-axis), thus senescence activation (mTOR is pre-requisite for geroconversion to senescence). And by that, I'm talking about 'intrinsic aging (first aging)' not Secondary - Health aging (which is driven 'by health' status' or the 'threshold' until it becomes too much and entering 'spontaneously' into senescence...- or not, and it is 'replicative senescence' over many replicative rounds and a long life (that is the intrinsic aging bit that determines your maximum lifespan)).

Just a 2 cents (i'm not explaining it at the best right now, it's very late and I'm passing out).

Posted by: CANanonymity at June 13th, 2017 3:46 AM

From an evolutionary staindpoint,our ancestors ate fruit full of fructose long before they cooked meat. If fructose dramatically increases Maillard reactions, I'm wondering why our cells haven't evolved mechanisms to remove Maillard reactions from the body. Then again, the answer may lie in the short livespans of our ancestors, meaning that Maillard reactions accumulated but not to a sufficient level until death for selection against them. And death came early and was not age-related.

Posted by: K. at June 13th, 2017 9:44 AM

Hi K. !

Great points. Just a 2 cent, you answered your question;
I think it's because, as you said from their short livespans, it was not such a problem;
exactly, it was not age-related but predator-related/environment dangers-related mostly.
People would die of predators rather than of aging/diseases (although they did die of disease too : there was not study that verified bones of ancient hominins; they saw the apes and other types branches (H.Sapiens, Neanderthal, Australopithecus, etc) got cancer - the bones showed obvious 'bone cancer' and tumors; and weaking of the bone (Bone Mineral Density) due to these tumors forming then (so, cancer has been something that is on Earth since the dawn of time - Dinosaurs got cancer, and many other animals - some animals are lucky though and evolved powerful mechanisms that stop tumor formation (such as elephants, whom should be 'Filled' with cancer/tumors by their size/cellularity, but are not not because they are more copies of special P53 gene tumor-supressor variants; and elephants were hear long ago (Mammoths and Mastodont ancestors); other ones like sharks or naked mole rats - never get cancer or rarely (by cell contact inhibition mechanism and hard stromal barriers that stop metastasis dead in its track); same for these apes millions of years ago - or even farther with dinosaurs.

Also, we have to seperate health from aging - there would be no need to evolve Maillard reactions removing mechanism - because as you said, life was short; so no point - reproduction was made early and specie 'goal accomplished', early. There was no use, but not only that it demonstrated that they Could live longer they just didn't have the chance to from hostile environment - it Did happen that some of them (the lucky ones) live to their near maximum lifespan (seeing individuals whom would 60-70...80 years...Back Then; it was rare, but it did happen). To say, that No advanced hominins lived Ever beyond 60 is most bs; because their MLSP (maximum lifespan) was just never attained for they were killed before that (by predators).
But what if they Hermits living in a cave and always protected; and lived Fully and Unharmed ever...then, yes that is 'lab-environment' (that mice get), you get protection and you have a lot more chances of reaching individual/specie MLSP. There, I'm sure Some would have strive a little bit longer and showed the (real) MLSP of these then-humans. That explains a bit why we, still, haven't got the machinery to remove Maillard reactions. There was no need, we died too young - but now, it's a problem, because so many people Live Long (unharmed no predators/no hunting) - they die 'of disease' attained from old age limit/decaying/dysfunctional body by multiple rounds (years) of cell replication. It has an inherent limit (as seen with centenarians whom still die at 122, they don't go on to live 350...they die then; it's about the human MLSP - now, we 'brush it' far more than ever; we 'test' the body to its limit because we keep our health so good and so 'guarded'; this gives a slow-aging phenotype/we transfer this to our children (genes) whom have a chance of living a 100 (Centenarians offsprings)). They call it the 'grand-mothering' theory, grand-mothers allowed humanity to 'live long' for they transfered their 'longevity genes'. Parental nurturing (back then in apes) was nill (and it still is, it is not a feature of these apes, but mosty H.Sapiens), with H.Sapiens nurturing/parenting - And Grand-Parenting (Grand-Ma). There is a clear connection of longevity 'genes' by grand-mother(ing) and the transfer of their 'hardier' maternal mitochondrias at conception (since mitochondrias are very 'vulnerable' (IMM innermembranes are highly oxidative environments by IMM Complex I-V ROS emission there that destroys IMM phospholipids/fatty acids required for membrane ordering/fluidity and certain viscosity/cristae formation)
theirs are less (while males mitochondrias are weaker and more exposed from having less capacity to quench these ROS emissions/or are more 'susceptible' in general because they have less genomic stability (females have 2 X chromosomes (XX are gene loaded) males have Xy chromosomes, less stable by a small poor-gene y chromosome; it's one of the major reason why males die younger than women; they have inherently 'poorer/compromised' genome from birth, handicapped right from birth - they are mores sturdy and muscled because of more mTOR, females are smaller and less musclemass - less mTOR - longer lifespan. It's also why women are more frail and 'at risk' when developping diseases (it kills them more when it Does happen; men survive them more (but die younger) from more mTOR/fitness protecting mechanism)). Don't ask yourself why there is 90 centenarian women for 10 centenarian men (9/10 women, 1/10 men that reach 100s).

Just 2 cent.

Posted by: CANanonymity at June 13th, 2017 11:12 AM

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