The Biochemistry of Mammalian Hibernation as a Possible Basis for Therapies

Researchers are attempting to understand the biochemistry of limb and organ regeneration, exceptional cancer resistance, and hibernation in a number of species in order to see whether they can form the basis for therapies or enhancements in humans. Here, hibernation is the focus:

Novel adaptations discovered in hibernating animals may reveal ways to mitigate injuries associated with strokes, heart attacks and organ transplants. A person typically takes a long time to recover from cardiac surgery or organ transplant. This is in part because organ tissue is damaged when blood flow ceases or is reduced when a heart stops or an organ is removed. Tissue is also damaged when blood flow is restored and the body's metabolic machinery is not able to safely handle the returning rush of oxygenated blood. Protection of tissues following cardiac arrest or organ transplant has remained an elusive scientific target, despite significant research and promising data.

In 2009, researchers began collaborating to identify how a hibernating Arctic ground squirrel's heart can survive what is akin to repeated cardiac arrests. Unlike other animals, Arctic ground squirrels can lower their metabolism to 2 percent of their normal rate, which allows them to essentially shut down bodily functions they don't need and, importantly, puts their organs in a state of suspended animation. The researchers collected and analyzed proteins associated with heart muscle from cooled, hibernating Arctic ground squirrels in which blood flow had been stopped. They repeated the analyses on heart proteins from active summer Arctic ground squirrels and rats, which don't hibernate.

By comparing the various proteins produced and the metabolic changes within each animal, they identified novel internal adaptive mechanisms by which ground squirrels cope with cold and other stressors and how those mechanisms relate to blood flow problems associated with cardiac surgery. One such mechanism is the ability of hibernators to exclusively use lipids, which include fats, vitamins and hormones, as metabolic fuel instead of burning carbohydrates, as humans do during surgeries. Understanding this unique model of extreme metabolic flexibility may help scientists develop strategies that enable doctors to "switch" the metabolism of a patient who has suffered a stroke, cardiac injury or hypothermia to resemble that of a hibernator and thereby improve survival and recovery. The authors anticipate that the knowledge gained from this study could be applied to organ protection in nonhibernators and ultimately in patients undergoing heart surgery and transplantation, and for victims of cardiac arrest, trauma and hypothermia.

Link: https://www.iab.uaf.edu/news/news_release_by_id.php?release_id=135

Comments

Hi there !

Interesting ! This could turn out helpful, especially the limb/organ regeneration (like geckos/salamanders/lizards
cell transdifferentiation to regrow their cut-off limbs/tails...regrow a human arm or leg after losing it. But 'don't lose your head' (pun!) over losing your other limbs (joke)).
Regrowing your head would still not stop you from dying from losing it in the first place.
It's the regrowing of organs that has me more interested, limbs ok, but organs...that's a whole different thing.
If we could regrow/regenerate our organs, except perhaps brain, to the exact same state during youth; that would be a form of rejuvenation.

Exceptional cancer resistance by (NMRs) naked mole rats (large hyaluronan molecules, plump skin for hypoxic environment, altered p53-p16-p21 levels and stronger stromal cell barriers that inhibit tumor propagation to other organs)
is definitely something we can do with; although, this is mixed stuff. Certain studies showed an actual increase in hyaluronic acid (HA) during human cancers (neoplastic remodelling is what is happening). Inflammation is characterized
by higher amount of short-chain/fractured hyaluronan while anti-inflammation in ECM has more long-chained hyaluronan. Still, this is inconclusive, an small and large chain HA have been found during pathological remodelling (like fibrosis).
ECM remodelling is complex and cancer neoplasticity ECM remodelling is too; it messes up HA, not like in naked mole rats. I'm not so sure increasing long-chain HA would amount to all that much, in humans, plumper youthful skin, like a naked mole rat, such as in little children or babies
would not stop cancer (kigs gets cancers...anyways and have higher HA and plumper skin/tougher organ stromal barriers). Our cell density/organ complexity/size are the risk/longevity thing, naked mole rat should outlive us since it has 'youth features/negligeable senescence features'; it doesn't.
It doesn't get cancer though, but its aging, is still faster than ours). I am guessing there is cancer resistance/longevity vs reproduction evolutionnary selection tug going on (for they are hyposexual/infertile serfs most of them but the single queen who gets all the sex/reproduction, live 30 years for a rodent is extreme,and live in hypoxic subterrains/hypoxia (3-10%)...no oxygen, a perfect oxygen level for tumor formation. Evolution selected 'cancer resistance' in them...not in us, we live in 20% ambient oxygen, not a 'friendly-tumor' environment; as such it was not 'as' selected in us than naked-mole rats.
They're evolutionarily 'honed' for cancer resistance in their cancer-breeding hypoxic-environment; we can apply some of their tricks; but it's far more than just HA; their genetic is cancer proof through other mechanism (p53/TNF-a variant for example).

Ground squirrel hibernation reaches bear/other animal hibernation; these animals 'feed' themselves big time, sometimes packing 2-times their weight in fatty layers for the arrival of the winter (bears get extra-fat for winter hibernation).
During this torpor this use/feed-off/get energy of their fatty layers they gained before entering hibernation state. Although an interesting mechanism for long-term hibernation in hibernating animals, I feel this would not really apply in humans.
Small-type of hibernation could be possible, but long-term I'm not sure. Like metabolic-shutdown controlled-hypothermia in humans is somewhat possible but you have to check the heart continuously/pulse. In humans, it's more complicated, fat usage for energy is
what happens during 'ketosis'/ketotic state (ketone bodies); ketosis makes you lose weight fast but is not some state you should continuously be in; as there's an accumulation of ketone bodies; acidic/acid formation (the pH lowers). Excess acidification has some serious dangers.
Ketosis also lowers metabolism and switches to fatty/beta-oxidation metabolism, just like hibernation. How low could we go with ketosis, I don't know, but severe hypometabolism is dangerous/fatal, for humans. what's more is you can't talk about hibernation methods helping for people
who have had heart attacks or heart diseases...the heart may less strained by reduced demand/hypometabolism/low pulse/low blood-pressure...but it uses fat as energy. Fat (saturated, monounsatured) is the main driver of heart attacks (LDL cholesterol accumulation by ingestion of it/liver producing way too much LDL cholesterol (Which gets oxidized/and contribute to foam cell macrophage ROS in arteries when uptaking LDL in atherosclerotic lesions, causing the unstable plaques to rupture and create deadly arterial clots) when fed these fats is the number 1 killer in atherosclerosis), when you 'pack' on weight for hibernation you are basically on 'overkill' mode for someone suffering from fat-caused heart failure.
This approach is misguided and fat usage is, again, like other therapies, dangerous/risky stuff; for healthy thin/lean people with no complications or family-history of heart problems; possibly. Not for the rest of heart disease sufferers. Too risky. A 'bell-curved' mortality graph curve shows that people die - more - when carbohydrates for daily energy usage are cut down and switched to fat and/or proteins instead. Carbohydrates are vital for humans, centenarians all survived on mostly 'enough' carbs, not excess carbs. Which is about 50gr carbs per meal, total 150g carbs per day equalling 200 calories per meal for 600 calories a day (the bell-shaped curve shows that 600 calories/day is magic 'CR-like' number for longer lifespan and lowest mortality (control of blood glucose/diabetes/accelerated aging/not getting fat with age).

Metabolic Effects of the Very-Low-Carbohydrate Diets
1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2129159/

Posted by: CANanonymity at June 24th, 2016 10:15 AM

PS: ''The effects of low carbohydrate diets on insulin sensitivity depend on what is used to replace the dietary carbohydrate, and the nature of the subjects studied. Dietary carbohydrates may affect insulin action, at least in part, via alterations in plasma free fatty acids. In normal subjects a high-carbohydrate/low-GI breakfast meal reduced free fatty acids by reducing the undershoot of plasma glucose, whereas low-carbohydrate breakfasts increased postprandial free fatty acids.

Why is it disease-prone? Because high serum free fatty acids are implicated in various disease states, especially immune related (and also diabetes in some cases). High serum FFA and very low trigs that we see among those who VLC are associated with nascent autoimmunity, especially rheumatic autoimmunity.''

Ketosis has some drawbacks anyway you see it, serum FFA rises and that is a big problem (one study showed that blood FFAs are correlated to MLSP in mammals, of course going on fatty diet vs carbs will make FFA rise), wether (not) 'harmless' dietary ketosis or harmful diabetic ketoacidosis; both are good temporarily in the immediate; in long term, adverse effects can happen (hypometabolism, brain migraines/damages (cholesterol/fat fueled brain can induce these debilitating migraines/brain microvascular damage when blood glucose reaching brain for its usage is too low; as seen in hypoglycemia).

Posted by: CANanonymity at June 24th, 2016 10:43 AM

PPS: typo/precision: ''one study showed that blood FFAs are *inversely* correlated to MLSP in mammals''

(when plasma FFAs rise, mammalian MLSP (Maximum Lifespan) reduces in mammals of various decades-different longevities, mostly long-chained peroxidizable-prone DHA/EPA/ARAs but also shorter-chains, total FFAs is what is important).

''...elevated FFA levels are associated with insulin resistance and high blood glucose'' (ironic that very low carbs/ketotic diet would increase FFAs, which would cause rebound glucose elevation and insulin resistance;
'rebound diabetes' we could almost call this diabetes type 4 (for diabetes type 3 is basically Alzheimer's (who also have fibrils/amyloide formation by excess glucose/glycated hemoglobin HbA1C))

Plasma long-chain free fatty acids predict mammalian longevity
2. http://www.nature.com/articles/srep03346

The mystery of C. elegans aging: An emerging role for fat
3. http://www.ucl.ac.uk/~ucbtdag/Ackerman_2012.pdf

Mammalian life-span determinant p66shcA mediates obesity-induced insulin resistance
4. http://www.pnas.org/content/107/30/13420.full

Posted by: CANanonymity at June 24th, 2016 11:03 AM

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