Jamie Barger (UW) - CR as a "Hibernation Mimetic"
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He is a hibernation biologist.

Hibernation is an "ancestoral condition", and CR may bring about a similar
inherited response.

Studied hibernating ground squirrel in Alaska.

What is hibernation? It is not sleeping. Neural activity is near zero during
hibernation, while it isn't during sleep.

Hibernation - way of reducing metabolism when energy is scarce.

Sometimes daily, sometime extended period of time. "Diapause" in simpler
animals. Some hibernation is hard-wired - some animals hibernate in winter,
when food normally scarce, even when abundant food available. Others tie
hibernation to short-term food availability.

Part 1: Similarities between CR and hibernation at metabolic level

Walford originated the idea.

Both are coordinated system-wide adaptation to decease in food/energy
availability.

Both downregulate energy metabolism, and shift the metabolic substrate use
(glucose spared, fats used more for energy).

In ground squirrels (GS) - metabolic rate decreased, and body temperature
drops dramatically - sometimes below freezing by a bit! Amazing. GS warm up
on a periodic basis to normal temperature (~98deg F) for a short time,
without waking up or eating.

Black bear (BB) body temp drop isn't nearly as large (a few degrees F
98-93deg F) and no periodic warming.

Monkey body temperature goes down overnight. CR Monkeys have lower average
body temperature.

Michael Rae says rats *do* drop in body temperature, just not as much as in
mice.

In ground squirrels, during short (few hours) rewarming phase during
hibernation, hypometabolism precedes hypothermia. So animals downregulate
metabolism, which results in hypothermia. So it isn't the cold (hypothermia)
that triggers reduction in metabolism. Instead, the animal *chooses* to
downregulate metabolism, and this reduction results in less heat generation,
and eventual hypothermia.

Hibernation is an active depression of metabolism.

Adaptive response to minimize energy dissipation when resources are limited.

Part 2: In addition to parallel macroscopic metabolism changes, similar
cellular signaling mechanisms involved in both.

C. elegans - go into hibernation like response (Dauer state) in response to
food shortage.

Involves insulin signaling cascade - little insulin released, which results
in hypometabolic state, via the daf2 gene.

Daf2 and insulin receptor genes are similar.

Levels of IGF1, GH and insulin are lowered in CR mammals.

Genetically manipulating IGF-1 (downregulating it) in mice may lead to
increased lifespan.

FIRKO mouse - genetic mutants with no insulin receptor. They live longer.

IGF-1 receptor knockout mice live longer.

Laron dwarf mice have lower level of IGF-1, and live (on average) 50%
longer. These mice have similar mutation as human mice. Unclear whether
human dwarfs live longer.

Is insulin signaling reduced in hibernators? - Yes, in ground squirrels
anyway!  Suggesting similar mechanisms between CR and hibernation.

Part 3: Do hibernators live longer?

Within species, Turkish hamsters that hibernate longer, live longer. "Good"
hibernators within species live ~50% longer live spending 18-30% of life
hibernating.  Also, looks like a robust increase in max lifespan. They do
spend more of their life unconscious, but it is still a win...

Michael Rae - coldness may be part of the CR mechanism - particularly
against cancer.

Michael Rae - Hibernation upregulates neural protection mechanisms.