Further Investigations of Neuropeptide Y and the Hypothalamus in Calorie Restriction

A number of lines of research suggest that the benefits of calorie restriction for health and longevity largely derive from increased cellular housekeeping processes such as autophagy. For example, the calorie restriction response requires neuropeptide Y (NPY), and here researchers explore the linkage of NPY with autophagy. They suggest that the role of autophagy in calorie restriction is indirect, and that it is a lynchpin part of the process only because a portion of the brain involved in the global control of metabolism responds to the level of autophagic activity:

One thing that has been clear for a while now is that autophagy is at the center of the aging process. Low levels of autophagy (cells with impaired "housekeeping") are linked to aging and age-related neurodegenerative disorders. This is easily explained as autophagy clears the cells "debris" keeping them in good working order. That the process is so important in the brain is no surprise either, because neurons are less able to replenish themselves after cell damage or death. But about a year ago a remarkable new discovery was made: the hypothalamus, which is a brain area that regulates energy and metabolism, was identified as a control center for whole-body aging.

Calorie restriction increased autophagy in the hypothalamus but also boosted levels of the molecule NPY, and mice without NPY do not respond to calorie restriction. Furthermore NPY, like autophagy, diminishes with age. All this, together with the new identified role of the hypothalamus suggested that this brain area and NPY were the key to the rejuvenating effects of calorie restriction. The researchers started by taking neurons from the hypothalamus of mice and put them growing in a medium that mimicked a low caloric diet, to then measure their autophagy. Like expected, their autophagy levels in this calorie restriction-like medium were much higher than normal. But if NPY was blocked, the medium had no consequences on the neurons. So calorie restriction's effect on hypothalamic autophagy appeared to depend on NPY.

To test this, next the researchers tested mice genetically modified to produce higher than normal quantities of NYP in their hypothalamus, and found higher levels of autophagy supporting their theory that autophagy was controlled by NPY. In conclusion, calorie restriction seems to work by increasing the levels of NPY in the hypothalamus, which in turn trigger an increase in autophagy in these neurons, "rejuvenating" them and delaying aging signs by restoring their ability to control whole-body aging.

Link: http://www.science20.com/catarina_amorim/mechanism_to_delay_aging_identified-154209


Unlike most other brain areas, the role of the hypothalamaus is, as I understand it, to secrete various factors that govern systemic homeostasis. Since it's not an identity-critical structure and its role is non-local signaling, could it be possible to replace or augment its function through tissue located elsewhere in the body? I'm thinking of strategies that have been proposed for replacing lost pancreatic function.

Posted by: José at March 26th, 2015 10:28 AM

Epigenetic reprogramming would be a better option via circulating youthful blood factors.

Posted by: Steve H at March 26th, 2015 12:17 PM

A 2009 paper on the same subject -
"Hungry for Life: How the arcuate nucleus and neuropeptide Y may
play a critical role in mediating the benefits of calorie restriction"
- ends with the observation:
"Taking into account the profound effects of CR on the appetite regulating
machinery of the hypothalamus and NPY—the key central hunger signal that
mayplay a critical role in transducing CR’s benefits—it may be that the very effectiveness of CRstems from the same hunger-inducing phenomena that CR mimetic research seeks to repress."

Also, perhaps worth noting is that a number of polyphenols/flavonoids suppress NPY production.

Posted by: Lou Pagnucco at March 28th, 2015 6:26 PM

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