Fight Aging!

AMP-activated protein kinase (AMPK) is one one of the usual suspects whenever the research community considers calorie restriction, exercise, increased cellular quality control, and other ways to slightly slow the pace of degenerative aging. Search the Fight Aging! archives and you'll find many mentions over the years. In the publicity materials and paper linked below researchers take a modest step forward to better understand why AMPK is important: it appears a lynchpin regulator linking nutrient intake and one of the mechanisms of mitochondrial quality control.

All of the fundamental cellular responses to the environment are linked, and any given protein tends to play many different roles. Thus AMPK is a nutrient sensor, activated by low energy intake, which explains the link to calorie restriction. It also responds to changes that occur with exercise in much the same way, however. Once AMPK is more active, a grand cascade of varied mechanisms are set in motion, and researchers spend a great deal of time sifting through this immense complexity to understand how it produces modest benefits to health and longevity. Many interesting connections have been made. For example, calorie restriction requires functional autophagy in order to extend life, and calorie restriction is associated with raised levels of autophagy. AMPK activation, achieved artificially in absence of environmental changes, increases levels of autophagy. It all ties together in this way, but there is still much to be done to fill in the details.

Autophagy is the name given to a collection of mechanisms that clear out damaged proteins and cellular components, delivering them to locations in the cell capable of breaking down and recycling the parts for later use. One of the more important cellular components are mitochondria, the swarming bacteria-like power plants responsible for creating chemical energy stores, among other tasks. Many lines of evidence link mitochondrial damage to the pace of aging, and mitochondrial dysfunction to age-related disease. Anything that impacts mitochondria is interesting to the aging research community, and here AMPK is shown to have a fairly profound effect:

How the cell's power station survives attacks

Mitochondria, the power generators in our cells, are essential for life. When they are under attack - from poisons, environmental stress or genetic mutations - cells wrench these power stations apart, strip out the damaged pieces and reassemble them into usable mitochondria. Scientists have uncovered an unexpected way in which cells trigger this critical response to threats, offering insight into disorders such as mitochondrial disease, cancer, diabetes and neurodegenerative disease - particularly Parkinson's disease, which is linked to dysfunctional mitochondria.

In an average human cell, anywhere from 100 to 500 mitochondria churn out energy in the form of ATP molecules, which act like batteries to carry power to the rest of the cell. At any given time, one or two mitochondria fragment (fission) or reform (fusion) to cycle out any damaged parts. But when a poison - like cyanide or arsenic - or other dangers threaten the mitochondria, a mass fragmentation takes place. Researchers have known for years that mitochondria undergo this fragmentation when treated with drugs that affect the mitochondria, but the biochemical details of how the mitochondria damage is sensed and how that triggers the rapid fission response has not been clear until now.

Researchers found that when cells are exposed to mitochondria damage, a central cellular fuel gauge, the enzyme AMPK, sends an emergency alert to mitochondria instructing them to break apart into many tiny mitochondrial fragments. Interestingly, AMPK is activated by the widely used diabetes therapeutic metformin, as well as exercise and a restricted diet. The new findings suggest that some of the benefits from these therapies may result from their effects in promoting mitochondrial health. This new role of rapidly triggering mitochondrial fragmentation "really places AMPK at the heart of mitochondria health and long-term well-being."

To uncover exactly what happens in those first few minutes, the team used the gene editing technique CRISPR to delete AMPK in cells and showed that, even when poison or other threats are introduced to the mitochondria, they do not fragment without AMPK. This indicates that AMPK somehow directly acts on mitochondria to induce fragmentation. The group then looked at a way to chemically turn on AMPK without sending attacks to mitochondria. To their surprise, they found that activating AMPK alone was enough to cause the mitochondria to fragment, even without the damage.

AMP-activated protein kinase mediates mitochondrial fission in response to energy stress

Mitochondria undergo fragmentation in response to electron transport chain (ETC) poisons and mitochondrial DNA-linked disease mutations, yet how these stimuli mechanistically connect to the mitochondrial fission and fusion machinery is poorly understood. We found that the energy-sensing adenosine monophosphate (AMP)-activated protein kinase (AMPK) is genetically required for cells to undergo rapid mitochondrial fragmentation after treatment with ETC inhibitors. Moreover, direct pharmacological activation of AMPK was sufficient to rapidly promote mitochondrial fragmentation even in the absence of mitochondrial stress.

Another interesting topic to consider in this context is the ability of cells to rejuvenate their mitochondria completely in response to reprogramming. The creation of induced pluripotent stem cells has been shown to regenerate damaged mitochondria. Either the same or a similar process occurs in the very early stages of embryonic development, as the damage of aging is near-completely wiped away by the internal transformations of the few cells present at the time. Thus there are clearly mechanisms capable of this in the space of states that a cell can adopt, though this doesn't necessarily mean that any of them are accessible to an adult without the accompaniment of severe adverse consequences. Profound cellular transformations are generally not something you'd want to happen to large proportions of your cells at any one time.