A Perspective on the Garbage Catastrophe of Aging

We age because damage accumulates at the lowest levels of our biological structures, in and around the protein machinery of our cells. But an individual is not a static structure: we are not like buildings or cars because our machinery can repair and replace itself to an impressive degree. Cells accumulate enormous numbers of defects in their proteins and large component parts - such as mitochondria - on a day to day basis, and garbage in the form of metabolic waste products and broken or proteins accumulates constantly. The vast majority of these issues are repaired and removed extremely quickly.

The real downward slope in aging occurs when the mechanisms governing repair and maintenance start to fade. The advocates of programmed aging would say that this decline is the result of an unfortunate continuation of genetic programs that were necessary or advantageous in early life, but now become harmful. But most of the research community think that it's all still damage - it's just that the dynamic relationship between damage and health in a self-repairing system is much more complex than it is in a static structure. Damage accumulates, and some forms of damage cause a breakdown in the systems that remove damage: hence you wind up with what is known as the garbage catastrophe.

Researchers can explain genetic degenerative diseases that only manifest after a few decades of life in terms of this failure of maintenance: an individual that suffers far more damage than others due to an errant gene has cells that can keep up the pace in youth, but which lose the battle earlier in the process of declining repair with age. Neurodegenerative conditions like Parkinson's disease can be framed in this way as garbage catastrophes: the genetic associations determine who is being more rapidly damaged in some cell populations and thus more quickly overwhelmed.

Processes of cellular repair, such as autophagy, are considered important in how metabolism determines longevity: most methods of extending life by slowing aging in laboratory animals involve increased levels of autophagy, implying cells and cellular mechanisms that are less damaged for longer periods of time. Calorie restriction, for example, boosts autophagy. Scientists have been looking into increased autophagy as the basis for therapies for some years, as in this recent example of ongoing research into the genetic condition of Huntington's disease:

NIH-funded study finds that quickly clearing away damaged proteins may help prevent neurodegenerative disorders

Researchers investigated how cells deal with different forms of huntingtin, the protein involved in Huntington's. The mutant version of huntingtin is longer, and contains three building blocks of the protein repeated an abnormal number of times. These repeats in huntingtin are what cause it to misfold, eventually leading to neuron death and the symptoms of the disease.

The researchers found that the amount of time the mutant protein remained in the cell predicted neuronal survival: shorter mean lifetimes of mutant huntingtin were associated with longer neuronal survival. A shorter mean lifetime indicates that a protein does not remain in the cell for a long time, and that proteostasis is working effectively to clear it away. This suggests that improving proteostasis in Huntington's brains may improve neuronal survival.

To test this idea, the researchers activated Nrf2, a protein known to regulate protein processing. When Nrf2 was turned on, the mean lifetime of huntingtin was shortened, and the neuron lived longer. "Nrf2 seems like a potentially exciting therapeutic target. It is profoundly neuroprotective in our Huntington's model and it accelerates the clearance of mutant huntingtin. One surprising finding from these experiments was the significance of single cells' ability to clear mutant huntingtin. It turned out that this ability largely predicted their susceptibility, whether that neuron came from the most vulnerable region of the brain - the striatum - or the cortex, which is less vulnerable."

The findings indicate that the toxicity of the damaged proteins may cause neurodegeneration by interfering with the proteostasis system, affecting how quickly they are cleared from neurons. The researchers explored potential mechanisms behind differences in proteostasis. One way that cells normally get rid of proteins is through autophagy - a process in which proteins are packed up into spheres and then broken down. Results in this paper suggested that neurons increased the rate of autophagy when they sensed that the mutant form of huntingtin was accumulating, indicating the autophagy system may be a drug target.

"These findings provide evidence that our brains have powerful coping mechanisms to deal with disease-causing proteins. The fact that some of these diseases don't cause symptoms we can detect until the fourth or fifth decade of life, even when the gene has been present since birth, suggests that those mechanisms are pretty good."

Nrf2 is involved in the beneficial hormetic response to low levels of damage associated with calorie restriction, exercise, and the like. Interestingly long-lived naked mole rats have more Nrf2 in their cells, and the same is true of other long-lived species that appear to share a more effective cellular repair and maintenance response than their shorter-lived peers. Research of this nature all suggests that greatly boosted autophagy is a good thing to aim for as the basis for a therapy of general application - it's something that everyone should have turned on all the time.


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