The Garbage Catastrophe of Aging and How to Avoid It

Aging just is damage accumulation

Aging is the accumulation of damage and nothing more. As the level of damage rises, cells and the tissue made from them function poorly, and this in turn causes increased risk of disease and death. This is the garbage catastrophe of aging.

What causes this rising level of damage? If we can answer that, we know what causes aging.

(Note that this is a different question from asking whether aging is programmed by evolution or not.)

When we, or any organisms, are young, our cells can repair damage, but as we get older, the damage repair mechanism is itself damaged. This leads to rising levels of damage and an inability to fix it.

The main mechanism for damage repair is autophagy, from the Greek for “self-eating”. Autophagy is the cellular self-cleansing process in which cellular organelles such as mitochondria and proteins within the cell are broken down and their components recycled for making new organelles and proteins.

Autophagy is a daily occurrence — or should be — with peaks and troughs of activity. The absence of food strongly increases the rate of autophagy, so that in young organisms at least, its rate rises dramatically overnight. Fasting even longer than overnight further increases the rate of autophagy.

Other interventions besides fasting also increase autophagy, for instance, exercise and certain drugs and supplements.

But in older organisms, the capacity for increasing autophagy in response to fasting or other stimuli decreases. This leads to a rising level of damage that interferes with cell function and is characteristic of aging.

Autophagy is crucial for the organism. Treatments that prolong lifespan, for example calorie restriction, fasting, or even genetic manipulation of insulin signaling, require the organism to possess an intact autophagy mechanism to work.1

No autophagy, no lifespan extension.

What leads to declining autophagy and a rising level of damage?

Accumulating damage itself leads to declining autophagy

When cellular organelles and proteins that are past their expiration date are broken down and recycled during autophagy, it turns out that some of the material cannot be completely disposed of. Much of this material is composed of lipofuscin, the toxic waste of aging.2

Lipofuscin is all but non-degradable, and it accumulates with age.

Autophagy takes place inside cellular vesicles, called lysosomes, which are formed for that specific purpose. The inside of the lysosome is kept at an acidic pH, so that the autophagic enzymes will function optimally. These enzymes are inserted into the lysosome, along with the material that is to be broken down, and autophagy proceeds.

Some fraction of the material is impervious to breakdown, however, and this forms lipofuscin.

As lipofuscin builds up in the lysosomes, it impedes the process of autophagy. The cell continues to pour autophagic enzymes into the lysosome, but these are increasingly ineffective, as lipofuscin absorbs them and renders them useless. The entire process of autophagy becomes weaker.

Why autophagy is necessary

Most people understand that the constituents of our bodies turn over regularly, being broken down and rebuilt on a constant basis. Most of the cells and material in our bodies are not the same as they were earlier, so that it can be truthfully said that we literally are not the same person we were a few years before.

For example, red blood cells have a lifespan of about 120 days. If you were to take a blood sample from a person and determine the age of each red blood cell, you would find few to none that were older than that.

All of the red blood cells in your body were created within the last four months.

Why does this happen, and why is it necessary?

The constituents — cells, their organelles, and structural proteins and lipids — are subject to wear and tear. The most important source of wear and tear is due to metabolism, i.e. life itself.

When cells burn energy sources in order to power the processes of life, this burning releases byproducts, called free radicals, and these can and do damage to surrounding cell components. Think of it as the exhaust from a power plant, the pollution of which can cause damage to the surrounding area.

Cells have developed ways of coping with the byproducts of burning cellular fuel. One way is to contain and control them with internal antioxidants, such as glutathione, catalase, and superoxide dismutase. These may be likened to scrubbers in the exhaust stacks of a power plant.

The other way that cells have developed to cope with the inevitable damage caused by fuel-burning is to periodically replace the damaged components. Hence the process of autophagy.

Mitochondria and aging

Mitochondria are the cellular organelles commonly called “the powerhouses of the cell”, because most of the fuel-burning takes place in them.

As such, mitochondria are subject to greater damage from oxidation — fuel-burning —  than other cell components.

Mitochondria are critical in aging. Older organisms have larger and more poorly functioning mitochondria, which pour out greater amounts of oxidizing free radicals, causing more and more damage.3

Since mitochondria are so subject to damage, they wear out, and cells use autophagy to eliminate damaged mitochondria, which are then replaced with new ones. This process must proceed efficiently for the cell to retain its full youthful function.  Quality control of mitochondria is essential.

So, as organisms age and autophagy declines, older and poorly functioning mitochondria become prevalent.

To maintain youthful, fully functional, and efficient mitochondria, autophagy must work properly. Yet as we’ve seen, autophagy declines with age.

Aging as a garbage catastrophe

The inefficient and incomplete breakdown of cellular organelles and other components leads to increasing amounts of waste inside lysosomes, and it never goes away. This is the garbage catastrophe of aging. (See reference 2.)

From this perspective, it might be predicted that:

(i) suppression of oxidative damage would enhance longevity;

(ii) accumulation of incompletely digested material (e.g. lipofuscin pigment) would interfere with cellular functions and increase probability of death;

(iii) rejuvenation during reproduction is mainly provided by dilution of undigested material associated with intensive growth of the developing organism; and

(iv) age-related damage starts to accumulate substantially when development is complete, and mainly affects postmitotic cells and extracellular matrix, not proliferating cells.

There is abundant support for all these predictions.

Prevention of the formation of lipofuscin, i.e. cellular garbage, and/or removal of it when it exists, is crucial to slowing or stopping aging. For that purpose, it may not only be necessary, but sufficient.

Consider that when a cell divides, any waste material inside that cell is now cut in half. This may be the mechanism by which stem cells, which can divide throughout the lifespan of an organism, maintain perpetual youth.

The dilution of waste material through cell division may also be the reason why even aged organisms always give birth to young progeny. By diluting the waste contents of gametes (sperm and eggs) continually, they’re maintained in a youthful state, with no aging damage.

Even when autophagy is inhibited, continually dividing cells are protected from damage accumulation.4 This provides strong support for the garbage catastrophe idea and for the anti-aging effects of continual cell division.

Unfortunately for us, most of our cells do not divide continually. Heart cells and neurons, for example. So we’re stuck with cells that accumulate damage, because they can’t dilute it by passing it to numerous daughter cells.

Lipofuscin

What is lipofuscin anyway? If we can determine its composition, we may be able to understand how to prevent it and how to eliminate it.

Lipofuscin is an “iron-catalyzed oxidation/polymerization of protein and lipid residues”.5

Iron-containing proteins, such as ferritin, are subject to the normal turnover of cell components, and are broken down inside the lysosome. When this happens, free iron reacts with proteins and lipids, forming lipofuscin.

The enzymes that normally break down proteins and lipids inside the lysosome are not capable of breaking the chemical bonds formed in this reaction and that characterize lipofuscin.

Another important source of lipofuscin is so-called AGE, or advanced glycation end-products.6 AGEs are formed by the non-enzymatic reaction of sugars with proteins, and they can be broken down by the cell with difficulty or not at all. They occur in everyone but are higher in diabetes, which is characterized by high blood sugar.7

Both iron and sugars are necessary for the formation of lipofuscin.

The garbage catastrophe theory and the evidence

Does everything outlined above agree with other evidence on aging and longevity? Consider the following.

  1. Calorie restriction and fasting promote longevity, and they both are associated with increased autophagy.
  2. Decreased insulin signaling promotes longevity, and it too is characterized by increased autophagy.
  3. Substances that promote longevity also increase autophagy, for example resveratrol, metformin, berberine, curcumin, and lithium.
  4. The amount of lipofuscin in a cell strongly correlates to the degree of dysfunctional mitochondria.8
  5. Some animals don’t age. The Hydra, a non-aging animal, continually renews its cells, i.e. it has no post-mitotic cells, thus diluting all its cellular damage, resulting in no aging.9

The scientist Alexei Terman, of Linkoping University in Sweden, writes (reference 2):

Clearly, if all damaged structures were renewed with perfect accuracy, aging would not occur. But the inevitability of aging suggests that the biological mechanisms of removal and re-synthesis are not perfect. Of these two processes, the one most suspect in the progression of aging is that of inefficient removal.

Full understanding of the nature of aging, therefore, requires an explanation of the reasons why the
renewal process is imperfect, even under the most favorable conditions. As argued here, the basis of this imperfection may be in the incomplete removal of damaged biological material, which is necessary to make room for newly synthesized structures. This, in turn, may derive from the unfortunate fact that some of these damaged products are difficult or impossible to digest, particularly by the lysosomal compartment.

How to prevent and/or slow aging

Iron

I’ve argued that iron is the primary driver of aging, and looking at aging from the standpoint of the garbage catastrophe lends new support to this idea. Why?

Because iron is required for the formation of lipofuscin, the cell’s toxic waste.

Therefore, to slow the formation of lipofuscin, keep iron levels in the low normal range. Ferritin is the body’s main iron-storage molecule, and the more you have of it, the more will be turned over on lysosomes and the more iron will be left there, creating lipofuscin and catalyzing chemical reactions that damage cell structures.

Intermittent fasting

Intermittent fasting (and calorie restriction, which few people are willing to do over the long term) activates autophagy potently. Therefore fasting increases the clearance of damage. In older people, whose cells are clogged with garbage that inhibits autophagy, fasting may bring the rate of autophagy back to youthful levels.

Autophagy boosters

Certain substances/drugs can boost autophagy. These include resveratrol, hydroxycitrate, curcumin.

Exercise

Exercise increases autophagy and thus the clearance of cellular damage.

Normal blood sugar

Keeping blood sugar in the low normal range will help to prevent the formation of advanced glycation end-products (AGE), one of the constituents of non-degradable cellular garbage.

Experimental treatments

There have been a few reports of substances that can clear lipofuscin from cells. If these were to pan out, they could turn out to be potent anti-aging interventions.

One such substance is a form of cyclodextrin, which is a cheap safe molecule that is already used as an excipient in medicines.10

This form of cyclodextrin upregulates autophagy and clears cellular junk.11

PS: You can read more about these issues in my books Dumping Iron and Stop the Clock.

Follow me on Twitter.

Check out my Supplements Buying Guide for Men, where you’ll find many of the anti-aging supplements mentioned in this article.

 

 

  1.  Jia, Kailiang, and Beth Levine. “Autophagy is required for dietary restriction-mediated life span extension in C. elegans.” Autophagy 3.6 (2007): 597-599.
  2.  Terman, Alexei. “Garbage catastrophe theory of aging: imperfect removal of oxidative damage?.” Redox Report (2013).
  3.  Weber, Tobias A., and Andreas S. Reichert. “Impaired quality control of mitochondria: aging from a new perspective.” Experimental gerontology 45.7 (2010): 503-511.
  4.  Stroikin, Yuri, et al. “Testing the “garbage” accumulation theory of ageing: mitotic activity protects cells from death induced by inhibition of autophagy.”Biogerontology 6.1 (2005): 39-47.
  5.  Terman, Alexei, and Ulf T. Brunk. “Lipofuscin.” The international journal of biochemistry & cell biology 36.8 (2004): 1400-1404.
  6.  Yin, Dazhong. “Biochemical basis of lipofuscin, ceroid, and age pigment-like fluorophores.” Free Radical Biology and Medicine 21.6 (1996): 871-888.
  7.  Kalousova, M., J. Skrha, and T. Zima. “Advanced glycation end-products and advanced oxidation protein products in patients with diabetes mellitus.”Physiological Research 51.6 (2002): 597-604.
  8.  Terman, Alexei, et al. “Aging of cardiac myocytes in culture: oxidative stress, lipofuscin accumulation, and mitochondrial turnover.” Annals of the New York Academy of Sciences 1019.1 (2004): 70-77.
  9.  Martinez, Daniel E. “Mortality patterns suggest lack of senescence in hydra.” Experimental gerontology 33.3 (1998): 217-225.
  10.  Song, Wensi, et al. “2-Hydroxypropyl-β-cyclodextrin Promotes Transcription Factor EB-mediated Activation of Autophagy IMPLICATIONS FOR THERAPY.” Journal of Biological Chemistry 289.14 (2014): 10211-10222.
  11.  Kilpatrick, Kiri, et al. “Genetic and chemical activation of TFEB mediates clearance of aggregated α-synuclein.” PloS one 10.3 (2015): e0120819.
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17 comments
The Garbage Catastrophe of Aging and How to Avoid It – Technology and Longevity Feed says August 15, 2016

[…] Original Article: The Garbage Catastrophe of Aging and How to Avoid It […]

Reply
Abelard Lindsey says August 15, 2016

This is essentially the SENS perspective on aging.

Reply
Daniel says August 15, 2016

Very informative, had no idea about iron ageing effects on us!! Any idea on how to take cyclodextrin without medicines?

Reply
    P. D. Mangan says August 15, 2016

    You can find cyclodextrin as a supplement at Amazon.

    Reply
Jerome Verhasselt says August 16, 2016

Great article!
I have one question. You write: “Prevention of the formation of lipofuscin, i.e. cellular garbage, and/or removal of it when it exists, is crucial to slowing or stopping aging. For that purpose, it may not only be necessary, but sufficient.”

This may be true for postmitotic (non-dividing) cells, but in cells that divide, won’t the telomere shortening process still result in aging and senescence?

I judge that telomere shortening and thymic involution are also “aging clocks” that must be addresses, as well as the “garbage catastrophe” clock.

Reply
    P. D. Mangan says August 16, 2016

    Thanks, Jerome! Cells that divide seem to have telomerase, the telomere-lengthening enzyme, turned on. If that’s the case, then no telomere shortening, no aging. For instance the hydra, referenced in the article, probably does this, and our own stem cells as well.

    Reply
      Jerome Verhasselt says August 16, 2016

      My research found that telomerase is only activated sufficiently in the germ (reproductive) line. In most of our somatic cells, it’s apparently not activated at all. (This appears to be how the “Hayflick Limit” is implemented). Meanwhile, human stem cells apparently *do* have telomerase activated to a significant (but apparently not sufficient) degree to prevent telomere shortening in these critical cells. I look forward to continuing this discussion.

      Reply
mudbone says August 18, 2016

“Consider that when a cell divides, any waste material inside that cell is now cut in half. This may be the mechanism by which stem cells, which can divide throughout the lifespan of an organism, maintain perpetual youth.”

Enjoyed the article but this statement I feel is somewhat misleading. Of course it is correct that when the cell divides the number of molecules of waste material and everything else is approximately cut in half (except for the DNA which will be exactly partitioned in half) but what likely really matters to the cell in whether the concentration of the waste material is reduced by dilution/division/autophagy. If the rate of accumulation of waste material is greater than the volume doubling time of the cell then the concentration of waste material will continue to increase in the cell and its progeny.

Reply
    P. D. Mangan says August 18, 2016

    mudbone, that’s certainly true, but generally, at least in humans, the accumulation of waste material like lipofuuscin takes place over many decades – it’s quite a slow process. So if you compare, say a cardiomyocyte to a stem cell, you can see how the stem cell would accumulate little damage.

    Reply
Rutner says September 11, 2016

Another factor critical in aging populations is the increasing lifelong accumulation of diverse antibodies against non pathogenic viruses like HSV, EBV etc in a process termed immunosenescence. Several aging markers were identified in blood of 80-90 year olds that allow differentiation of spritely from morbid seniors. Re telomer shortening and repair, a recent report in an MIT exhibit showed remarkable restoration of damaged telomeres including lenghtening detectable by electrophoresis after consumption of a single kiwi fruit per day. Other fruits may have similar effects.
Cyclodextrins can bind or capture certain small molecules, but how would these larger complexes be excreted.without further garbage overload?

Reply
Joshua says September 16, 2016

Very nice article. This site continues to deliver for me.

On the subject of autophagy enhancers, I have what many would consider to be good news: it seems coffee can be added to that list. A few studies seem to show it increases autophagy: http://www.waiworld.com/waitalk/phpBB3/viewtopic.php?t=3670

So go ahead and enjoy some black coffee with your fast — it’s doubly good for you. (Maybe even triply good, since the coffee might chelate a little iron too.)

Reply
ted says September 21, 2016

Hi PD,

In your opinion, is it possible to remove existing AGEs (advanced glycation products)?

Ted

Reply
Aging Starts Young - Rogue Health and Fitness says October 24, 2016

[…] means the accumulation of damage to tissues, cells, their organelles, and their constituent molecules (proteins and […]

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