Lysosomal Activity Declines With Aging

Lysosomes are roving garbage disposal and recycling units that exist in droves within your cells. One of their jobs is to break down damaged cellular machinery before it causes issues, and so that the component molecules can be reused. Another task is the disposal of unwanted or harmful biochemicals:

[Lysosomes] are used for the digestion of macromolecules from phagocytosis (ingestion of other dying cells or larger extracellular material, like foreign invading microbes), endocytosis (where receptor proteins are recycled from the cell surface), and autophagy (wherein old or unneeded organelles or proteins, or microbes that have invaded the cytoplasm are delivered to the lysosome).

If you've been following along these past few years, you'll know that autophagy is clearly very important in longevity. It is required for the life extension provided by calorie restriction, for example. If damaged cellular components are not cleared out rapidly, then their faulty operation will cause even more damage. This eventually spirals into what is known as the garbage catastrophe theory of aging. The cellular components of particular interest here are the mitochondria, the cell's powerplants: we know that mitochondrial damage contributes to aging, and that differences in mitochondrial function and structure between species correlate strongly with life span. It is very plausible that the primary reason autophagy is important in longevity is because this process destroys damaged mitochondria before they can cause further harm.

Given that lysosomes are the agents of autophagy, we should therefore be concerned if they fail or slow down with aging. Unfortunately, this is exactly what happens. There are at least two important processes underlying the failure of lysosomal function with aging. Firstly, there exist a great many biochemicals that lysosomes cannot break down. Once inside a lysosome, that junk is there to stay:

Lipofuscin is the name given to a gunk formed of many varied chemical byproducts of metabolism. It accumulates in your cells with age - and cause a great many problems in doing so. In particular, it accumulates in lysosomes, the recycling units of your cells that are tasked with breaking down unwanted chemical and components (the latter in the process called autophagy). Lysosomes in the old are bloated and inefficient, packed to the gills with lipofuscin that cannot be broken down by the enzymes available to your cells.

What to do about the accumulation of lysosomes rendered ineffective by biochemical junk? The SENS Foundation approach is research into a practical form of medical bioremediation:

The most promising approach is to enable cells to break the junk down so that [lysosomes] don't fill up after all. This can be accomplished by equipping the lysosome with new enzymes that can degrade the relevant material. The natural place to seek such enzymes is in soil bacteria and fungi, as these aggregates [such as lipofuscin], despite not being degraded in mammals, do not accumulate in soil in which animal carcasses are decaying, nor in graveyards where humans are decaying. This suggests that the micro-organisms present in soil have enzymes capable of breaking these aggregates down, and work now being carried on at Arizona State University has already confirmed this analysis.

The second process at work in the decline of lysosomal function was more recently established. Items to be recycled by lysosomes must be identified and steered to a lysosome, a process accomplished by cellular machinery that includes chaperone molecules and receptors on the lysosomes themselves. These lysosomal receptors decline with age, however, a change that may or may not result from the accumulation of biochemical junk discussed above.

The cells of all organisms have several surveillance systems designed to find, digest and recycle damaged proteins. ... One of these surveillance systems - responsible for handling 30 percent or more of damaged cellular protein - uses molecules known as chaperones to seek out damaged proteins. After finding such a protein, the chaperone ferries it towards one of the cell's many lysosomes ... Dr. Cuervo found that the chaperone surveillance system, in particular, becomes less efficient as cells become older, resulting in a buildup of undigested proteins within the cells. She also detected the primary cause for this age-related decline: a fall-off in the number of lysosomal receptors capable of binding chaperones and their damaged proteins.

Last year Cuervo demonstrated old mouse livers functioning as well as young mouse livers through genetic engineering of a breed that produced more lysosomal receptors. It remains to be seen whether this result holds for all tissues and organs, as well as what exactly is the root cause of age-related decline in receptors.

Lysosomal decline is typical of what researchers know of the causes of aging. There is a great deal of very detailed knowledge about the processes involved, some ongoing and very promising research, and a clear roadmap that describes how to produce therapies to reverse the problem. All that is missing is a vast funding effort, public awareness and support, and the will to develop those therapies. If the young of today age and die in the same way as their ancestors, it will be because we all chose to look the other way and do nothing.


Certainly there must be some foods and supplements that enhance
lysosomal activity and function. Please inform the public of any anecdotal or otherwise demonstrated work in this arena.

Posted by: Wm. James at August 12th, 2012 3:35 AM

My antiaging medical doctor told me that heavy metals also build up in the lysosomes and contribute to their decline. She has recommended time release alpha lipoic acid as a chelating agent to help remove such heavy metals. Does anyone know of any evidence to confirm this? Does anyone know of any supplements or off label use of FDA approved medications that are available to help remove garbage from the lysosomes?
The Life Extension Foundation has recommended the use of PQQ to promote the growth of new mitochondria. Does anyone know if PQQ would also promote growth of new lysosomes, or of any supplements that might do so?

Posted by: Ernest Edmundson at August 10th, 2013 2:32 PM

I use PQQ, 5mg/day.For autophagy try 50mg Resveratrol for a few days, Trehalose as a sugar substitute or diluent. Curcumine may also help, but add black pepper for a better bioavailability. Short term fasting (3-7days) could show similar effects like caloric restriction. These are things I'll try.
Some people think spermidine helps, but it's very complex to assess, I don't think supplementation is feasible. A healthy diet will provide you with some interconvertible polyamines, it's not like PQQ that is really low in food.

Posted by: Marco at November 8th, 2013 9:52 PM

check out spermidine supplementation

Posted by: michael j yaros at June 22nd, 2019 11:31 AM

Life Extension just came out with a supplement called Autophagy Renew. It is a combination of luteolin and piperlongumine.

Posted by: Ignatius Turchi at April 25th, 2021 12:08 PM

Centrophenoxine (Lucidril) is a nootropic that has long been known to reduce the buildup of lipofuscin in brain and other body tissue. Clearing out lipofuscin gives lysosomes less work to do.

Posted by: Jack at December 21st, 2022 10:28 AM
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