Does Autophagy slow aging and slow the progression of neuro-degenerative diseases ?

Warning: this is a reflection of my theoretical interest. A foolish person might mistake it for advice on how to delay aging. Do not take medical advice from me. I am an economist. Autophagy means self eating. It refers to the process through which cells send things in the cell to lysosomes to be broken down to their components. I will mainly type about macro-autophagy which refers to a fairly large volume surrounded by a double membrane called and autophagosome which fuses with the lysosome. Autophagosomes are large enough to engulf entire mitochondria (the organelle which produces ATP using glucose and oxygen). This is important because defective mitochondria can produce reactive oxygen species (ROS) (think hydrogen peroxide) which damage cells. Autophagy also removes aggregates of proteins stuck to each other. This may be very important as such aggregates have a role in Alzheimer’s disease and probably also Parkinson’s disease and Huntington’s disease

It is often argued that autophagy slows aging. This argument is largely based on the effect of molecules which promote autophagy slowing aging of rats and mice.

There is also very strong evidence that autophagy prevents (or delays) neurodegenerative diseases. Here the evidence is quite strong. (Homozygous) genetic defects ni proteins involved in autophagy cause increased risk of Parkinson’s disease and (different defects) Amyotrophic lateral sclerosis.

This makes chemical which stimulate autophage extremely interesting. Unfortunately the best known (don’t eat this at home kids) is Rapamycin which promotes autophagy by inactivating the Mammalian Target of Rapamycin complex 1 (MTORC1). Unfortunately this also Rapamycin an potent immunosuppressant, so it is very dangerous to eat it just because it does indeed slow rodent aging.

One approach to seek a safer promoter of autophagy is to develop molecules similar to Rapamycin (rapalogs) and check if they suppress the immune system, hoping they don’t Of course they do.

Update: How could I have forgotten to mention this in an earlier draft. Simvastatin is a pharmaceuitical which promotes autophagy. Satins are used to control high blooed cholesterol. They have a low chance of causing Rhabdomyolosis (overall a one in a million risk of causing death). I guessed that they reduc the risk of Alzheimer's disease. I just googled and found "Specifically, statin use demonstrated a 28% risk reduction in Alzheimer's disease, 18% risk reduction in vascular dementia, and 20% risk reduction in unspecified dementia." end update

There are definitely safe molecules which are alleged to promote autophagy. One is resveratrol. Long ago it was observed that large doses of resveratrol appeared to cause slower aging in rats. There is a fairly large literature on this topic in peer reviewed journals. As a result (somewhat embarrassingly) resveratrol is included in many unregulated dietary supplements (also you can buy it on Amazon.com). It is a natural compound (found in red grapes) with no known serious side effects, so it is basically not regulated.

There are two definite problems with resveratrol. Most of it is not absorbed by the intesting and most which is absorbed is rapidly metabolized by the liver. For it to be effective (for whole mammals such as ourselves) it must be very potent.

An very similar alternative molecule more of which is absorbed and which has a longer half life is pterostilbene (found in blueberries). There are many fewer articles in the peer literature on pterostilbene than on resveratrol.

Spermadine is a poly amine which promotes autophagy there is evidence that oral spermadine slows aging in mice.

As an aside – the peer reviewed biomedical literature is huge. Obscure journals are indexed on pubmed.ncbi.nlm.nih.gov . Finding something there does not mean it has cleared a high bar.

There are various articles which assert that relatively potent (and well absorbed) autophagy inducing pharmaceuticals have been found using high throughput screening. This is part of the effort to repurpose pharmacuticals – to find new uses for FDA approved pharmaceuticals. The point is that the FDA does not regulate doctors who can prescribe pharmaceuticals off label. They do not list the same molecules. Many cause lower blood pressure. Some are used to prevent migraines. They do not suppress the immune system.

The pharmaceutical on at least one of the lists include

Clonidine

Minoxidil (yes the stuff bald guys use to make hair grow – it also causes lower blood pressure if taken internally in higher doses)

Rilmenidine

and

Rizatriptan. (used for migrains does not lower blood pressure)