Enhancing Mitophagy to Improve Mitochondrial Function in Old Individuals

Mitochondria are the power plants of the cell, packaging chemical energy store molecules to power cellular operations. Mitochondrial function declines with aging, and as one might expect this drags down all aspects of cellular functioning with it. Evidence suggests that this form of degeneration is strongly connected to a failure of the quality control mechanism of mitophagy, which identifies and recycles damaged mitochondria. The proximate cause may be changes in mitochondrial dynamics, particular a diminished amount of fission, the splitting of larger mitochondrial into multiple smaller organelles, leaving too many large and broken mitochondria that cannot be effectively recycled. The connection between this and the known root causes of aging remain obscure.

It is plausible that mitochondrial function is so important to health that some benefit for older individuals can be obtained via forcing greater mitochondrial fission and mitophagy, via changing levels of regulatory proteins, even without addressing the underlying causes. The question at the end of the day is always the size of the effect, of course: even when significant gains are observed in short-lived species, it isn't necessarily the case that this will carry through into long-lived humans. Similarly, upregulating mitochondrial quality control might be far more useful for people with poor lifestyles than for those who have maintained their physical fitness. The research noted here is an example of the standard drug development process applied to the goal of upregulating mitophagy. A natural compound was discovered to boost mitophagy, and after further evaluation was taken into human clinical trials.

During aging, there is progressive decline in the cell's capacity to eliminate its dysfunctional elements by autophagy. Accumulating evidence has highlighted the decrease in the specific autophagy, or recycling, of dysfunctional mitochondria, known as mitophagy, in aging skeletal muscle. This can result in poor mitochondrial function in the skeletal muscle, and has been closely linked to slow walking speed and poor muscle strength in elderly individuals. Consequently, improving mitochondrial function in elderly people by restoring levels of mitophagy represents a promising approach to halt or delay the development of age-related decline in muscle health.

Urolithin A (UA) is a first-in-class natural food metabolite that stimulates mitophagy and prevents the accumulation of dysfunctional mitochondria with age, thereby maintaining mitochondrial biogenesis and respiratory capacity in cells, and, in the nematode Caenorhabditis elegans, improving mobility and extending lifespan. In rodents, UA improves endurance capacity in young rats and in old mice either fed a healthy diet or placed under conditions of metabolic challenge. Recently, UA was shown to have a favourable safety profile following a battery of standardized toxicological tests.

In this report, we detail the outcome of a first-in-human, randomized, double-blind, placebo-controlled clinical study with UA. We administered UA, either as a single dose or as multiple doses over a 4-week period, to healthy, sedentary elderly individuals. We show that UA has a favourable safety profile (primary outcome). UA was bioavailable in plasma at all doses tested, and 4 weeks of treatment with UA at doses of 500 mg and 1,000 mg modulated plasma acylcarnitines and skeletal muscle mitochondrial gene expression in elderly individuals (secondary outcomes). These observed effects on mitochondrial biomarkers show that UA induces a molecular signature of improved mitochondrial and cellular health following regular oral consumption in humans.

The present study reveals that UA induces a molecular signature response, in both the plasma and skeletal muscle of humans, resembling that observed as a consequence of a regular exercise regimen. It is important to highlight that our earlier work revealed that the stimulation of mitophagy by UA led to an induction of mitochondrial biogenesis and an enhancement of mitochondrial function, resulting in improved aerobic endurance and higher muscle strength in treated rodents. In humans, endurance exercise is well known to trigger mitochondrial biogenesis and fatty acid oxidation in the skeletal muscle to optimize efficient production of ATP by skeletal muscle cells under aerobic conditions. It has also been shown that exercise is a natural means of triggering mitophagy, making it particularly important to maintain an active lifestyle during aging, as it ultimately results in improved mitochondrial function in the muscle.

Link: https://doi.org/10.1038/s42255-019-0073-4

Comments

I think that cycling of periods of increased mytophagy filled by increased mitochondria division can give better results. I am taking ellagic acid, which is deemed to be the precursor for urolitihin produced by the gut bacteria. So far I see no measurable effects. An alternative approach could be a few days fast follows by breaking the fastest and excessive training. And cycle this regimen. Probably urolitin can enhance it. I hope it will bring some of the benefits of calorie restriction and fasting. For some people that could be the difference of being couch potato and solicit who can go for a walk

Posted by: Cuberat at June 20th, 2019 7:41 AM

To Cuberat
Another option is Nicotinamide
https://www.ncbi.nlm.nih.gov/pubmed/22493485

Its quite possible that all that hype of late about NR, NMN is working through NAM as oral consumption of those simply increase circulating NAM levels as shown in Rabinowitz lab paper on precursors metabolism

Posted by: Andriy Cherpakov at June 20th, 2019 7:58 AM

It doesn't appear that anybody is selling this in pure form, just pomegranate extracts. This is interesting because I remember feeling almost euphoric once after eating pomegranate; I wonder if this is why.

Posted by: bmack500 at June 20th, 2019 8:31 AM

There's a mitochondrial fission/fusion protocol (5 day) that has been published in the Longecity forums. I have no idea how well it works. But since its based on some of the things I'm already using, I see no reason not to try it out. I will try 10 or so rounds (10 weeks) of this early next year (after I complete my ALA chelation).

Posted by: Abelard Lindsey at June 20th, 2019 9:42 AM

@bmack500
Pomegranates, when ripe, have a lot of fructose. Your experience might be a sugar rush/boost.

@Andriy Cherpakov
Nad is definitely interesting. It seems that they have somehow different targets UR and NAD. probably they can ensure each other.

It remains to be problem that they work better than calorie restriction alone,, though

Posted by: Cuberat at June 20th, 2019 10:46 AM

@Abelard Lindsey
That would actually require a good study. The said study might be useful for training, v rehabilitation and graceful aging

Posted by: Cuberat at June 20th, 2019 11:03 AM

I have an animal study I'd like to suggest: Use EMS to exhaust animal muscle tissue to the extend a human heavy weight workout does. Does the biopsy show destruction of "larger mitochondrial" bodies contributing to mitophagy. As I've said before: Francois Henri Jack LaLanne died at 95 and wasn't very happy about it for his fans' sake.

Posted by: Tom Schaefer at June 20th, 2019 11:39 AM

Another option for mitophagy is spermidine
https://www.nature.com/articles/srep24700
BTW its now available on amazon and its not too expensive considering low dosage that needed and half life of 4 days

Posted by: Andriy Cherpakov at June 20th, 2019 12:22 PM

I'm planning on doing the protocol I mentioned previously because mitophagy and biogenesis are two separate processes that occur separately. The recent HrF2/PGC-1a work suggests that much of the mitochondrial dysfunction that causes aging is, in turn, a result of a imbalance between the mitophagy and biogenesis of mitochondria. This suggests that these functions are performed separately and that the compounds to enhance each of these functions have to be taken separately for beneficial results.

Posted by: Abelard Lindsey at June 20th, 2019 12:50 PM

I was just looking over some papers I downloaded earlier this year on NrF2 signaling. Apparently NrF2 signaling is involved in stem cell reprogramming as well, suggesting a link between mitochondrial maintenance (mitophagy/biogenesis) and cellular reprogramming (a method of epigenetic maintenance and regeneration). I don't know what these links are. But I'm sure research over the next few years ought to answer this question.

Posted by: Abelard Lindsey at June 20th, 2019 12:54 PM

Abelard - What do you think of the new supplement Phytochemical Combination PB125 which supposedly Activates the Nrf2 Pathway?
I can't find inexpensive spermidine on Amazon, what is it called? I've been taking a very expensive wheat germ extract.

Posted by: August at June 20th, 2019 10:27 PM

I don't know anything about this PB125. Your comment is the first time I've heard of it. I will have to do some searching around on the net.

Posted by: Abelard Lindsey at June 20th, 2019 11:21 PM

I am a 47yr old Caucasian male that takes testosterone replacement therapy that would be interested in participating in any mitochondrial stimulation experiments.

Posted by: William Beasley at August 10th, 2019 9:56 PM

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