Mitochondrial biogenesis (renewal) favors replication of high-functioning mitochondria, while the more damaged mitochondria are more subject to mitophagy, mitochondrial death and reabsorption -a form of autophagy. My question: Might exercise and mitochondrial-specific antioxidants possibly protect or even restore mitochondrial number, contents and quality? Can this help us in living a longer healthier life, and perhaps in the fight against prostate cancer?
Mitochondria, oxidative stress, and antioxidant defenses
The "Mitochondrial Theory of Aging" asserts mitochondria, the primary energy producing components of every cell, are strongly involved in production and leakage of destructive reactive oxygen species (ROS), considered as the main pathogenic agent of many aging related diseases, including the progression of cancers. The process damages DNA and all of the machinery of our cells. And leads to destructive inflammation and cell death (autophagy). These two processes, genetic mutations and inflammation, are the two key drivers of cancer progression ("The Hallmarks of Cancer").
Protecting our mitochondria and their functioning is clearly of paramount importance to health, survivorship and longevity. So I am submitting a review of the most important factors with evidence for helping in this endeavor. I hope to review (and not in just a single post) the following available means to promote mitochondrial, cellular and therefore human health:
Part I Exercise. Both aerobic exercise (aka cardiovascular or endurance), and Strength (resistance) training. Both components have very positive impacts on mitochondria.
Part II Nutritional and supplements to protect mitochondria. These include:
1) Coenzyme Q10 (ubiquinone)
2) Pyrroloquinoline quinone (PQQ)
3) Alpha-Lipoic acid (ALA)
4) L-Carnitine
5) NMN: Nucotinamide Mononucleotide
Then perhaps a Part III: Strategies, medications and supplements to help reduce baseline inflammation. Then I should address the opposing concerns, that mitochondrial biogenesis may be an enabler of cancer stem cell proliferation. Let's start now with exercise, beneficial in so many ways.
Exercise and Mitochondrial number, quality and function in aging Impact on Exercise Performance and Cellular Aging
"Loss of mitochondria is well known to occur in many muscles with age, but new results indicate that the capacity per mitochondrion can also decline in human skeletal muscles. These changes in mitochondrial capacity were discovered by comparing the mitochondrial functional limit - the muscle oxidative phosphorylation capacity (ATPmax) - with the mitochondrial content (Vv) of the muscle (6). Figure 2 shows that the mitochondrial phosphorylation capacity declined by half between the adult and elderly group in the VL, yet the mitochondrial content dropped only by 25% with age. This greater loss in mitochondrial function than in content points to a 30% reduction in the capacity of each mitochondrion to generate ATP.
"Aging, inactivity and disease cause degradation of mitochondria in number and in oxidative efficiency. Increased MT leakage of ROS accelerates degradation and accumulates mutations and genetic loss in MT. Uncoupling of respiratory chains decreases the amount of energy (ATP) that can be captured from oxidative electron transport chains (ETCs). Respiratory efficiency diminishes. Aerobic capacity declines."
Exercise capacity paralleling reduced mitochondrial capacity can drop by 50% in the elderly compared with young adults. Yet only half of this is due to decreased in mitochondrial content. The other half of the decline, 25% of total function, is due to diminished functioning of the remaining mitochondria. These are attributed to 1) reduced functioning of the Electron-Transport-Chain of oxidative respiration and also to 2) uncoupling of ATP production from the mitochondrial inner membrane proton gradient ("Uncoupling", H+ Leakage).
"Endurance training is well known to improve aerobic function of elderly subjects and increase mitochondrial content and oxidative enzyme activity of aged muscle in humans. A surprising result from our studies is the apparent reversal of energy uncoupling after 6 months of exercise training in elderly muscle. Figure 8 shows a 25% increase in phosphorylation capacity per mitochondrial volume (ATPmax/Vv) with endurance training in elderly VL muscle (6,14). This result was unexpected because the accumulation of irreversible mtDNA mutations is the prevailing hypothesis for the cause of mitochondrial dysfunction with age (27). These mtDNA mutations are thought to result in permanent defects in the ETC that are unlikely to be reversed with exercise training. However, the significant uncoupling measured in vivo in mouse and human skeletal muscle does not fit with mtDNA mutations but rather is consistent with direct oxidative damage to mitochondrial membranes resulting in increased H+ conductance of the IMM."
Decline in skeletal muscle mitochondrial function with aging in humans
"Cumulative mtDNA damage occurs in aging animals, and mtDNA mutations are reported to accelerate aging in mice. We determined whether aging results in increased DNA oxidative damage and reduced mtDNA abundance and mitochondrial function in skeletal muscle of human subjects. Studies performed in 146 healthy men and women aged 18–89 yr demonstrated that mtDNA and mRNA abundance and mitochondrial ATP production all declined with advancing age. Abundance of mtDNA was positively related to mitochondrial ATP production rate, which in turn, was closely associated with aerobic capacity and glucose tolerance. The content of several mitochondrial proteins was reduced in older muscles, whereas the level of the oxidative DNA lesion, 8-oxo-deoxyguanosine, was increased, supporting the oxidative damage theory of aging. These results demonstrate that age-related muscle mitochondrial dysfunction is related to reduced mtDNA and muscle functional changes that are common in the elderly."
To be continued. Paul/MB
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Well thought out presentation, MB. (Nick Lane would approve. I'm sure.) I'm trying to digest several long podcasts on hormones, health, fitness, and longevity hosted by Andrew Huberman as well as several of Peter Attia. The two I listened to today were Huberman discussing hormones with Dr. Kyle Gillette. (As with Peter Attia, Dr. Gillette has the benefit of being a practicing MD.) While not focusing on cellular functions of metabolism, there is discussion of supplements that are reported to improve metabolic energy and fitness.
Both Creatine and L-Carnitine were mentioned for their ability to enhance metabolism - as well as boosting Testosterone. Since I am currently on bicalutamide (which actually boosts T), my interests in supplements that may boost T/free-T departs from those on SOC-ADT that seeks to suppress T < 20. My last T lab was 770, but free-T is considerable below the target 2% of total T, so I am looking for ways to boost free-T, including supplements. Maybe a post to come on this topic later this month.
I also saw this rather surprising article about research indicating that one of the easiest ways to enhance longevity is to just stay well-hydrated! Here is a statement by one of the paper's authors and a link to the research paper in The Lancet:
Good hydration linked to healthy aging - NIH findings may provide early clues about increased risks for advanced biological aging and premature death, Peer-Reviewed Publication: NIH/National Heart, Lung and Blood Institute, News Release 2-Jan-2023.
Very interesting post, MateoBeach! The possibility of reversing some of these declines is very exciting to me, and consequently, the elucidation of what exactly may do so is as well. It seems to me that, when compared with the 0% gains of doing nothing (as many who consider aging irreversible do), even what might be considered "modest" improvements of 5-15% are still significant in terms of quality of life.
I take Nicotinamide mononucleotide (NMN), resveratrol, quercetin, methyl sulphonyl methane (MSM) in the hope of improved mitochondrial health and longevity. Also zinc, boron, iodine, Vit C, D, and K2. However I worry if the (localised) G 3+4 PCa is enjoying the benefits too.... I find a gin and tonic suppresses the worry.... I have a bag of alpha lipoic acid and L-carnitine which I wonder if I should recommence, but I can't seem to organise myself to take all the things that I think might be a good idea....
I’m convinced the benefits to your whole body and brain far outweigh the possible effects on cancer cell replication and metabolism. Cancer is metabolically flexible and doesn’t need healthy mitochondrial population for energy as much as we need for longevity and health span. Cheers.
I am not taking anything close like you in order to avoid bankruptcy. I understand that you feel better psychologically when you believe you are doing everything possible for yourself.
Caloric restriction (CR) mitigates many detrimental effects of aging and prolongs lifespan. CR has been suggested to increase mitochondrial biogenesis, thereby attenuating age-related declines in mitochondrial function; a concept that is challenged by recent studies. Here we show that lifelong CR in mice prevents age-related loss of mitochondrial oxidative capacity and efficiency, measured in isolated mitochondria and permeabilized muscle fibers. We find that these beneficial effects of CR occur without increasing mitochondrial abundance. Whole-genome expression profiling and large-scale proteomic surveys revealed expression patterns inconsistent with increased mitochondrial biogenesis, which is further supported by lower mitochondrial protein synthesis with CR. We find that CR decreases oxidant emission, increases antioxidant scavenging, and minimizes oxidative damage to DNA and protein. These results demonstrate that CR preserves mitochondrial function by protecting the integrity and function of existing cellular components rather than by increasing mitochondrial biogenesis.
Cell Metab. Author manuscript; available in PMC 2013 Dec 5.
Experts consider that DHT is between 3 and 10 times stronger than testosterone…
Expert Author Stephen Harrod Buhner (The Natural Testosterone Plan) believes that DHT demonstrates 10 times the androgen receptor uptake of testosterone.
Significantly he tells us that unlike testosterone, DHT is not converted into estrogen.
Going further, it actually blocks the aromatase enzyme that converts testosterone into estrogen… He concludes that as well as being stronger than testosterone, it is also a potent aromatase inhibitor.
Medical experts frequently try to demonise DHT and commonly blame it for the onset of prostate problems, but careful analysis of the problem has shown that it is the balance between androgen and estrogen that is the main concern.
Expert Author Jonathon Wright MD ( Maximise Your Vitality And Potency) tells us that the ratio between DHT and 4-androstenedione should be equal at 1:1
Curious too as I though the *sterides 5ARI's was playing with fire, ie, DHT... The mono therapy of *sterides and blocking DHT leading to upregulating AR signaling and over time those using the *sterides having androgen independent PCa. Definitely curious, and is a question, not conviction.
The cycling and interruption of any long term use may indeed be the factor preventing the upregulation... And yes, you would think there would be more intensive studies considering the effect DHT has on PCa.
Quote from study;
There is abundant evidence that androgens influence the development of prostate cancer.3,24,25 AR is a ligand–activated intracellular transcription factor belonging to the family of steroid hormone receptors that also includes ER, glucocorticoid receptor, progesterone receptor, and mineralocorticoid receptor.[26]
Finasteride can up-regulate the expression of androgen receptor (AR) in benign prostatic hyperplasia and prostate cancer LNCaP cells. It is believed that the conversion of testosterone to dihydrotestosterone decreases after the use of finasteride, and the low level of dihydrotestosterone environment leads to the transformation of androgen-dependent prostate cancer to androgen-independent prostate cancer, which leads to clonal growth of high-grade prostate cancer.[27]
Finasteride reduces the production of dihydrotestosterone. In the short run, it reduces the stimulation of hormones to normal tissues and cancer cells, and inhibits the growth of cancer cells to some extent. However, with the prolongation of time, due to long-term low-level dihydrotestosterone stimulation of the original cancer tissue, AR in cancer tissue can be up-regulated and amplified, leading to the occurrence of higher-grade prostate cancer...
Perhaps consider having the discussion and sharing information on Creatine and related in a separate post thread? Thank you.
I take metformin and a statin in hopes of inhibiting or slowing down disease progression. Some of that research seems to explain my difficulties using the stair climber in my 3 times a week gym workouts. After a year of no stair climber availability due to the covid gym shutdown I am having a difficult time restoring my cardio fitness. Other measures of fitness, like the ability to do pull-ups at my age (72), would indicate that I am pretty fit. Still dogging it on that stair climber though. I do interval training and seems like I need longer rest intervals.
Go slow and build gradually. I doubt that Metformin and Statin are cause of the decreased climbing strength and endurance. Stairs are a tough workout! I mostly exercise outdoors with just one super intense strength session in a gym per week. But walk or hike or mix with jog most days. Going uphill with a weighted pack (Rucking) is really good for core and leg strength. On my flat walks I add in sets of long stride lunges (50 at a time, and knee-high step ups on benches or planers (20 each leg), as well as inclined Push up sets (50-60) and pull ups or rows wherever I can find a suitable place. You will get there. Though the testosterone on my modified BAT makes progress much easier. Keep it up! 👍💪
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New Mitochondrial enzyme target, and a chance for Oligometastatic patients to step up--MetaCure trial-some information
BLUE SKY NEWS - AUGUST 2022
