Restoring mitochondrial function may be sufficient to reverse aging

[haidut]

The findings of the study may not sound very novel to my readers, however please keep in mind that the vast majority of anti-aging studies so far have only looked at slowing (not even stopping) aging. Actually reversing aging is the Holy Grail of gerontology, and to date very few studies have demonstrated anything of note in that regard. I posted about one such study several years ago, demonstrating reversal of biomarkers of immune system aging in humans by administering DHEA - a steroid that has known immunostimulating effects, likely due to its ability to oppose glucocorticoids. Another interesting property of DHEA is the ability to raise the metabolic rate, though the mainstream medical dogma considers such effects to be pro-aging. The study below is one of the first to demonstrate that that: (1) aging is characterized by a distinct decline of OXPHOS/metabolism, and that (2) actually raising the metabolic rate, by improving mitochondrial function (OXPHOS), has anti-aging effects. This evidence directly contradicts the so-called rate-of-living theory, on which most anti-aging research has relied so far. Aspirin, progesterone, thyroid, DHEA, androgens, caffeine, niacinamide, glycine/gelatin, sodium, magnesium, etc are all substances with known pro-metabolic effects and should be able to replicate many of the findings of the study below.

Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan - Nature Aging
Roundworm lifespan extended in mitochondria study
Roundworms' anti-aging could help researchers to stop human aging

"...A double membrane surrounds each mitochondrion. The interior layer has accordion-style pleats. Age-related declines in the voltage potential (the ability to transfer charged particles across the inner membrane) have been noted in earlier modeling studies by others. Numerous essential functions of these cellular organelles, such as the synthesis of energy molecules, immunological signaling, and genetic regulation, are driven by the mitochondrial membrane potential. “Decreased mitochondrial membrane potential is an attractive explanation for the complex dysfunctions of aging. However, it is unclear if lessening of the mitochondria voltage potential is a cause or a consequence of cellular aging,” said researchers in their study, which was published in Nature Aging on December 30. To achieve the elusive goal of verifying causality, the researchers used optogenetics, a technology that uses light to precisely manipulate a biological process inside a cell. Using a light-activated proton pump, they were able to specifically increase the mitochondrial membrane potential in the cells of adult roundworms. This instrument was dubbed "mitochondria-ON." The scientists' three different strains of roundworms experienced several age-associated indicators of aging reversed by the optogenetics method, which also reproducibly increased the treated worms' lifetime compared to untreated worms."

 

[Regina]

The findings of the study may not sound very novel to my readers, however please keep in mind that the vast majority of anti-aging studies so far have only looked at slowing (not even stopping) aging. Actually reversing aging is the Holy Grail of gerontology, and to date very few studies have demonstrated anything of note in that regard. I posted about one such study several years ago, demonstrating reversal of biomarkers of immune system aging in humans by administering DHEA - a steroid that has known immunostimulating effects, likely due to its ability to oppose glucocorticoids. Another interesting property of DHEA is the ability to raise the metabolic rate, though the mainstream medical dogma considers such effects to be pro-aging. The study below is one of the first to demonstrate that that: (1) aging is characterized by a distinct decline of OXPHOS/metabolism, and that (2) actually raising the metabolic rate, by improving mitochondrial function (OXPHOS), has anti-aging effects. This evidence directly contradicts the so-called rate-of-living theory, on which most anti-aging research has relied so far. Aspirin, progesterone, thyroid, DHEA, androgens, caffeine, niacinamide, glycine/gelatin, sodium, magnesium, etc are all substances with known pro-metabolic effects and should be able to replicate many of the findings of the study below.

Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan - Nature Aging
Roundworm lifespan extended in mitochondria study
Roundworms' anti-aging could help researchers to stop human aging

"...A double membrane surrounds each mitochondrion. The interior layer has accordion-style pleats. Age-related declines in the voltage potential (the ability to transfer charged particles across the inner membrane) have been noted in earlier modeling studies by others. Numerous essential functions of these cellular organelles, such as the synthesis of energy molecules, immunological signaling, and genetic regulation, are driven by the mitochondrial membrane potential. “Decreased mitochondrial membrane potential is an attractive explanation for the complex dysfunctions of aging. However, it is unclear if lessening of the mitochondria voltage potential is a cause or a consequence of cellular aging,” said researchers in their study, which was published in Nature Aging on December 30. To achieve the elusive goal of verifying causality, the researchers used optogenetics, a technology that uses light to precisely manipulate a biological process inside a cell. Using a light-activated proton pump, they were able to specifically increase the mitochondrial membrane potential in the cells of adult roundworms. This instrument was dubbed "mitochondria-ON." The scientists' three different strains of roundworms experienced several age-associated indicators of aging reversed by the optogenetics method, which also reproducibly increased the treated worms' lifetime compared to untreated worms."

I reckon calcium would be one of the "etc"s.

Caffeine is about the only listed substance that the typical American is actively consuming.

Thx!

 

[akgrrrl]

I love this place more every year.
Thankyou Haidut for your stewardship in our PeatyPlace with cutting edge studies and personal integrity.

 

[cs3000]

the study below is one of the first to demonstrate that that: (1) aging is characterized by a distinct decline of OXPHOS/metabolism, and that (2) actually raising the metabolic rate, by improving mitochondrial function (OXPHOS), has anti-aging effects. This evidence directly contradicts the so-called rate-of-living theory, on which most anti-aging research has relied so far. Aspirin, progesterone, thyroid, DHEA, androgens, caffeine, niacinamide, glycine/gelatin, sodium, magnesium, etc are all substances with known pro-metabolic effects and should be able to replicate many of the findings of the study below.

your other thread was informative about this part from what i took from it. the study in the thread about increased cellular aging with glycolysis.
shows many people who have mitochondrial dysfunction are skinny ,
because their metabolic rate is high from the excess glycolysis instead

so we can jack up our metabolism by glycolysis in an unhealthy way. i.e taking things that increase metabolic rate is not good enough alone the metabolic rate increase has to be from oxidative phosphorylation instead of glycolysis

I was wondering about aspirin so i looked into it,
aspirin or the metabolite salicylate is a mitochondrial uncoupler in cell studies , so going by that alone it could be a negative / increase aging.
but it looks like at least in doses ~1gram, it doesn't induce uncoupling in the body, apart from where it's applied topically.

actually in vivo there's a benefit as it helps restore some of the electron transport chain complexes (as long as you watch the stomach issues red blood counts & stomach issues)

Effect of Aspirin on Mitochondrial Dysfunction and Stress in the Pancreas and Heart of Goto-Kakizaki Diabetic Rats

Mitochondrial damage: a possible mechanism of the “topical” phase of NSAID induced injury to the rat intestine | Gut

~1g aspirin
Of the NSAIDs studied in the rat, aspirin by gavage (and intraperitoneally)8 is the only conventional NSAID, apart from nabumetone,27 that does not cause small intestinal ulcers. None of the animals receiving aspirin by gavage had small intestinal ulcers whereas those receiving it directly into the small bowel had severe, extensive and confluent small intestinal ulceration distal to the administration site of aspirin, suggesting that the lack of apparent small intestinal toxicity of orally administered aspirin may be due to lack of the “topical” effect because of rapid absorption. Aspirin is clearly toxic to the gastric mucosa, but it has been particularly difficult to explain why it does not cause small intestinal damage regardless of the route of administration (orally or parenterally).
Here, we show that when aspirin is instilled directly into the small intestine it is associated with uncoupling of intestinal mitochondrial oxidative phosphorylation and/or inhibition of electron transport and leads to severe small intestinal ulceration, but not when given by gastric gavage. This suggests that aspirin is so rapidly absorbed by the gastroduodenal mucosa following ingestion14 and that insufficient concentrations are achieved in the more distal small intestine (along with its lack of excretion in bile) to affect mitochondria and hence it does not exert a “topical” action at this site or cause damage. Indeed the gastric “barrier breaking” effect of aspirin is only seen following ingestion and not after intravenous administration9 ,47 of moderate doses. Parenteral aspirin in large doses does, however, cause stomach damage, possibly because blood borne, highly acidic NSAIDs, accumulate in gastric mucosal cells

The “topical” effect of NSAIDs is most pronounced at the site of drug absorption following ingestion. Absorbed NSAIDs are largely (over 99%) bound to albumin28 so that an effective concentration for mitochondrial uncoupling may not be reached in other tissues. Certainly, there was no evidence of uncoupling of small intestinal mitochondria when indomethacin was administered parenterally to rats with ligated bile ducts.

^ So the summary seems to be aspirin doesn't cause uncoupling when in the bloodstream, at least in usual doses ~1g or less. because its mostly bound to albumin. meaning tissue levels reach really low amounts compared to what you see with direct topical application that causes damage with coupling.

another example of in vitro studies being different from in vivo studies. because when you introduce complexities of the body ***t is different

-------------
more info from a paper by Egil Fosslien
(aspirin part maybe limited to where it sits topically or to the stomach taken orally)

Defective OXPHOS may be caused by insufficient fuel supply, by defective electron transport chain enzymes (Complexes I - IV), lack of the electron carrier coenzyme Q10, lack of oxygen due to ischemia or anemia, or excessive membrane leakage, resulting in insufficient mitochondrial inner membrane potential for ATP synthesis by the F0F1-ATPase.
Human tissues can counteract OXPHOS defects by stimulating mitochondrial biosynthesis; however, above a certain threshold the lack of ATP causes cell death.
Many agents affect OXPHOS. Several nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit or uncouple OXPHOS and induce the 'topical' phase of gastrointestinal ulcer formation. Uncoupled mitochondria reduce cell viability. The Helicobacter pylori induces uncoupling.

The uncoupling that opens the membrane pores can activate apoptosis. Cholic acid in experimental atherogenic diets inhibits Complex IV, cocaine inhibits Complex I, the poliovirus inhibits Complex II, ceramide inhibits Complex III, azide, cyanide, chloroform, and methamphetamine inhibit Complex IV. Ethanol abuse and antiviral nucleoside analogue therapy inhibit mtDNA replication.
By contrast, melatonin stimulates Complexes I and IV and Gingko biloba stimulates Complexes I and III. Oral Q10 supplementation is effective in treating cardiomyopathies and in restoring plasma levels reduced by the statin type of cholesterol-lowering drugs.
Luft’s syndrome, a mitochondrial functional disorder involving loose coupling and a greatly elevated basic metabolic rate despite normal thyroid metabolism

Presently, it is realized that a gradual decline in ATP generation with age induces loss of stamina, memory, vision, and hearing and contributes to aging-related diseases such as cardiovascular disease and diabetes [16]. In addition, many exogenous agents, even therapeutic ones such as acidic nonsteroidal anti-inflammatory drugs (NSAIDs), can inhibit the mitochondrial energy system [17] and cause disease
The generation of the mitochondrial membrane potential requires an adequate supply of metabolites to Complexes I and II of the electron transport chain. For instance, aspirin inhibits β-oxidation and the delivery of metabolites to the electron transport chain [27] and reduces the mitochondrial fuel supply and energy flux.
Electrons from the metabolites must be efficiently carried via coenzyme-Q10 (Q10) to Complex III, and then via cytochrome c and Complex IV to oxygen. An ample supply of oxygen as electron acceptor must be provided. Uninhibited, effective proton pumping by Complexes I, III, and IV must deposit the released energy as an electrical charge across the mitochondrial inner membrane. Salicylate and indomethacin can inhibit the electron transport chain. The electron transport may be reduced or blocked by an inadequate supply of oxygen. Blood flow reduction due to atherosclerosis, reduction in oxygen carrying capacity due to anemia or smoking,

Compensatory increase of mitochondrial synthesis may occur in the presence of other causes of defective oxidative phosphorylation

Diseases of oxidative phosphorylation often occur together with impaired β-oxidation. Reduced flux through the respiratory chain increases the NADH/NAD+ ratio. Beta-oxidation is inhibited and produces secondary carnitine deficiency. Generation of reactive oxygen species increases and α-tocopherol is depleted probably because of consumption due to lipid peroxidation

Experimentally, the oxidative stress can be enhanced by gene inactivation of the antioxidant enzyme glutathione peroxidase-1 (Gpx1) in the mutant mouse. It is normally highly expressed in the mouse liver. The presence of the mutated Gpx1-gene causes a significant increase in hydrogen peroxide release by the liver mitochondria. Moreover, it markedly degrades the efficiency of mitochondrial oxidative phosphorylation as evidenced by a significant reduction in the respiratory control ratio [41].
The increase in the number of mitochondria in the atherosclerotic lesion indicates enhanced synthesis in an attempt to compensate for dysfunction of the mitochondrial bioenergetics system [increased mitochondria is not necessarily a good thing - should be working more efficiently]

Diabetes causes impairment of glucose uptake into cells. It is an independent risk factor for atherosclerosis [102]. The pancreatic β-cell depleted of mtDNA does not secrete insulin [103]. Beta cells with mtDNA mutations show a defective mitochondrial inner membrane potential and induce diabetes. Insulin resistance is closely related to the regulation by uncoupling proteins and other energy regulators [103]. The high-glucose environment induces glycation of proteins. The concurrent ROS-generation induces apoptosis in vascular cells involved in complications of diabetes mellitus [103].
In the rat model of diabetes induced by streptozotocin (STZ) the mitochondrial oxidative phosphorylation is significantly reduced. However, the ATP generation can be completely restored by physical training even if the plasma glucose or insulin levels remain essentially unaltered
Importantly, even if an agent itself does not affect oxidative phosphorylation, one of its metabolites might do so. As an example, salicylate, a main metabolite of aspirin, but not aspirin itself, uncouples oxidative phosphorylation
Because of the shared pathway from acetyl-CoA via farnesyl, the administration of a statin-type of cholesterol-lowering drug that inhibits HMG-CoA reductase reduces the synthesis not only of cholesterol, but also of Q10, and lowers the blood level of Q10.
A sufficient supply of iron is necessary to prevent dysfunction of iron-containing OXPHOS enzymes.


Thyroid hormone enhances oxidative phosphorylation as shown by thyroidectomy in the rat model of hypothyroidism. Removal of the thyroid reduces ATPase activity by over 30% in the liver mitochondria. In the rat, thyroid hormone up-regulates the expression of selected nuclear genes that encode OXPHOS complex sub-units

Mitochondria from thyroxin-treated rats incubated with succinate as substrate showed an ex vivo increase in the respiration rate of almost 50%, and there was a 10% increase in the membrane potential compared with mitochondria from normal, non-treated rats [246]

Antioxidants limit lipid peroxidation and decrease prostaglandin synthesis [300]. The risk of oxygen-derived free radical damage can be significantly reduced Oral supplementation with 100 mg of Q10 daily benefited nearly two-thirds of the patients. Those with dilated cardiomyopathy showed the most clinical improvement Administration of Q10 significantly reverses exercise-induced abnormalities of oxidative phosphorylation of the brain of patients with known mitochondrial enzyme defects.

 

[Eberhardt]

your other thread was informative about this part from what i took from it. the study in the thread about increased cellular aging with glycolysis.
shows many people who have mitochondrial dysfunction are skinny ,
because their metabolic rate is high from the excess glycolysis instead

so we can jack up our metabolism by glycolysis in an unhealthy way. i.e taking things that increase metabolic rate is not good enough alone the metabolic rate increase has to be from oxidative phosphorylation instead of glycolysis

I was wondering about aspirin so i looked into it,
aspirin or the metabolite salicylate is a mitochondrial uncoupler in cell studies , so going by that alone it could be a negative / increase aging.
but it looks like at least in doses ~1gram, it doesn't induce uncoupling in the body, apart from where it's applied topically.

actually in vivo there's a benefit as it helps restore some of the electron transport chain complexes (as long as you watch the stomach issues red blood counts & stomach issues)

Effect of Aspirin on Mitochondrial Dysfunction and Stress in the Pancreas and Heart of Goto-Kakizaki Diabetic Rats

View attachment 48081
View attachment 48082

Mitochondrial damage: a possible mechanism of the “topical” phase of NSAID induced injury to the rat intestine | Gut

^ So the summary seems to be aspirin doesn't cause uncoupling when in the bloodstream, at least in usual doses ~1g or less. because its mostly bound to albumin. meaning tissue levels reach really low amounts compared to what you see with direct topical application that causes damage with coupling.

another example of in vitro studies being different from in vivo studies. because when you introduce complexities of the body ***t is different

-------------
more info from a paper by Egil Fosslien
(aspirin part likely limited to where it sits topically or to the stomach taken orally)

Thanks. I actually in 12 years of peating never seen a satisfactory explanation of the two different types of high metabolism.

 

[cs3000]

Thanks. I actually in 12 years of peating never seen a satisfactory explanation of the two different types of high metabolism.

OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases - Communications Biology

A meta-analysis of 17 cohorts of mitochondrial disease patients reveals that OxPhos defects are associated with signs of hypermetabolism. Experiments in patient-derived fibroblast show that mitochondrial OxPhos defects trigger hypermetabolism in a cell-autonomous manner and this is linked to...

www.nature.com

https://raypeatforum.com/community/threads/the-cancer-metabolism-drives-aging-in-humans.49606/

thats a nice insightful one haidut posted recently

before i thought the issue with glycolysis was it not producing enough atp. but even with it restoring enough ATP to replace oxidative phosphorylation its a problem
because of the decreased efficiency , leading to more wear & tear faster cellular aging and less complex more basic cells

uncoupling is one of the reasons for the unhealthy high metabolism , because of this glycolysis:OXPHOR ratio shift . (otto warburg talked a little about it in his paper on the basis for cancer being mitochondria oxidative phosphorylation loss shifting complex cells to basic cells relying on fermentation).

but this paper also mentions other contributors in the study. like DNA instability, probably from toxins causing oxidative stress and too few antioxidant enzymes or substances to balance , maybe inflammation creating dysfunction, or prolonged deficit of oxygen to tissues from slow blood flow etc, creating this shift to excess glycolysis ratio

This cell-autonomous state of hypermetabolism occurs despite near-normal OxPhos coupling efficiency, excluding uncoupling as a general mechanism. Instead, hypermetabolism is associated with mitochondrial DNA instability, activation of the integrated stress response (ISR), and increased extracellular secretion of age-related cytokines and metabokines including GDF15. OxPhos defects accelerate telomere erosion and epigenetic aging per cell division, consistent with evidence that excess energy expenditure accelerates biological aging.
OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases - Communications Biology
A usual suspect to explain decreased cellular and physiological bioenergetic efficiency is the uncoupling of the OxPhos machinery. While this article was under revision, a case of clinically suspected hypermetabolism in twin boys harboring a complex V (FoF1 ATP synthase) defect was reported104. Introducing the pathogenic mutation in fibroblasts increased basal OCR, where the underlying mechanism involves elevated proton leak and uncoupling. This agrees with the first reported case of mitochondrial disease by Luft, a woman with uncoupled skeletal muscle mitochondria suffering from severe, documented hypermetabolism105. This uncoupling phenotype differs from our observations, which indicate no sign of uncoupling in SURF1-mutant hypermetabolic fibroblasts – in fact, significantly lower (−35%) proton leak and higher (+10%) coupling efficiency (Fig. 2j, k).

On the other hand, the Oligo treatment targeting the complex V did cause a marginally significant (−28%) reduction in coupling efficiency and punctual elevations in proton leak across the lifespan (Fig. 3g, h) [oligo is used as a ATP inhibitor to shift from OXPHOR to glycolysis - is an uncoupler]
These results point to a potential role of OxPhos uncoupling as a partial contributor to hypermetabolism in the Oligo model. However, other cellular data, as well as the physiological results from our meta-analysis where only a minority of patients had mutations affecting the FoF1 ATP synthase, call attention to uncoupling-independent, energy-demanding processes as more general causes of hypermetabolism deserving further investigation.

also it confused me why some studies show longevity boost in rodents from uncoupling mitochondria , where others show longevity boost from coupling. my initial take is maybe the uncoupling studies have the rodents exposed to high levels of PUFA,
healthy oxidative phosphorylation metabolism produces more ROS . maybe this reactive oxygen species generation is so harmful in a high PUFA diet that shifting them more towards glycolysis is less damaging than the oxidative damage from the ROS+PUFA

but if thats the case the oxidative phosphorylation ROS isnt the problem , the oxidative stress from the interactions with the easily oxidized toxins is. which is probably why theres a 20% reduction in mortality link in humans with high vitamin c levels

These in vivo data thus provide additional converging evidence, beyond the clinical data in Fig. 1, that mitochondrial OxPhos defects impair whole-body energetic efficiency and cause physiological hypermetabolism in mammals.

 

[S.Holmes]

Bump