The "cancer metabolism" drives aging in humans

haidut

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A truly monumental study, as it is perhaps the first one to demonstrate that "aging" in human cells is entirely under metabolic control. What can I say - Ray Peat right again! Unfortunately, the way the actual study has been worded has been, once again, criminally mis-represented by mainstream media to state the exact opposite of what the study findings were. Namely, the study identified that a deficiency of OXPHOS and, compensatorily, elevation of glycolysis - i.e. the "cancer metabolism" - drives the aging process. For some strange reason, the study chose the word "hypermetabolism" to refer to the hyperlycolytic state, though it makes it quite clear numerous times that the "hypermetabolism" discussed hereby is actually a state of low OXPHOS and high glycolysis. Whether that choice of words was an unfortunate mistake or deliberate manipulation, time will tell. What matters is that the press picked up that poor choice of words and ran with the story that "overactive cell metabolism" drives aging. That press claim is not only in contradiction to the gist of what the study found, but it will invariably be seen by all sorts of public health agencies as a confirmation of the (in)famous "rate of living" theory. I included the popular press article (first link below) for reference, but due to the garbage "journalism" it contains I decided to quote directly from the study, unlike other posts of mine. Perhaps the most revealing finding from the study was that in healthy, non-senescent cells the ATP production is derived from an OXPHOS:glycolysis metabolic ratio of about 2:1. Namely, in a healthy, non-aged cell, about 2/3 of the ATP is derived from OXPHOS and the other 1/3 from glycolysis. In contrast, in aged (and sick) cells, this OXPHOS:glycolysis ratio for ATP synthesis changes over to 1:4 - i.e. more than completely reversed, in favor of glycolysis. Thus, just as in cancer, the aged cells ramp up their glycolysis to produce the same amount of ATP as healthy cells. So in a way, in cancer and in aging, a cell has to "run" twice as fast just to keep up. As the study shows, this inefficient, glycolytic metabolism directly results in mitochondrial (and possibly nuclear) DNA instability, which can, of course, directly cause cancer. In addition, the study demonstrated that the deranged metabolism also resulted in massive release of inflammatory cytokines, increase in (wasteful) energy-consuming pathways, and telomere shortening. In fact, the Hayflick limit (HL) of the hyperglycolytic cells was 53% lower than the healthy ones! Now, as Dr. Peat has mentioned in the past, the HL is likely a fake limit on cellular division, but it does have its uses when comparing aging with healthy cells, and such a drastic shortening is likely to result in much higher risk of a number of degenerative diseases, especially ones of the brain and muscles (Alzheimer's Parkinson's, Huntington's, ALS, etc).

Assuming the study findings are replicated by other scientists the path to retarding, or even reversing, aging seems rather simple. Namely, increase mitochondrial activity while suppressing excessive glycolysis. Thyroid, aspirin, methylene blue and various other quinones such as vitamin K, progesterone, saturated fats, vitamins B1/B3, androgens, etc all have a sizeable pile of evidence in regards to promoting OXPHOS and/or suppressing excessive glycolysis. Moreover, most of these substances have already been demonstrated to extend maximum lifespan in-vivo.

Overactive cell metabolism linked to biological aging
OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases - Communications Biology

"...In control cells, the balance of estimated ATP derived from OxPhos and glycolysis was 64:36%, such that under our specific tissue culture conditions (physiological 5.5 mM glucose, with glutamine, pyruvate, and fatty acids), healthy fibroblasts derived the majority of ATP from OxPhos. In contrast, SURF1 deficiency robustly shifted the relative OxPhos:Glycolysis contribution to 23:77% (p = 4.1e − 6, g = −5.1), reflecting a significant shift in OxPhos-deficient cells towards an alternative, and therefore less energy efficient, metabolic strategy (Fig. 2g, h). As expected, removing glucose from the media did not substantially affect growth in control cells, but the absence of glucose was lethal to SURF1 cells within 5 days, confirming their dependency on glycolysis for survival (Supplementary Fig. 3)."

"...Integrating available clinical and animal data together with our longitudinal fibroblast studies has revealed hypermetabolism as a conserved feature of mitochondrial OxPhos defects. A major advantage of our cellular system is that it isolates the stable influence of genetic and pharmacological OxPhos perturbations on energy expenditure, independent of other factors that may operate in vivo. Thus, these data establish the cell-autonomous nature of hypermetabolism. Moreover, despite the diverging mode of action of SURF1 and Oligo models, as well as some divergent molecular responses, both models converge on the same hypermetabolic phenotype, adding confidence around the generalizability of this phenomenon. Our data also rule out mitochondrial uncoupling as a main driver of hypermetabolism in SURF1 patient-derived fibroblasts, and instead implicate the activation of energy-demanding gene regulatory programs, including but likely not limited to increased metabokine/cytokine secretion, which can compete with growth and longevity (Fig. 9). Our resource cellular lifespan data provide several novel observations that agree with previous work79, and that are relevant to understanding how primary mitochondrial OxPhos defects triggers core physiological and phenotypic hallmarks of aging and mitochondrial diseases."

"...Finally, given the deleterious effect of hypermetabolism-causing OxPhos defects on the lifespan of patients with mitochondrial diseases and in animal models, these genome-wide data prompted us to examine how OxPhos defects and hypermetabolism relate to dynamic genomic markers of cellular aging and senescence. The complete population doubling curves of each donor (Fig. 8a) provided initial evidence that cellular lifespan was reduced in SURF1 and Oligo-treated cells. The Hayflick limit (i.e., the total number of cell divisions56) was, on average, 53% lower in SURF1 cells (p = 0.072, g = 2.0), and Oligo decreased the Hayflick limit by 40% (p < 0.066, g = 2.0) relative to the untreated cells of the same donor (Fig. 8a, b). Interestingly, the magnitude of these effects (40–53%) on total population doubling loosely corresponds to the 3–4 decade loss in human lifespan documented among adults with mitochondrial diseases (see Fig. 1g, h), which would represent 38–50% for an average 80-year life expectancy."

"...Third, mitochondrial OxPhos defects dramatically increased the telomere erosion rate per cell division, despite the adaptive transcriptional upregulation of telomere protection complex components. This effect of mitochondria on telomeres agrees with the variable telomere maintenance in mtDNA conplastic mice88, with the life-shortening effect of pathogenic mtDNA variants32 and OxPhos defects in mice34, and with the reduced lifespan in patients with mtDNA disease shown in Fig. 1g, h. A study in skeletal muscle of children with high heteroplasmic mtDNA mutations also reported excessively short telomeres, similar in length to the telomeres of healthy 80-year-old controls83. Because skeletal muscle is a post-mitotic tissue, this previous result also implies that OxPhos defects could accelerate telomere attrition at a disproportionate rate, or perhaps independent from cell division, as suggested by the disconnect between the loss of telomeric repeats and genome replication/cell division observed in our hypermetabolic fibroblasts. Beyond severe OxPhos defects, mild alterations of OxPhos function driven by mild, common variants in complex I subunits genes, may also shape disease risk89 and influence lifespan90."

"...Fourth, our longitudinal RNASeq and DNAm datasets reveal conserved recalibrations implicating developmental and translation-related pathways, as well as cell–cell communication, with OxPhos defects and hypermetabolism. These identified pathways overlap with previously identified multi-omic overrepresentation analysis performed on iPSC-derived neurons from SURF1 patients92. In both this and our study, neural development, cell signaling, morphogenesis, cell cycle, and metabolism were the predominant processes altered in SURF1-related disease. The induction of these energetically-demanding pathways that constrain growth at the cellular and possibly at the organismal level41, could help explain why a major feature of pediatric mitochondrial disorders (including our SURF1 donors) is a neurodevelopmental delay, and also why adult patients commonly display short stature (restricted growth)30. In relation to cell-cell communication, we note that the biomarker picture of adult patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is dominated, as in our fibroblast models, by elevated (not reduced) signaling and metabolic markers in blood72. Thus, the organism under metabolic stress does not initiate an energy-saving hypometabolic state with reduced signaling activity, but instead activates energivorous stress responses (ISRs), which must divert and consume energetic resources, thereby forcing an apparent tradeoff with other processes such as growth and longevity pathways."

"...Finally, the OxPhos defects in our fibroblasts triggered a shift toward glycolytic ATP production. ...For example, although basal respiration was markedly lower in SURF1 cells, the maximal FCCP-uncoupled respiration in SURF1 cells was relatively preserved (see Fig. 2b and Supplementary Fig. 2c). This result implies a cellular decision to route metabolic flux towards an energetically less efficient pathway (i.e., glycolysis). This could be explained on the basis of energetic constraints and proteome efficiency, since the proteome cost of OxPhos is at least double that of glycolytic fermentation19. Thus, cells can “choose” to divert metabolic flux towards glycolysis even when OxPhos is at least partially functional, as in cancer, because of rising intracellular energetic constraints driven by hypermetabolism. We note again that hypermetabolism is apparent across multiple animal models of primary OxPhos defects, manifesting as an elevated cost of living, even during rest and sleep in mice10,24,25,26. In particular, deep phenotyping of Ant1−/− mice across three studies25,95,96 reveals a systemic physiological picture highly consistent with mitochondrial diseases, including excessive mitochondrial biogenesis, elevated circulating catecholamine levels, severe hypermetabolism (+82 to −85% REE) when adjusted for lower physical activity levels, reduced adiposity, elevated mtDNAcn, and mtDNA instability, and decreased median lifespan. 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. Identifying hypermetabolism as a feature of the mitochondrial diseases may be clinically relevant as it provides an explanatory framework for some of the major symptoms in affected patients. First, fatigue and exercise intolerance are evolutionary conserved, subjective experiences that arise when the organism consumes more energy than it would under optimal conditions (e.g., subjective fatigue during the oxygen debt after strenuous exercise, or during an infection). Thus, symptoms of fatigue could be direct consequences of impaired metabolic efficiency and hypermetabolism."

"...Third, alcohol appears to be poorly tolerated and associated with symptom onset in some patients with mtDNA defects97,98,99, but the basis for alcohol intolerance remains unknown. Alcohol itself causes hypermetabolism in healthy individuals—increasing whole-body REE by as much as 16%, and inhibiting lipid oxidation by 31–36%100,101. Alcohol may therefore aggravate pre-existing hypermetabolism, thus imposing further energetic constraints on vital cellular or physiological functions."

"...Overall, the meta-analysis of clinical data from hundreds of patients and two cellular models of OxPhos dysfunction identifies hypermetabolism as a feature of mitochondrial diseases. Our longitudinal patient-derived fibroblasts data delineate some of the cellular and molecular features of OxPhos-induced hypermetabolism, including sustained induction of the ISR, genome instability, hypersecretion of cyto/metabokines, and genome-wide DNA methylation and transcriptional recalibrations that emphasize the upregulation of energy-dependent processes related to signaling and communication (see Fig. 9). A resource webtool with all data from this study, including the longitudinal RNAseq and DNAm data, is available and can be explored for genes or processes of interest (see Data Availability Statement). Altogether, these translational data, therefore, provide a basis to rationalize some unexplained clinical features of mitochondrial diseases and suggest that intracellular and systemic energy tradeoffs (rather than ATP deficiency) may contribute to the pathogenesis of mitochondrial diseases. The proposed explanatory framework of cellular and physiological hypermetabolism calls for well-controlled studies to further understand the extent to which hypermetabolism is a bystander or a harbinger of morbidity and early mortality in patients with mitochondrial diseases. Our translational findings highlight the need for collaborative partnerships that bridge the cellular, clinical, and patient-reported aspects of mitochondrial diseases and aging."
 
Last edited:

LadyRae

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Mar 20, 2021
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I can't wait to see how various YouTube and fitness influencers squawk about this on their podcasts.... Who will correctly interpret the study? 😉
 

LeeLemonoil

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Nice one.

But why on earth do the authors of the original study start speculating and interpreting their findings even in the abstract and nature doesn’t redact that?
 

NewACC

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A truly monumental study, as it is perhaps the first one to demonstrate that "aging" in human cells is entirely under metabolic control. What can I say - Ray Peat right again! Unfortunately, the way the actual study has been worded has been, once again, criminally mis-represented by mainstream media to state the exact opposite of what the study findings were. Namely, the study identified that a deficiency of OXPHOS and, compensatorily, elevation of glycolysis - i.e. the "cancer metabolism" - drives the aging process. For some strange reason, the study chose the word "hypermetabolism" to refer to the hyperlycolytic state, though it makes it quite clear numerous times that the "hypermetabolism" discussed hereby is actually a state of low OXPHOS and high glycolysis. Whether that choice of words was an unfortunate mistake or deliberate manipulation, time will tell. What matters is that the press picked up that poor choice of words and ran with the story that "overactive cell metabolism" drives aging. That press claim is not only in contradiction to the gist of what the study found, but it will invariably be seen by all sorts of public health agencies as a confirmation of the (in)famous "rate of living" theory. I included the popular press article (first link below) for reference, but due to the garbage "journalism" it contains I decided to quote directly from the study, unlike other posts of mine. Perhaps the most revealing finding from the study was that in healthy, non-senescent cells the ATP production is derived from an OXPHOS:glycolysis metabolic ratio of about 2:1. Namely, in a healthy, non-aged cell, about 2/3 of the ATP is derived from OXPHOS and the other 1/3 from glycolysis. In contrast, in aged (and sick) cells, this OXPHOS:glycolysis ratio for ATP synthesis changes over to 1:4 - i.e. more than completely reversed, in favor of glycolysis. Thus, just as in cancer, the aged cells ramp up their glycolysis to produce the same amount of ATP as healthy cells. So in a way, in cancer and in aging, a cell has to "run" twice as fast just to keep up. As the study shows, this inefficient, glycolytic metabolism directly results in mitochondrial (and possibly nuclear) DNA instability, which can, of course, directly cause cancer. In addition, the study demonstrated that the deranged metabolism also resulted in massive release of inflammatory cytokines, increase in (wasteful) energy-consuming pathways, and telomere shortening. In fact, the Hayflick limit (HL) of the hyperglycolytic cells was 53% lower than the healthy ones! Now, as Dr. Peat has mentioned in the past, the HL is likely a fake limit on cellular division, but it does have its uses when comparing aging with healthy cells, and such a drastic shortening is likely to result in much higher risk of a number of degenerative diseases, especially ones of the brain and muscles (Alzheimer's Parkinson's, Huntington's, ALS, etc).

Assuming the study findings are replicated by other scientists the path to retarding, or even reversing, aging seems rather simple. Namely, increase mitochondrial activity while suppressing excessive glycolysis. Thyroid, aspirin, methylene blue and various other quinones such as vitamin K, progesterone, saturated fats, vitamins B1/B3, androgens, etc all have a sizeable pile of evidence in regards to promoting OXPHOS and/or suppressing excessive glycolysis. Moreover, most of these substances have already been demonstrated to extend maximum lifespan in-vivo.

Overactive cell metabolism linked to biological aging
OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases - Communications Biology

"...In control cells, the balance of estimated ATP derived from OxPhos and glycolysis was 64:36%, such that under our specific tissue culture conditions (physiological 5.5 mM glucose, with glutamine, pyruvate, and fatty acids), healthy fibroblasts derived the majority of ATP from OxPhos. In contrast, SURF1 deficiency robustly shifted the relative OxPhos:Glycolysis contribution to 23:77% (p = 4.1e − 6, g = −5.1), reflecting a significant shift in OxPhos-deficient cells towards an alternative, and therefore less energy efficient, metabolic strategy (Fig. 2g, h). As expected, removing glucose from the media did not substantially affect growth in control cells, but the absence of glucose was lethal to SURF1 cells within 5 days, confirming their dependency on glycolysis for survival (Supplementary Fig. 3)."

"...Integrating available clinical and animal data together with our longitudinal fibroblast studies has revealed hypermetabolism as a conserved feature of mitochondrial OxPhos defects. A major advantage of our cellular system is that it isolates the stable influence of genetic and pharmacological OxPhos perturbations on energy expenditure, independent of other factors that may operate in vivo. Thus, these data establish the cell-autonomous nature of hypermetabolism. Moreover, despite the diverging mode of action of SURF1 and Oligo models, as well as some divergent molecular responses, both models converge on the same hypermetabolic phenotype, adding confidence around the generalizability of this phenomenon. Our data also rule out mitochondrial uncoupling as a main driver of hypermetabolism in SURF1 patient-derived fibroblasts, and instead implicate the activation of energy-demanding gene regulatory programs, including but likely not limited to increased metabokine/cytokine secretion, which can compete with growth and longevity (Fig. 9). Our resource cellular lifespan data provide several novel observations that agree with previous work79, and that are relevant to understanding how primary mitochondrial OxPhos defects triggers core physiological and phenotypic hallmarks of aging and mitochondrial diseases."

"...Finally, given the deleterious effect of hypermetabolism-causing OxPhos defects on the lifespan of patients with mitochondrial diseases and in animal models, these genome-wide data prompted us to examine how OxPhos defects and hypermetabolism relate to dynamic genomic markers of cellular aging and senescence. The complete population doubling curves of each donor (Fig. 8a) provided initial evidence that cellular lifespan was reduced in SURF1 and Oligo-treated cells. The Hayflick limit (i.e., the total number of cell divisions56) was, on average, 53% lower in SURF1 cells (p = 0.072, g = 2.0), and Oligo decreased the Hayflick limit by 40% (p < 0.066, g = 2.0) relative to the untreated cells of the same donor (Fig. 8a, b). Interestingly, the magnitude of these effects (40–53%) on total population doubling loosely corresponds to the 3–4 decade loss in human lifespan documented among adults with mitochondrial diseases (see Fig. 1g, h), which would represent 38–50% for an average 80-year life expectancy."

"...Third, mitochondrial OxPhos defects dramatically increased the telomere erosion rate per cell division, despite the adaptive transcriptional upregulation of telomere protection complex components. This effect of mitochondria on telomeres agrees with the variable telomere maintenance in mtDNA conplastic mice88, with the life-shortening effect of pathogenic mtDNA variants32 and OxPhos defects in mice34, and with the reduced lifespan in patients with mtDNA disease shown in Fig. 1g, h. A study in skeletal muscle of children with high heteroplasmic mtDNA mutations also reported excessively short telomeres, similar in length to the telomeres of healthy 80-year-old controls83. Because skeletal muscle is a post-mitotic tissue, this previous result also implies that OxPhos defects could accelerate telomere attrition at a disproportionate rate, or perhaps independent from cell division, as suggested by the disconnect between the loss of telomeric repeats and genome replication/cell division observed in our hypermetabolic fibroblasts. Beyond severe OxPhos defects, mild alterations of OxPhos function driven by mild, common variants in complex I subunits genes, may also shape disease risk89 and influence lifespan90."

"...Fourth, our longitudinal RNASeq and DNAm datasets reveal conserved recalibrations implicating developmental and translation-related pathways, as well as cell–cell communication, with OxPhos defects and hypermetabolism. These identified pathways overlap with previously identified multi-omic overrepresentation analysis performed on iPSC-derived neurons from SURF1 patients92. In both this and our study, neural development, cell signaling, morphogenesis, cell cycle, and metabolism were the predominant processes altered in SURF1-related disease. The induction of these energetically-demanding pathways that constrain growth at the cellular and possibly at the organismal level41, could help explain why a major feature of pediatric mitochondrial disorders (including our SURF1 donors) is a neurodevelopmental delay, and also why adult patients commonly display short stature (restricted growth)30. In relation to cell-cell communication, we note that the biomarker picture of adult patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is dominated, as in our fibroblast models, by elevated (not reduced) signaling and metabolic markers in blood72. Thus, the organism under metabolic stress does not initiate an energy-saving hypometabolic state with reduced signaling activity, but instead activates energivorous stress responses (ISRs), which must divert and consume energetic resources, thereby forcing an apparent tradeoff with other processes such as growth and longevity pathways."

"...Finally, the OxPhos defects in our fibroblasts triggered a shift toward glycolytic ATP production. ...For example, although basal respiration was markedly lower in SURF1 cells, the maximal FCCP-uncoupled respiration in SURF1 cells was relatively preserved (see Fig. 2b and Supplementary Fig. 2c). This result implies a cellular decision to route metabolic flux towards an energetically less efficient pathway (i.e., glycolysis). This could be explained on the basis of energetic constraints and proteome efficiency, since the proteome cost of OxPhos is at least double that of glycolytic fermentation19. Thus, cells can “choose” to divert metabolic flux towards glycolysis even when OxPhos is at least partially functional, as in cancer, because of rising intracellular energetic constraints driven by hypermetabolism. We note again that hypermetabolism is apparent across multiple animal models of primary OxPhos defects, manifesting as an elevated cost of living, even during rest and sleep in mice10,24,25,26. In particular, deep phenotyping of Ant1−/− mice across three studies25,95,96 reveals a systemic physiological picture highly consistent with mitochondrial diseases, including excessive mitochondrial biogenesis, elevated circulating catecholamine levels, severe hypermetabolism (+82 to −85% REE) when adjusted for lower physical activity levels, reduced adiposity, elevated mtDNAcn, and mtDNA instability, and decreased median lifespan. 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. Identifying hypermetabolism as a feature of the mitochondrial diseases may be clinically relevant as it provides an explanatory framework for some of the major symptoms in affected patients. First, fatigue and exercise intolerance are evolutionary conserved, subjective experiences that arise when the organism consumes more energy than it would under optimal conditions (e.g., subjective fatigue during the oxygen debt after strenuous exercise, or during an infection). Thus, symptoms of fatigue could be direct consequences of impaired metabolic efficiency and hypermetabolism."

"...Third, alcohol appears to be poorly tolerated and associated with symptom onset in some patients with mtDNA defects97,98,99, but the basis for alcohol intolerance remains unknown. Alcohol itself causes hypermetabolism in healthy individuals—increasing whole-body REE by as much as 16%, and inhibiting lipid oxidation by 31–36%100,101. Alcohol may therefore aggravate pre-existing hypermetabolism, thus imposing further energetic constraints on vital cellular or physiological functions."

"...Overall, the meta-analysis of clinical data from hundreds of patients and two cellular models of OxPhos dysfunction identifies hypermetabolism as a feature of mitochondrial diseases. Our longitudinal patient-derived fibroblasts data delineate some of the cellular and molecular features of OxPhos-induced hypermetabolism, including sustained induction of the ISR, genome instability, hypersecretion of cyto/metabokines, and genome-wide DNA methylation and transcriptional recalibrations that emphasize the upregulation of energy-dependent processes related to signaling and communication (see Fig. 9). A resource webtool with all data from this study, including the longitudinal RNAseq and DNAm data, is available and can be explored for genes or processes of interest (see Data Availability Statement). Altogether, these translational data, therefore, provide a basis to rationalize some unexplained clinical features of mitochondrial diseases and suggest that intracellular and systemic energy tradeoffs (rather than ATP deficiency) may contribute to the pathogenesis of mitochondrial diseases. The proposed explanatory framework of cellular and physiological hypermetabolism calls for well-controlled studies to further understand the extent to which hypermetabolism is a bystander or a harbinger of morbidity and early mortality in patients with mitochondrial diseases. Our translational findings highlight the need for collaborative partnerships that bridge the cellular, clinical, and patient-reported aspects of mitochondrial diseases and aging."
But @haidut do this study says that stopping ageing is as easy as increasing "normal" uncoupled oxidative metabolism? Or reduction of such metabolism is just a sign of aging and the reason is different?
 

NewACC

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@haidut because in the end there is a strange reason, which contradicts the seeming simplicity of stopping aging, that any experiment directed by all means to improve this very metabolism hasn't achieved immortality and is unlikely to be able to. But what is the reason, the animals were metabolically healthy even in very advanced years, but they still died. Is the reason for the high-PUFA diet all other sorts of flaws in the researches?
 
Last edited:

NewACC

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A truly monumental study, as it is perhaps the first one to demonstrate that "aging" in human cells is entirely under metabolic control. What can I say - Ray Peat right again! Unfortunately, the way the actual study has been worded has been, once again, criminally mis-represented by mainstream media to state the exact opposite of what the study findings were. Namely, the study identified that a deficiency of OXPHOS and, compensatorily, elevation of glycolysis - i.e. the "cancer metabolism" - drives the aging process. For some strange reason, the study chose the word "hypermetabolism" to refer to the hyperlycolytic state, though it makes it quite clear numerous times that the "hypermetabolism" discussed hereby is actually a state of low OXPHOS and high glycolysis. Whether that choice of words was an unfortunate mistake or deliberate manipulation, time will tell. What matters is that the press picked up that poor choice of words and ran with the story that "overactive cell metabolism" drives aging. That press claim is not only in contradiction to the gist of what the study found, but it will invariably be seen by all sorts of public health agencies as a confirmation of the (in)famous "rate of living" theory. I included the popular press article (first link below) for reference, but due to the garbage "journalism" it contains I decided to quote directly from the study, unlike other posts of mine. Perhaps the most revealing finding from the study was that in healthy, non-senescent cells the ATP production is derived from an OXPHOS:glycolysis metabolic ratio of about 2:1. Namely, in a healthy, non-aged cell, about 2/3 of the ATP is derived from OXPHOS and the other 1/3 from glycolysis. In contrast, in aged (and sick) cells, this OXPHOS:glycolysis ratio for ATP synthesis changes over to 1:4 - i.e. more than completely reversed, in favor of glycolysis. Thus, just as in cancer, the aged cells ramp up their glycolysis to produce the same amount of ATP as healthy cells. So in a way, in cancer and in aging, a cell has to "run" twice as fast just to keep up. As the study shows, this inefficient, glycolytic metabolism directly results in mitochondrial (and possibly nuclear) DNA instability, which can, of course, directly cause cancer. In addition, the study demonstrated that the deranged metabolism also resulted in massive release of inflammatory cytokines, increase in (wasteful) energy-consuming pathways, and telomere shortening. In fact, the Hayflick limit (HL) of the hyperglycolytic cells was 53% lower than the healthy ones! Now, as Dr. Peat has mentioned in the past, the HL is likely a fake limit on cellular division, but it does have its uses when comparing aging with healthy cells, and such a drastic shortening is likely to result in much higher risk of a number of degenerative diseases, especially ones of the brain and muscles (Alzheimer's Parkinson's, Huntington's, ALS, etc).

Assuming the study findings are replicated by other scientists the path to retarding, or even reversing, aging seems rather simple. Namely, increase mitochondrial activity while suppressing excessive glycolysis. Thyroid, aspirin, methylene blue and various other quinones such as vitamin K, progesterone, saturated fats, vitamins B1/B3, androgens, etc all have a sizeable pile of evidence in regards to promoting OXPHOS and/or suppressing excessive glycolysis. Moreover, most of these substances have already been demonstrated to extend maximum lifespan in-vivo.

Overactive cell metabolism linked to biological aging
OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases - Communications Biology

"...In control cells, the balance of estimated ATP derived from OxPhos and glycolysis was 64:36%, such that under our specific tissue culture conditions (physiological 5.5 mM glucose, with glutamine, pyruvate, and fatty acids), healthy fibroblasts derived the majority of ATP from OxPhos. In contrast, SURF1 deficiency robustly shifted the relative OxPhos:Glycolysis contribution to 23:77% (p = 4.1e − 6, g = −5.1), reflecting a significant shift in OxPhos-deficient cells towards an alternative, and therefore less energy efficient, metabolic strategy (Fig. 2g, h). As expected, removing glucose from the media did not substantially affect growth in control cells, but the absence of glucose was lethal to SURF1 cells within 5 days, confirming their dependency on glycolysis for survival (Supplementary Fig. 3)."

"...Integrating available clinical and animal data together with our longitudinal fibroblast studies has revealed hypermetabolism as a conserved feature of mitochondrial OxPhos defects. A major advantage of our cellular system is that it isolates the stable influence of genetic and pharmacological OxPhos perturbations on energy expenditure, independent of other factors that may operate in vivo. Thus, these data establish the cell-autonomous nature of hypermetabolism. Moreover, despite the diverging mode of action of SURF1 and Oligo models, as well as some divergent molecular responses, both models converge on the same hypermetabolic phenotype, adding confidence around the generalizability of this phenomenon. Our data also rule out mitochondrial uncoupling as a main driver of hypermetabolism in SURF1 patient-derived fibroblasts, and instead implicate the activation of energy-demanding gene regulatory programs, including but likely not limited to increased metabokine/cytokine secretion, which can compete with growth and longevity (Fig. 9). Our resource cellular lifespan data provide several novel observations that agree with previous work79, and that are relevant to understanding how primary mitochondrial OxPhos defects triggers core physiological and phenotypic hallmarks of aging and mitochondrial diseases."

"...Finally, given the deleterious effect of hypermetabolism-causing OxPhos defects on the lifespan of patients with mitochondrial diseases and in animal models, these genome-wide data prompted us to examine how OxPhos defects and hypermetabolism relate to dynamic genomic markers of cellular aging and senescence. The complete population doubling curves of each donor (Fig. 8a) provided initial evidence that cellular lifespan was reduced in SURF1 and Oligo-treated cells. The Hayflick limit (i.e., the total number of cell divisions56) was, on average, 53% lower in SURF1 cells (p = 0.072, g = 2.0), and Oligo decreased the Hayflick limit by 40% (p < 0.066, g = 2.0) relative to the untreated cells of the same donor (Fig. 8a, b). Interestingly, the magnitude of these effects (40–53%) on total population doubling loosely corresponds to the 3–4 decade loss in human lifespan documented among adults with mitochondrial diseases (see Fig. 1g, h), which would represent 38–50% for an average 80-year life expectancy."

"...Third, mitochondrial OxPhos defects dramatically increased the telomere erosion rate per cell division, despite the adaptive transcriptional upregulation of telomere protection complex components. This effect of mitochondria on telomeres agrees with the variable telomere maintenance in mtDNA conplastic mice88, with the life-shortening effect of pathogenic mtDNA variants32 and OxPhos defects in mice34, and with the reduced lifespan in patients with mtDNA disease shown in Fig. 1g, h. A study in skeletal muscle of children with high heteroplasmic mtDNA mutations also reported excessively short telomeres, similar in length to the telomeres of healthy 80-year-old controls83. Because skeletal muscle is a post-mitotic tissue, this previous result also implies that OxPhos defects could accelerate telomere attrition at a disproportionate rate, or perhaps independent from cell division, as suggested by the disconnect between the loss of telomeric repeats and genome replication/cell division observed in our hypermetabolic fibroblasts. Beyond severe OxPhos defects, mild alterations of OxPhos function driven by mild, common variants in complex I subunits genes, may also shape disease risk89 and influence lifespan90."

"...Fourth, our longitudinal RNASeq and DNAm datasets reveal conserved recalibrations implicating developmental and translation-related pathways, as well as cell–cell communication, with OxPhos defects and hypermetabolism. These identified pathways overlap with previously identified multi-omic overrepresentation analysis performed on iPSC-derived neurons from SURF1 patients92. In both this and our study, neural development, cell signaling, morphogenesis, cell cycle, and metabolism were the predominant processes altered in SURF1-related disease. The induction of these energetically-demanding pathways that constrain growth at the cellular and possibly at the organismal level41, could help explain why a major feature of pediatric mitochondrial disorders (including our SURF1 donors) is a neurodevelopmental delay, and also why adult patients commonly display short stature (restricted growth)30. In relation to cell-cell communication, we note that the biomarker picture of adult patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is dominated, as in our fibroblast models, by elevated (not reduced) signaling and metabolic markers in blood72. Thus, the organism under metabolic stress does not initiate an energy-saving hypometabolic state with reduced signaling activity, but instead activates energivorous stress responses (ISRs), which must divert and consume energetic resources, thereby forcing an apparent tradeoff with other processes such as growth and longevity pathways."

"...Finally, the OxPhos defects in our fibroblasts triggered a shift toward glycolytic ATP production. ...For example, although basal respiration was markedly lower in SURF1 cells, the maximal FCCP-uncoupled respiration in SURF1 cells was relatively preserved (see Fig. 2b and Supplementary Fig. 2c). This result implies a cellular decision to route metabolic flux towards an energetically less efficient pathway (i.e., glycolysis). This could be explained on the basis of energetic constraints and proteome efficiency, since the proteome cost of OxPhos is at least double that of glycolytic fermentation19. Thus, cells can “choose” to divert metabolic flux towards glycolysis even when OxPhos is at least partially functional, as in cancer, because of rising intracellular energetic constraints driven by hypermetabolism. We note again that hypermetabolism is apparent across multiple animal models of primary OxPhos defects, manifesting as an elevated cost of living, even during rest and sleep in mice10,24,25,26. In particular, deep phenotyping of Ant1−/− mice across three studies25,95,96 reveals a systemic physiological picture highly consistent with mitochondrial diseases, including excessive mitochondrial biogenesis, elevated circulating catecholamine levels, severe hypermetabolism (+82 to −85% REE) when adjusted for lower physical activity levels, reduced adiposity, elevated mtDNAcn, and mtDNA instability, and decreased median lifespan. 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. Identifying hypermetabolism as a feature of the mitochondrial diseases may be clinically relevant as it provides an explanatory framework for some of the major symptoms in affected patients. First, fatigue and exercise intolerance are evolutionary conserved, subjective experiences that arise when the organism consumes more energy than it would under optimal conditions (e.g., subjective fatigue during the oxygen debt after strenuous exercise, or during an infection). Thus, symptoms of fatigue could be direct consequences of impaired metabolic efficiency and hypermetabolism."

"...Third, alcohol appears to be poorly tolerated and associated with symptom onset in some patients with mtDNA defects97,98,99, but the basis for alcohol intolerance remains unknown. Alcohol itself causes hypermetabolism in healthy individuals—increasing whole-body REE by as much as 16%, and inhibiting lipid oxidation by 31–36%100,101. Alcohol may therefore aggravate pre-existing hypermetabolism, thus imposing further energetic constraints on vital cellular or physiological functions."

"...Overall, the meta-analysis of clinical data from hundreds of patients and two cellular models of OxPhos dysfunction identifies hypermetabolism as a feature of mitochondrial diseases. Our longitudinal patient-derived fibroblasts data delineate some of the cellular and molecular features of OxPhos-induced hypermetabolism, including sustained induction of the ISR, genome instability, hypersecretion of cyto/metabokines, and genome-wide DNA methylation and transcriptional recalibrations that emphasize the upregulation of energy-dependent processes related to signaling and communication (see Fig. 9). A resource webtool with all data from this study, including the longitudinal RNAseq and DNAm data, is available and can be explored for genes or processes of interest (see Data Availability Statement). Altogether, these translational data, therefore, provide a basis to rationalize some unexplained clinical features of mitochondrial diseases and suggest that intracellular and systemic energy tradeoffs (rather than ATP deficiency) may contribute to the pathogenesis of mitochondrial diseases. The proposed explanatory framework of cellular and physiological hypermetabolism calls for well-controlled studies to further understand the extent to which hypermetabolism is a bystander or a harbinger of morbidity and early mortality in patients with mitochondrial diseases. Our translational findings highlight the need for collaborative partnerships that bridge the cellular, clinical, and patient-reported aspects of mitochondrial diseases and aging."
maybe you need perfect sterility and absolute absence of stress? Well, then it should be recognized that in the current conditions of human existence, immortality is impossible. But you can simply stop the signs of aging and increase the quality of human life in every possible way.
 

LA

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@haidut Thank you very much for taking the time to post that information.
I confess I am a huge fan of Vitamin C for surviving everything and extending life. Vit C helped my mother live another 30 years and some - after she was diagnosed with Lymphoma. She studied the book he wrote entitled "one answer to cancer" this archive has some pointers too:
 

FitnessMike

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@haidut Thank you very much for taking the time to post that information.
I confess I am a huge fan of Vitamin C for surviving everything and extending life. Vit C helped my mother live another 30 years and some - after she was diagnosed with Lymphoma. She studied the book he wrote entitled "one answer to cancer" this archive has some pointers too:
what vitamin C are you taking, i found orange juice to be messing with my bladder...
 

LA

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what vitamin C are you taking, i found orange juice to be messing with my bladder...
My husband purchases Vitamin C powder. He buys brands that use "Q-C". He looks for products that state: "Contains Q-C" - in case your budget needs something more economical - he also purchases the Vitacost brand of 'Vitamin C Powder' as a back-up and also uses it to clean our water-distiller. We 'usually' do not use it for our daily Vit C saturation unless there is nothing else available. We avoid Vit-C tablets.

Except for the *short time* that Trader Joes carried Orange Juice from 100% Organic Florida Orange Juice, which was excellent, OJ is a huge-no for me.

I also read on a few of your other postings that you were/are experiencing bladder problems. Have you had this problem tested in case you need antibiotics? I hope for the best for you.
 

LucyL

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@haidut Thank you very much for taking the time to post that information.
I confess I am a huge fan of Vitamin C for surviving everything and extending life. Vit C helped my mother live another 30 years and some - after she was diagnosed with Lymphoma. She studied the book he wrote entitled "one answer to cancer" this archive has some pointers too:
How did your mother use Vitamin C for lymphoma?
 

Hugh Johnson

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@haidut because in the end there is a strange reason, which contradicts the seeming simplicity of stopping aging, that any experiment directed by all means to improve this very metabolism hasn't achieved immortality and is unlikely to be able to. But what is the reason, the animals were metabolically healthy even in very advanced years, but they still died. Is the reason for the high-PUFA diet all other sorts of flaws in the researches?
Even Peat got old and died.

Not to diminish his accomplishments, he saved countless lives. And aging still seems to happen. There is something missing in our understanding.
 

NewACC

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Even Peat got old and died.

Not to diminish his accomplishments, he saved countless lives. And aging still seems to happen. There is something missing in our understanding.
I am sure that this is all caused by the lack of the possibility of sterility, as in experiments on cells. In any case, we will starve, re-oxidize PUFAs, fight oxidative stress, even to the minimal extent that the "Ray Peat approach" suggests. Therefore, our task is to fight against the signs of aging and its consequences. To prevent death in turn, apparently we are not yet capable, and why we must?
 

cs3000

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Glucose substitution prolongs maintenance of energy homeostasis and lifespan of telomere dysfunctional mice

? basically in mice with the telomere shortened cells like the OP study mentioned seeing in the humans with OXPHOR dysfunction , the sugar didnt stop glycolysis , lactate and pyruvate went up higher so its probably increasing glycolysis more, but the glucose feeding brought in more OXPHOR ratio maybe? as the electron chain complexes restored.
the diet was switching their 50% of calories as starches to 50% as glucose ,
prolonged lifespan 20%.
their calories taken in went up even though intake was the same , because the glucose calories were digested more than the starches. so that helped offset the starvation with the increased metabolic rate from baseline in the telomere shortened rats
their T cells in thymus restored. The beneficial effects of glucose substitution [in telomere shortened rats] appear to be in part mediated by increases in IGF-1 and mTOR signalling

The results of this study could have relevance for the treatment of elderly humans that show accumulation of DNA damage, dysfunctional telomeres, suppression of the somatotrophaxis and mitochondriopathies36–38. There is evidence that 1/3–2/3 of geriatric patients are malnourished, and decreased body weight is directly associated with shortened survival in these patients39. These data indicate that defects in energy homeostasis represent a major factor limiting lifespan at advanced human age
 
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Vinny

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I always have to go back and study OXPHOS vs glycolysis. I feel like I still can't explain it yet to my brother.
Dear Regina,
If at certain point you have time and desire, please, imagine that I`m your brother, not very smart one but willing to learn, and explain to me what is OXPHOS and glycolysis, and how to get the best of them. Your answer will be very much appreciated. Regards.
 

LA

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How did your mother use Vitamin C for lymphoma?
The quick answer is she took 10 grams of Vitamin C crystals daily.
I should have added the attachment and notes to this posting by Haidut /Georgi D


if Charlie or Blossom or can transfer what I added here to this thread it might be more appropriate. I'll wait to see what develops and will add more info if needed. I had a teacher who was in touch with LP or one of his students
 

golder

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The quick answer is she took 10 grams of Vitamin C crystals daily.
I should have added the attachment and notes to this posting by Haidut /Georgi D


if Charlie or Blossom or can transfer what I added here to this thread it might be more appropriate. I'll wait to see what develops and will add more info if needed. I had a teacher who was in touch with LP or one of his students
This has really piqued my interest, my dad has lymphocytic leukaemia and the high dose vitamin C is something I’m looking into. Is there any way you could provide somewhere useful to start my research? Thanks very much in advance!
 

LA

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This has really piqued my interest, my dad has lymphocytic leukaemia and the high dose vitamin C is something I’m looking into. Is there any way you could provide somewhere useful to start my research? Thanks very much in advance!
I apologize for my unavoidable delay. Here is the story:
---In April – once upon a time - my mother went to her doctor with a complaint regarding pain in her body. She was given a CT scan that day and the results were not good.
---June 7 she had an exploratory operation via an incision from center of her chest to 3 inches below her navel. It was discovered that she had a 15" mass. It was affirmed as being Non-Hodgkin's Lymphoma, which started on the Jejunum and metastasized to other organs. Therefore the surgeon did not remove it and sealed the opening.
---June 29 she began receiving Chemotherapy
August 07, another Scan and more chemo
November 11, same as above
November 30, same as above
The final chemotherapy treatment was on January 18 of the following year.
A few months later she had CT scans on April 9, which showed she was clear
June 21 - still clear, August 09 - still clear, and finally on Aug 17 she was given the all clear and okay you are recovered from her physician.

In the beginning we were not told anything until my dad asked me go with him to the hospital on June 29 following her June 7 exploratory operation and consultations with her doctors. In the evening I phoned my astrology teacher, voice teacher, chiropractor and who had been a US military nurse during WW2 (before I was on the planet) she knew many things. She was an amazing person and was often a guest at my parents' home for Thanksgiving dinners and etc.
My teacher knew many people including Linus Pauling and other healers such as Adele Davis and founders of health food stores and herbal stores in LA's alt-health-mecca

The advice from LP/or associate was that my mother should continue with the Chemo due to problems that could occur since chemotherapy had already been started. Since she had been diagnosed with having Non-Hodgkin's it was felt that 10grams of Vitamin C powder per day throughout the day, not all at once, would be enough. We also received the book "One Answer to Cancer" by Linus Pauling and read it

My mother fully recovered and lived another 30 years until she slipped on a throw rug and broke her ribs.
==
Here are a few snips from an easy to understand, non-pedantic, printed book, which is for sale in many places although no longer on the Internet Archive:
Nutrition Almanac, Third Edition, by Lavon J. Dunne, 1990 printing

VITAMIN C (ASCORBIC ACID)
pages 44 thru 47
There are updates although I have never seen one of the newer ones in person. From what I saw online it looks like lower quality paper so IF it is lower quality paper the text "might" not be as sharp.
I found the one I have in a used book store.
SNIPS : : :
- Most vitamin C is out of the body in 3 or 4 hours.
- To maintain adequate serum level, the vitamin should be taken through the day..
- Excess vitamin C carried to the bladder may prevent bladder cancer.
- vitamin C is a "stress vitamin" - used up even more rapidly under stressful conditions
- The larger the dose, the less absorbed
- Injection of several grams of sodium ascorbate into the bloodstream is more effective than the same amount taken by mouth
- Baking soda creates an alkaline medium that destroys vitamin C
- when vit C is given for therapeutic reasons dosage is very important

Also, in an Adele Davis Book entitled "Let's Get Well" pgs 382, 383 .. 'Cancer and Stress' she wrote ... probably malnutrition invariably precedes all malignancies [snip] particularly in Hodgkin's disease, or cancer of the lymph glands . . .and then she wrote about making sure to focus on nutrition and also emphasized vitamin E
Best wishes with your father – never give up hope
 

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