Iñigo San Millán Profile picture
Aug 3 9 tweets 2 min read Read on X
🧠On Alzheimer’s as a metabolic disease 👇
🧵
1) The more we learn about brain metabolism, the clearer it becomes: Alzheimer’s is not primarily a disease of amyloid plaques. It is a metabolic disease.
Let’s talk about what that means, and why the current paradigm must change:
2) The brain is the most glucose-demanding organ per unit volume. It’s a metabolic powerhouse of incredible efficiency…until it’s not.
When mitochondrial function declines, glucose metabolism falters and neuronal biogenetics fails, the stage is set for neurodegeneration.
3) The amyloid hypothesis, which has dominated Alzheimer’s research for decades, remains just that; a hypothesis which has failed to produce effective therapies. Meanwhile, the bioenergetic theory has robust scientific, mechanistic and clinical support.
4) Studies show that glucose uptake in the brain begins to decline decades before symptoms appear.
This precedes plaque accumulation. It is a warning sign that brain metabolism is breaking down.
5) What causes this decline?
Often, it is part of a larger systemic issue: insulin resistance, mitochondrial dysfunction, and metabolic inflexibility. In a vast number of people, AD is accompanied by previous glucose metabolism disorders like pre-diabetes or T2D.
Alzheimer’s is downstream of a broken metabolic system.
6) We must shift the focus from late-stage intervention to early detection and prevention targeting:
-Brain mitochondrial function
-Brain bioenergetics, specially glucose metabolism
-Lifestyle interventions: exercise, diet, metabolic therapy
7 If we keep treating Alzheimer’s as a protein-accumulation disorder, we will continue to fail.
If we treat it as a brain bioenergetic collapse, we open the door to prevention, to meaningful intervention, and possibly even reversal in early stages.
8) Because Alzheimer’s a systemic metabolic disease, not just a neurological one, we are likely to see Alzheimer’s manifesting at younger ages in metabolically unhealthy populations. Can we imagine a society where millions develop AD in their 40’s-50’s?…It would be the end of societies as we know them…
9) Bottom line:
Alzheimer’s is a metabolic disease of the brain. The paradigm must evolve: from neurocentric to metabolic, from symptomatic to preventative and from treatment to early intervention.

Unless we shift gears quickly,
we will keep missing the target, while the disease strikes younger populations and more often.
#Alzheimers #BrainMetabolism #Mitochondria

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More from @doctorinigo

Jun 27
🔬 CANCER'S ENERGY CRISIS: TIME TO TARGET LACTATE!

For over a century, cancer’s metabolic hallmark has been clear: high glycolytic rates even in the presence of oxygen. Otto Warburg identified this paradox, which we now understand as a powerful adaptive mechanism, not a flaw.

👇Here’s a summary of how lactate lies at the center of cancer metabolism, signaling, and therapy 🧵
1/7 The Warburg Effect is more than an anomaly or a curiosity. It reflects a fundamental reprogramming of cancer cell bioenergetics. Cancer cells downregulate mitochondrial oxidative phosphorylation (OXPHOS) and rely primarily on cytosolic glycolysis, funneling glucose into pyruvate and converting it into lactate, even when oxygen is abundant.
2/7 We call this process Lactagenesis. It is not metabolic overflow. It is a regulated shift that supports proliferation, survival, and invasion. Lactate is not waste product. It is a central player in tumor biology.
Read 9 tweets
May 12
Muscle acidosis is real and it decreases performance significantly. However, Lactate is NOTthe reason for muscle acidosis.
Free thread depicting the role of lactate during hgh intensity exercise: 🧵😉 👇
During high-intensity exercise, skeletal muscle experiences a significant increase in protons (H⁺) concentration, leading to a decrease in intracellular pH and therefore increasing skeletal muscle acidosis. These protons come mainly from:
1) ATP hydrolysis is the primary source of H⁺during exercise. H⁺build up in the cytosol leading to decreased in muscle pH.
ATP + H₂O → ADP + HPO₄²⁻+ H⁺

2) Lactate formation from pyruvate receives ("buffers") one H⁺ from the oxidation of NADH to NAD+ during glycolysis. This step is the only possible step for the regeneration of NAD+ so that glycolysis can continue and REDOX status can be maintained. Hence, Lactate DOES NOT cause acidosis as it is NOT a source of protons (H⁺). The “acid” simply doesn’t exist.
Read 8 tweets
Jan 11
🧵Thread: They role of Mitochondrial DNA (mtDNA) mutations in cancer🧵

Some thoughts I tried to put together...

1) Although in 1923 Otto Warburg already suggested that mitochondrial function was key for cancer development. In the last decade, the Warburg effect has finally re-emerged in a very strong manner after being buried for many decades. Nowadays, it is a mainstream concept...
2) While it is great that finally the Warburg Effect is viewed by the scientific community as a key piece of the cancer puzzle, it has brought some significant misunderstanding and misinformation to the general population. Such as intellectually cheap and lazy concepts like “sugar causes cancer” (a very wrong way to understand the Warburg Effect) or that Cancer is purely a Metabolic Disease.
3) All diseases ultimately succumb to cellular metabolic and bioenergetics dysfunction. Hence, one could argue that all diseases are metabolic diseases because of this condition. However, we know that this is not right for many diseases.

In the case of cancer there is absolutely no doubt that genetic mutations play a significant role, although at the same time, metabolic dysfunction and reprogramming are also hallmarks of cancer. Hence, in the field of cancer, both genetics and cellular metabolism are intertwined, although it is very possible that we cannot affirm that cancer is neither solely a genetic nor a metabolic disease, but both. Until we don’t elucidate this transcendental question in cancer, we won’t be able to corner Cancer.
Read 7 tweets
Aug 20, 2024
1/5 Our most recent study just upladed to bioRxiv for free download.
"Metabolic and Cellular Differences Between Sedentary and Active Individuals at Rest and During Exercise".
biorxiv.org/content/10.110…
2/5 Our study investigates the metabolic and muscle bioenergetics underpinning the apparent health of sedentary individuals, considering the significant prevalence of non-communicable diseases associated with physical inactivity.
3/5 Using muscle biopsies and graded exercise testing, our research study delineated distinct variations in mitochondrial respiration, substrate oxidation capacities, and overall muscle bioenergetics between sedentary and moderately active groups.
Read 6 tweets
Nov 28, 2023
1/9 The field of nutrition in oncology has become quite controversial in the last years. Mainly, because of misconceptions regarding cancer metabolism around the Warburg Effect...
thelancet.com/journals/lanon…
2/9 The Warburg Effect is finally "mainstream" in oncology research but also a cause of misconceptions out there... The article is an interesting one about this controversy. In my opinion, in general, the article is well presented and I agree with most of it.
3/9 This is a figure from the article article summarizing some of the main controversies and misconceptions around the Warburg Effect and oncology nutrition... Image
Read 9 tweets
Apr 18, 2023
A thread on how IMHO bicarbonate doesn’t work to “decrease” lactate from muscles
First of all, bicarbonate is one of the oldest supplements out there. It has been used for decades for this purpose. Like many supplements that don’t work, they tend to resurface 20-30 years later…
Blood pH is 7.35-7.45 and one of the most sacred homeostatic states for human body. 3 main elements “threaten” blood pH: CO2, electrolyte concentrations and weak acid concentrations. During high intensity exercise and pathological stress, these elements are threats to blood pH.
Our body possess a large pool of bicarb to constantly defend the physiological & sacred pH of 7.35-7.45. This is key as if your blood pH ⬇️ or ⬆️ over those ranges you could simply die. Hence, exogenous bicarb will normally be neutralized as blood pH cannot ⬇️ homeostatic levels
Read 7 tweets

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