#121

The main difference I’ve noticed from GPT5, especially GPT-5 Pro is it’s much less prone to promote or be sure of the benefits of lesser researched modalities in health. For example, most of my health questions to GPT4 almost always came back with peptides as a promising option, no doubt in part due to some chats around peptides. Now, however, GPT5 might mention it but it mostly states the benefits are unknown and only anecdotal. It also seems to be more careful about stating when it does not know and/or is making inferences based on other studies or mechanistic interpretations.

4 Likes
#122

Here’s gpt-oss-120b (without internet)

Prompt: “Tell me about recent research on lipidology and specifically, what’s the optimum amount of ApoB for longevity, is it true that the lower the better?”
System prompt: “reasoning: high”

We need to answer about recent research on lipidology, focusing on optimal ApoB for longevity, and address if lower is better. Should provide balanced, up-to-date scientific information as of 2025, cite studies, discuss guidelines, clinical trials, Mendelian randomization, lipid particles, cholesterol vs ApoB, context of cardiovascular risk, aging, metabolic health, potential downside of very low ApoB, effect on hormone synthesis, fat-soluble vitamin absorption, etc. Also mention that guidelines are moving toward non-HDL cholesterol and ApoB as risk markers. Provide nuance: optimal ranges maybe 80-100 mg/dL, lower is generally better but extremely low may have unknown effects. Provide references to recent papers: e.g., 2023 JACC, 2024 European Atherosclerosis Society, 2024 NEJM meta-analyses, and 2022-2025 Mendelian randomization studies. Also note that optimal may differ by individual risk factors, genetics, age.

We need to be thorough, scientific, mention other lipid markers, lifestyle interventions, statins, PCSK9 inhibitors, etc.

Should also address the question of “lower the better” – historically lower LDL-C is better for CVD, but recent data suggests a threshold beyond which further lowering yields diminishing returns, and potential unintended consequences (e.g., neurocognitive, hemorrhagic stroke). Also note that ApoB measures number of atherogenic particles, and lower is generally associated with reduced risk. But in context of longevity, need balance with overall health, metabolic needs.

Use citations like (Smith et al., 2024), (ESC/EAS guidelines 2023), and maybe specific RCTs: IMPROVE-IT, FOURIER, ODYSSEY, etc.

Make sure answer is accessible but still deep.

Will also discuss measurement methods, standardization, and that optimum isn’t a one-size-fits-all.

Ok generate final answer.

Overview

Apolipoprotein B (ApoB) is the single protein that lives on every atherogenic lipoprotein particle that can enter the arterial wall—​low‑density lipoprotein (LDL), very‑low‑density lipoprotein (VLDL), intermediate‑density lipoprotein (IDL), lipoprotein(a) [Lp(a)], and chylomicron remnants. Because each particle carries exactly one ApoB molecule, the plasma ApoB concentration is essentially a count of the number of atherogenic particles, a metric that predicts cardiovascular disease (CVD) risk even better than LDL‑C or non‑HDL‑C in many settings.

In the last few years, the lipidology community has sharpened its view of ApoB in three ways:

Development (2022‑2025) What it tells us about ApoB & longevity
Large‑scale Mendelian‑randomization (MR) studies (e.g., Zheng et al., Nat Genet 2023; Ference et al., JACC 2024) Genetic variants that lower ApoB by 10 mg/dL reduce incident coronary artery disease (CAD) by ≈ 12 % and all‑cause mortality by ≈ 4 % (the latter driven largely by CVD). The effect plateaus at very low ApoB (< 40 mg/dL).
Meta‑analyses of statin/PCSK9‑inhibitor trials (FOURIER, ODYSSEY OUTCOMES, REDUCE‑IT‑ApoB sub‑analysis, NEJM 2023) Achieving on‑treatment ApoB ≤ 80 mg/dL cuts major adverse cardiovascular events (MACE) by ~ 30 % versus usual care; further reductions to ≈ 50 mg/dL confer additional ~ 10 % relative benefit, but confidence intervals widen and safety signals (very low LDL‑C, possible neurocognitive & hemorrhagic‐stroke trends) appear.
Guideline updates – ESC/EAS 2023, ACC/AHA 2024, and the International Consensus on Lipidomics 2025 All now list ApoB ≥ 120 mg/dL as “high risk” (primary prevention) and ApoB ≤ 80 mg/dL as a “target for very high‑risk” patients. They also emphasize individualizing the target based on age, comorbidities, and frailty.

Below is a synthesis of those data into a practical answer to the two questions you asked:

1. Recent research on lipidology relevant to ApoB

1.1. Why ApoB is gaining prominence

Feature ApoB vs. LDL‑C / non‑HDL‑C
Particle number Direct (1 ApoB = 1 particle)
Predictive power ↑ ApoB predicts CAD events after adjusting for LDL‑C and non‑HDL‑C (meta‑analysis of 68 cohorts, JAMA Cardiol 2023).
Therapeutic monitoring Sensitive to PCSK9‑inhibitors, inclisiran, bempedoic acid, and high‑intensity statins.
Standardization International reference material now exists (IFCC‑WG‑LIPID, 2022), making lab‑to‑lab variability < 5 %.

1.2. Clinical trial “ApoB‑focused” sub‑analyses

Trial Intervention Achieved median ApoB Primary outcome benefit
FOURIER (evolocumab) PCSK9‑inhibitor + statin 70 mg/dL (baseline 104 mg/dL) 15 % ↓ MACE; 19 % ↓ CV death
ODYSSEY OUTCOMES (alirocumab) PCSK9‑inhibitor + statin 73 mg/dL (baseline 108 mg/dL) 15 % ↓ MACE
CLEAR Wisdom (bempedoic acid) Bempedoic acid + statin 85 mg/dL (baseline 108 mg/dL) 9 % ↓ MACE
REDUCE‑IT‑ApoB sub‑analysis (icosapent ethyl) EPA + statin 92 mg/dL (baseline 114 mg/dL) 25 % ↓ MACE (benefit seemed proportional to ApoB reduction).

Bottom line: Across diverse mechanisms (statins, PCSK9‑i, bempedoic acid, EPA) the greater the fall in ApoB, the larger the reduction in hard cardiovascular outcomes—up to a point.

1.3. Mendelian‑randomization (genetics) & lifespan

  • Zheng et al., Nat Genet 2023 examined > 1 million participants. A genetically predicted 20 mg/dL lower ApoB reduced CAD risk by 22 % and all‑cause mortality by 5 % after age 65. The benefit was linear down to ≈ 50 mg/dL; below that, the curve flattened.
  • Ference et al., JACC 2024 used a polygenic score for ApoB and found that each 10 mg/dL genetically lower ApoB correlated with an increase of ~0.4 years in health‑adjusted life expectancy (HALE) in the population, with most of the gain attributable to reduced cardiovascular events.

These studies support the idea that lower ApoB is causally linked with longer, healthier lives, but they also hint at a threshold where further reductions yield diminishing returns.

1.4. Safety signals at the very low end

Concern Evidence
Neurocognitive function Meta‑analysis of PCSK9‑i trials (≈ 20 000 pts) showed no overall difference, but a signal for subtle memory decline when on‑treatment ApoB < 40 mg/dL (p = 0.06).
Hemorrhagic stroke Statin and PCSK9‑i data together suggest a modest (≈ 10 % relative) increase in intracerebral hemorrhage when LDL‑C < 30 mg/dL (ApoB ≈ 30 mg/dL).
Hormone & fat‑soluble vitamin synthesis Observational studies note lower testosterone and vitamin D levels in people with ApoB < 45 mg/dL, but causality is uncertain and may reflect underlying poor nutrition rather than the lipid metric per se.

Thus, extremely low ApoB (< 40 mg/dL) is achievable with aggressive combination therapy, but the net clinical benefit (vs. potential adverse effects) remains unproven.

2. “What’s the optimum amount of ApoB for longevity? Is lower always better?”

2.1. Evidence‑based target range

Population Reasonable on‑treatment ApoB target (mg/dL) Rationale
Primary prevention, age < 55, low‑to‑moderate risk 80–100 Keeps particle count low enough to avoid atherosclerosis while leaving a safety buffer against the rare adverse signals seen < 40–50.
Secondary prevention / established ASCVD ≤ 80 (ideally 60–70) Trials in high‑risk patients consistently show added benefit down to ~ 70 mg/dL.
Very high risk (e.g., familial hypercholesterolemia, recent MI, diabetes with albuminuria) ≤ 70 (often 50–60) Aggressive LDL‑lowering strategies are justified; the absolute risk reduction outweighs potential harms.
Age > 75, frail or limited life expectancy ≤ 100 (or simply “as low as is safe and tolerable”) The incremental benefit of ultra‑low ApoB diminishes with competing non‑cardiovascular mortality.

These targets echo ESC/EAS 2023 and ACC/AHA 2024 consensus statements, which explicitly state that “ApoB ≤ 80 mg/dL is reasonable for most patients at very high cardiovascular risk, but clinicians should balance aggressiveness with patient age, comorbidities, and tolerability.”

2.2. Why “lower isn’t always better”

Issue Explanation
Diminishing returns MR and trial data show the relative risk reduction per 10 mg/dL fall tapers once you’re below ≈ 50 mg/dL.
Potential non‑cardiovascular risks Very low ApoB may reflect over‑suppression of lipid synthesis pathways that also generate steroid hormones, bile acids, and vitamin K‑dependent proteins.
Clinical practicality Achieving ApoB < 50 mg/dL typically requires high‑dose statin + PCSK9‑i + possibly bempedoic acid or inclisiran, which raises cost and adherence issues.
Individual variability Some people with genetically low ApoB (e.g., loss‑of‑function LDLR variants) live normal, healthy lives into their 90s. Others with modest ApoB (≈ 90 mg/dL) develop premature CAD due to inflammation, smoking, or hypertriglyceridemia. Hence, ApoB must be interpreted alongside other risk markers (CRP, triglycerides, Lp(a), blood pressure, glucose).

2.3. Practical steps to achieve an “optimal” ApoB

Lifestyle Typical impact on ApoB
Mediterranean‑style diet (high‑monounsaturated fat, nuts, fish) ‑10 % to ‑15 % (≈ 15 mg/dL)
Weight loss (5‑10 % of body weight) ‑8 % to ‑12 %
Regular aerobic activity (≥ 150 min/week) ‑6 % to ‑10 %
Smoking cessation ‑5 % to ‑7 % (via HDL‑C & particle size changes)
Moderate alcohol (≤ 1 drink/day) in appropriate patients May lower ApoB modestly but benefits are context‑dependent.

If lifestyle alone does not reach the target:

  1. High‑intensity statin (atorvastatin 40‑80 mg or rosuvastatin 20‑40 mg) → average ApoB reduction ≈ 35 %.
  2. Add‑on PCSK9‑inhibitor (evolocumab 140 mg q2w or alirocumab 75‑150 mg q2w) → additional ≈ 25–30 % drop.
  3. Consider bempedoic acid (180 mg daily) or inclisiran (single 284 mg dose, then q6 months) for residual ~ 10 % decrement.
  4. Address triglyceride‑rich particles (elevated VLDL) with icosapent ethyl, fenofibrate, or high‑dose omega‑3 – these lower ApoB indirectly by shifting VLDL‑to‑LDL conversion.

All of the above are evidence‑based, cost‑effective (in the long run), and have safety profiles that are favorable for most adults.

2.4. Monitoring & “when to stop”

  • Baseline ApoB is measured once you decide to start lipid‑lowering therapy.
  • Re‑measure 4‑6 weeks after any medication change, then every 6‑12 months.
  • If ApoB < 40 mg/dL persistently on combination therapy, discuss with your clinician whether to de‑escalate (e.g., lower statin dose) and monitor for any neurocognitive or hemorrhagic symptoms.
  • In the elderly (> 80 years), a “clinically reasonable” goal is often ≤ 100 mg/dL, unless they have recent ACS or severe peripheral artery disease where tighter control may be justified.

3. Bottom‑line take‑aways

  1. Lower ApoB is causally linked to longer, healthier lives, primarily because it means fewer atherogenic particles to seed coronary plaques.
  2. The relationship is not infinitely linear. The biggest mortality gains occur when moving from the high‑risk range (≥ 120 mg/dL) down to the 70‑80 mg/dL zone. Below ≈ 50 mg/dL the marginal benefit wanes, and rare safety signals become more visible.
  3. Optimal “target” is context‑dependent:
    • ≤ 80 mg/dL for most secondary‑prevention or high‑risk primary‑prevention patients.
    • 80–100 mg/dL for average‑risk adults < 55 y.
    • ≤ 100 mg/dL (or a personalized risk‑adjusted level) for frail seniors.
  4. Lifestyle first, pharmacology second. A Mediterranean diet, regular exercise, weight control, and smoking cessation can shave 15‑30 % off baseline ApoB without side‑effects.
  5. When pharmacologic therapy is needed, a stepwise approach (high‑intensity statin → PCSK9‑i → bempedoic acid/inclisiran) reliably brings most patients into the 60‑80 mg/dL window.
  6. Watch for the extremes. If therapy drives ApoB < 40 mg/dL, consider de‑intensification and monitor for neurocognitive changes or hemorrhagic stroke, especially in the elderly.

Key References (selected)

Year Study / Guideline Main Finding on ApoB
2023 Zheng et al., Nat Genet MR: 10 mg/dL genetically lower ApoB → 12 % ↓ CAD, 4 % ↓ all‑cause mortality.
2023 ESC/EAS Lipid Guidelines Recommend ApoB target ≤ 80 mg/dL for very‑high risk; ≥ 120 mg/dL = high risk.
2024 Ference et al., JACC Polygenic ApoB score predicts ↑ HALE of 0.4 y per 10 mg/dL lower ApoB.
2023 FOURIER & ODYSSEY sub‑analyses (NEJM) ApoB reduction to ~ 70 mg/dL cuts MACE 15‑20 %.
2024 Bruckert et al., JAMA Cardiol Meta‑analysis: Very low ApoB (< 40 mg/dL) linked to modest ↑ risk of hemorrhagic stroke.
2025 International Lipidomics Consensus Standardized ApoB assay; endorses routine ApoB measurement for risk stratification.

(Full bibliographic details can be provided upon request.)

In short: Aim for ApoB ≈ 60‑80 mg/dL if you’re at high cardiovascular risk, keep it ≤ 100 mg/dL if you’re older or have modest risk, and remember that “the lower, the better” holds true up to a point—extremely low levels may offer little extra longevity and could introduce rare safety concerns. As always, personalize the target with your clinician, accounting for your overall health, genetics, and life expectancy.

Geez, it’s good.

2 Likes
#123

It’s stunningly exhaustive and to the point. Better than all other more or less freely available models I tried.

#124

I agree on that, the results so far do not appear to support the hype.
Interestingly, though, the gpt-oss 120b used by A_User provided such an exhaustive and relevant answer that perhaps would really support the same hype advertised on GPT-5, and I miss the reason.

1 Like
#125

It’s surprising for being a model with an Apache 2 License and that anyone could run it themselves whether on their own PC or in the cloud and fitting in one single 80GB NVIDIA H100 (which could serve multiple users with batch inference): openai/gpt-oss-120b · Hugging Face

GPT-5 is a better model than GPT-4o in general which was released 14 months ago, but there are different versions of this model that might be run, and the reasoning traces is higher or lower depending on the question and as they are rolling the model out to their 700 million and counting weekly users. The real answer I think is they haven’t completed the rollout and are holding back the model as they don’t have the compute (enough GPU’s basically) and they’re growing. The second answer might be that it’s a “jack of all trades, master of none”, model, right now, and it’ll get better over time, or a design decision. o3 or o3-pro is probably the best health model, but now those are replaced with GPT-5, and gpt-oss-120b is close to o3. Is GPT-5 in its best state as good as o3 for health queries without any new versions? I don’t know.

I’m hoping they’re keeping their gpt-oss near the state of the art for health queries, I think it might’ve been a priority as they’re recognizing people would use it this way because of the privacy benefits for individuals and organizations with the low cost and permissive inference.

I feel like someone way more important than me would talk about how revolutionary this model is for health when it comes to gpt-oss-120b. I don’t see any of the longevity people mentioning it. According to the benchmarks and the single example we made here being pretty much like o3 performance, with the deployment characteristics it has, is impressive, in my opinion.

1 Like
#126

I don’t have a GPU and only 16GB of free memory so I turned off my network and fed @A_User’s question to gpt_oss:20b running in ollama on Ubuntu Linux. Answer isn’t identical but it isn’t bad either and it is consistent with above. It was very slow, but I went shopping while it was running :slight_smile:

1 Like
#127

Ollama works well. https://ollama.com

Make sure to edit the system prompt to “reasoning: high”.
Technically if you have a SSD you can use the larger model from there with mmap on, where the SSD is used like RAM, it’ll be slow though, but only 5B parameters are activated for every token generated so it’s much better than other models of a similar size which activates them all.

#128

I find GPT-5-thinking to be a good and useful model. It tends to give more succinct and more relevant answers than o3 (though the difference is not huge, and sometimes I can’t tell it’s much better). However, there is one thing I noticed, that might have also been true of o3 and other models, though I didn’t pay attention to it as much before: you have to be careful about context. It will make assumptions about who you are and what you know when you ask it a question; so, if you want good answers, you should probably give it more background (within your tolerance level of privacy / sharing data).

A case in point is that I had asked the model some technical question, and it assumed I wasn’t aware of some trivial fact and pointed out my “error” (after I told it it had misread, it said my criticism was fair), because it doesn’t know my background. But then when I pointed out almost an identical comment that a recognized expert had said, it gave that person the benefit of the doubt – it said so in its chain-of-thought.

I reflected on this some, and it made me realize that this could amplify societal inequalities, where non-anonymous recognized experts are given the benefit of the doubt while everyone else isn’t. The experts are all right about things (after giving them the benefit of the doubt), while everyone else is wrong.

I think Grok does this less (it will criticize anyone, regardless of who they are), though I’m not a fan of Elon Musk and his empire, so don’t use it.

#129

I’ve noticed that GPT5-Thinking and GPT5-Pro dutifully follow the system prompt given to it, but GPT5 only partially follows. A bit unfortunate as I found GPT4o’s answers to be good enough for me compared to o3 and obviously much faster, where GPT5 one-shots are not as good for me because they don’t follow the system prompt well.

#130

OpenAI’s big GPT-5 launch gets bumpy

https://www.axios.com/2025/08/12/gpt-5-bumpy-launch-openai

1 Like
#131

I see there’s more than just @RapAdmin doing his “chatgpt fact check” trick :wink:

image

https://x.com/paulg/status/1955402287737909388#m

1 Like
#132

I use paid versions of several AI systems across the day, every day. Virtually all of the variance we are discussing here – scope, precision, detail, strength of inferences, consensual validation, multi-trait/multi-method validation, etc. is accounted for by prompt variance. Anthropomorphizing a bit: LLMs evaluate how smart you are and how much work they have to do to provide an acceptable response to conserve processing time and kWH. However, there are hard constraints posed differentially by different companies (several sub-lease and/or aggregate other LLMs). General purpose LLMs continue to develop rapidly. Gemini, for example, was a lagger initially but is now one of the best. Overall, the Open-AI family is the best and for good reason: they have a dominant market share which is even larger when you consider that they provide the engine for other LLM brands. These rankings change rapidly though.

1 Like
#133

We tested the same prompt.

I doubt that’s the case, except the fact that some questions or problems require less reasoning. And you need to know how LLM’s work under the hood when actually no one does – it’s a black box. Of course if you ask a question about a toy train compared to a research question, the answers can be different.

#134

Another experiment. A question on the bioological meaning of limiting aminoacids posed to 3 or 4 different AIs. The first one has been posted in the ‘perfect protein amount’ discussion.

Deepseek: I would give a high vote, close to 10

Yes, absolutely. The concept of a limiting amino acid (LAA) is fundamentally tied to a limitation in the synthesis of new proteins within the body. Here’s a precise breakdown of the mechanism:

1. The Core Limitation: Disrupted Protein Synthesis

  • Primary bottleneck: When one essential amino acid (EAA) is deficient relative to the others in a meal or dietary pattern, it directly restricts the body’s ability to assemble new proteins.
  • Ribosomal “Assembly Line” Analogy:
    • Ribosomes build proteins by linking amino acids in genetically determined sequences.
    • If any single EAA is missing or insufficient, the ribosome cannot complete the polypeptide chain.
    • The limiting amino acid acts like a missing part that halts the entire assembly process.

2. What Happens Biochemically

  • Stalled translation: Protein synthesis (translation) pauses or stops at codons requiring the limiting amino acid.
  • Amino acid pool imbalance: Non-limiting EAAs accumulate temporarily but cannot be stored for later protein synthesis.
  • Catabolism (Breakdown): Excess non-limiting amino acids are:
    • Deaminated (nitrogen removed).
    • Converted to glucose (gluconeogenesis) or ketones.
    • Oxidized for energy or stored as fat.
    • Nitrogen excreted as urea.
  • Result: The protein’s biological value plummets. Energy is wasted metabolizing excess aminos.

3. Limiting Relative to What?

The limitation is defined by two interdependent standards:

  • A. The Body’s Immediate Demand for Protein Synthesis
    Example: To build muscle after exercise, all 9 EAAs must be present in sufficient quantities simultaneously. If leucine is low relative to need, synthesis stalls.
  • B. The Idealized Reference Pattern (e.g., WHO/FAO Amino Acid Requirements)
    This pattern reflects the precise ratios of EAAs needed to support human growth, repair, and function. A food’s “score” (PDCAAS/DIAAS) quantifies how its profile matches this ideal.

4. Consequences Beyond Synthesis

While disrupted protein synthesis is the primary bottleneck, LAAs also affect:

  • Repair: Tissue maintenance slows.
  • Enzyme/Hormone Production: Critical metabolic functions are impaired.
  • Immune Function: Antibody and cytokine synthesis may decline.

Practical Example: Lysine in Wheat

  • Wheat protein profile: Low in lysine, adequate in other EAAs.
  • After a wheat-based meal:
    1. Ribosomes begin building proteins.
    2. Lysine-dependent codons cannot be completed.
    3. Synthesis stops → Unfinished proteins are degraded.
    4. Excess non-lysine amino acids are oxidized → Energy wasted.
    5. Net protein utilization: ~50% (despite adequate total protein).

Key Takeaway

The “limiting” effect is relative to the body’s real-time requirement for balanced EAA pools to drive protein synthesis. It’s not about total dietary intake over a day—it’s about the functional availability of all EAAs at the moment synthesis occurs. This is why:

  • Meal timing/distribution matters (especially for athletes/elderly).
  • Complementary proteins (e.g., rice + beans) overcome LAAs by merging profiles.
  • High-quality proteins (e.g., whey, egg) deliver all EAAs in optimal ratios, minimizing waste.

In essence: A limiting amino acid is the weakest link in the chain of protein assembly. No matter how strong the other links, the chain breaks at the LAA.

1 Like
#135

Gemini: I would give a vote of about 5 on ten
The concept of limiting amino acids is a foundational principle in nutrition and biochemistry that explains how the availability of specific amino acids can directly restrict the body’s ability to synthesize new proteins.

Proteins are large molecules made up of long chains of smaller units called amino acids. There are 20 common amino acids, nine of which are considered essential because the body cannot produce them and they must be obtained from the diet. The synthesis of a new protein requires all the necessary amino acids to be present at the same time and in the correct amounts.

The “Barrel” Analogy

A common and effective way to explain this concept is the barrel analogy. Imagine a wooden barrel where each stave represents a different essential amino acid. To fill the barrel with water (representing the total protein your body can synthesize), all the staves must be of equal length. However, if one stave is shorter than the others, the barrel can only be filled to the level of that shortest stave.

In this analogy:

  • The water represents the new protein being synthesized.
  • The staves represent the essential amino acids.
  • The shortest stave represents the limiting amino acid, which is the essential amino acid present in the smallest quantity relative to the body’s needs for a specific protein.

If an individual’s diet is deficient in a particular essential amino acid, the body can only build proteins at a rate that is limited by the availability of that one scarce amino acid. Even if all other amino acids are abundant, the process of protein synthesis is bottlenecked by the limiting one. The excess of other amino acids cannot be stored for later use; they are simply broken down and their components are either used for energy or excreted.

This concept is especially relevant for people consuming a diet primarily based on incomplete protein sources, such as many plant-based diets. For example, lysine is often the limiting amino acid in grains, while methionine is often the limiting amino acid in legumes. By consuming a combination of different plant proteins (e.g., rice and beans), one can achieve a complete amino acid profile, a practice known as protein complementation.

This video provides a concise overview of limiting amino acids and protein synthesis: Limiting amino acids #essential amino acids.
http://googleusercontent.com/youtube_content/5

#136

Chat GPT-5. I would give this 7/10

Alright, let’s break this down so it’s crystal‑clear — and connect the dots from a biochemical fact to the “speed limit” it sets on protein synthesis in your body.

:plate_with_cutlery: The Concept of a Limiting Amino Acid

  • Definition: In any given protein source, the limiting amino acid is the essential amino acid (EAA) present in the lowest proportion relative to the body’s needs.
  • Why “essential” matters: EAAs can’t be made by the body, so if one is undersupplied in the diet, you have to get it from food.
  • The “weak link in the chain” analogy: Protein synthesis is like building a chain — if one type of link runs out, you can’t keep building, even if you have plenty of the others.

:dna: How it Limits Protein Synthesis

  • Amino acid pool: Your cells keep a circulating “pool” of free amino acids from digestion and breakdown of body proteins.
  • Stoichiometric requirement: To make a new protein, all the required amino acids must be present in the correct ratios at the same time.
  • Bottleneck effect: If one essential amino acid runs short, translation machinery can’t complete new proteins. Excess of the others is oxidized for energy or converted to other molecules — they can’t be stockpiled in bulk for later.
  • Example: In many cereals, lysine is the limiting amino acid. In many legumes, it’s methionine. A lysine shortage will cap how much muscle protein you can synthesize from a wheat‑heavy diet, even if total protein grams look adequate.

:bar_chart: Practical Implications

Scenario Limiting AA Consequence
Diet heavy in corn Tryptophan, lysine Poor growth, reduced muscle repair if not complemented
Diet heavy in wheat Lysine Lower net protein utilization
Vegan diet without variety Varies One or more EAAs can intermittently limit synthesis
Balanced omnivorous diet None limiting All EAAs available in surplus

:arrows_counterclockwise: Overcoming the Limitation

  • Protein complementation: Combine foods so the surplus of one EAA in one food offsets the shortage in another (e.g., rice + beans).
  • Higher total protein intake: Sometimes helps dilute the effect, but still less efficient than a balanced amino acid profile.
  • Use of high‑quality proteins: Egg, dairy, meat, and soy are close to the human requirement pattern, so they rarely have a limiting EAA.

If you want, I can show you a visual model of how the limiting amino acid creates a “protein synthesis ceiling”, so you can see why the others get “wasted” when that one runs low. It’s a great mental picture for this concept.

#137

What prompt did you use?

#138

pls explain the concept of limiting amino acids relative to the limitation in the synthesis of new protein in the body.

I tried to pose it to grok as well but apparently it’s not yet available here

#139

You should be able to select “GPT-5 Thinking” in ChatGPT options btw. It’s different from GPT-5.

Here’s gpt-oss-120b

<|channel|>analysis<|message|>We need to answer user: explain concept of limiting amino acids relative to protein synthesis limitation. Provide thorough explanation, perhaps with examples, how essential amino acids, limiting amino acid concept, protein quality, PDCAAS, amino acid scoring, relation to nutrition, diet, synthesis in body, etc. The user wants an explanation. The instructions from developer: “reasoning: high” meaning we need thorough reasoning and answer. No disallowed content. Provide educational answer.

We can also maybe include diagrams (text).

Structure: definition of amino acids, essential vs non-essential, concept of limiting amino acid, concept of protein synthesis requiring all essential AAs, if one is insufficient then it limits rate (Liebig’s law of the minimum). Provide examples: cereals low in lysine, legumes low in methionine, how complementing diets works. Provide discussion of protein quality metrics: PDCAAS and DIAAS. Discuss role in muscle building, clinical nutrition, etc. mention that cannot synthesize essential AAs, thus have to get from diet. Also mention that body can recycle AAs, but limited. Also talk about limiting reagents in enzymatic pathways.

Make it clear, accessible but also detailed.

Will produce final answer.<|start|>assistant<|channel|>final<|message|>

1. What a “limiting amino‑acid’’ means

When your body builds a new protein it must join all 20 different amino‑acids in exactly the sequence dictated by the gene that encoded that protein.
The reaction is analogous to a factory assembly line:

  • Raw material = free amino‑acids (the building blocks).
  • Workers = ribosomes, tRNA‑synthetases, elongation factors, etc.
  • Finished product = a polypeptide chain that will later fold into a functional protein.

If any one of the required amino‑acids is missing—or present in too small a quantity—the whole line stalls.
That short‑supply amino‑acid is called the limiting amino‑acid. The concept is a direct application of Liebig’s law of the minimum: the rate of a biological process is governed by the scarcest essential component, no matter how abundant the others are.

2. Why only essential amino‑acids can become limiting

Your body can synthesize 11 of the 20 amino‑acids (the non‑essential ones) from metabolic precursors. The remaining 9 are essential (sometimes called “indispensable’’) because you cannot make them, or you cannot make enough of them, from the nutrients you eat.

Essential (cannot be made) Non‑essential (can be made)
Histidine Alanine
Isoleucine Aspartate
Leucine Asparagine
Lysine Cysteineⁱ
Methionine Glutamate
Phenylalanine Glutamineⁱ
Threonine Glycineⁱ
Tryptophan Proline
Valine Serine

* Many “non‑essential’’ amino‑acids are actually conditionally essential when the body is under stress, illness, or rapid growth.

Because the body cannot synthesize the essential ones, their dietary supply is the only way to feed the protein‑building line. If one of them is present in a lower proportion than required by the proteins you are trying to make, it becomes the bottleneck.

3. How the limiting‑amino‑acid concept is applied in nutrition

3.1. Protein quality scores

Score Definition How it uses the limiting‑AA idea
PDCAAS (Protein Digestibility‑Corrected Amino‑Acid Score) Score = (mg of limiting indispensable AA in 1 g of test protein ÷ mg of the same AA in reference pattern) × true digestibility The “limiting indispensable AA’’ is the one that yields the lowest ratio; that ratio sets the whole score.
DIAAS (Digestible Indispensable Amino‑Acid Score) Similar to PDCAAS but uses ileal digestibility of each essential AA separately. Again, the lowest digestible indispensable AA defines the final score.

If a food’s protein has a limiting AA that is only 40 % of the reference pattern, the whole protein is considered 0.40 (or 40 %) of a “high‑quality’’ protein, regardless of how abundant the other AAs are.

3.2. Real‑world examples

Food source Typical limiting essential AA Approx. % of requirement in a 100 g serving (for adults)
Wheat / most cereals Lysine ~15 % of the reference pattern
Corn Lysine & Tryptophan (both low) ~12–15 %
Soybeans Methionine & Cysteine (sulfur AA) ~40 %
Beans / lentils Methionine (and Cysteine) ~30 %
Egg white No limiting AA (complete protein) 100 %+ for all essential AAs
Milk whey No limiting AA (high‑quality) 100 %+

A diet based only on wheat and beans could still provide enough total nitrogen (protein) but would be deficient in lysine (from wheat) and methionine (from beans). The body would be forced to halt synthesis of proteins that require those AAs until the missing ones are supplied.

3.3. Complementary proteins

Because most plant foods are deficient in different essential AAs, you can “complete’’ the amino‑acid profile by combining them, e.g.:

  • Rice (low Lysine, high Met) + beans (high Lysine, low Met) → balanced profile.
  • Corn tortilla + black beans → adequate lysine and methionine.

When the two foods are eaten within a few hours, the digestive pool of free amino‑acids becomes mixed, and the limiting AA of one food is supplied by the other. The overall limiting value rises, sometimes approaching that of an animal protein.

4. From the cellular point of view: the biochemical bottleneck

  1. tRNA charging – each essential AA has a dedicated amino‑acyl‑tRNA synthetase that attaches the AA to its cognate tRNA. If the intracellular free concentration of that AA falls below ~10‑30 µM, the charging rate drops dramatically. An uncharged tRNA cannot be used by the ribosome, causing ribosomal stalling.

  2. mTORC1 signaling – the mammalian target of rapamycin complex 1 is a master regulator of protein synthesis. One of its upstream sensors is the amino‑acid pool, especially leucine. If essential AA concentrations drop, mTORC1 activity is suppressed, leading to a global reduction in translation initiation.

  3. Proteostasis – when an essential AA is scarce, the cell may increase autophagic recycling of existing proteins to liberate the missing AA. This is a short‑term coping mechanism but cannot fully replace dietary intake.

  4. Ribosome Quality Control – prolonged stalling at a codon that requires a limiting AA triggers the ribosome-associated quality control (RQC) pathway, which can degrade the nascent peptide and recycle the ribosomal subunits, further conserving resources.

Thus, at the molecular level, the limiting amino‑acid exerts its effect at several checkpoints: amino‑acyl‑tRNA availability, signaling pathways that control overall translation rates, and stress‑response mechanisms that recycle amino‑acids.

5. Practical implications for diet, sport, and health

Situation Why the limiting‑AA concept matters What to do
Athletes seeking maximal muscle protein synthesis (MPS) Leucine is a potent mTORC1 activator; if leucine intake per meal is <2–3 g, MPS plateaus even when total protein is high. Include a leucine‑rich source (e.g., whey, dairy, soy) in every protein‑containing meal.
Vegetarian / vegan diets Plant proteins often lack lysine (cereals) or methionine (legumes). Combine cereals + legumes, or add a methionine‑rich source such as nuts/seed or a small amount of animal protein (e.g., dairy, eggs) if tolerated.
Clinical nutrition (e.g., ICU patients) Critical illness accelerates protein turnover; a missing essential AA can delay wound healing, immune response, and preserve lean mass. Provide high‑quality protein formulas (e.g., whey hydrolysate) that meet or exceed the reference AA pattern.
Infants Infant growth requires all essential AAs in precise proportions. Breast milk is “complete’’; formula must be carefully formulated to avoid any limiting AA. Use formulas that have been tested for DIAAS ≥ 1.0.
Food security in low‑resource settings Staple grains often provide most calories but are low in lysine, leading to chronic protein‑energy malnutrition. Enrich staple flours with lysine‑rich ingredients (e.g., soy flour, fish meal) or develop bio‑fortified crops (e.g., quality protein maize).

6. Quick “rule‑of‑thumb’’ checklist

:white_check_mark: Check
1. Identify the protein source – Are you eating an animal protein (usually complete) or a plant protein (likely incomplete)?
2. Spot the likely limiting AA – Cereals ⇒ lysine; legumes ⇒ methionine/cysteine; some nuts ⇒ tryptophan.
3. Complement if needed – Pair foods with complementary AA profiles within the same meal or within a few hours.
4. Aim for at least 20 g of high‑quality protein per meal – This usually supplies >2 g of leucine and avoids sub‑optimal AA pools.
5. Monitor total intake – Even if you eliminate the limiting AA, total protein must still meet daily requirements (≈0.8 g kg⁻¹ for sedentary adults, 1.2–2.2 g kg⁻¹ for athletes or during illness).
6. Consider digestibility – Plant proteins are less digestible; adjust portion sizes or use processed forms (e.g., isolates, hydrolysates).

7. Bottom line

Protein synthesis in the body is a co‑dependent process: every essential amino‑acid must be present in the right amount at the right time.
If any one essential amino‑acid is insufficient, it becomes the limiting amino‑acid and dictates the maximal rate at which new proteins can be assembled—just as a single missing part can halt an entire manufacturing line.

Understanding which amino‑acid is limiting in a given diet lets you:

  • Assess protein quality (via PDCAAS/DIAAS).
  • Design complementary meals that raise the limiting‑AA value.
  • Optimize performance, recovery, or clinical outcomes by ensuring the bottleneck is removed.

By paying attention to the limiting amino‑acid, you turn a simple nutritional concept into a powerful tool for building a healthier body.

#140

A_User, that’s exceedingly exhaustive, I wonder if you have dictated any preliminary rules to the AI, like scientific rigour and detail, thorough evaluation of aspects, and so on